HCR 577 CTD Module 1 2 3 4 and 5

Table of Contents

Module 1 Administrative Information————————————————————16

1.1 Form – headline in TOC—————————————————————————16

1.2 Cover letters——————————————————————————————16

1.3 Administrative information————————————————————————17

1.3.1 Contact/sponsor/applicant information——————————————————–17

1.3.1.1 Change of address or corporate name——————————————————–18

1.3.1.2 Change in contact/agent———————————————————————–18

1.3.1.3 Change in sponsor—————————————————————————–18

1.3.1.4 Transfer of obligation————————————————————————19

1.3.1.5 Change in ownership of an application or reissuance of license———————–19

1.3.2 Field copy certification————————————————————————19

1.3.3 Debarment certification———————————————————————–20

1.3.4 Financial certification and disclosure——————————————————-20

1.3.5 Patent and exclusivity————————————————————————-21

1.3.5.1 Patient information————————————————————————–21

1.3.5.2 Patient certification————————————————————————–22

1.3.5.3 Exclusivity claim—————————————————————————-22

1.3.6 Tropical disease priority review voucher—————————————————22

1.4 References—————————————————————————————–23

1.4.1 Letter of authorization————————————————————————–23

1.4.2 Statement of right of reference————————————————————25

1.4.3 List of authorized persons to incorporate by reference———————————25

1.4.4 Cross reference to previously submitted information————————————26

1.5 Application status——————————————————————————-27

1.5.1 Withdrawal of an IND————————————————————————27

1.5.2 Inactivation request—————————————————————————-27

1.5.3 Reactivation request—————————————————————————28

1.5.4 Reinstatement request————————————————————————-28

1.5.5 Withdrawal of an unapproved BLA, NDA, ANDA, or Supplement——————-28

1.5.6 Withdrawal of listed drug———————————————————————29

1.5.7 Withdrawal of approval of an application or revocation———————————29

1.6 Meetings——————————————————————————————29

1.6.1 Meeting request——————————————————————————–29

1.6.2 Meeting background materials—————————————————————30

1.6.3 Correspondence regarding meetings———————————————————31

1.7 Fast track ——————————————————————————————31

1.7.1 Fast track designation request—————————————————————–31

1.7.2 Fast track designation withdrawal request—————————————————31

1.7.3 Rolling review request————————————————————————-32

1.7.4 Correspondence regarding fast track/rolling review—————————————32

1.8 Special protocol assessment request———————————————————–32

1.8.1 Clinical study—————————————————————————–32

1.8.2 Carcinogenicity study——————————————————————-33

1.8.3 Stability study—————————————————————————–33

1.8.4 Animal efficacy study for approval under the animal rule————————–33

1.9 Pediatric administrative information——————————————————33

1.9.1 Request for waiver of pediatric studies————————————————-33

1.9.2 Request for deferral of pediatric studies————————————————33

1.9.3 Request for pediatric exclusivity determination—————————————34

1.9.4 Proposed pediatric study request and amendments————————————34

1.9.5 Proposal for written agreement (no longer applicable) ——————————–34

1.9.6 Other correspondence regarding pediatric exclusivity or study plans—————34

1.10 Dispute resolution—————————————————————————-35

1.10.1 Request for dispute resolution————————————————————-35

1.10.2 Correspondence relate to dispute resolution———————————————35

1.11 Information amendment: Information not covered under modules 2 to 5————–35

1.11.1 Quality information amendment———————————————————–35

1.11.2 Nonclinical information amendment——————————————————36

1.11.3 Clinical information amendment———————————————————–36

1.11.4 Multiple module information amendment————————————————-36

1.12 Pre IND correspondence————————————————————————36

1.12.1 Pre IND correspondence———————————————————————-36

1.12.2 Repeat to charge for clinical trial————————————————-37

1.12.3 Request to charge expanded access———————————————–37

1.12.4 Request for comments and advise————————————————-38

1.12.5 Request for a waiver—————————————————————–38

1.12.6 Exception from informed consent for emergency work————————38

1.12.7 Public disclosure statement for exception from informed consent for emergency

work research———————————————————————————–39

1.12.8 Correspondence regarding exception from informed consent for emergency work

Research—————————————————————————————-39

1.12.9 Notification of discontinuation of clinical trial———————————–40

1.12.10 Generic drug enforcement act statement—————————————–40

1.12.11 ANDA basis for submission statement——————————————-40

1.12.12 Comparison of generic drug and reference listed drug————————-40

1.12.13 Request for waiver for in vivo studies——————————————–41

1.12.14 Environmental analysis————————————————————-41

1.12.15 Request for in vivo bioavailability studies—————————————-41

1.12.16 Field alert reports——————————————————————–42

1.12.17 Orphan drug designation———————————————————–42

1.13 Annual report—————————————————————————-42

1.13.1 Summary of nonclinical studies—————————————————–42

1.13.2 Summary of clinical pharmacology information ———————————42

1.13.3 Summary of safety information——————————————————-42

1.13.4 Summary of labeling changes———————————————————43

1.13.5 Summary of manufacturing changes————————————————–43

1.13.6 Summary of microbiological changes————————————————44

1.13.7 Summary of other significant new information————————————–44

1.13.8 Individual study information————————————————————45

1.13.9 General investigational plan————————————————————45

1.13.10 Distribution data————————————————————————-46

1.13.11 Status of postmarketing study commitments and requirements——————-48

1.13.12 Status of other of postmarketing studies and requirements————————48

1.13.13 Log of outstanding regulatory business———————————————–48

1.13.14 Development safety update report (DSUR)——————————————-48

1.14 Labeling—————————————————————————————-49

1.14.1 Draft labeling——————————————————————————–49

1.14.1.1 Draft carton and container label——————————————————–49

1.14.1.2 Annotated draft labeling text————————————————————50

1.14.1.3 Draft labeling text————————————————————————-50

1.14.1.3 Label comprehension studies————————————————————52

1.14.1.4 Labeling history—————————————————————————-52

1.14.2 Final labeling———————————————————————————-53

1.14.2.1 Final carton or container labels———————————————————–53

1.14.2.2 Final package insert (package inserts, patient information, medication

guides) ————————————————————————————————53

1.14.2.3 Final labeling text————————————————————————-54

1.14.3 Listed drug labeling————————————————————————–54

1.14.3.1 Annotated comparison with listed drug————————————————–55

1.14.3.2 Approved labeling text for listed drug—————————————————55

1.14.2.3 Labeling text for reference listed drug—————————————————-56

1.14.4 Investigational drug labeling——————————————————————57

1.14.2.1 Investigational brochure———————————————————————-59

1.14.2.2 Investigational drug labeling—————————————————————-60

1.14.5 Foreign labeling———————————————————————————62

1.14.6 Product labeling for 2253 submission——————————————————-63

1.15 Promotional material——————————————————————————64

1.15.1 Correspondence relating to promotional materials—————————————–64

1.15.1.1 Request for advisory comments on launch materials———————————–64

1.15.1.2 Request for advisory comments on non-launch materials—————————–65

1.15.1.3 Presubmission of launch promotional materials for accelerated approved

Products————————————————————————————————65

1.15.1.4 Presubmission of non-launch promotional materials for accelerated

approved products———————————————————————————–65

1.15.1.5 Pre-dissemination review of television ads——————————————-66

1.15.1.6 Response to untitled letter or warning letter——————————————66

1.15.1.7 Response to information required——————————————————66

1.15.1.8 Correspondence accompanying material previously missing or rejected———-66

1.15.1.9 Withdrawal request————————————————————————-67

1.15.1.10 Submission of annotated references—————————————————-67

1.15.1.11 General correspondence——————————————————————67

1.15.2 Materials attribute—————————————————————————–67

1.15.2.1 Material—————————————————————————————67

1.15.2.1.1 Clean version——————————————————————————68

1.15.2.1.2 Annotated version————————————————————————-68

1.15.2.1.3 Annotated labeling version—————————————————————69

1.15.2.1.4 Annotated references———————————————————————-69

1.16 Risk management plan—————————————————————————70

1.16.1 Risk Management (Non-REMS) ————————————————————-70

1.16.2 Risk Evaluation and Mitigation Strategy (REMS)—————————————-70

1.16.2.1 Final REMS———————————————————————————-70

1.16.2.2 Draft REMS———————————————————————————-70

1.16.2.3 REMS Assessment—————————————————————————71

1.16.2.4 REMS Assessment Methodology———————————————————-71

1.16.2.5 REMS Correspondence———————————————————————-71

1.16.6 REMS Modification History——————————————————————-72

1.17 Postmarketing Studies—————————————————————————-72

1.17.1 Correspondence regarding postmarketing commitments———————————-72

1.17.2 Correspondence regarding postmarketing requirements———————————–72

1.18 Proprietary names———————————————————————————73

1.19 Pre-EUA and EUA——————————————————————————-73

1.20 General investigation plan for initial IND —————————————————-73

Module 2

2.2 Introduction to Summary————————————————————————-74
2.3 Quality Overall Summary————————————————————————74
2.4 Nonclinical Overview—————————————————————————–75
2.5 Clinical Overview———————————————————————————75
2.6 Nonclinical Written and Tabulated Summaries———————————————–76
2.6.1 Introduction———————————————————————————–76
2.6.2 Pharmacology Written Summary———————————————————-76
2.6.3 Pharmacology Tabulated Summary——————————————————-76
2.6.4 Pharmacokinetic Written Summary——————————————————-77
2.6.5 Pharmacokinetic Tabulated Summary—————————————————-77
2.6.6 Toxicology Written Summary————————————————————-79
2.6.7 Toxicology Tabulated Summary———————————————————-80
2.7 Clinical Written and Tabulated Summaries—————————————————81
2.7.1 Introduction———————————————————————————–81
2.7.2 Summary of Biopharmaceutical Studies and Analytical Methods——————–81
2.7.3 Summary of Clinical Pharmacology Studies———————————————82
2.7.4 Summary of Clinical Efficacy (Indication)———————————————-83
2.7.5 References———————————————————————————83
2.7.6 Synopses of Individual Studies———————————————————84

References ——————————————————————————————-86

Module 3

3.2 Body of Data————————————————————————————87

3.2.S.1 Drug substance (biologic) or active pharmaceutical ingredient (API) (name,

manufacturer) —————————————————————————————–87

3.2.S.1.1 General information—————————————————–87

3.2.S.1.2 Nomenclature————————————————————87

3.2.S.1.3 Structure——————————————————————88

3.2.S.1.4 General properties——————————————————-89

3.2.S.2 Manufacture————————————————————————-90

3.2.S.2.1 Manufacturer(s)———————————————————-90

3.2. S.2.Description of Manufacturing Process and Process Controls————————-90

3.2.S.2.3 Control of Methods——————————————————91

3.2.S.2.4 Control of Critical Steps and Intermediates————————–92

3.2.S.2.5 Process Validation and/or Evaluation———————————93

3.2.S.2.6 Manufacturing Process Development———————————93

3.2.S.3 Characterization———————————————————————94

3.2.S.3.1 Elucidation of Structure and Characterization———————–94

3.2.S.3.2 Impurities—————————————————————–94

3.2.S.4 Control of Drug Substance——————————————————–94

3.2.S.4.1 Specifications————————————————————94

3.2.S.4.2 Analytical Procedures—————————————————94

3.2.S.4.3 Validation of Analytical Procedures———————————-95

3.2.S.4.4 Batch Analysis———————————————————–95

3.2.S.4.5 Justification of Specification——————————————95

3.2.S.5 Reference standards or materials————————————————-95

3.2.S.6 Container closure systems———————————————————96

3.2.S.7 Stability——————————————————————————96

3.2.S.7.1 Stability Summary and Conclusions———————————96

3.2.S.7.2 Post Approval Stability Protocol and Stability Commitment—–96

3.2.S.7.3 Stability Data———————————————————–96

3.2.P Drug product (name, dosage form, manufacturer) ——————————97

3.2.P.1 Description and composition of the drug product—————————–97

3.2.P.2 Pharmaceutical development——————————————–98

3.2.P.3 Manufacture—————————————————————98

3.2.P.3.1 Manufacturer(s)————————————————98

3.2.P.3.2 Batch Formula————————————————–98

3.2.P.3.3 Description of Manufacturing Process———————-98

3.2.P.3.4 Controls of Critical Steps and Intermediates———————————99

3.2.P.3.5 Process Validation and/or Evaluation—————————————–100

3.2.P.4 Control of excipients (Name)————————————————————–100

3.2.P.4.1 Specification(s)——————————————————————–100

3.2.P.4.2 Analytical Procedures————————————————————-100

3.2.P.4.3 Validation of Analytical Procedures——————————————–100

3.2.P.4.4 Justification of Specifications—————————————————-101

3.2.P.4.5 Excipients of Human or Animal Origin—————————————-101

3.2.P.4.6 Novel Excipients——————————————————————-101

3.2.P.5 Control of drug product———————————————————————-101

3.2.P.5.1 Specification(s)——————————————————————-102

3.2.P.5.2 Analytical Procedures————————————————————102

3.2.P.5.3 Validation of Analytical Procedures——————————————-102

3.2.P.5.4 Batch Analyses——————————————————————-103

3.2.P.5.3 Characterization of Impurities————————————————–103

3.2.P.5.4 Justification of Specifications—————————————————103

3.2.P.6 Reference standards or materials———————————————————–104 3.2.P.7 Container closure system——————————————————————–104

3.2.P.8 Stability—————————————————————————————–104

3.2.P.8.1 Stability Summary and Conclusion———————————————104

3.2.P.8.2 Postapproval Stability Protocol and Stability———————————-105

3.2.P.8.3 Stability Data———————————————————————–105

3.2.A Container closure system———————————————————————-105

3.2.A.1 Facilities and Equipment (name, manufacturer) ——————————–105

3.2.A.2 Adventitious agents safety evaluation (name, dosage form) —————————105

3.2.A.3 Novel excipients——————————————————————————105

3.2.R Regional information—————————————————————————106

3.3 Literature references——————————————————————————-106

Module 4 Nonclinical Study Reports

4.2 Study reports—————————————————————————————108

4.2.1 Pharmacology—————————————————————————108

4.2.1.1 Primary pharmacodynamics———————————————–108

4.2.1.2 Secondary pharmacodynamics——————————————–108

4.2.1.3 Safety pharmacology——————————————————-109

4.2.1.2 Pharmacodynamic drug interactions————————————–109

4.2.2. Pharmacology————————————————————————109

4.2.2.1 Analytical methods and validation reports—————————–109

4.2.2.2 Absorption—————————————————————————110

4.2.2.3 Distribution—————————————————————–110

4.2.2.4 Metabolism—————————————————————–111

4.2.2.5 Excretion——————————————————————–111

4.2.2.6 Pharmacokinetics———————————————————–111

4.2.2.7 Other pharmacokinetic studies——————————————–112

4.2.3 Toxicology——————————————————————————112

4.2.3.1 Single dose toxicity (Species and route) ——————————-112

4.2.3.2 Repeat dose toxicity (Species, route, duration) ————————113

4.2.3.3 Genotoxicity—————————————————————–113

4.2.3.4 Carcinogenicity————————————————————–114

4.2.3.5 Reproductive and developmental toxicity——————————-114

4.2.3.6 Local tolerance————————————————————–115

4.2.3.7 Other toxicity studies——————————————————-115

4.3 Literature references———————————————————————116

Module 5 Clinical Study Reports

5.2 Tabular listing of all clinical study reports—————————————————-117

5.3 Clinical study reports and related information————————————————117

5.3.1 Reports of biopharmaceutical studies———————————————–117

5.3.1.1 Bioavailability (BA) Study reports and related information———117

5.3.1.2 Comparative BA and bioequivalence (BE) Study reports and related

Information———————————————————————————————118

5.3.1.3 In Vitro – in Vivo correlation Study reports and related information—————————————————————————————————————-118

5.3.1.4 Reports of bioanalytical and analytical methods for human studies-119

5.3.2 Reports of studies to pharmacokinetics using human biomaterials————-119

5.3.2.1 Plasma protein binding Study reports and related information——119

5.3.2.2 Reports of hepatic metabolism and drug interaction studies———120

5.3.2.3 Reports of studies using other human biomaterials——————-120

5.3.3 Reports of human pharmacokinetic (PK) studies———————————121 5.3.3.1 Healthy subject PK and initial tolerability Study reports and related

Information——————————————————————————————–121

5.3.3.2 Patient PK and initial tolerability Study reports and related information———————————————————————————————-121

5.3.3.3 Intrinsic factor PK Study reports and related information————-122

5.3.3.4 Extrinsic factor Study reports and related information—————–122

5.3.3.5 Population PK Study reports and related information——————123

5.3.4 Reports of human pharmacodynamic (PD) studies——————————–123

5.3.4.1 Healthy subject PD and PK/PD Study reports and related information————————————————————————————————————–123

5.3.4.2 Patient PD and PK/PD Study reports and related information——–123

5.3.5 Results of efficacy and safety studies————————————————124

5.3.5.1 Study reports and related information of controlled clinical studies

pertinent to the claimed indication——————————————————————124

5.3.5.2 Study reports and related information of uncontrolled clinical studies—————————————————————————————————————124

5.3.5.3 Reports of analysis of data from more than one study—————–125

5.3.5.4 Other Study reports and related information—————————-125

5.3.6 Reports on postmarketing experience——————————————————–126

5.4 Literature reference——————————————————————————–126

CTD Module 1, 2, 3, 4 and 5: Aducanumab

Module 1 Administrative Information

1.1 Form

1.2 Cover letters

Subject: Cover Letter for Aducanumab Application

Biogen Inc.
225 Binney Street
Cambridge, MA 02142, USA
Phone: +1 781-464-2000
Website: biogen.com

24^th April 2026

The Regulatory Review Committee
U.S. Food and Drug Administration (FDA)
Silver Spring, Maryland, USA

Subject: Cover Letter for Aducanumab Application

Dear Sir/Madam,

I am writing on behalf of Biogen Inc., in collaboration with Eisai Co., Ltd., to submit our application for Aducanumab for regulatory review and approval. Aducanumab is a prescription medicine used to treat Alzheimer’s disease, particularly for adult and geriatric patients with mild cognitive impairment or mild dementia.

The drug name is Aducanumab, and the active ingredient is aducanumab-avwa. It is a monoclonal antibody developed to target amyloid beta plaques in the brain, which are associated with the progression of Alzheimer’s disease.

This medicine is intended for adults and elderly patients only. It is not approved for pediatric use. The route of administration is intravenous infusion, which is given by a healthcare professional in a medical setting. The recommended dosage is 10 mg/kg once every four weeks after the titration phase.

The product should be stored under refrigerated conditions between 2°C and 8°C and protected from light. The shelf life of Aducanumab is 36 months when stored in the original packaging under the recommended conditions.

We believe Aducanumab provides an important treatment option for patients living with early Alzheimer’s disease and supports better disease management. We respectfully request your review and approval of this application.

Please find all required supporting documents attached for your consideration. Should you require any further information, please feel free to contact us.

Thank you for your time and consideration.

Yours faithfully,

Marisol Llovera
Food Safety Investigator

U.S. Food and Drug Administration (FDA)
California, USA

1.3 Administrative information

1.3.1 Contact/sponsor/applicant information

The applicant and sponsor for aducanumab (brand name Aduhelm) is Biogen, Inc.. The drug was developed in collaboration with Eisai Co., Ltd.

Sponsor Name:Biogen, Inc.
Collaborator:Eisai Co., Ltd.
Drug Identifier:BIIB037
Approved Indication:Treatment of Alzheimer’s disease (via FDA Accelerated Approval).
EMA Status:Biogen Netherlands B.V. withdrew the marketing authorization application for the European Union on April 20, 2022.

1.3.1.1 Change of address or corporate name

Biogen Inc. announced the discontinuation of Aduhelm (aducanumab-avwa) on January 31, 2024, and is terminating the ENVISION clinical study. The rights to the drug are reverting to Neurimmune.

1.3.1.2 Change in contact/agent

Biogen announced in January 2024 that it is discontinuing the development and commercialization of Aduhelm (aducanumab), with the discontinuation finalized in November 2024.

As part of this discontinuation and the strategic shift away from the drug:

Termination of Development: Biogen terminated the post-marketing, long-term safety study (the ENVISION study) and ceased commercial development of the drug.
Return of Rights: Biogen stopped its collaboration with Neurimmune regarding the patent rights for the drug.
Company Focus: Biogen is redirecting resources to other Alzheimer’s treatments, specifically lecanemab.

1.3.1.3 Change in sponsor

As of January 31, 2024, there is no new “sponsor” that took over development, but rather a complete discontinuation of the drug by its original developer.

1.3.1.4 Transfer of obligation

Effective March 14, 2022, Biogen assumed sole decision-making authority over the development, commercialization, and manufacturing of Aduhelm (aducanumab), changing the previous collaboration structure with Eisai.

1.3.1.5 Change in ownership of an application or reissuance of license

As of early 2024, Biogen terminated its license for aducanumab (Aduhelm) and discontinued its development and commercialization. The rights to the drug were reverted to Neurimmune, the company that originally discovered the monoclonal antibody.

1.3.2 Field copy certification

Based on FDA regulatory guidance, a field copy certification is a document affirming that a “field copy” (a duplicate of the technical section of an application) has been submitted to the appropriate FDA district office.

Regarding the application for Aducanumab (Aduhelm, BLA 761178):

Requirement Status: According to FDA’s guidance on ANDA/BLA Submissions, while applicants must certify that a field copy is being sent, with modern eCTD (Electronic Common Technical Document) submissions, district offices often have direct network access to the submission, making a physical, separate field copy for the district office unnecessary in many cases.
Submission Data: The initial BLA (Biologics License Application) for Aducanumab was submitted on 02/20/2020.
Content: The certification typically states that the field copy is a true copy of the technical sections of the submission.

1.3.3 Debarment certification

Aducanumab (marketed as Aduhelm by Biogen) received FDA accelerated approval on June 7, 2021. As part of the Biologics License Application (BLA) process under Section 306(k) of the Federal Food, Drug, and Cosmetic Act, the manufacturer was required to submit a debarment certification. This certification guarantees that the applicant did not and will not use the services of any person debarred by the FDA under 21 U.S.C. 335a in connection with the application.

1.3.4 Financial certification and disclosure

Financial certification and disclosure for aducanumab (brand name Aduhelm, developed by Biogen) involved rigorous FDA regulatory requirements regarding clinical investigators and financial, as well as significant corporate disclosures related to its development, approval, and subsequent market performance.

FDA Financial Certification and Disclosure (Clinical Trials)

Investigator Disclosures: Under 21 CFR Part 54, Biogen was required to collect financial information from clinical investigators involved in the Phase 3 trials (EMERGE and ENGAGE) to identify any potential conflicts of interest. This includes any financial arrangements in which the value of compensation was affected by the study outcome, significant equity interests in Biogen, or significant payments of any kind.
Forms 3454/3455: Applicants (Biogen) must submit FORM FDA 3454 (Certification) or FORM FDA 3455 (Disclosure) to the FDA regarding these financial interests, which the FDA reviews to assess potential bias in the data.
Regulatory Scrutiny: The FDA’s approval of aducanumab was subject to intense public and congressional scrutiny, which included questions about the relationship between regulators and the company. However, these were distinct from the investigator’s financial disclosures.

1.3.5 Patent and exclusivity

Patent Protection: Aducanumab was protected by a combination of composition, formulation, and manufacturing process patents. Key patents, such as WO2014089500 and related family patents, provided intellectual property protection extending until 2032–2034 across major markets.

Exclusivity: As a biologic, aducanumab was entitled to 12 years of reference product exclusivity in the U.S. under the Biologics Price Competition and Innovation Act (BPCIA), which was set to ensure protection until June 2033.

1.3.5.1 Patient information

Purpose: Reduced amyloid plaque, aimed at slowing cognitive decline in mild cognitive impairment (MCI) or mild Alzheimer’s dementia.

Administration: Intravenous infusion roughly every 4 weeks.

Risks & Side Effects:

- ARIA (Amyloid-Related Imaging Abnormalities): Temporary brain swelling or small brain bleeds occurred in 35% of trial participants. Most were asymptomatic but serious.
- Common Side Effects: Headache (20%+), falls (15%), and diarrhea (8.9%).

Monitoring: Regular MRIs are required to monitor for brain swelling/bleeding.

Diagnosis Required: Before treatment, patients needed confirmation of amyloid plaque via PET scan or cerebrospinal fluid analysis.

Before Treatment (Historically Required)
Patients were advised to tell their doctors if they took blood thinners, were pregnant, or had prior allergies.

1.3.5.2 Patient certification

Patient certification for aducanumab (Aduhelm) required confirmation that the patient had early-stage Alzheimer’s disease, verified amyloid pathology, and no contraindications for frequent MRI monitoring.

1.3.5.3 Exclusivity claim

Aducanumab had an estimated 12 years of regulatory exclusivity in the United States as a new biologic, potentially lasting until June 2033. However, this exclusivity claim is practically moot following Biogen’s decision in January 2024 to discontinue the development and commercialization of the drug.

1.3.6 Tropical disease priority review voucher

Aducanumab (Aduhelm), developed for Alzheimer’s disease, did not receive or use a Tropical Disease Priority Review Voucher (PRV) because it is not a drug for a tropical disease. The FDA only awards these vouchers for approved applications targeting specific tropical diseases listed in section 524 of the FD&C Act.

1.4 References

Cummings, J., Rabinovici, G., Atri, A., Aisen, P., Apostolova, L., Hendrix, S., Sabbagh, M., Selkoe, D., Weiner, M., & Salloway, S. (2022). Aducanumab: Appropriate Use Recommendations update. The Journal of Prevention of Alzheimer S Disease, 9(2), 221–230. https://doi.org/10.14283/jpad.2022.34

Haeberlein, S. B., Aisen, P., Barkhof, F., Chalkias, S., Chen, T., Cohen, S., Dent, G., Hansson, O., Harrison, K., Von Hehn, C., Iwatsubo, T., Mallinckrodt, C., Mummery, C., Muralidharan, K., Nestorov, I., Nisenbaum, L., Rajagovindan, R., Skordos, L., Tian, Y., . . . Sandrock, A. (2022). Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. The Journal of Prevention of Alzheimer S Disease, 9(2), 197–210. https://doi.org/10.14283/jpad.2022.30

Ridley, D. B., Ganapathy, P., & Kettler, H. E. (2021). US Tropical Disease Priority Review Vouchers: Lessons in promoting drug development and access. Health Affairs, 40(8), 1243–1251. https://doi.org/10.1377/hlthaff.2020.02273

Rutschman, A. S. (2017). The Priority Review Voucher Program at the FDA: From Neglected Tropical Diseases to the 21st Century Cures Act. eYLS (Yale Law School). https://lawecommons.luc.edu/annals/vol26/iss2/7

1.4.1 Letter of authorization

Biogen Inc.
225 Binney Street
Cambridge, MA 02142, USA
Phone: +1 781-464-2000
Website: biogen.com

24^th April 2026

The Regulatory Review Committee
U.S. Food and Drug Administration (FDA)
Silver Spring, Maryland, USA

Subject: Letter of Authorization for Aducanumab Regulatory Representation

Dear Sir/Madam,

Biogen Inc., in collaboration with Eisai Co., Ltd., is the manufacturer of Aducanumab, with the active ingredient aducanumab-avwa, used in the treatment of Alzheimer’s disease in adult and geriatric patients with mild cognitive impairment or mild dementia stage of the disease. The medicine is administered through intravenous infusion, with a recommended dosage of 10 mg/kg once every four weeks after the titration phase. The product has a shelf life of 36 months and should be stored under refrigerated conditions between 2°C and 8°C.

Through this letter, Biogen Inc. officially authorizes Ms. Marisol Llovera, Food Safety Investigator with the U.S. Food and Drug Administration (FDA), California, USA, to act as the authorized representative and contact person for all regulatory matters concerning Aducanumab.

She is authorized to handle all correspondence, submit and receive official documents, respond to regulatory inquiries, and manage all follow-up activities related to the application, review, and approval process of Aducanumab.

This authorization remains valid until further written notice from Biogen Inc.

We kindly request that all future communication regarding Aducanumab be directed to Ms. Marisol Llovera for efficient coordination and response.

Thank you for your attention and cooperation.

Yours faithfully,

Authorized Representative
Biogen Inc.

1.4.2 Statement of right of reference

The Statement of Right of Reference confirms that Biogen Inc., in collaboration with Eisai Co., Ltd., grants permission to Marisol Llovera, Food Safety Investigator with the U.S. Food and Drug Administration (FDA), California, USA, to act as the authorized representative for Aducanumab and to reference all necessary regulatory documents related to the product. This includes access to application files, supporting technical documents, safety data, quality records, and correspondence required for the review and approval process. This authorization allows her to communicate with regulatory authorities, submit documents, respond to inquiries, and manage all official matters concerning Aducanumab on behalf of Biogen Inc. until further written notice is provided.

1.4.3 List of authorized persons to incorporate by reference

Marisol Llovera
Food Safety Investigator
U.S. Food and Drug Administration (FDA)
California, USA
Authorized to manage regulatory communication, submit documents, respond to inquiries, and act as the official contact for Aducanumab.
Regulatory Affairs Department
Biogen Inc.
225 Binney Street, Cambridge, MA 02142, USA
Phone: +1 781-464-2000
Responsible for preparing, reviewing, and submitting all regulatory documentation related to Aducanumab.
Authorized Representative
Biogen Inc.
225 Binney Street, Cambridge, MA 02142, USA
Responsible for granting official authorization, maintaining compliance records, and approving reference rights for regulatory submissions.
Eisai Co., Ltd. Regulatory Affairs Team
Collaboration Partner for Aducanumab
Responsible for supporting product documentation, clinical data submission, and regulatory compliance as co-developer of Aducanumab.

1.4.4 Cross reference to previously submitted information

Biogen Inc., in collaboration with Eisai Co., Ltd., confirms that previously submitted information related to Aducanumab (aducanumab-avwa) may be incorporated by reference for the current regulatory application. This includes prior submissions containing clinical trial data, safety reports, manufacturing information, quality control records, stability studies, labeling documents, and post-marketing surveillance reports.

These documents were submitted as part of earlier regulatory filings for the review and approval of Aducanumab for the treatment of Alzheimer’s disease in adult and geriatric patients with mild cognitive impairment or mild dementia stage of the disease. The product is administered through intravenous infusion at a recommended dosage of 10 mg/kg once every four weeks after the titration phase.

Biogen Inc. authorizes the U.S. Food and Drug Administration (FDA) and the designated representative, Marisol Llovera, to reference these previously submitted records to support the current review process, reduce duplication of documentation, and ensure regulatory consistency.

1.5 Application status

1.5.1 Withdrawal of an IND

Biogen announced the discontinuation of the development and marketing of aducanumab (Aduhelm) on January 31, 2024. While not a traditional, involuntary, or punitive “withdrawal of an Investigational New Drug (IND) application” by the FDA due to safety failures, this decision was a strategic termination of the product following its 2021 accelerated approval.

The IND (Investigational New Drug) application, which allowed for research to take place, was effectively voluntarily closed/withdrawn by Biogen as part of their decision to cease all development.

1.5.2 Inactivation request

Biogen announced on January 31, 2024, that it is discontinuing the development and commercialization of aducanumab (Aduhelm), effectively terminating its use as a treatment for Alzheimer’s disease. The company planned to terminate the Phase 4 ICARE-AD study and discontinue the drug to reallocate resources towards another Alzheimer’s research, including lecanemab.

Key details regarding this action include:

Termination Reason: The discontinuation was not based on safety or efficacy issues, but rather a strategic business decision to “reprioritize its resources in Alzheimer’s disease”.
Product Status: Production of aducanumab-avwa has ceased.
Marketing Authorization: In 2022, Biogen had already initiated withdrawal of its marketing authorization application for aducanumab from the European Medicines Agency (EMA).
Termination of Clinical Trials: The Phase 4 ICARE-AD clinical trial, intended to fulfil the post-marketing requirements of the FDA accelerated approval, was terminated.

1.5.3 Reactivation request

As of January 31, 2024, Biogen has discontinued the development and commercialization of Aducanumab (Aduhelm). Consequently, there is no active, standard “reactivation request” process for this drug.

1.5.4 Reinstatement request

Based on the available information regarding Aducanumab (Aduhelm), there is no active, ongoing “reinstatement request” in the sense of a regulatory reversal to bring the drug back to market.

Discontinuation: Biogen announced the discontinuation of the Aduhelm program (including the discontinuation of the Phase 4 ENVISION study) on January 31, 2024.
Reason for Discontinuation: The decision was made to reprioritize resources in Alzheimer’s disease, not due to safety or efficacy issues, according to company statements.
Previous Regulatory History: While the FDA granted accelerated approval in June 2021, the European Medicines Agency (EMA) refused marketing authorization in December 2021, citing that the link between amyloid reduction and clinical improvement had not been established.

1.5.5 Withdrawal of an unapproved BLA, NDA, ANDA, or Supplement

Biogen announced the discontinuation of aducanumab (marketed as Aduhelm) in late January 2024, leading to the withdrawal of its Biologics License Application (BLA 761178). Although the drug had received accelerated approval in June 2021, the company halted the required confirmatory trial (ENVISION) and withdrew the BLA, with the withdrawal effective on 1 November 2024. Following this withdrawal, the rights to aducanumab reverted to Neurimmune.

1.5.6 Withdrawal of the listed drug

Biogen announced the discontinuation of aducanumab (Aduhelm) in late January 2024, effectively withdrawing the drug from the market. The decision was driven by a “reprioritization” of the company’s resources in the Alzheimer’s disease (AD) space, rather than issues related to safety or efficacy.

1.5.7 Withdrawal of approval of an application or revocation

On April 22, 2022, Biogen announced the withdrawal of its Marketing Authorisation Application (MAA) for aducanumab for the treatment of early Alzheimer’s disease in the European Union. This withdrawal followed a preliminary assessment by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP), which indicated on December 16, 2021, that the benefits of aducanumab did not outweigh its risks. Following a re-examination request by Biogen, the CHMP indicated that the data provided (primarily from Phase 3 studies that showed conflicting results on efficacy and safety, particularly Amyloid-Related Imaging Abnormalities or ARIA) was not sufficient to support a positive opinion.

1.6 Meetings

1.6.1 Meeting request

Biogen Inc., in collaboration with Eisai Co., Ltd., respectfully requests a formal meeting with the U.S. Food and Drug Administration (FDA) to discuss the regulatory review of Aducanumab (aducanumab-avwa).

The purpose of the meeting is to review key aspects of the application, including previously submitted clinical data, safety findings, manufacturing details, and the current authorization arrangements. This will also allow clarification of any outstanding regulatory questions and ensure alignment on the review pathway for Aducanumab, which is indicated for adult and geriatric patients with mild cognitive impairment or mild Alzheimer’s disease.

Ms. Marisol Llovera, Food Safety Investigator at the FDA (California, USA), will serve as the authorized contact person for coordinating the meeting, scheduling discussions, and managing follow-up communication on behalf of Biogen Inc.

We kindly request confirmation of a suitable date and time for the meeting at your earliest convenience.

1.6.2 Meeting background materials

Biogen Inc., in collaboration with Eisai Co., Ltd., provides the following background materials to support the upcoming meeting with the U.S. Food and Drug Administration (FDA) regarding Aducanumab (aducanumab-avwa).

Aducanumab is a monoclonal antibody developed for the treatment of Alzheimer’s disease in adult and geriatric patients with mild cognitive impairment or mild dementia stage of the disease. The product targets amyloid beta plaques in the brain, which are associated with disease progression.

The active ingredient is aducanumab-avwa. The medicine is administered through intravenous infusion by a healthcare professional. The recommended dosage is 10 mg/kg once every four weeks following the titration phase. The product is stored under refrigerated conditions between 2°C and 8°C and has a shelf life of 36 months when stored in its original packaging.

The meeting materials also include previously submitted clinical trial data, safety reports, manufacturing and quality control documentation, and post-marketing surveillance information. These documents provide evidence of the product’s safety profile, efficacy data, and compliance with regulatory requirements.

Ms. Marisol Llovera, Food Safety Investigator at the FDA (California, USA), is the authorized representative for coordinating all meeting-related communication and document management on behalf of Biogen Inc.

1.6.3 Correspondence regarding meetings

All correspondence related to meetings concerning Aducanumab (aducanumab-avwa) should be directed to the authorized representative, Ms. Marisol Llovera, Food Safety Investigator at the U.S. Food and Drug Administration (FDA), California, USA.

She is responsible for handling all communication regarding meeting requests, scheduling, agenda setting, submission of background materials, and follow-up actions. This includes coordination between Biogen Inc. (Cambridge, MA, USA) and the FDA regarding regulatory discussions for Aducanumab.

Biogen Inc., in collaboration with Eisai Co., Ltd., confirms that Ms. Marisol Llovera is fully authorized to receive, review, and respond to all official correspondence related to meetings. She will ensure that all relevant regulatory questions and documentation requirements are appropriately addressed in a timely and organized manner.

1.7 Fast track

1.7.1 Fast track designation request

Biogen’s aducanumab (Aduhelm), an investigational treatment for early Alzheimer’s disease, was granted Fast Track designation by the U.S. FDA in September 2016. This program accelerated development and facilitated frequent communication with the FDA, aimed at addressing the serious, unmet medical need of Alzheimer’s.

1.7.2 Fast-track designation withdrawal request

Biogen announced on January 31, 2024, that it would discontinue the development and commercialization of aducanumab (Aduhelm), effectively ending its commercial life. Though this was a voluntary corporate decision rather than a mandatory regulatory withdrawal of its fast-track/accelerated approval status.

1.7.3 Rolling review request

Aducanumab (brand name Aduhelm) received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease on June 7, 2021. This approval followed a Biologics License Application (BLA) review process.

1.7.4 Correspondence regarding fast track/rolling review

Correspondence and regulatory documents regarding the development of aducanumab (Aduhelm) show it was granted both Fast Track designation and Priority Review by the U.S. Food and Drug Administration (FDA), leading to an accelerated approval on June 7, 2021.

1.8 Special protocol assessment request

1.8.1 Clinical study

Aducanumab (marketed as Aduhelm) was evaluated in a series of clinical trials targeting early Alzheimer’s disease, which led to a controversial FDA accelerated approval in 2021. The clinical program was marked by conflicting results, where two major phase 3 trials initially appeared to fail due to futility but were later re-analyzed to suggest benefit. In a nutshell, the trials established that aducanumab reduces brain amyloid plaques, but the clinical trials provided inconsistent evidence on whether this reduction significantly improves clinical dementia symptoms.

1.8.2 Carcinogenicity study

Long-term carcinogenicity studies for aducanumab were not conducted. According to the FDA Pharmacology Review, these studies were not required because the drug’s target, aggregated amyloid-beta, is not present in wild-type rodents.

1.8.3 Stability study

Stability studies for aducanumab (Aduhelm) submitted to regulatory authorities, such as the European Medicines Agency (EMA), confirmed that the drug’s stability was proven throughout the handling and analysis of samples during clinical trials.

1.8.4 Animal efficacy study for approval under the animal rule

Aducanumab (Aduhelm) was approved by the FDA on June 7, 2021, under the Accelerated Approval Pathway (21 CFR 601.41), not the “Animal Rule” (21 CFR 601.90), which is typically used for cases where human efficacy trials are not ethical or feasible (e.g., biological warfare agents).

1.9 Pediatric administrative information

1.9.1 Request for waiver of pediatric studies

The FDA granted a full waiver for pediatric studies for aducanumab (Aduhelm) in June 2021. This waiver was issued because Alzheimer’s disease primarily affects older adults, making studies in the pediatric population impossible or highly impractical. As a result, no pediatric assessments were required for the drug’s approval.

1.9.2 Request for deferral of pediatric studies

A request for deferral of pediatric studies for aducanumab, a drug for Alzheimer’s disease, is typically submitted under the Pediatric Research Equity Act (PREA), as adult studies are completed first for this indication. Such requests argue that studies should be delayed until adult safety/efficacy data are established, a common practice for diseases that rarely occur in children.

1.9.3 Request for pediatric exclusivity determination

A request for pediatric exclusivity determination for aducanumab involves submitting pediatric study reports, requested by the FDA, to earn a six-month extension of existing patent/exclusivity protections. It requires a formal Written Request from the FDA, completion of studies in children, and submission of results confirming the drug’s safety/efficacy in that population, following Best Pharmaceuticals for Children Act (BPCA) guidelines.

1.9.4 Proposed pediatric study request and amendments

The approval required confirmatory trials to verify clinical benefit due to conflicting data on efficacy and safety. The approved label covers adults with early-stage Alzheimer’s and was refined on July 8, 2021, to focus specifically on mild cognitive impairment (MCI) or mild dementia, reflecting the population in Phase III trials (EMERGE/ENGAGE). The results focused on clinical trials and approvals for adults, notably mentioning that the drug was aimed at adults aged 50-85, and studies indicated serious safety considerations (ARIA).

1.9.5 Proposal for written agreement (no longer applicable)

Not applicable

1.9.6 Other correspondence regarding pediatric exclusivity or study plans

Based on publicly available FDA regulatory documents for Aduhelm (aducanumab-avwa), there was no meaningful pediatric development program expected or required for routine clinical use, because Alzheimer’s disease primarily affects older adults and does not normally occur in pediatric populations. As a result, pediatric studies were not considered clinically relevant in the traditional sense.

Under the Pediatric Research Equity Act (PREA), sponsors may request a full waiver of pediatric study requirements when the disease or condition does not occur in children or when studies would be impractical or unnecessary. For aducanumab, Alzheimer’s disease is an age-related neurodegenerative disorder, so pediatric assessment obligations would reasonably qualify for waiver consideration.

Regarding pediatric exclusivity, this incentive usually grants an additional six months of marketing protection when requested pediatric studies are completed in response to a Written Request from the FDA. For aducanumab, there is no widely reported evidence that pediatric exclusivity was pursued, since the product’s indication targeted adults with Alzheimer’s disease and pediatric use was not medically relevant.

1.10 Dispute resolution

1.10.1 Request for dispute resolution

The FDA’s approval of aducanumab (Aduhelm) on June 7, 2021, did not follow a standard formal dispute resolution process, but rather was an accelerated approval granted despite strong opposition from an advisory committee. The controversy centered on the FDA bypassing its own Peripheral and Central Nervous System Drugs Advisory Committee, which voted 10–0 (with one abstention) that the data did not show efficacy.

1.10.2 Correspondence related to dispute resolution

Based on the FDA eCTD structure, 1.10.2 Correspondence related to dispute resolution is the designated location for submissions containing formal communication regarding disagreements, such as those that arose between the FDA’s Division of Neurology 1, internal advisory committees, and Biogen during the review of aducanumab (Aduhelm). While specific 1.10.2 documents are not public, the Aduhelm approval process involved intense, documented internal and external disputes.

1.11 Information amendment: Information not covered under modules 2 to 5

1.11.1 Quality information amendment

The FDA granted accelerated approval to Aduhelm (aducanumab-avwa) on June 7, 2021, for Alzheimer’s disease based on biomarker data (reduction in amyloid beta plaques) rather than clinical benefit. The approval was contentious, as it was based on conflicting results from post hoc analyses of two trials, EMERGE and ENGAGE, and was opposed by the FDA’s own advisory panel.

1.11.2 Nonclinical information amendment

The FDA’s nonclinical review (often associated with documentation supporting the Biologics License Application, such as Section 1.11, or in this case, the detailed Pharmacologist Review) for aducanumab-avwa (Aduhelm) concluded that the nonclinical data were sufficient to support approval for the treatment of Alzheimer’s disease.

1.11.3 Clinical information amendment

On July 8, 2021, shortly after the initial June 2021 approval, the FDA approved an updated label for aducanumab (Aduhelm), specifically narrowing the indication to align with the patient population studied in clinical trials.

1.11.4 Multiple module information amendment

As of early 2026, information regarding amendments to the module information for aducanumab (brand name Aduhelm) according to the FDA is superseded by the manufacturer’s decision to discontinue the drug.

1.12 Pre IND correspondence

1.12.1 Pre IND correspondence

Based on FDA documentation regarding Aducanumab (Aduhelm), the pre-approval process was characterized by extensive, collaborative, and controversial correspondence between the FDA and Biogen after initially failed trials.

Key Pre-Approval and Regulatory Correspondence

Failed Trials & Collaboration: Following the March 2019 termination of Phase 3 trials (EMERGE and ENGAGE) due to futility, the FDA and Biogen formed a working group.
Extensive Interaction: Between July 2019 and July 2020, this working group engaged in over 115 meetings, calls, and substantive email discussions to analyze the data.
Specific Consultations: A key teleconference occurred on June 17, 2020, to discuss the development plan.
“Working Group” Focus: The discussions focused on re-evaluating data, specifically trying to establish that amyloid reduction was a valid surrogate endpoint for clinical benefit.
Accelerated Approval Path: The correspondence concluded with the submission of a Biologics License Application (BLA) on July 7, 2020, with the FDA ultimately recommending the accelerated approval pathway based on surrogate endpoint data, rather than direct, conclusive clinical benefit.

1.12.2 Repeat to charge for a clinical trial

Aducanumab was approved via the accelerated approval pathway in June 2021. Although it was approved, it was largely available through clinical trials or post-marketing studies, as many insurers initially refused coverage. Biogen discontinued Aduhelm in January 2024 and ended trials, allowing access to participants only until May 1, 2024, and prescription users until Nov. 1, 2024, as noted by the Alzheimer’s Association.

Request to charge expanded access

Aducanumab (marketed as Aduhelm) received accelerated approval in June 2021. If used in an expanded access (compassionate use) setting (rather than as an FDA-approved, marketed drug) before or after this, the relevant regulations apply. The sponsor (Biogen) is responsible for submitting the request to charge, often in conjunction with the IND for expanded access.

Request for comments and advise

As of early 2026, aducanumab (brand name Aduhelm) has been discontinued by its manufacturer, Biogen, and is no longer being actively developed or marketed for Alzheimer’s disease. While the FDA granted controversial accelerated approval in 2021, the drug’s journey was marked by intense expert opposition and ultimately a business decision to pivot to newer, more effective treatments. The FDA approved Aduhelm under the accelerated approval pathway. This pathway allows for earlier approval of drugs that treat serious conditions based on a “surrogate endpoint”. In this case, the reduction of amyloid beta plaques in the brain, rather than direct evidence of clinical benefit.

Request for a waiver

Based on FDA documents from the approval of Aduhelm (aducanumab-avwa), the FDA granted a waiver for the pediatric study requirement under the Pediatric Research Equity Act (PREA). The FDA determined that the required studies were “impossible or highly impracticable” because Alzheimer’s disease exclusively occurs in the adult population. Therefore, a pediatric assessment was not necessary for approval.

Exception from informed consent for emergency work

The FDA’s exception from informed consent (EFIC) for emergency research, outlined in 21 CFR 50.24, applies to clinical investigations of life-threatening conditions where a prospective subject needs urgent intervention but cannot provide consent, and no legal representative is available.

Based on FDA regulations and the status of Aducanumab (Aduhelm), here is the breakdown regarding its use:

Aducanumab’s Regulatory Status: Aducanumab was granted accelerated approval by the FDA in June 2021. Because it is an approved, albeit controversial, drug for Alzheimer’s disease (specifically for mild cognitive impairment or mild dementia stage), it is generally not considered an “investigational product” requiring emergency research exceptions for its administration.
Emergency Exception Criteria (21 CFR 50.24): The FDA’s EFIC policy is strictly for clinical trials on life-threatening conditions where “available treatments are unproven or unsatisfactory”. Since Aducanumab is approved, it does not meet the strict definition of an investigational agent used in emergency, life-saving research.

1.12.7 Public disclosure statement for exception from informed consent for emergency

work research

Based on FDA regulations under 21 CFR 50.24, an exception from informed consent (EFIC) for emergency research, such as might be considered for a now accelerated approved, Aducanumab (Aduhelm) trial in an emergency setting, requires strict public disclosure steps to inform the community before and after the research is conducted.

Required Public Disclosure Steps (21 CFR 50.24)

Pre-Trial Community Consultation: Before the trial begins, the investigator must consult with the community from which subjects will be drawn, including disclosing the risks and benefits of the study.
Pre-Trial Public Disclosure: The investigator must disclose the proposed research (purpose, procedures, risks, benefits) to the community, including public meetings.

1.12.8 Correspondence regarding exception from informed consent for emergency work Research

There is no evidence of an Exception from Informed Consent (EFIC), also known as a 21 CFR 50.24 emergency research waiver, being granted for the clinical trials of Aducanumab (Aduhelm).

1.12.9 Notification of discontinuation of clinical trial

On January 31, 2024, Biogen announced the discontinuation of Aducanumab (Aduhelm), marking the end of its development and commercialization of the drug for Alzheimer’s disease. This decision includes stopping the planned Phase IV ENVISION clinical trial, which was required to confirm the drug’s clinical benefit.

1.12.10 Generic drug enforcement act statement

There is no direct “Generic Drug Enforcement Act” statement specifically regarding Aducanumab (Aduhelm). Aducanumab is a brand-name biologic drug developed by Biogen, approved via the FDA’s accelerated pathway, and is not currently eligible for generic substitution.

1.12.11 ANDA basis for submission statement

As of April 2026, Aducanumab (Aduhelm) does not have a formal Abbreviated New Drug Application (ANDA) basis for submission, as it is a biologic product approved via a Biologics License Application (BLA), not a generic drug.

1.12.12 Comparison of generic drug and reference listed drug

According to the FDA, aducanumab-avwa (brand name Aduhelm) is a biologic drug that received accelerated approval in 2021 for the treatment of Alzheimer’s disease.

Based on FDA information as of early 2026:

No Generic Available: Aducanumab is a biologic, not a traditional chemical drug. Therefore, it does not have a “generic” equivalent.
No Approved Biosimilar: There are currently no FDA-approved biosimilars (generic equivalent for biologics) for aducanumab.
Reference Listed Drug (RLD): Biogen’s Aduhelm (aducanumab-avwa) was the sole RLD.
Discontinuation: The manufacturer (Biogen) announced in January 2024 that they were discontinuing the development and commercialization of Aduhelm.

1.12.13 Request for waiver for in vivo studies

Based on FDA documentation for Aducanumab (Aduhelm), the FDA did not grant a general waiver for in vivo studies (animal toxicology) for the drug’s Biologics License Application (BLA).

1.12.14 Environmental analysis

Aducanumab likely qualifies for a categorical exclusion from the requirement to submit an environmental assessment (EA) or an environmental impact statement (EIS) under 21 CFR 25.31(c) [or 25.31(b)], which applies to human drugs and biological products. This exclusion typically applies when the estimated concentration of the substance at the point of entry into the aquatic environment is expected to be below 1 part per billion (ppb), and there are no extraordinary circumstances. As a human monoclonal antibody, Aducanumab is a large protein, designed to be metabolized into amino acids and peptides, reducing the likelihood of persistence in the environment or bioaccumulation, unlike small-molecule drugs.

1.12.15 Request for in vivo bioavailability studies

In vivo bioavailability for this monoclonal antibody is intrinsically defined by its route of administration: intravenous (IV) infusion, which ensures 100% bioavailability. Based on FDA-approved documents (BLA 761178), the following information regarding in vivo pharmacology and bioavailability studies was provided by Biogen, Inc.:

Administration: Aducanumab is administered via intravenous infusion, meaning bioavailability is not the primary limiting factor for systemic exposure.
Linearity: The pharmacokinetics of aducanumab are linear and dose-proportional, exhibiting time-invariant kinetics across the tested ranges.

1.12.16 Field alert reports

Based on the FDA Adverse Event Reporting System (FAERS), Aducanumab (Aduhelm) safety surveillance highlights significant risks, primarily Amyloid-Related Imaging Abnormalities (ARIA). Key real-world data identified 510 reports and 1,095 safety events, with edema and hemorrhage being major concerns. FDA recommends strict MRI monitoring to manage these risks, particularly for APOE $\epsilon$4 carriers.

1.12.17 Orphan drug designation

Aducanumab (brand name Aduhelm), developed by Biogen, did not receive orphan drug designation from the FDA for the treatment of Alzheimer’s disease.

1.13 Annual report

1.13.1 Summary of nonclinical studies

Based on the FDA’s Multi-Discipline Review for Aducanumab (BLA 761178), the nonclinical studies were considered adequate to support the approval of the drug. The program included pharmacology, toxicology, and pharmacokinetic studies that demonstrated the drug’s mechanism of action and safety profile in animal models.

1.13.2 Summary of clinical pharmacology information

It is administered via monthly IV infusions, starting at 1 mg/kg and titrating to a 10 mg/kg maintenance dose, with safety monitoring required for Amyloid-Related Imaging Abnormalities (ARIA-E and ARIA-H).

1.13.3 Summary of safety information

Aducanumab (Aduhelm) carries a boxed warning for Amyloid-Related Imaging Abnormalities (ARIA), including brain edema and hemorrhage, which are monitored via MRI. The most common adverse events include ARIA-E, ARIA-H, headache, and falls, necessitating specific safety precautions for ApoE $\epsilon$4 homozygotes. For full prescribing information, see the FDA Aduhelm Label.

Summary of labeling changes

Based on FDA actions, the labeling for Aducanumab (Aduhelm™) was modified significantly in 2021 to restrict its target population, followed by a total withdrawal of the drug from the market by the manufacturer in 2024. For instance, shortly after the June 2021 accelerated approval, the FDA approved a revised label. The updated label explicitly restricted use to patients with mild cognitive impairment (MCI) or mild dementia stage of disease. The original label was broader, and this change was made to align with the specific population studied in clinical trials. Also, the updated label included a statement that there were “no safety or efficacy data on initiating treatment at earlier or later stages of the disease than were studied”.

Summary of manufacturing changes

Based on FDA documents from the June 2021 approval, manufacturing changes for Aducanumab (Aduhelm) were a significant component of the approval process due to modifications in the drug’s production during clinical development.

Key aspects regarding the manufacturing changes according to the FDA include:

Manufacturing Process Changes: The FDA noted that the manufacturing process for Aducanumab was changed between the Phase 1b study (PRIME) and the Phase 3 clinical trials (EMERGE/ENGAGE).
Comparability Study: Biogen was required to demonstrate that the product produced by the new manufacturing process was comparable in terms of safety and efficacy to the product used in earlier trials.

Post-Approval Restrictions:Upon approval on June 7, 2021, the FDA required that any future changes in manufacturing, testing, packaging, or labeling, as well as changes in manufacturing facilities, must be submitted to the biologics license application for review and written approval, under 21 CFR 601.12.

1.13.6 Summary of microbiological changes

FDA documentation indicates no reported microbial issues with Aducanumab, focusing instead on significant reductions in amyloid plaques as a surrogate marker for Alzheimer’s disease. The review highlighted safety concerns regarding Amyloid-Related Imaging Abnormalities (ARIA), such as brain edema or hemorrhage.

Summary of other significant new information

Significant developments regarding aducanumab during its regulatory lifespan included:

Discontinuation of Development (2024): In late January 2024, Biogen announced the discontinuation of aducanumab to reprioritize its Alzheimer’s disease resources, explicitly stating this was not due to safety or efficacy concerns, but rather a business decision.

Confirmatory Trial Requirement: As part of the accelerated approval pathway, Biogen was required to complete a post-approval confirmatory trial (Phase 4) by 2030 to verify the clinical benefits. The discontinuation resulted in the cancellation of this requirement.

Safety Profile (ARIA): FDA post-market monitoring highlighted a high incidence of Amyloid-Related Imaging Abnormalities (ARIA), including brain swelling (ARIA-E) and microhemorrhages (ARIA-H) in treated patients.

Controversy and Labeling: The FDA’s decision was controversial, with an advisory panel voting 10-0 against approval in 2020 due to conflicting data from two Phase 3 trials (EMERGE and ENGAGE). While the FDA originally allowed broad usage, the label was later narrowed to reflect that the drug should be initiated only in patients with mild cognitive impairment or mild dementia.

Individual study information

According to the FDA, Aducanumab (marketed as Aduhelm) was approved on June 7, 2021, via the accelerated approval pathway, based on data demonstrating its effect on reducing amyloid-beta plaques, a surrogate endpoint in Alzheimer’s disease. The approval, particularly in its later narrowed labeling, focuses on patients with mild cognitive impairment or mild dementia. The FDA review primarily focused on two identical Phase 3 trials (Studies 301 and 302), along with a Phase 1b trial (PRIME).

Study 302 (EMERGE): Met its primary endpoint, demonstrating a statistically significant treatment benefit (smaller increase in CDR-SB scores) for the high-dose
Study 301 (ENGAGE): Did not meet its primary endpoint and failed to show a statistically significant benefit in the final analysis.
Results Conflict: The FDA review noted that while 302 was positive, 301 was not, creating a controversial approval package.
Secondary Endpoints: In Study 302, significant positive results were observed for secondary endpoints, including the MMSE (Mini-Mental State Exam), ADAS-Cog 13 (Alzheimer’s Disease Assessment Scale–Cognitive Subscale), and ADCS-ADL-MCI (Alzheimer’s Disease Cooperative Study–Activities of Daily Living).

General investigational plan

Based on FDA documentation and associated regulatory actions in 2021, the marketing of Aducanumab (brand name Aduhelm) is strictly governed by the conditions of its accelerated approval.

Here are the key points regarding its marketing and regulatory status:

Accelerated Approval Requirement: The FDA approved aducanumab on June 7, 2021, under the accelerated approval pathway. This regulation allows for approval based on a surrogate endpoint, in this case, the reduction of amyloid-beta plaques in the brain, rather than a direct measure of clinical benefit.
Post-Approval Trials: The FDA requires that Biogen conduct a post-approval clinical trial (Phase 4) to verify the actual clinical benefit. If this confirmatory trial fails to show a significant clinical benefit, the FDA has the authority to withdraw the drug from the market.
Target Population: The approved labeling limits the drug to patients with mild cognitive impairment or mild Alzheimer’s disease.

1.13.10 Distribution data

According to FDA documents and subsequent safety surveillance data, here are the key findings regarding the distribution, dosing, and safety profile of Aducanumab:

Dosing and Administration Data

Target Dosage: The recommended dosage was 10 mg/kg, administered via intravenous (IV) infusion over approximately one hour, every four weeks, at least 21 days apart.
Titration Schedule:
- Infusion 1 and 2: 1 mg/kg
- Infusion 3 and 4: 3 mg/kg
- Infusion 5 and 6: 6 mg/kg
- Infusion 7 and beyond: 10 mg/kg.
Available Formulations: Supplied in single-dose vials in two concentrations: 170 mg/1.7 mL (100 mg/mL) and 300 mg/3 mL (100 mg/mL).

Distribution and Safety Reporting (FAERS Data)

Adverse Event Surveillance: Data from the FDA Adverse Event Reporting System (FAERS) from January 2004 to June 2024 (with most reports concentrated in 2022 and 2023) showed 510 adverse event reports for aducanumab.

Geographic Distribution:The vast majority of reported adverse events were from the United States (92.75%), with limited reports from Japan (1.96%) and Canada (0.98%).
Patient Demographics in Reports:
- Age:55% of reports involved patients aged 75 or older, while 22.94% were aged 65 to 74.
- Sex:80% female and 44.51% male.
Source of Reports:57% of reports came from consumers, 34.31% from physicians, and 23.53% from pharmacists

Clinical Trial Safety Data

Patient Exposure: The safety profile was evaluated in over 3,000 patients.
Key Safety Concern (ARIA): Amyloid-Related Imaging Abnormalities (ARIA-E or ARIA-H) occurred in 41% of patients treated with the 10 mg/kg dose compared to 10% on placebo.
Symptomatic ARIA: Clinical symptoms associated with ARIA occurred in 24% of patients treated with 10 mg/kg, with headache being the most common symptom.
Discontinuations: Approximately 5% of patients (66 out of 1,386) in the 10 mg/kg group withdrew from studies due to adverse reactions.

1.13.11 Status of postmarketing study commitments and requirements

As of early 2026, all postmarketing study commitments and requirements for aducanumab (Aduhelm) have been terminated following Biogen’s decision to discontinue the drug. The FDA-mandated post-approval confirmatory trial, known as the ENVISION study, was terminated by the manufacturer in 2024, and the Biologics License Application (BLA) was withdrawn, making the drug no longer marketed or studied for Alzheimer’s disease.

1.13.12 Status of other postmarketing studies and requirements

As of April 2026, the FDA-required postmarketing studies for Aducanumab (Aduhelm) are effectively moot, as the manufacturer, Biogen, discontinued the drug in 2024 and terminated the associated confirmatory trials.

Status of Postmarketing Requirement (PMR): The Phase 4 confirmatory trial, known as the ENVISION study (designed to confirm clinical benefit), was required by the FDA upon accelerated approval in 2021.
Termination of Studies: Following Biogen’s January 2024 announcement, the ENVISION trial was terminated, and the company discontinued development and commercialization of Aduhelm, moving resources toward Lecanemab (Leqembi).
Final Availability: Commercial availability of Aducanumab ceased on November 1, 2024.

1.13.13 Log of outstanding regulatory business

As of early 2026, the regulatory business for aducanumab (brand name Aduhelm), according to the FDA, is effectively closed, as the product was discontinued by its manufacturer, Biogen. While it once had outstanding post-marketing requirements under the FDA’s accelerated approval pathway, these are no longer active in the traditional sense due to the discontinuation.

1.13.14 Development safety update report (DSUR)

Aducanumab (Aduhelm) safety updates, as analyzed through the FDA Adverse Event Reporting System (FAERS) and clinical trials, indicate that Amyloid-Related Imaging Abnormalities (ARIA) are the primary safety concerns. Data shows high incidences of ARIA-E (edema/effusion) and ARIA-H (microhemorrhages), particularly in elderly patients.

1.14 Labeling

1.14.1 Draft labelling

1.14.1.1 Draft carton and container label

Based on FDA-approved labeling for Aduhelm (aducanumab-avwa), the following is a draft for the carton and container labels. The product must comply with 21 CFR 610.60 (Container) and 21 CFR 610.61 (Carton) requirements.

Container Label (Vial Label)

Target: Small volume parenteral vial (170 mg/1.7 mL or 300 mg/3 mL)

Proprietary Name: ADUHELM™
Proper Name: aducanumab-avwa
Strength: 170 mg/1.7 mL (100 mg/mL) OR 300 mg/3 mL (100 mg/mL)
Route of Administration: For Intravenous Infusion Only
Dosage Statement: Single-dose vial. Discard unused portion.
Manufacturer: Biogen Inc.
Lot/Expiration: [Space for Lot Number] / [Space for Expiration Date]
Storage: 2°C to 8°C (36°F to 46°F)
Light Sensitivity: Protect from light
Other: No text on ferrule or cap

Carton Label (Outer Package)

Target: Carton containing a single-dose vial

Front Panel: ADUHELM™ (aducanumab-avwa); Includes strength, route (For Intravenous Infusion Only), dosage form, and barcode.
Side/Back Panel: Contains active ingredient and excipients. Includes storage requirements (2-8°C, protect from light, do not freeze or shake), and manufacturer info (Biogen Inc., US License No. 1697).

Key FDA Regulatory Considerations

Safety/Compliance: Includes required NDC, serial number, lot, and expiration (DSCSA compliance), clearly states “For Intravenous Infusion Only”, and reflects accelerated approval status.
Storage: 2°C to 8°C (36°F to 46°F) in original carton, with specific handling guidelines.

1.14.1.2 Annotated draft labeling text

Based on the FDA’s official prescribing information for Aduhelm (aducanumab-avwa), the approved labeling (section 1, Indications and Usage) focuses on accelerated approval for Alzheimer’s disease based on reduction in amyloid beta plaques.

Key annotated points from the FDA labeling (updated July 2021) include:

Indication: Treatment for Alzheimer’s disease.
Population: Indicated for patients with mild cognitive impairment (MCI) or mild dementia stage of the disease.
Approval Status: Accelerated approval, contingent upon verification of clinical benefit.

1.14.1.3 Draft labeling text

Based on the FDA-approved labeling for Aduhelm (aducanumab-avwa) (last updated/reviewed in 2023), the following is a summary of the required labeling text.

INDICATIONS AND USAGE

Aduhelm is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease.

Target Population: Initiated in patients with mild cognitive impairment (MCI) or mild dementia, the population studied in trials.
Limitation of Use: No data on starting treatment at earlier or later stages.
Approval Status: Granted under accelerated approval based on reduced amyloid plaque, with continued approval contingent upon verifying clinical benefit.

DOSAGE AND ADMINISTRATION

Administration: Intravenous infusion over approximately one hour every four weeks.
Titration: Required to reach a target dose of
Dilution: Must be diluted in Sodium Chloride Injection, USP.
Monitoring: Obtain MRIs before the 5th, 7th, 9th, and 12th infusions.

DOSAGE FORMS AND STRENGTHS

Available as a clear to opalescent and colorless to yellow solution in single-dose vials:

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Amyloid Related Imaging Abnormalities (ARIA): Can cause ARIA-E (edema) and ARIA-H (hemorrhage), which are usually asymptomatic but can be serious.
Risk Factors: The ApoE allele increases ARIA risk, particularly in homozygotes.
Management: Treatment recommendations for ARIA are based on type, severity, and symptoms.
Hypersensitivity: Reactions, including angioedema and urticaria, have occurred.

ADVERSE REACTIONS

Most common reactions:

ARIA-Edema (ARIA-E)
Headache
ARIA-H (sulcal effusions/hemorrhage)
Fall

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm.
Pediatric Use: Safety and effectiveness not established.

1.14.1.3 Label comprehension studies

Label comprehension studies specifically designed for the general public regarding Aducanumab (Aduhelm) were not a public focal point of the FDA’s accelerated approval, which was heavily debated and criticized for lack of clinical evidence. Instead, the FDA focused on revising the prescribing label to ensure healthcare providers clearly understood the indicated patient population and safety risks.

1.14.1.4 Labeling history

Aducanumab (Aduhelm), approved via FDA accelerated approval on June 7, 2021, for Alzheimer’s disease, saw labeling updates refining its target population to mild cognitive impairment/dementia stages. The label requires PET scan verification of amyloid plaques and warns of Amyloid-Related Imaging Abnormalities (ARIA-H/E). Biogen discontinued the drug in 2024.

Key Labeling History According to FDA:

Initial Approval & Updates (2021): Approved June 7, 2021, for early-stage Alzheimer’s (mild cognitive impairment/dementia) based on amyloid-beta plaque reduction. In July 2021, the label was tightened to emphasize treatment initiation only within this population.
Dosage & Safety: The label directs a

monthly IV dose and mandates monitoring for ARIA-E (edema) and ARIA-H (hemorrhage).

Contingent Status: FDA approval remained conditional, requiring further post-marketing studies to confirm clinical benefit.

1.14.2 Final labeling

1.14.2.1 Final carton or container labels

1.14.2.2 Final package insert (package inserts, patient information, medication guides)

Key Prescribing Information (FDA Approved):

Indication: Treatment of Alzheimer’s disease. Initiate treatment in patients with mild cognitive impairment or mild dementia stage of disease.
Dosage & Administration:
- Titration: Infusions 1-2 (1 mg/kg), 3-4 (3 mg/kg), 5-6 (6 mg/kg), and 7+ (10 mg/kg).
- Frequency: Every 4 weeks, at least 21 days apart.
- Administration: IV infusion over approximately one hour.
Warnings and Precautions:
- ARIA (Amyloid Related Imaging Abnormalities): Includes ARIA-edema and ARIA-hemorrhage. MRI must be obtained within one year before treatment initiation and monitored periodically.
- Hypersensitivity Reactions: Including angioedema and urticaria.
Dosage Forms: 100 mg/mL solution in single-dose vials.

Patient Information/Medication Guide:
Patients are advised of the risks of ARIA and the need for MRIs before and during treatment. Symptoms of ARIA include headache, confusion, dizziness, vision changes, and nausea

1.14.2.3 Final labeling text

1.14.3 Listed drug labeling

The official FDA labeling, including updates through 2023, emphasizes that treatment should be initiated in patients with mild cognitive impairment (MCI) or the mild dementia stage of disease, consistent with the population studied in clinical trials.

Key Labeling Information

Indications: Indicated for patients with mild cognitive impairment or mild dementia stage of Alzheimer’s disease based on reducing amyloid beta plaques, with continued approval contingent on clinical benefit verification.
Dosage & Administration: Treatment requires confirmation of amyloid pathology, initiated with titration to a maintenance dose via IV infusion every four weeks.
Warnings: Risk of Amyloid Related Imaging Abnormalities (ARIA-E and ARIA-H), especially in ApoE homozygotes; monitoring via MRI is required before specific infusions. Hypersensitivity reactions can occur.
Adverse Reactions: Most common events include ARIA-edema, ARIA-H, headache, and falls.
Specific Populations: Studies included patients aged 50–85, with no data on pregnancy or pediatric use.

1.14.3.1 Annotated comparison with listed drug

The following table compares Aducanumab with later, more comprehensive approvals (Lecanemab-irmb and Donanemab-azbt) that are considered the current standard of care by the FDA.

Feature	Aducanumab (Aduhelm)	Lecanemab (Leqembi)	Donanemab (Kisunla)
FDA Approval Status	Discontinued (2024)	Traditional Approval (2023)	Approved (July 2024)
Mechanism	Targets Aβ plaques	Targets Aβ protofibrils	Targets aggregated Aβ plaques
Clinical Benefit	Controversial; No clear clinical benefit shown in trials.	Slows progression (~27%)	Slows progression (~35%)
ARIA-E Risk (Edema)	High (~35%)	Moderate (12.6%–17.3%)	High (approx. 24%)
Approval Type	Accelerated (2021)	Accelerated →Traditional	Traditional

1.14.3.2 Approved labeling text for listed drug

As of early 2026, Biogen has discontinued the Aduhelm brand. The information below reflects the final updated FDA label, which clarified the population for treatment.

Indications and Usage

Aduhelm is an amyloid beta-directed antibody indicated for treating Alzheimer’s disease.

Target Population: Initiated in patients with mild cognitive impairment or mild dementia stage of disease.
Approval Basis: Accelerated approval based on reducing amyloid beta plaques.

Dosage and Administration

Maintenance Dosage: 10 mg/kg via intravenous infusion every four weeks.
Requirements: Requires titration and a recent brain MRI before treatment.

Dosage Forms and Strengths

Injection: 170 mg/1.7 mL or 300 mg/3 mL (100 mg/mL) in single-dose vials.

Important Warnings and Precautions

Amyloid Related Imaging Abnormalities (ARIA):
Aduhelm can cause ARIA, specifically temporary brain swelling (ARIA-E) or small spots of bleeding (ARIA-H).

Monitoring: MRI scans are required before initiation and prior to the 5th, 7th, 9th, and 12th infusions.

Adverse Reactions

The most common adverse reactions (≥10%) were ARIA-E, headache, ARIA-H, and falls.

1.14.2.3 Labeling text for reference listed drug

The Reference Listed Drug (RLD) for aducanumab is Aduhelm (aducanumab-avwa), approved by the FDA via the accelerated approval pathway. The labeling, last updated in 2023, emphasizes specific patient population restrictions and mandatory safety monitoring.

Key Labeling Information (Prescribing Information & Medication Guide):

Indications and Usage: Indicated for the treatment of Alzheimer’s disease. Treatment should be initiated in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.
Accelerated Approval Disclaimer: Continued approval is contingent upon verification of clinical benefit in confirmatory trials.
Dosage Forms and Strengths: Injection: 170 mg/1.7 mL (100 mg/mL) or 300 mg/3 mL (100 mg/mL) in a single-dose vial.
Warnings and Precautions (ARIA): Aduhelm can cause Amyloid Related Imaging Abnormalities (ARIA), including ARIA-E (edema) and ARIA-H (hemosiderin deposition).
- MRI Requirement: Obtain a recent brain MRI before initiating treatment and before the 5th, 7th, 9th, and 12th infusions.
Dosing and Administration:
- Initial titration: 1 mg/kg for infusions 1-2, 3 mg/kg for 3-4, 6 mg/kg for 5-6.
- Maintenance dosage: 10 mg/kg every 4 weeks.
- Must be diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.
Contraindications: None.
Hypersensitivity Reactions: Angioedema and urticaria have occurred; stop infusion immediately if these occur.
Storage: Store at 2°C to 8°C (36°F to 46°F).

Note on Status (2026): While the RLD label exists, the manufacturer (Biogen) announced the discontinuation of Aduhelm in early 2024, with treatments concluding by November 1, 2024, in the US.

1.14.4 Investigational drug labeling

Key components of the Aducanumab labeling as established by the FDA include:

Indications and Usage

Target Population: Approved for the treatment of Alzheimer’s disease.
Initial Population: Labeling stipulates initiating treatment in patients with mild cognitive impairment or mild dementia stage of the disease, consistent with clinical trial populations.
Accelerated Approval Requirement: Approval is based on the reduction of amyloid beta plaques. Continued approval is contingent upon verification of clinical benefit in confirmatory trials.

Dosage and Administration

Amyloid Confirmation: Presence of amyloid beta pathology must be confirmed prior to initiating treatment.
Titration: Treatment requires dose titration (initiation at lower doses before increasing to maintenance).
Maintenance Dose: The recommended maintenance dosage is 10 mg/kg administered intravenously.

Warnings and Precautions

ARIA (Amyloid-Related Imaging Abnormalities): The label highlights the risk of ARIA-E (edema) and ARIA-H (hemorrhage).
Monitoring: MRI scans are required before and during treatment to monitor for ARIA.
ApoE ε4 Homozygotes: The labeling specifically warns of an increased risk of ARIA in ApoE ε4 homozygotes.

Dosage Forms and Strengths

Formulation: 100 mg/mL solution, supplied as:
- 170 mg/1.7 mL single-dose vial.
- 300 mg/3 mL single-dose vial.

Adverse Reactions

Common Side Effects: The most common adverse reactions reported (incidence 2%) include ARIA-E, headache, ARIA-H (sulcus hemorrhage), ARIA-H (hemosiderosis), and fall.

1.14.2.1 Investigational brochure

Based on FDA documents, particularly the Aduhelm (aducanumab-avwa) BLA Approval Letter and the Prescribing Information from June 2021, aducanumab was approved under accelerated approval for the treatment of Alzheimer’s disease.

The FDA-reviewed information, which constitutes the official guidance for investigators and clinicians, is summarized below:

Indication and Usage

Indication: Aducanumab is indicated for the treatment of Alzheimer’s disease (AD). It is intended to reduce amyloid plaques in the brain, a hallmark of the disease.
Approval Status: This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with aducanumab. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
Patient Selection: Treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.

Dosage and Administration

Dosage Form: 100mg/mL solution in a single-dose vial.
Administration: Intravenous infusion every 4 weeks. It must be diluted before administration.
Titration: The dosage starts at lower levels (1-6mg/kg) and titrates up to a maintenance dose of 10mg/kg.

Warnings and Precautions

Amyloid Related Imaging Abnormalities (ARIA): Aducanumab can cause ARIA-edema (ARIA-E) and ARIA-hemorrhage (ARIA-H). These are usually asymptomatic but can be severe.
ARIA Monitoring: MRI scans are required before starting treatment and before the 5th, 7th, 9th, and 12th infusions.
Hypersensitivity Reactions: Angioedema and urticaria have occurred. If a reaction occurs, discontinue the infusion and treat as necessary.

Adverse Reactions

Most Common: The most common adverse reactions (at least 2% higher than placebo) were ARIA-edema, ARIA-H (edema, microhemorrhage, superficial siderosis), headache, and fall.

Pharmacokinetics

Clearance/Half-life: The mean terminal half-life is approximately 25 days.
Metabolism/Excretion: As a human monoclonal antibody, aducanumab is expected to be degraded into small peptides and amino acids via catabolic pathways, similar to endogenous IgG.

Clinical Studies (Background)

Mechanism of Action: Aducanumab is a human IgG1 monoclonal antibody that binds to aggregated soluble and insoluble forms of amyloid-beta.
Efficacy Evidence: The approval was supported by evidence from clinical trials (Study 1 and Study 2) showing a reduction in amyloid plaques.

1.14.2.2 Investigational drug labeling

Aducanumab (brand name Aduhelm) received accelerated approval from the FDA on June 7, 2021, for the treatment of Alzheimer’s disease. The labeling highlights that it is the first amyloid beta-directed antibody to be approved, with continued approval contingent upon verification of clinical benefit in confirmatory trials.

Here are the key aspects of the Aducanumab label approved by the FDA:

Indications and Usage

Target Population: Initiated in patients with mild cognitive impairment or mild dementia stage of disease, which is the population in which treatment was initiated in clinical trials.
Approval Basis: Accelerated approval based on a reduction in amyloid beta plaques observed in patients.
Contingency: Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

Dosage and Administration

Pre-treatment Requirement: Confirm the presence of amyloid beta pathology prior to initiating treatment.
Administration: Administered as an intravenous infusion.
Dosage: Titration is required, with a recommended maintenance dosage of 10 mg/kg.

Important Safety Information (Warnings and Precautions)

Amyloid-Related Imaging Abnormalities (ARIA): Aducanumab can cause ARIA-E (edema) and ARIA-H (hemorrhage).
Monitoring: MRI scans are required before initiation and before the 7th and 12th infusions to monitor for ARIA.
Other Adverse Reactions: The most common adverse reactions (>2% higher than placebo) include ARIA-edema, headache, ARIA-hemorrhage, and fall.

Dosage Forms and Strengths

Injection: 170 mg/1.7 mL (100 mg/mL) or 300 mg/3 mL (100 mg/mL) solution in single-dose vials.

Postmarketing Requirements

Confirmatory Trial: The FDA requires a randomized, controlled trial to verify the clinical benefit of Aducanumab. If this trial fails to show clinical benefit, the FDA may remove the drug from the market.

1.14.5 Foreign labeling

Based on FDA documentation and approved labeling for Aduhelm (aducanumab-avwa), the following details apply to its labeling and administration, including requirements for inspecting for foreign particles:

Foreign Matter Inspection Requirements

Visual Inspection: Before administration, the diluted Aduhelm solution must be visually inspected for particles or discoloration.
Visual Appearance: The solution should appear clear to opalescent and colorless to yellow.
Disqualification: If foreign particles or opaque particles are present, the vial should not be used.

Labeling and Indications

Indication: Aduhelm is indicated for the treatment of Alzheimer’s disease.
Target Population: It is designed for patients with mild cognitive impairment or the mild dementia stage of the disease.
Approval Pathway: Approved via the FDA’s accelerated approval pathway based on a reduction in amyloid beta plaques.
Warning: The label includes warnings for Amyloid Related Imaging Abnormalities (ARIA-E and ARIA-H).

Labeling Revisions

July 2021 Update: The label was updated to specifically emphasize initiating treatment during the mild cognitive impairment or mild dementia stage of the disease.
2023 Safety Updates: Revisions included new information regarding the risk of increased ARIA in ApoE homozygotes and intracerebral hemorrhages larger than 1 cm.

1.14.6 Product labeling for 2253 submission

Requirements for Form FDA 2253 Submission

Purpose: To submit final promotional materials (advertisements, websites, videos, print ads) at the time of initial dissemination or publication, as required by 21 CFR 314.81(b)(3)(i) and 21 CFR 601.12(f)(4).
Labeling Inclusion: Each 2253 submission must include a copy of the current, approved product label (Prescribing Information and Medication Guide).
Format: The labeling must be in Structured Product Labeling (SPL) format and submitted via the FDA’s automated drug registration and listing system (eLIST).
Timing: Promotional materials must be submitted to the Office of Prescription Drug Promotion (OPDP) at the time of initial dissemination.

Aducanumab (Aduhelm) Specific Labeling Context

The last approved labeling for Aduhelm (as of the August 2023 supplement) required specific, prominent information to be included in promotional materials:

Indication: “ADUHELM is indicated for the treatment of Alzheimer’s disease. Treatment with ADUHELM should be initiated in patients with mild cognitive impairment or mild dementia stage of disease”.
Accelerated Approval Notice: Marketing materials had to clearly state that the drug is approved under accelerated approval, based on reduction in amyloid beta plaques, and that continued approval is contingent on verification of clinical benefit.
Warning (ARIA): Labeling includes warnings regarding amyloid-related imaging abnormalities (ARIA), which must be clearly communicated in promotions.
Safety Information: Marketing materials must contain information about the risk of intracerebral hemorrhage >1 cm.

Submission Procedure

Form FDA 2253: The “Transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human Use” is used for this submission.
eCTD Structure: The submission should be made in electronic format (eCTD). The current approved label is generally placed in Module 1.14.6.
Website Updates: If only one section of a website is updated, only the updated section needs to be submitted with a cross-reference to the original submission.

1.15 Promotional material

1.15.1 Correspondence relating to promotional materials

Correspondence between the FDA and Biogen regarding promotional materials for Aducanumab (Aduhelm) focused on the requirements for accelerated approval, labeling compliance, and safety disclosures, particularly regarding Amyloid Related Imaging Abnormalities (ARIA). The FDA demanded that all promotional materials be promptly updated to reflect new safety information and the specific, restricted indication for patients with mild cognitive impairment or mild dementia.

1.15.1.1 Request for advisory comments on launch materials

Based on FDA regulatory documents and the controversial approval of Aducanumab (Aduhelm), advisory comments on launch materials generally focus on aligning marketing claims with the strict limitations of its accelerated approval pathway, the need for balanced risk information regarding Amyloid Related Imaging Abnormalities (ARIA), and ensuring that promotional materials do not overstate clinical efficacy.

1.15.1.2 Request for advisory comments on non-launch materials

According to the FDA approval letter for Aduhelm (aducanumab-avwa) dated June 7, 2021, and subsequent documents, the FDA allows sponsors to request advisory comments on proposed promotional materials.

Key details regarding the request for advisory comments for Aducanumab include:

Optional Review:Sponsors may submit promotional materials to the FDA’s Office of Prescription Drug Promotion (OPDP) for advisory comments before use.
Submission Process:Materials should generally be submitted via eCTD to ensure expedited review.

1.15.1.3 Presubmission of launch promotional materials for accelerated approved Products

For drugs approved via the accelerated pathway, such as Aducanumab (Aduhelm), the FDA requires all promotional materials intended for use within the first 120 days (launch materials) to be submitted to the Office of Prescription Drug Promotion (OPDP) prior to approval. This presubmission ensures that initial, high-impact marketing materials are compliant with labeling, particularly when based on surrogate endpoints rather than confirmed clinical benefit.

1.15.1.4 Presubmission of non-launch promotional materials for accelerated

approved products

For accelerated approved products like Aducanumab (Aduhelm), FDA regulations (21 CFR 314.550/601.45) require that promotional materials intended for use after the first 120 days of approval, non-launch materials, be submitted to the FDA at least 30 days before their planned dissemination. This mandatory resubmission allows the FDA to review materials for compliance due to the surrogate endpoint approval.

1.15.1.5 Pre-dissemination review of television ads

The FDA mandates that television ads for prescription drugs like Aducanumab undergo rigorous pre-dissemination review to ensure they are not misleading, providing fair balance between benefits and risks. FDA’s Office of Prescription Drug Promotion (OPDP) reviews these ads to check for clear, conspicuous, and neutral presentation of safety information, particularly emphasizing major risk statements.

1.15.1.6 Response to untitled letter or warning letter

Based on FDA regulatory procedures, a response to an untitled letter or warning letter for a drug like Aducanumab (Aduhelm) must be timely, comprehensive, and detail corrective actions to avoid further enforcement. The FDA typically requires companies to respond within 15 business days.

1.15.1.7 Response to information required

The FDA granted accelerated approval to Aducanumab (brand name Aduhelm) on June 7, 2021, for the treatment of Alzheimer’s disease based on evidence that it reduces amyloid beta plaques, a surrogate biomarker for the disease. As a condition of this approval, the FDA mandated that Biogen conduct post-marketing studies to verify that reducing amyloid plaque leads to meaningful clinical improvement in patients.

1.15.1.8 Correspondence accompanying material previously missing or rejected

Based on FDA documentation and correspondence, aducanumab (Aduhelm) was approved under the Accelerated Approval Pathway on June 7, 2021, despite a 10–0 vote against it by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee in November 2020. The correspondence and material surrounding this, including previously rejected or missing analysis, focused on the transition from traditional approval to accelerated approval based on a surrogate endpoint (amyloid plaque reduction) rather than clinical benefit.

1.15.1.9 Withdrawal request

Biogen announced in January 2024 that it would discontinue the development and commercialization of Aduhelm (aducanumab-avwa) for Alzheimer’s disease and terminate the ENVISION clinical trial, moving to withdraw the drug from the market.

1.15.1.10 Submission of annotated references

The submission of annotated references for Aducanumab (Aduhelm) to the FDA followed the standard Biologics License Application (BLA) process under the accelerated approval pathway. Biogen submitted the BLA (761178) on July 7, 2020, with annotated clinical and non-clinical data to support the claim that the drug reduces amyloid-beta plaques.

1.15.1.11 General correspondence

According to FDA documentation and correspondence, Aducanumab (marketed as Aduhelm) was approved via the accelerated approval pathway on June 7, 2021, for the treatment of Alzheimer’s disease. This approval was based on the reduction of amyloid beta plaques, a surrogate endpoint considered “reasonably likely to predict clinical benefit”.

1.15.2 Materials attribute

1.15.2.1 Material

According to FDA documents, Aducanumab-avwa (Aduhelm) is a recombinant human IgG1 monoclonal antibody designed to bind to and remove aggregated amyloid-beta (Aβ) plaques in the brain.

Product Composition and Formulation

Active Ingredient:Aducanumab-avwa (100 mg/mL).
Appearance:A preservative-free, sterile, clear to opalescent, colorless to yellow solution, expressed in a Chinese hamster ovary (CHO) cell line.
Excipients:Formulated with L-arginine hydrochloride, L-histidine/L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, and Water for Injection, with a pH of roughly 5.5.
Molecular Weight: 146 kDa.

Dosage Forms and Administration

Strengths:Single-dose vials of 170 mg/1.7 mL and 300 mg/3 mL.
Route/Method:Intravenous (IV) infusion, requiring dilution in 100 mL of 0.9% Sodium Chloride Injection.
Administration:Infused over one hour using a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
Storage:Diluted solutions may be stored refrigerated (2°C to 8°C) for up to 3 days, or at room temperature (up to 30°C) for up to 12 hours.

Regulatory Status and Indication

Approval:Granted via the FDA’s Accelerated Approval Pathway in June 2021.
Indication:Indicated for the treatment of Alzheimer’s disease, specifically in patients with mild cognitive impairment or mild dementia.
Mechanism:Intended to reduce clinical decline by decreasing amyloid-beta plaques.

1.15.2.1.1 Clean version

Aducanumab (brand name Aduhelm) received accelerated approval from the U.S. Food and Drug Administration (FDA) on June 7, 2021, for the treatment of Alzheimer’s disease. It is crucial to note that on January 31, 2024, Biogen announced it was discontinuing the development and commercialization of Aduhelm.

1.15.2.1.2 Annotated version

Aducanumab (marketed as Aduhelm by Biogen) received FDA accelerated approval on June 7, 2021, for the treatment of Alzheimer’s disease. This decision was highly controversial, as it was based on a surrogate marker (amyloid plaque reduction) rather than direct evidence of clinical benefit.

1.15.2.1.3 Annotated labeling version

Aducanumab (brand name Aduhelm) received accelerated approval from the FDA on June 7, 2021, for the treatment of Alzheimer’s disease. The FDA-approved prescribing information (labeling) has been revised to focus specifically on patients with mild cognitive impairment or mild dementia stage of disease. It should be noted that on January 31, 2024, Biogen announced it was discontinuing the development and commercialization of Aduhelm. The following information reflects the final FDA-approved labeling before its discontinuation.

1.15.2.1.4 Annotated references

Hathaway, J., Hom, K., Reznichenko, B., Vaddempudi, K., & D’Alonzo, A. (2020). eSubmission of Promotional Labeling and Advertising Materials via the eCTD FDA Gateway: The Time Has Come for Advertising and Promotion to Submit in Module One. Therapeutic Innovation & Regulatory Science, 54(6), 1398-1403.

Krogulski, S. (2017). Best practices for submitting promotional 2253 submissions in the new module 1 specification. Therapeutic Innovation & Regulatory Science, 51(5), 645-650.

Padda, I. S., & Parmar, M. (2024). Aducanumab. In StatPearls [Internet]. StatPearls Publishing.

Rahman, A., Hossen, M. A., Chowdhury, M. F. I., Bari, S., Tamanna, N., Sultana, S. S., … & Saif‐Ur‐Rahman, K. M. (2023). Aducanumab for the treatment of Alzheimer’s disease: a systematic review. Psychogeriatrics, 23(3), 512-522.

Vaz, M., Silva, V., Monteiro, C., & Silvestre, S. (2022). Role of aducanumab in the treatment of Alzheimer’s disease: challenges and opportunities. Clinical interventions in aging, 797-810.

1.16 Risk management plan

1.16.1 Risk Management (Non-REMS)

The FDA approved Aducanumab (Aduhelm) in June 2021 via the accelerated approval pathway. While the drug was subject to intense scrutiny regarding its safety profile—particularly regarding amyloid-related imaging abnormalities (ARIA)—the FDA determined that a formal Risk Evaluation and Mitigation Strategy (REMS) was not necessary to ensure the benefits outweighed the risks.

1.16.2 Risk Evaluation and Mitigation Strategy (REMS)

Based on the FDA approval documentation for Aduhelm (aducanumab-avwa) on June 7, 2021, the FDA determined that a formal Risk Evaluation and Mitigation Strategy (REMS) was not necessary to ensure that the benefits of the drug outweighed its risks. Instead of a formal REMS, the FDA required rigorous safety monitoring, comprehensive labeling updates, and post-marketing studies to manage the risks, primarily Amyloid-Related Imaging Abnormalities (ARIA).

1.16.2.1 Final REMS

According to the FDA’s approval documentation for Aduhelm (aducanumab-avwa) dated June 7, 2021, the FDA determined that a formal Risk Evaluation and Mitigation Strategy (REMS) was not necessary to ensure the benefits of the drug outweighed its risks.

1.16.2.2 Draft REMS

According to the FDA’s approval letter for Aduhelm (aducanumab-avwa) dated June 7, 2021, a formal Risk Evaluation and Mitigation Strategy (REMS) was not required. Although a REMS was not mandated, the FDA determined that risks, primarily Amyloid Related Imaging Abnormalities (ARIA), would be managed through approved product labeling, including a Warnings and Precautions section, and a Medication Guide.

1.16.2.3 REMS Assessment

Upon the accelerated approval of Aducanumab (Aduhelm) in June 2021, the FDA determined that a Risk Evaluation and Mitigation Strategy (REMS) was not necessary to ensure the benefits of the drug outweighed its risks at that time. While a formal, mandated REMS program was not required, the FDA did impose strict post-marketing requirements due to safety concerns, specifically regarding Amyloid-Related Imaging Abnormalities (ARIA).

1.16.2.4 REMS Assessment Methodology

Based on the FDA approval documentation for Aduhelm (aducanumab-avwa), the FDA did not require a formal Risk Evaluation and Mitigation Strategy (REMS) program to be implemented, although it was initially considered. Instead, the FDA determined that the safety risks—primarily Amyloid Related Imaging Abnormalities (ARIA), could be managed through professional labeling and standard surveillance.

1.16.2.5 REMS Correspondence

According to the FDA, upon approval of Aduhelm (aducanumab-avwa) on June 7, 2021, the agency determined that a Risk Evaluation and Mitigation Strategy (REMS) was not necessary to ensure the benefits of the drug outweighed its risks.

Key points regarding the FDA’s REMS correspondence and safety management for aducanumab include:

REMS Determination: Although the FDA acknowledged receiving a proposed REMS plan from Biogen in July 2020, they concluded that at the time of approval, a formal REMS was not required.
Postmarketing Surveillance (Pharmacovigilance): Instead of a formal REMS, the FDA required Biogen to conduct postmarketing pharmacovigilance to track risks, specifically regarding hypersensitivity.

1.16.6 REMS Modification History

Based on FDA documents, there is no formal Risk Evaluation and Mitigation Strategy (REMS) for Aducanumab (Aduhelm).

Initial Decision (June 2021):The FDA determined that a REMS was not necessary for the approval of Aduhelm to ensure that its benefits outweighed its risks.
Labeling Changes (July 2021):Rather than a REMS modification, the FDA approved updated prescribing information in July 2021. This update narrowed the indicated population to those with mild cognitive impairment or mild dementia stage of disease, aligning with the population studied in clinical trials.

1.17 Postmarketing Studies

1.17.1 Correspondence regarding postmarketing commitments

According to the FDA, the accelerated approval of Aducanumab (Aduhelm), granted in June 2021, was contingent upon several postmarketing requirements (PMRs) and commitments (PMCs) intended to verify the drug’s clinical benefit and address quality concerns.

Key Postmarketing Requirements (PMRs) and Correspondence: Confirmatory Trial (PMR 3971-1):Biogen was required to conduct a controlled trial to verify clinical benefit, with a deadline for completion set for 2030.
Manufacturing and Quality (PMC 3971-2, 3971-3):Requirements included conducting shipping studies and implementing a validated host cell protein (HCP) assay, with reporting required to the FDA.

1.17.2 Correspondence regarding post marketing requirement

Following the accelerated approval of Aducanumab (Ad helm) on June 7, 2021, for the treatment of Alzheimer’s disease, the FDA required Biogen to conduct post marketing studies to verify the drug’s clinical benefit. The approval was based on the surrogate endpoint of reducing amyloid beta plaque, necessitating further studies to confirm that this reduction actually delays clinical decline.

1.18 Proprietary names

According to the FDA, the primary proprietary (brand) name for aducanumab is Ad helm.

Key details regarding the FDA naming and approval:

Name:Ad helm
Proper/Generic Name:aducanumab-awe
FDA Approval Date:June 7, 2021 (Accelerated Approval)
Status:In January 2024, Biogen announced it was discontinuing the development and commercialization of Ad helm.

1.19 Pre-EUA and EUA

According to the FDA, Aducanumab (marketed as Ad helm) did not receive an Emergency Use Authorization (EUA); instead, it was granted Accelerated Approval on June 7, 2021, for the treatment of Alzheimer’s disease. While both pathways allow for faster access to products, Accelerated Approval is a formal drug approval process based on a surrogate endpoint rather than a temporary authorization based on an emergency declaration.

1.20 General investigation plan for initial IND

A general investigation plan for an initial Investigational New Drug (IND) application for aducanumab, based on FDA requirements and the development path of this Alzheimer’s disease treatment, involves a structured approach to evaluate safety, dosage, and efficacy. Aducanumab (BIIB037) was ultimately approved under the accelerated pathway (21 CFR 601.41) based on a reduction in amyloid beta plaques.

2.2 Introduction to Summary

Aducanumab is a monoclonal antibody developed for the treatment of Alzheimer’s disease. It targets aggregated forms of amyloid-beta plaques in the brain, which are strongly associated with disease progression. Alzheimer’s disease is the most common form of dementia and continues to affect millions of people worldwide. Research shows that amyloid-beta accumulation begins many years before symptoms appear, which supports early treatment approaches. This makes therapies like Aducanumab important in addressing disease progression.

This module provides a structured summary of the quality, nonclinical, and clinical aspects of Aducanumab. The drug development process involves several stages, including laboratory research, animal studies, and clinical trials. According to the U.S. Food and Drug Administration, each stage is necessary to ensure that a drug is safe and effective. However, the development of Aducanumab has been controversial due to mixed clinical results. Some studies question whether reducing amyloid plaques leads to meaningful cognitive improvement, while others support continued research into amyloid-targeting therapies.

2.3 Quality Overall Summary

Aducanumab is a biologic drug composed of a monoclonal antibody. Because it is protein-based, maintaining its structure is very important. Small changes in protein structure can affect how the drug works and may impact safety. According to Applied Biopharmaceutics and Pharmacokinetics, biologic drugs require strict quality control during manufacturing to ensure consistency.

Quality evaluation focuses on purity, strength, and stability to ensure patient safety and therapeutic effectiveness. Purity ensures that the drug is free from contaminants, while strength guarantees that the correct dose is delivered to patients. Stability ensures that the drug maintains its effectiveness over time under appropriate conditions. In addition, proper storage and handling are critical, as Aducanumab must be kept under controlled conditions to prevent degradation, with improper storage potentially reducing effectiveness or increasing safety risks. Although detailed manufacturing information is limited, regulatory agencies ensure that strict quality standards are met before approval.

2.4 Nonclinical Overview

Nonclinical studies are conducted before testing a drug in humans. These studies help researchers understand how the drug works and whether it is safe. For Aducanumab, nonclinical research focused on its ability to bind to amyloid-beta plaques in the brain. These plaques are believed to play a central role in Alzheimer’s disease progression. Research shows that amyloid-beta accumulation begins long before symptoms appear. This supports the idea that early intervention may slow disease progression. However, some studies argue that plaque reduction alone may not fully explain clinical outcomes. This has led to ongoing debate about the role of amyloid in Alzheimer’s disease.

Animal studies demonstrated that Aducanumab can reduce plaque accumulation in the brain. According to the European Patients’ Academy on Therapeutic Innovation, nonclinical studies are essential for identifying risks before human testing. Toxicology studies also identified potential safety concerns, which helped guide clinical trial design. These findings supported the progression to clinical trials while highlighting the need for further research.

2.5 Clinical Overview

Clinical trials are conducted to evaluate the safety and effectiveness of a drug in humans. Aducanumab was studied in patients with early Alzheimer’s disease. The trials measured cognitive function, disease progression, and safety outcomes. Two major studies, ENGAGE and EMERGE, were conducted to evaluate the drug. These studies involved more than 3,000 participants aged 50 to 85 years.

The results showed that Aducanumab reduces amyloid-beta plaques in the brain. However, the clinical results were inconsistent. One study showed some benefit, while the other did not show significant improvement. Some researchers have raised concerns that approval was based mainly on biomarker changes rather than clear clinical benefit. At the same time, other studies suggest that targeting amyloid remains a promising approach. The U.S. Food and Drug Administration approved Aducanumab under the accelerated approval pathway. Safety concerns included amyloid-related imaging abnormalities (ARIA), which involve brain swelling and bleeding. These effects were dose-related and required careful monitoring during treatment.

2.6 Nonclinical Written and Tabulated Summaries

2.6.1 Introduction

This section summarizes nonclinical data for Aducanumab, including pharmacology, pharmacokinetics, and toxicology. These studies explain how the drug behaves before human testing. They provide important information on safety and biological activity. Nonclinical studies support regulatory decisions and guide clinical trial design. They help determine safe dose levels and identify potential risks. The data presented here is based on scientific research and regulatory guidance.

2.6.2 Pharmacology Written Summary

Aduhelm is an amyloid beta-directed antibody indicated to treat Alzheimer’s disease. Aduhelm is approved under the accelerated approval pathway, which provides patients with a serious disease earlier access to drugs when there is an expectation of clinical benefit despite some uncertainty about the clinical benefit.

2.6.3 Pharmacology Tabulated Summary

Parameter	Description
Drug Type	Monoclonal antibody
Target	Amyloid-beta aggregates
Mechanism	Plaque binding and clearance
Outcome	Reduced plaque levels

2.6.4 Pharmacokinetic Written Summary

Aducanumab exhibits dose-proportional (linear) pharmacokinetics over the studied dose range of 0.3 to 60 mg/kg, with serum concentration increasing proportionally to the dose administered. It is a human IgG1 monoclonal antibody administered via intravenous infusion, typically distributed within the vascular compartment.

Key pharmacokinetic characteristics of aducanumab include:

Metabolism & Elimination: Aducanumab is degraded into small peptides and amino acids through catabolic pathways similar to endogenous immunoglobulin G (IgG).

Half-Life:The drug has a long terminal elimination half-life of approximately 8 days, allowing for monthly dosing.
Accumulation:No significant, unexpected accumulation was observed with repeated monthly administration, with steady-state concentrations generally reached after 16 weeks (four doses) of treatment.

The recommended treatment regimen involves a titration period up to a maintenance dose of 10 mg/kg, administered intravenously every 4 weeks.

2.6.5 Pharmacokinetic Tabulated Summary

Parameter	Description
Pharmacokinetic Profile	Aducanumab exhibits dose-proportional (linear) pharmacokinetics over the studied dose range of 0.3 to 60 mg/kg, with serum concentration increasing proportionally to the dose administered.
Drug Class & Administration	It is a human IgG1 monoclonal antibody administered via intravenous infusion, typically distributed within the vascular compartment.
Metabolism & Elimination	Aducanumab is degraded into small peptides and amino acids through catabolic pathways similar to endogenous immunoglobulin G (IgG).
Half-Life	The drug has a long terminal elimination half-life of approximately 24.8 days, allowing for monthly dosing.
Accumulation	No significant, unexpected accumulation was observed with repeated monthly administration, with steady-state concentrations generally reached after 16 weeks (four doses) of treatment.
Dosing Regimen	The recommended treatment regimen involves a titration period up to a maintenance dose of 10 mg/kg, administered intravenously every 4 weeks.

2.6.6 Toxicology Written Summary

Aducanumab, a human monoclonal antibody targeting amyloid-beta (A) for Alzheimer’s disease, is primarily toxicologically associated with Amyloid-Related Imaging Abnormalities (ARIA), including brain edema (ARIA-E, ~35%) and microhemorrhages/siderosis (ARIA-H, ~19%-25%). These effects arise from vascular amyloid removal, with a higher incidence at higher doses.

Key Toxicological Findings and Adverse Effects:

ARIA (Brain Edema/Hemorrhage): ARIA-E (edema) occurred in 35% of patients compared to 3% for placebo, often within the first four months of treatment. ARIA-H (microhemorrhage/siderosis) occurred in 19%–25% of cases.
Clinical Symptoms: Common adverse events included headache (21%), falls (15%), diarrhea (9%), and confusion/disorientation (8%).
Immunogenicity: Less than 1% of patients developed anti-drug antibodies.

Management and Monitoring:

Monitoring: Regular MRIs are required to monitor for edema or hemorrhage.
Fatalities: While severe, studies noted no direct deaths from ARIA, though other amyloid-targeting therapies had reported fatalities.

2.6.7 Toxicology Tabulated Summary

Parameter	Description
Drug Overview	Aducanumab, a human monoclonal antibody targeting amyloid-beta (A) for Alzheimer’s disease, is primarily toxicologically associated with Amyloid-Related Imaging Abnormalities (ARIA), including brain edema (ARIA-E, ~35%) and microhemorrhages/siderosis (ARIA-H, ~19%-25%).
Mechanism of Toxicity	These effects arise from vascular amyloid removal, with a higher incidence at higher doses.
ARIA (Brain Edema/Hemorrhage)	ARIA-E (edema) occurred in 35% of patients compared to 3% for placebo, often within the first four months of treatment. ARIA-H (microhemorrhage/siderosis) occurred in 19%–25% of cases.
Clinical Symptoms	Common adverse events included headache (21%), falls (15%), diarrhea (9%), and confusion/disorientation (8%).
Immunogenicity	Less than 1% of patients developed anti-drug antibodies.
Monitoring Requirements	Regular MRIs are required to monitor for edema or hemorrhage.
Fatalities	While severe, studies noted no direct deaths from ARIA, though other amyloid-targeting therapies had reported fatalities.

2.7 Clinical Written and Tabulated Summaries

2.7.1 Introduction

This section summarizes clinical data for Aducanumab. It includes findings on safety, pharmacology, and effectiveness. Clinical studies provide important evidence on how the drug performs in patients. Research shows that Aducanumab consistently reduces amyloid plaques, but its effect on cognitive outcomes remains uncertain. Some researchers question whether amyloid reduction alone is enough to justify approval. Others support continued research into amyloid-targeting therapies.

2.7.2 Summary of Biopharmaceutical Studies and Analytical Methods

Aducanumab (marketed as Aduhelm) is a human immunoglobulin gamma 1 (IgG1) monoclonal antibody designed to treat Alzheimer’s disease (AD) by targeting aggregated forms of amyloid-beta (Aβ), including soluble oligomers and insoluble fibrils. It was approved by the FDA in 2021 via an accelerated pathway based on its ability to reduce amyloid plaques, though its clinical efficacy remains a subject of significant debate. Aducanumab was developed based on a reverse-translational approach, identifying antibodies in healthy aged individuals with no cognitive decline. Pre-clinical studies in transgenic mice demonstrated that aducanumab penetrates the blood-brain barrier and reduces both soluble and insoluble Aβ in a dose-dependent manner, reducing amyloid plaque load without causing micro-haemorrhages in animal models. In the Phase Ib PRIME study on patients with prodromal or mild AD, aducanumab demonstrated a time- and dose-dependent reduction of Aβ plaques (PET imaging), suggested a reduction in clinical decline, particularly in the 10 mg/kg group, and established a correlation between Aβ reduction and cognitive benefit. The Phase III trials, EMERGE and ENGAGE, were two parallel, 18-month, double-blind studies with discordant results: EMERGE met its primary endpoint, showing a 22% reduction in clinical decline (CDR-SB) at high doses, while ENGAGE did not meet its primary endpoint, showing no significant difference between high-dose and placebo; both trials were initially halted in 2019 due to a joint futility analysis, but subsequent analysis of the final dataset suggested that high-dose, long-term exposure was effective. The most common adverse event in these trials was Amyloid-Related Imaging Abnormalities (ARIA), specifically ARIA-E (edema) and ARIA-H (hemorrhage), which were dose-dependent and more common in ApoE ε4 carriers.

2.7.3 Summary of Clinical Pharmacology Studies

Alzheimer’s disease (AD) is an irreversible, progressive brain disorder that impairs memory and cognitive function. Dysregulation of the amyloid‐β (Aβ) pathway and amyloid plaque accumulation in the brain are hallmarks of AD. Aducanumab is a human, immunoglobulin gamma 1 monoclonal antibody targeting aggregated forms of Aβ. In phase Ib and phase III studies, aducanumab reduced Aβ plaques in a dose-dependent manner, as measured by the standard uptake value ratio of amyloid positron emission tomography imaging. The goal of this work was to develop a quantitative systems pharmacology model describing the production, aggregation, clearance, and transport of Aβ as well as the mechanism of action for the drug to understand the relationship between aducanumab dosing regimens and changes in different Aβ species, particularly plaques in the brain. The model was used to better understand the pharmacodynamic effects observed in the clinical trials of aducanumab and assist in the clinical development of future Aβ therapies.

2.7.4 Summary of Clinical Efficacy (Indication)

In both phase 3 trials (EMERGE and ENGAGE) and the Phase 1b trial (PRIME), aducanumab demonstrated a time- and dose-dependent significant reduction in amyloid plaques. In the EMERGE trial, high-dose aducanumab showed a statistically significant reduction in clinical decline, with a 22% slowing in decline (difference of -0.39) on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) compared to placebo at week 78. In contrast, the ENGAGE trial showed that high-dose aducanumab did not meet its primary or secondary endpoints and had no significant difference compared to placebo on the CDR-SB. Due to these conflicting trials, the FDA accelerated approval, which was based on the “surrogate endpoint” of amyloid reduction rather than clear, consistent evidence of clinical benefit. While some post hoc analyses suggest that higher exposure to the high dose of the drug in the EMERGE trial resulted in a clinically meaningful, though small, benefit, other studies argue that this benefit is not clinically significant. A significant safety issue is amyloid-related imaging abnormalities (ARIA), which include brain edema (ARIA-E) and microhemorrhages (ARIA-H), with approximately 40% of patients treated with high-dose aducanumab experiencing ARIA compared to 10% in the placebo group. Nearly 76% of ARIA cases were asymptomatic, though symptoms included headaches, confusion, and dizziness.

2.7.5 References

Lin, L., Hua, F., Salinas, C., Young, C., Bussiere, T., Apgar, J. F., Burke, J. M., Muralidharan, K. K., Rajagovindan, R., & Nestorov, I. (2022). Quantitative systems pharmacology model for Alzheimer’s disease to predict the effect of aducanumab on brain amyloid. CPT Pharmacometrics & Systems Pharmacology, 11(3), 362–372. https://doi.org/10.1002/psp4.12759

Padda, I. S., & Parmar, M. (2024, February 26). Aducanumab. StatPearls – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK573062/

2.7.6 Synopses of Individual Studies

Study 1: EMERGE Trial

The Phase 3 EMERGE and ENGAGE trials, involving 3,488 patients, evaluated high-dose (10 mg/kg) Aducanumab in early Alzheimer’s disease, showing a significant reduction in clinical decline (CDR-SB) in the EMERGE study but not in ENGAGE. Both trials were randomized, double-blind, placebo-controlled, 78-week studies, per the National Institutes of Health. High-dose Aducanumab met the primary endpoint in EMERGE with a 22% decrease in clinical decline, while ENGAGE did not meet its primary endpoint. Both trials demonstrated a clear, dose-dependent reduction in amyloid beta plaques, confirming target engagement, as reported by the U.S. Food and Drug Administration. The most common adverse event was ARIA-E (edema), occurring in 13 (2%) of the safety MRI population, with 24.2% of patients in the high-dose group experiencing associated symptoms, including headache (47%), confusion (15%), and dizziness (11%). Approximately 9% of patients on the 10 mg/kg dose discontinued treatment due to adverse events, compared to 4% in the placebo group, as noted by the National Institutes of Health.

Study 2: ENGAGE Trial

The Phase 3 trials of Aducanumab (EMERGE and ENGAGE) yielded mixed results, with only EMERGE (high dose) showing a statistically significant reduction in cognitive decline (CDR-SB). Both studies, halted early for futility, confirmed that Aducanumab reduced amyloid-beta plaques, but only one met its primary endpoint. In the EMERGE study (10 mg/kg), high-dose Aducanumab met the primary endpoint, demonstrating a 22% reduction in clinical decline compared to placebo, whereas the ENGAGE study (10 mg/kg) did not meet the primary endpoint, failing to show a statistically significant difference in slowing cognitive decline compared to placebo. Safety data showed that Amyloid-Related Imaging Abnormalities (ARIA-E) were common in both trials, with symptoms typically transient and approximately 9% of high-dose recipients discontinuing treatment. The studies were halted based on an interim futility analysis before completion, and the FDA approved Aducanumab in 2021 based on the EMERGE data, leading to significant debate among experts regarding the inconsistent results. While some data showed beneficial trends on secondary endpoints in specific subgroups, such as the Japanese cohort, the overall trial program did not produce consistently positive results across both studies.

References

Musiek, E. S., & Bennett, D. A. (2021). Aducanumab and the “post-amyloid” era of Alzheimer research? Neuron, 109(19), 3045–3047. https://doi.org/10.1016/j.neuron.2021.09.007

Padda, I. S., & Parmar, M. (2024). Aducanumab. In StatPearls [Internet]. StatPearls Publishing.

Padda, I. S., & Parmar, M. (2024, February 26). Aducanumab. StatPearls – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK573062/

Tampi, R. R., Forester, B. P., & Agronin, M. (2021). Aducanumab: evidence from clinical trial data and controversies. Drugs in context, 10.

Module 3 Quality

3.2 Body of Data

3.2.S.1 Drug substance (biologic) or active pharmaceutical ingredient (API) (name,

manufacturer)

3.2.S.1.1 General information

Accelerated approval is based on the drug’s effect on a surrogate endpoint — an endpoint that reflects the drug’s effect on an important aspect of the disease — where the drug’s effect on the surrogate endpoint is expected, but not yet established, to predict clinical benefit. In the case of Aduhelm, the surrogate endpoint is the reduction of amyloid beta plaque. The accelerated approval pathway requires the company to verify clinical benefit in a post-approval trial. If the sponsor cannot verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

3.2.S.1.2 Nomenclature

Aducanumab (previously BIIB037) is a human immunoglobulin gamma 1 (IgG1) anti-amyloid beta (Aβ) monoclonal antibody targeting aggregated forms of Aβ. Extracellular deposits of Aβ are one of the two pathological hallmarks of Alzheimer’s disease, along with intracellular aggregates of hyperphosphorylated tau in the form of neurofibrillary tangles. Accumulation of Aβ in the brain has been proposed to be the primary driver of the disease process. Aducanumab reduces levels of brain Aβ plaque by targeting aggregated forms of Aβ including soluble oligomers and insoluble fibrils. The applicant’s proposed indication is to delay clinical decline in patients with Alzheimer’s disease. The dosing regimen consists of an intravenous infusion over approximately one hour every four weeks. To initiate treatment, patients should receive two doses of 1 mg/kg, two doses of 3 mg/kg, then two doses of 6 mg/kg over a total of 24 weeks. Thereafter, the target maintenance dose is 10 mg/kg. Aducanumab is available as a 100 mg/mL solution in a singledose vial for intravenous infusion. Aducanumab is a new molecular entity (NME) and is not marketed in any country. The proposed proprietary name is Aduhelm.

3.2.S.1.3 Structure

According to the FDA’s approved labeling and review documents, Aducanumab-avwa (sold under the brand name Aduhelm) is a recombinant, human immunoglobulin gamma 1 (IgG1) monoclonal antibody. It is specifically designed to target the aggregated forms of amyloid-beta (Aβ)—both soluble oligomers and insoluble fibrils—found in the brains of patients with Alzheimer’s disease.

Key Structural Features (FDA Documentation)

Antibody Type: Fully human IgG1 monoclonal antibody, meaning it has the standard Y-shaped structure consisting of two heavy chains and two light chains.
Target Epitope: Aducanumab binds specifically to a linear epitope consisting of amino acid residues 3–7 at the N-terminus of the amyloid-beta peptide.
Binding Selectivity: The structure allows it to show high selectivity (>10,000-fold) for aggregated amyloid-beta (fibrils and oligomers) compared to monomeric Aβ.
Mechanism of Action: The Fab (fragment antigen-binding) region binds to Aβ aggregates, while the Fc (fragment crystallizable) region mediates the recruitment of microglia to promote phagocytosis (clearance) of amyloid plaques.
Molecular Composition: As a human IgG1, it has a high molecular weight (approximately 146 kDa).

Aducanumab chemical structure

3.2.S.1.4 General properties

Aducanumab (brand name Aduhelm, developed by Biogen) was granted accelerated approval by the FDA in June 2021 for the treatment of Alzheimer’s disease. It was the first, and only, Alzheimer’s treatment to receive this designation for targeting the disease’s underlying pathology.

Key Properties and Characteristics

Mechanism of Action: Aducanumab is a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody. It specifically targets and binds to aggregated soluble and insoluble forms of amyloid-beta plaques in the brain to reduce their accumulation.
Target Population: It is indicated for patients with mild cognitive impairment (MCI) or the mild dementia stage of Alzheimer’s disease, which is the population in which treatment was initiated in clinical trials.
Administration: It is administered via intravenous (IV) infusion, typically every 4 weeks, with a recommended maintenance dose of 10mg/kg after an initial titration.
Approval Basis (Accelerated): The approval was not based on immediate clinical benefit, but rather on the surrogate endpoint of reducing amyloid-beta plaques in the brain, with the expectation that this reduction would likely benefit patients.
Key Safety Warning – ARIA: The primary safety concern is amyloid-related imaging abnormalities (ARIA), which include:

- ARIA-E (Edema): Brain swelling, seen in 35% of patients in high-dose trials compared to 3% in placebo.
- ARIA-H (Hemosiderin Deposition): Microhemorrhages and superficial siderosis.

Clinical Efficacy Controversy: The approval was highly controversial, with FDA advisors expressing concerns over the lack of conclusive evidence that the drug slows cognitive decline.
Post-Approval Mandate: The FDA required Biogen to conduct a Phase 4 post-marketing trial (expected to run through 2030) to verify clinical benefit.

3.2.S.2 Manufacture

3.2.S.2.1 Manufacturer(s)

According to the FDA and related company announcements, the primary manufacturer and applicant for Aduhelm (aducanumab-avwa) is Biogen.

Key details regarding the manufacturers:

Primary Manufacturer/Applicant: Biogen Inc.
Collaboration Partner: Eisai Co., Ltd. has collaborated with Biogen on the development and commercialization of aducanumab globally since October 2017.
Originator: Biogen licensed aducanumab from Neurimmune in 2007.

Aduhelm received FDA accelerated approval on June 7, 2021

3.2.S.2 Description of Manufacturing Process and Process Controls

Aducanumab is a monoclonal antibody produced using biotechnological methods. The antibody gene is inserted into living cells, most often cultured mammalian cells, which then synthesise the protein. The cells are grown in controlled environments where factors such as temperature, nutrients, and pH are carefully monitored to ensure consistent production. Once produced, the antibody is then harvested and purified through a series of procedures to remove impurities and yield a high-quality product. The U.S. Food and Drug Administration requires that biologic drugs such as aducanumab comply with the rigorous current Good Manufacturing Practice (cGMP) standards to maintain safety, purity, and potency.

During manufacturing, process controls are implemented in order to ensure consistency of the products. These include in-process testing, such as checking cell growth, protein yield, and contamination levels. Critical quality attributes—like protein structure, binding ability, and absence of contaminants—are also tested during and after purification. The FDA wants manufacturers to certify these processes, i.e. they have to demonstrate that the manufacturing processes are always capable of producing a product that fully satisfies specifications. This is of particular concern to monoclonal antibodies such as aducanumab, which are complex and sensitive to minor alterations in production conditions.

Furthermore, the FDA demands continuous quality control even after approval. To ensure the drug remains effective over time, manufacturers must apply control methods such as batch testing, environmental monitoring, and stability studies. For aducanumab, which is administered as an intravenous biologic therapy, sterility and proper formulation are critical controls. The FDA directive mandates that devices should also undergo a review of any changes in the manufacturing process and must be approved by the FDA to guarantee they do not interfere with the quality or clinical work of the products.

3.2.S.2.3 Control of Methods

The U.S. Food and Drug Administration approved aducanumab under the accelerated approval pathway, which is meant for drugs that treat serious conditions and address unmet medical needs using a surrogate endpoint. In this case, the FDA accepted the reduction of amyloid-beta plaques as “reasonably likely” to predict patient benefit, even though clinical trial results were mixed. As a condition of approval, Biogen is required to perform a Phase 4 randomized controlled trial to demonstrate clinical benefit, and the FDA may revoke the drug should it fail to demonstrate it. The drug is approved specifically for patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease. Therapy must be dosed with a gradual increase to a maintenance dose administered as an intravenous infusion every 4 weeks, and monitored by MRI to identify amyloid-related imaging abnormalities (ARIA), including brain swelling or bleeding. The approval was controversial because an FDA advisory committee voted against it due to limited evidence, and two Phase 3 trials, the EMERGE trial and ENGAGE trial, were stopped early for futility.

3.2.S.2.4 Control of Critical Steps and Intermediates

According to the FDA documentation of approving Aducanumab (also known as Aduhelm), the management of key processes and intermediates is aimed at ensuring that the production of a human monoclonal antibody is conducted consistently by using recombinant DNA. The Office of Biotechnology Products (OBP) of the FDA assessed the CMC (Chemistry, Manufacturing, and Controls) and deemed the process, including critical intermediates and manufacturing controls, to be satisfactory.

Key aspects of the manufacturing control strategy for Aducanumab, approved under accelerated approval, include:

Drug Substance (DS) & Drug Product (DP) Control: The manufacturing process includes rigorous controls to manage the identity, strength, quality, and purity of the antibody.
Critical Process Parameters (CPPs): While specific, highly detailed proprietary parameters (e.g., precise bioreactor settings) are redacted from public summaries, the FDA verified that the process controls established by Biogen were sufficient to manage the variability of the biologic drug.
Final Sterile Filtration: The date of manufacture is defined as the date of final sterile filtration of the formulated drug product, which is a critical step in the FDA’s approval letter.

3.2.S.2.5 Process Validation and/or Evaluation

The validation and evaluation of aducanumab (Aduhelm) a humanized antibody targeting amyloid-beta plaques in Alzheimer’s disease, became highly scrutinized, with an accelerated approval of the drug by the FDA in 2021 and a voluntary market recall by Biogen in 2024 because of low uptake and an inability to find clinical benefit. The assessment of this drug consisted of phase 3 clinical trials with conflicting outcomes, with special emphasis on surrogate biomarker reduction (A plaque) rather than direct, consistent clinical improvement.

3.2.S.2.6 Manufacturing Process Development

Aducanumab (marketed as Aduhelm) is a human IgG1 monoclonal antibody developed by Biogen in partnership with Eisai, and it originated from a reverse translation platform created by Neurimmune. The antibody was identified through examining blood cells of healthy elderly individuals with a slow progression of cognition, which allowed researchers to find antibodies capable of attacking amyloid-beta plaques associated with Alzheimer disease. To ensure production, Biogen spent heavily on manufacturing scale, with plants in North Carolina and a massive facility in Switzerland fitted with several high-volume bioreactors, which were granted Good Manufacturing Practice (GMP) accreditation in 2021 and can manufacture up to 10 metric tons per year. The manufacturing process focused on producing high-quality antibodies that strongly bind to amyloid plaques in the brain. In addition, analytical methods were carefully developed to ensure product quality, including techniques to isolate the drug from biological samples and chromatographic methods for separation. These were verified as accurate, precise, and stable, which assists in providing consistent and reliable manufacturing results even when the product was on the road to its accelerated approval and subsequent discontinuation in 2021.

3.2.S.3 Characterization

3.2.S.3.1 Elucidation of Structure and Characterization

3.2.S.3.2 Impurities

Oxidized Heavy Chains
Light Chain C-Terminal Truncation

3.2.S.4 Control of Drug Substance

3.2.S.4.1 Specifications

For Aducanumab, one simple specification is: oxidized heavy chains should not exceed a set limit (e.g., ≤5%) in the final product. This helps maintain product quality and is in line with expectations from the U.S. Food and Drug Administration.

3.2.S.4.2 Analytical Procedures

In the case of Aducanumab, high-performance liquid chromatography (HPLC) is used to separate and quantify impurities such as oxidized heavy chains, while capillary electrophoresis (CE) helps evaluate charge variants. Mass spectrometry is then applied to confirm the molecular structure and identify modifications like truncation.

These procedures serve the purpose of ensuring that the product is of a quality that is expected of the U.S. Food and Drug Administration.

3.2.S.4.3 Validation of Analytical Procedures

In the case of Aducanumab, the typical instruments employed to analyse drug substances are HPLC systems to test impurities, capillary electrophoresis to test charge variants, and mass spectrometry to characterise the structure. These are common tools to guarantee quality and consistency in accordance with the expectations of the U.S. Food and Drug Administration.

3.2.S.4.4 Batch Analysis

In the case of Aducanumab, batch analysis can be conducted by testing each manufactured batch to ensure that it meets a set of quality standards before being released. This involves the assessment of identity, purity, potency and impurity levels through validated procedures like HPLC and mass spectrometry. The results are checked against accepted specifications to develop consistency and safety. These are steps that are mandated by the present Good Manufacturing Practice regulations established by the U.S. Food and Drug Administration.

3.2.S.4.5 Justification of Specification

For Aducanumab, one key specification is purity (e.g., ≥95% monomer content).

3.2.S.5 Reference standards or materials

With reference to the assessment of Aducanumab, a reference standard is the most effective method to refer to as a benchmark to find out the actual presence or extent of disease against which the diagnostic or curative capability of the drug is compared. For Aducanumab, which targets amyloid-β plaques in Alzheimer’s disease, the reference standard is not a single test but typically a combination of well-established measures used in clinical trials and validation studies.

3.2.S.6 Container closure systems

The container closure system for Aduhelm consists of a clear glass vial that holds the drug, sealed with a rubber stopper and covered by an aluminum cap with a flip-off top. This design keeps the medicine sterile and safe until use. It is a single-use vial, meaning it does not contain preservatives and should only be used once to avoid contamination. The selected materials are designed to preserve the drug, a sensitive biologic, and ensure that it does not degrade or stick to the container.

3.2.S.7 Stability

3.2.S.7.1 Stability Summary and Conclusions

In the case of Aduhelm, the stability of the drug substance directly influences the stability of the end drug product. The drug substance is a monoclonal antibody, which is sensitive to heat, light, and changes in pH. When it starts to degenerate, it may either aggregate or become inactive. This will diminish the effectiveness of the drug and can cause safety risks. In cases where the substance is stable, the end product is safe and effective in storage and use. Therefore, controlling conditions like temperature and handling is important to maintain overall product stability.

3.2.S.7.2 Post Approval Stability Protocol and Stability Commitment

For Aduhelm, the drug substance expiry exceeds 18 months; therefore, a Post-Approval Stability Protocol will be included. This protocol ensures continued monitoring of the drug’s quality, safety, and effectiveness over its shelf life after approval.

3.2.S.7.3 Stability Data

12 months: This is often quoted for the monoclonal antibody when stored under appropriate long-term conditions (such as at 20 degrees Celsius when aliquoted).
Refrigerated Storage: If stored refrigerated (at 4 degrees Celsius), the product is generally stable for shorter periods, with some guidelines recommending a maximum of 2 weeks.
Diluted Solution: Once diluted for administration, the solution can be stored under refrigeration for up to 3 days or at room temperature for up to 12 hours

3.2.P Drug product (name, dosage form, manufacturer)

Proprietary Name (Brand Name): Aduhelm
Established Name (Generic Name): aducanumab-avwa
Dosage Form and Strength: Injection: 170 mg/1.7 mL (100 mg/mL) or 300 mg/3 mL (100 mg/mL) in a single-dose vial
Administration Route: Intravenous (IV) infusion
Manufacturer/Applicant: Biogen Inc

3.2. P. 1 Description and composition of the drug product

Active Ingredient: Each vial contains 100 mg/mL of aducanumab-avwa.
Formulation: It is supplied as a sterile, preservative-free, clear-to-opalescent, and colorless-to-yellow solution.
Inactive Ingredients (Excipients): The formulation contains L-arginine hydrochloride, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, and Water for Injection.
pH: The solution has an approximate pH of 5.5.
Molecular Weight: Aducanumab-avwa has an approximate molecular weight of 146 kDa

3.2.P.2 Pharmaceutical development

The pharmaceutical development of Aduhelm, according to the FDA, focused on creating a stable intravenous formulation of a monoclonal antibody that targets amyloid-beta in Alzheimer’s disease. The procedure involved the selection of appropriate ingredients to ensure that the proteins stayed intact and did not form aggregates. It also involved developing a reliable manufacturing process and a sterile vial system to protect the drug. Research was conducted to maintain the product as safe, effective, and stable throughout storage and use.

3.2.P.3 Manufacture

3.2.P.3.1 Manufacturer(s)

The manufacturer of Aduhelm (aducanumab-avwa) is Biogen (specifically Biogen MA, Inc.)

3.2.P.3.2 Batch Formula

According to the FDA-approved prescribing information, Aduhelm (aducanumab-avwa) is a sterile, preservative-free solution for intravenous infusion, formulated at a concentration of 100 mg/mL. The formula per mL includes 100 mg of the active ingredient, aducanumab-avwa, along with L-arginine hydrochloride, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, and Polysorbate 80, adjusted with water for injection to a pH of 5.5.

3.2.P.3.3 Description of Manufacturing Process

Aduhelm (aducanumab-avwa) is a biologic drug produced with the use of living cells. It is a fully human IgG1 monoclonal antibody designed to target harmful amyloid-beta clumps in the brain. These clumps include soluble oligomers and insoluble plaques, which are linked to Alzheimer’s disease. The antibody was originally identified from healthy older adults using a method called reverse translational medicine. This helped scientists find a naturally occurring antibody with strong binding ability.

The manufacturing process begins with recombinant DNA technology. Researchers place the antibody gene into the mammalian cells. These cells are then cultured in bulk bioreactors where they express the antibody under controlled conditions. After production, the antibody is carefully purified to remove impurities. The process ends with sterile filtration, which ensures the final product is free from microorganisms. The FDA defines the date of manufacture as the point when this final filtration is completed.

Once purified, Aduhelm is formulated into a sterile liquid solution for intravenous use. It appears colorless to slightly yellow and is placed in single-dose vials. Before administration, it must be diluted with sodium chloride injection. To ensure stability, the drug is stored in refrigerated conditions (usually 2 degrees Celsius to 8 degrees Celsius). It has a shelf life of about 30 months from the date of manufacture when stored properly.

3.2.P.3.4 Controls of Critical Steps and Intermediates

The control of critical steps in making Aduhelm was handled under strict FDA biologics guidelines. The goal was to ensure the antibody stayed pure and consistent in every batch. In-process controls were employed during production to check on significant conditions like temperature, pH and incubation time. Each step in the cell culture and purification process was carefully managed. This helped remove unwanted materials like cell debris, host cell proteins, and residual DNA.

Moreover, critical intermediate steps were monitored closely during production. Quality and yield were tested on materials obtained in the early and middle steps, including the harvested cell culture and purification pools. These tests assisted in ensuring that the purification was taking place. These controls were reviewed and approved by the FDA to make sure that the final product was safe and of good quality.

3.2.P.3.5 Process Validation and/or Evaluation

The FDA granted accelerated approval to Aduhelm (aducanumab-avwa) on June 7, 2021, for the treatment of Alzheimer’s disease. This decision was based on a surrogate endpoint, meaning it relied on reducing amyloid-beta plaques in the brain rather than directly measuring clinical benefit. The approval was highly controversial, as an FDA advisory committee had previously voted that the clinical trials did not demonstrate effective evidence.

3.2.P.4 Control of excipients (Name)

3.2.P.4.1 Specification(s)

Dosage Forms and Strengths

Aduhelm is supplied as a clear to opalescent and colorless to yellow solution for intravenous infusion, available in single-dose vials:

170 mg/1.7 mL (100 mg/mL) injection.
300 mg/3 mL (100 mg/mL) injection

Indications and Usage

Target Population: Treatment of Alzheimer’s disease.
Stage of Disease: It is designed to be initiated in patients with mild cognitive impairment or mild dementia.
Approval Basis: Accelerated approval based on the reduction of amyloid beta plaques in the brain, a surrogate endpoint.

3.2.P.4.2 Analytical Procedures

Binding Selectivity (ELISA)
Immunoprecipitation/Dot Blots

3.2.P.4.3 Validation of Analytical Procedures

High-Performance Liquid Chromatography (HPLC) System
Mass Spectrometer (e.g., Lumos Tribrid Orbitrap)
Surface Plasmon Resonance (SPR) System (e.g., Biacore)

3.2.P.4.4 Justification of Specifications

According to the U.S. Food and Drug Administration (FDA), the specifications for Aduhelm (aducanumab-avwa) were justified based on clinical trial data demonstrating a significant, dose- and time-dependent reduction of amyloid beta plaque in the brain, a surrogate biomarker for Alzheimer’s disease. The approval was granted under the Accelerated Approval Pathway, which allows for approval based on a surrogate endpoint that is “reasonably likely to predict clinical benefit”

3.2.P.4.5 Excipients of Human or Animal Origin

Chinese Hamster Ovary (CHO) Cell Line:
Water for Injection:

3.2.P.4.6 Novel Excipients

L-Arginine hydrochloride (31.60 mg): A commonly used amino acid stabilizer in biologics.
L-Histidine/L-Histidine hydrochloride monohydrate (0.60 mg / 3.39 mg): An amino acid buffer system used to maintain pH.
Polysorbate 80 (0.50 mg): A surfactant (wetting agent) used to reduce aggregation.

3.2.P.5 Control of drug product

According to FDA guidance, unopened vials of Aducanumab (Aduhelm) should be stored refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light, and they must not be frozen or shaken. For the diluted solution after preparation, it should be used promptly; if not used immediately, it may be stored refrigerated at 2°C to 8°C for up to 24 hours, and this time includes the duration of the infusion. The diluted solution should also be protected from light and should not be shaken.

3.2.P.5.1 Specification(s)

Indication: Treatment of Alzheimer’s disease. It is specifically intended for patients with mild cognitive impairment (MCI) or mild dementia stage of disease, which is the population in which treatment was initiated in clinical trials.
Mechanism of Action: A recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody that acts as an amyloid beta-directed antibody, targeting aggregated soluble and insoluble forms of amyloid beta plaques in the brain.
Approval Pathway: Accelerated Approval (21 CFR 601.41).

3.2.P.5.2 Analytical Procedures

Size Exclusion Chromatography (SEC): Used to assess the purity of the drug substance and drug product by measuring the levels of high molecular weight species (aggregates) and low molecular weight species (fragments).
Ion Exchange Chromatography (IEX): Employed to analyze the charge heterogeneity of the monoclonal antibody, which helps ensure batch-to-batch consistency in the glycoform and modification profile.
Cell-Based Bioassay (Potency Assay): Used to measure the biological activity of aducanumab by evaluating its binding affinity to amyloid-beta aggregates, which is directly related to its mechanism of action

3.2.P.5.3 Validation of Analytical Procedures

According to the FDA, validation of analytical procedures for a biological product like Aducanumab (Aduhelm) is a formal and documented process. It demonstrates that an analytical method is reliable, reproducible, and suitable for its intended purpose, including assessing the identity, strength, quality, purity, and potency of the drug substance or product.

3.2.P.5.4 Batch Analyses

Testing of Critical Quality Attributes (CQAs): The API (active pharmaceutical ingredient) is tested for quality characteristics, including high-affinity binding to amyloid beta aggregates, purity, strength, and identity.
Final Sterile Filtration & Formulation Monitoring: The drug product is evaluated for clarity, color, and sterility (clear to opalescent/colorless to yellow) after the final sterile filtration process.
Visual Inspection of Containers: Each vial of the final batch is inspected to ensure the absence of opaque particles, discoloration, or foreign particulates, following 21 CFR 610.60(e)

3.2.P.5.3 Characterization of Impurities

Product-Related Impurities (Aggregates):
Product-Related Impurities (Charge Variants):
Process-Related Impurities (Host Cell Proteins):

3.2.P.5.4 Justification of Specifications

The FDA granted accelerated approval to aducanumab (Aduhelm) for the treatment of Alzheimer’s disease on June 7, 2021, based on a justification that the drug’s reduction of amyloid-beta plaques in the brain is “reasonably likely” to predict clinical benefit. This decision was heavily justified by the substantial, dose- and time-dependent reduction of amyloid plaques shown in clinical trials, particularly in Study 103, which the agency interpreted as a valid surrogate endpoint for a disease-modifying Alzheimer’s treatment.

3.2.P.6 Reference standards or materials

Reference standards or materials are highly purified, well-characterized substances (e.g., APIs, impurities) used as benchmarks to determine the identity, purity, potency, and quality of unknown materials. They provide the “known” value for analytical tests, calibration, and validation, ensuring scientifically valid and compliant results.

3.2.P.7 Container closure system

The container closure system for Aducanumab (marketed as Aduhelm by Biogen) is designed for a preservative-free, sterile monoclonal antibody solution for intravenous infusion. It is made of glass vials that are of high quality, capped by rubber stoppers and flip-off caps to guarantee sterility and to guard the biologics against contamination.

3.2.P.8 Stability

3.2.P.8.1 Stability Summary and Conclusion

According to FDA-approved labeling, Aduhelm (aducanumab-avwa) should be stored carefully to maintain its quality. Unopened vials must be kept refrigerated at 2°C to 8°C (36°F to 46°F) in their original carton to protect from light, and they should not be frozen or shaken; they have a shelf life of 30 months under these conditions, although they may be kept at room temperature (up to 25°C/77°F) for up to 24 hours if needed. After dilution with 0.9% Sodium Chloride, the solution should ideally be used immediately. Still, it can be stored in a refrigerator (2°C to 8°C) for up to 3 days or at room temperature (up to 30°C/86°F) for up to 12 hours. It must not be frozen. During handling, the solution should be inspected for particles or discoloration, only the recommended diluent should be used, and since it is a single-dose product, any unused portion must be discarded.

3.2.P.8.2 Postapproval Stability Protocol and Stability

Based on the FDA approval documentation for Aduhelm (aducanumab-avwa), the approved dating period (expiry) for the drug product is 30 months when stored at 2-8°C. Because this expiry is greater than 18 months, a post-approval stability protocol is required.

3.2.P.8.3 Stability Data

According to FDA approval documentation, the dating period (shelf life) for Aduhelm (aducanumab-avwa) is 30 months from the date of manufacture when stored at the recommended refrigerated temperature of 2°C to 8°C (36°F to 46°F).

3.2.A Container closure system

3.2.A.1 Facilities and Equipment (name, manufacturer)

Aducanumab (brand name: Aduhelm, generic name: aducanumab-avwa) was developed and manufactured by Biogen Inc. The drug substance for Aduhelm was approved to be manufactured at Biogen MA, Inc. (Research Triangle Park, North Carolina, USA). The final formulated product was filled, labeled, and packaged at Biogen U.S. Corporation.

3.2.A.2 Adventitious agents safety evaluation (name, dosage form)

Viruses
Mycoplasma
Bacteria (e.g., Proteobacteria, Firmicutes)
Fungi/Yeast
Parasites/Mycobacteria

3.2.A.3 Novel excipients

L-Arginine Hydrochloride (31.60 mg/mL)
L-Methionine (1.49 mg/mL)
L-Histidine/L-Histidine Hydrochloride Monohydrate (0.60 mg/mL and 3.39 mg/mL)
Polysorbate 80 (0.50 mg/mL)
Water for Injection (WFI)

3.2.R Regional information

Aducanumab is not typically considered a combination product requiring a specialized, proprietary device (e.g., an autoinjector). Instead, it is supplied in single-dose vials and administered as a controlled intravenous (IV) infusion.

The administration requires standard IV equipment, including intravenous tubing, a bag of 0.9% Sodium Chloride (100 mL), and a sterile, low-protein-binding, 0.2 or 0.22 micron in-line filter. Alternatively, the drug is diluted and administered intravenously over approximately one hour, once every four weeks.

As Aducanumab is administered via standard, commercially available IV infusion sets, the drug itself does not have a 510(k) clearance number for a proprietary administration device. The “sterile, low-protein binding, 0.2 or 0.22 micron in-line filter” is a component standard in medical facilities and authorized for use by the FDA.

3.3 Literature references

Alexander, G. C., Emerson, S., & Kesselheim, A. S. (2021). Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. Jama, 325(17), 1717-1718.

Barenholtz Levy, H. (2022). Accelerated approval of aducanumab: Where do we stand now? Annals of Pharmacotherapy, 56(6), 736-739.

Liu, K. Y., & Howard, R. (2021). Can we learn lessons from the FDA’s approval of aducanumab?. Nature Reviews Neurology, 17(11), 715-722.

Padda, Inderbir S., and Mayur Parmar. “Aducanumab.” StatPearls [Internet]. StatPearls Publishing, 2024.

Vaz, M., Silva, V., Monteiro, C., & Silvestre, S. (2022). Role of aducanumab in the treatment of Alzheimer’s disease: challenges and opportunities. Clinical interventions in aging, 797-810.

Module 4 Nonclinical Study Reports

4.2 Study reports

4.2.1 Pharmacology

4.2.1.1 Primary pharmacodynamics

Aducanumab (Aduhelm) is a human monoclonal IgG1 antibody that functions as an amyloid-directed agent designed to treat Alzheimer’s disease by targeting the underlying pathology rather than just symptoms. Its primary pharmacodynamic action involves binding with high affinity to soluble oligomers and insoluble fibrils of amyloid plaques in the brain, facilitating their clearance via microglial-mediated phagocytosis. By removing these aggregates, which are thought to cause neurotoxicity, synaptic loss, and cognitive decline, aducanumab aims to reduce the amyloid burden, with plaque levels showing a dose- and time-dependent decrease. Aducanumab is administered via intravenous infusion every 4 weeks. Following a titration schedule, the maintenance dosage is determined by a healthcare provider. The treatment typically involves a titration schedule:

Infusion 1 & 2: Initial lower dose
Infusion 3 & 4: Intermediate dose
Infusion 5 & 6: Further increased dose
Infusion 7 and beyond: Target maintenance

4.2.1.2 Secondary pharmacodynamics

According to the U.S. Food and Drug Administration review of Aduhelm (aducanumab), secondary pharmacodynamics focus on reducing other harmful processes linked to Alzheimer’s disease, beyond just clearing amyloid plaques. The primary aim is to identify any off-target effects, potential safety risks, and aid in the selection of the most promising drug candidate. This is mostly done using laboratory tests (in vitro), where the drug is screened against different receptors, enzymes, and ion channels, often using fast, high-throughput methods to reduce the need for animal testing. In general, this process examines any unpredictable or unintended impacts of the drug on the main body systems like the heart, lungs and brain.

4.2.1.3 Safety pharmacology

According to the data provided by the U.S. Food and Drug Administration and prescriptive information about Aduhelm, the primary safety issue is Amyloid-Related Imaging Abnormalities (ARIA). ARIA may appear on MRI scans as brain swelling (ARIA-E) or fluid buildup, and also as small areas of bleeding or iron deposits (ARIA-H). Due to this risk, patients should undergo a brain MRI within 1 year before commencing treatment and remain under surveillance throughout treatment. Moreover, the drug has not been established to be safe in cases where the patient already has some brain conditions, including superficial siderosis, multiple minor brain bleeds, or larger brain hemorrhages before the start of treatment.

4.2.1.2 Pharmacodynamic drug interactions

According to the U.S. Food and Drug Administration prescribing information for Aduhelm, there are no formal drug interaction studies because this monoclonal antibody is not broken down by the cytochrome P450 system. However, there are important safety considerations when it is used with other treatments. As an example, care should be taken when administering anticoagulants or clot-dissolving medications, which can lead to a higher risk of brain bleeding associated with amyloid-related imaging abnormalities (ARIA-H). In addition, patients with Apolipoprotein E ε4 in both copies of the gene have a higher risk of ARIA, which should be considered when evaluating treatment safety.

4.2.2. Pharmacology

4.2.2.1 Analytical methods and validation reports

The U.S. Food and Drug Administration reviewed the analytical method validation of Aduhelm as part of its approval. The validation confirmed that the drug has a high standard of identity, strength, quality, purity and potency, as monoclonal antibodies demand. A potency assay was one of the major areas where aducanumab was confirmed to bind to toxic forms of amyloid-beta, assisting in the clearance of plaques associated with Alzheimer’s disease. In addition, analytical methods such as electrophoresis and chromatography were validated to ensure they can accurately distinguish the active drug from impurities, including aggregated proteins.

4.2.2.2 Absorption

The U.S. Food and Drug Administration indicates that the relevance of the concept of absorption to Aduhelm is associated with the pharmacokinetic characteristics of the drug when administered intravenously. Unlike oral drugs, it is delivered directly into the bloodstream, so traditional absorption does not apply. Rather, its intake, dispersion, and excretion are significant since they demonstrate the way the drug gets to the brain and how it acts in the long run. These properties assisted in showing that the drug is capable of reducing amyloid-beta plaques in a dose- and time-dependent way, which aided its expedited approval to treat Alzheimer’s disease.

4.2.2.3 Distribution

The U.S. Food and Drug Administration reports that dose and its interactions with amyloid beta in the brain are important factors that affect the distribution and exposure of Aduhelm. The drug shows dose-dependent exposure, meaning that as the dose increases (from 1 to 10 mg/kg), the amount of drug in the body increases proportionally, with higher doses needed to achieve effective levels in the central nervous system. In addition, as an antibody that targets amyloid beta, a significant portion of the drug binds to these proteins in the brain, which affects how much remains in the bloodstream and supports its action in treating Alzheimer’s disease.

4.2.2.4 Metabolism

According to the U.S. Food and Drug Administration, Aduhelm is not metabolized by the cytochrome P450 system like many small-molecule drugs. Rather, it is degraded in the body similarly to natural immunoglobulin G (IgG). The antibody is degraded by enzymes into small peptides and amino acids, which can then be reused to build new proteins or used for energy. Due to this pathway, other drugs that influence P450 enzymes are unlikely to interact with the drug, making it unlikely to be affected by metabolic drug interactions.

4.2.2.5 Excretion

The excretion and metabolism of Aduhelm are similar to the normal breakdown of immunoglobulin G (IgG) proteins, according to the U.S. Food and Drug Administration. Catabolic processes break the drug down into small peptides and amino acids, which are reused in the body or turned into energy. In contrast to most drugs, it is not excreted via the liver or kidney and is not dependent on cytochrome P450 enzymes. Due to this fact, patients with kidney or liver impairment do not require any dose adjustment because the drug is safely excreted by means of natural body processes.

4.2.2.6 Pharmacokinetics

The U.S. Food and Drug Administration declares Aduhelm as a monoclonal antibody that helps to decrease amyloid-beta plaques in the brain, and its pharmacokinetics exhibit predictable and constant behavior in the body. It is administered by intravenous infusion, i.e. it is introduced into the bloodstream in its full availability. Liver enzymes do not degrade the drug but gradually break it down into small peptides and amino acids via natural body processes, like other antibodies. Elimination occurs through this gradual breakdown, allowing the drug to remain in the body for a long time, with stable levels reached after about 16 weeks of monthly dosing. Its effects increase proportionally with the dose given, and drug interactions are unlikely because it does not rely on cytochrome P450 enzymes. However, like other protein-based treatments, there is a possibility that the body may develop antibodies against it, which could affect how it is cleared.

4.2.2.7 Other pharmacokinetic studies

According to the U.S. Food and Drug Administration review, pharmacokinetic trials of Aduhelm centered on the behavior of the drug as a monoclonal antibody. The drug is broken down into small peptides and amino acids through natural body processes, similar to immunoglobulin G, rather than by cytochrome P450 enzymes. Because of this, no formal drug–drug interaction studies were done, and it is unlikely to interact with drugs that affect these enzymes. In addition, no specific studies were conducted in patients with kidney or liver impairment, since the drug is not cleared through these organs. The main safety concern linked to its pharmacokinetics is the risk of amyloid-related imaging abnormalities (ARIA), including brain swelling and bleeding, especially at higher doses, which is why regular MRI monitoring is recommended during treatment.

4.2.3 Toxicology

4.2.3.1 Single dose toxicity (Species and route)

Aduhelm (aducanumab) is given only through an intravenous (IV) infusion. It is dissolved in 100 mL of 0.9% Sodium Chloride Injection, USP, before administration. The infusion takes about one hour and is given once every four weeks, with at least 21 days between doses. According to the FDA clinical trial results, the primary dose-limiting adverse event is Amyloid Related Imaging Abnormalities (ARIA), which consists of ARIA-E (brain swelling or fluid buildup) and ARIA-H (small brain bleeding or iron deposits). In single-dose clinical studies, doses up to 30 mg/kg were generally tolerated, but higher doses of 60 mg/kg caused serious adverse events, especially symptomatic ARIA. Animal studies also showed that high doses of a similar antibody caused changes in brain blood vessels, including inflammation and bleeding. Genotoxicity and carcinogenicity was not necessary because Aduhelm is a human monoclonal antibody. Due to the risk of ARIA, the FDA requires a recent brain MRI within one year before starting treatment, and the drug must be given using a gradual dose increase from 1 mg/kg to 10 mg/kg to improve safety.

4.2.3.2 Repeat dose toxicity (Species, route, duration)

According to the FDA records, such as the 761178Orig1s000 Pharmacology Review and the approved label, repeat-dose toxicity studies in aducanumab (Aduhelm) were conducted in monkeys and transgenic mice in order to support its clinical use. In a major monkey study, cynomolgus monkeys were injected with high doses of up to 300 mg/kg per week over a period of four weeks, which is significantly higher than the human dose, and there were no adverse effects. In a separate six-month study using aged Tg2576 mice, no clear toxic effects were seen with repeated dosing of aducanumab. However, in humans, repeated dosing is commonly linked to Amyloid-Related Imaging Abnormalities (ARIA), such as temporary brain swelling (ARIA-E) and small brain bleeds (ARIA-H). These effects are controlled by routine MRI observation prior to some infusion. Overall, the FDA concluded that the nonclinical data, including these repeat-dose studies, were sufficient to support the approval of aducanumab.

4.2.3.3 Genotoxicity

The FDA notes that aducanumab (Aduhelm) was not the subject of any formal genotoxicity studies. This is the norm with monoclonal antibodies due to their mechanism of action. Aducanumab is not a small-molecule drug but a large protein, and it is not likely to react or bind to or destroy DNA. Scientifically, it is disintegrated into amino acids in the body and is unlikely to get into the cell nucleus to cause mutations. Other non-clinical observations revealed that reproductive and developmental research in rats did not harm fertility and embryo development. Also, carcinogenicity studies were not done because the drug’s target, aggregated amyloid-beta, is not found in normal (wild-type) rodents.

4.2.3.4 Carcinogenicity

According to the FDA’s approval documents for aducanumab (Aduhelm), including the nonclinical findings review and prescribing information, no carcinogenicity studies were conducted in animals. The FDA accepted the sponsor’s justification because aducanumab targets aggregated amyloid-beta, which is not present in normal rodents, making such studies less meaningful. In addition, as a monoclonal antibody, aducanumab is not expected to interact with DNA or cause cancer. Nevertheless, the FDA is categorical that the impact of aducanumab on cancer risk in humans is unclear. Similarly, genotoxicity studies were not performed for the same scientific reasons. Reproductive studies in rats showed no harmful effects on fertility or embryo development. In general, both the FDA and the Executive Carcinogenicity Assessment Committee concurred that the existing toxicology data were adequate and that carcinogenicity studies were unnecessary to approve it.

4.2.3.5 Reproductive and developmental toxicity

Based on preclinical data for Aduhelm (aducanumab-avwa), animal studies did not show direct or indirect harm to a fetus or offspring, although their relevance is limited because the drug targets amyloid-beta, which is not naturally found in rats. In reproductive research, rats were treated to a dose of 1000 mg/kg/week and did not exhibit any adverse effects on fertility, mating or development of embryos during the early stage. Moreover, the administration of the drug to pregnant rats during organ development did not result in any birth defects or fetal mortality. However, there are no adequate human data to determine the risk during pregnancy, including the risk of birth defects or miscarriage. There is also no information on whether aducanumab is present in human breast milk, or its effects on infants or milk production. Therefore, decisions about breastfeeding should consider both the benefits to the child and the mother’s need for treatment.

4.2.3.6 Local tolerance

According to FDA-approved labeling and safety considerations, the local tolerance of Aduhelm (aducanumab-avwa) is generally manageable with no significant reports of severe injection site reactions as significant adverse effects. The medication is administered as an intravenous (IV) infusion over approximately an hour at four-week intervals. The majority of safety issues are not associated with local tissue response but with the systemic effect. According to the FDA, hypersensitivity reactions are possible, such as angioedema (severe swelling) and urticaria (hives), but this is a whole-body allergic reaction, not local irritation at the infusion site. Regarding safety monitoring, the FDA did not mandate a Risk Evaluation and Mitigation Strategy (REMS) over local administration concerns, but rather concentrated on Amyloid Related Imaging Abnormalities (ARIA) monitoring.

4.2.3.7 Other toxicity studies

Following the FDA review of Aduhelm (aducanumab-avwa) in the treatment of Alzheimer disease, a number of nonclinical toxicity studies were conducted to determine its safety. Although the main safety concern in clinical trials was Amyloid Related Imaging Abnormalities (ARIA), animal studies showed some dose-related effects, especially in the brain’s blood vessels. In a 6-month study in mice with Tg2576, increased doses were associated with alterations in brain blood vessels, including mild inflammation, thickening, and increased incidence of bleeding and clotting. Conversely, general and reproductive research in rats did not demonstrate any adverse impact on fertility or embryo development, with some discrepancy observed in the repeat-dose toxicity results. Overall, the FDA concluded that the nonclinical data were adequate to support the approval of Aduhelm.

4.3 Literature references

Ali, R., Gupta, G. D., & Chawla, P. A. (2022). Aducanumab: A new hope in Alzheimer’s disease. Health Sciences Review, 4, 100039. https://doi.org/10.1016/j.hsr.2022.100039

Haddad, H. W., Malone, G. W., Comardelle, N. J., Degueure, A. E., Poliwoda, S., Kaye, R. J., … & Kaye, A. D. (2022). Aduhelm, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer’s Disease: A comprehensive review. Health psychology research, 10(2), 37023.

Maulden, A. (2022). Ignoring the experts: Implications of the FDA’s Aduhelm approval. American Journal of Law & Medicine, 48(1), 108–133. https://doi.org/10.1017/amj.2022.15

Nisticò, R., & Borg, J. J. (2021). Aducanumab for Alzheimer’s disease: A regulatory perspective. Pharmacological Research, 171, 105754. https://doi.org/10.1016/j.phrs.2021.105754

Vaz, M., Silva, V., Monteiro, C., & Silvestre, S. (2022). Role of aducanumab in the treatment of Alzheimer’s disease: challenges and opportunities. Clinical interventions in aging, 797-810.

Module 5 Clinical Study Reports

5.2 Tabular listing of all clinical study reports

Study Type	Author	Clinical Study Site
Phase 3 Randomized, Double-Blind, Placebo-Controlled Clinical Trial (EMERGE Study)	Marisol Llovera Almeida	Cognitive Neurology Excellence Center – Early Alzheimer’s Unit
Phase 3 Randomized, Double-Blind, Placebo-Controlled Clinical Trial (ENGAGE Study)	Marisol Llovera Almeida	Memory and Brain Research Institute – Neurodegenerative Trials Division

5.3 Clinical study reports and related information

5.3.1 Reports of biopharmaceutical studies

5.3.1.1 Bioavailability (BA) Study reports and related information

According to FDA documents, Aduhelm (aducanumab-avwa) is administered only via intravenous (IV) infusion. This route is the approved method in clinical practice for patients with Alzheimer’s disease. In early development, a Phase 1 study in healthy volunteers found that the absolute bioavailability after subcutaneous administration was 54%. However, this route is not used in clinical treatment. Aducanumab exhibits linear pharmacokinetics, with drug exposure increasing proportionally across doses from 1 mg/kg to 10 mg/kg. The drug also shows moderate accumulation in the body, with a mean accumulation ratio of 1.7 when given once every four weeks. Steady-state levels are typically reached within 16 weeks of repeated dosing. Overall, although bioavailability was studied via the subcutaneous route, all approved uses and clinical data are based on intravenous infusion.

5.3.1.2 Comparative BA and bioequivalence (BE) Study reports and related

Information

According to FDA materials and clinical pharmacology reports, Aduhelm (aducanumab-avwa) received approval on June 7, 2021, under the accelerated approval program in Alzheimer’s disease. It is a monoclonal antibody which is administered as an intravenous infusion at a rate of 100 mg/mL. Because it is a biologic drug, traditional bioavailability (BA) and bioequivalence (BE) studies, which are common for small-molecule drugs, were not required as part of its approval. Instead, the FDA used exposure-response analysis, pharmacokinetic and toxicokinetic studies to assess the drug. Its approval was mainly based on its capacity to minimize amyloid beta plaques in the brain, which is viewed as a surrogate marker of clinical benefit. In addition, pharmacokinetic data showed a clear relationship between drug exposure and plaque reduction, supporting dose selection. The higher dosages, in particular 10 mg/kg, yielded more amyloid plaque reductions than the lower dosages and placebo. All in all, the lack of traditional BA and BE studies was mitigated by the solid clinical evidence of pharmacology that supported dosing and regulatory approval.

5.3.1.3 In Vitro – in Vivo correlation Study reports and related information

The FDA established an in vitro–in vivo correlation (IVIVC) for Aduhelm by linking laboratory-based binding to amyloid-beta (Aβ) aggregates with the drug’s ability to clear plaques in the brain. This relationship served as a surrogate endpoint for evaluating treatment effectiveness. Evidence showed that aducanumab reduces amyloid plaques in a dose-dependent manner. Based on this correlation, the drug received accelerated approval despite inconsistent evidence connecting plaque reduction to meaningful cognitive improvement.

5.3.1.4 Reports of bioanalytical and analytical methods for human studies

Bioanalytical methods for Aduhelm (aducanumab-avwa), according to FDA documentation, focused on measuring the drug’s concentration in human serum to assess pharmacokinetics and support its pharmacodynamic effect on reducing amyloid plaques. The techniques were thoroughly tested and applied in major clinical trials, like EMERGE, ENGAGE, and PRIME. To quantify the total aducanumab levels in serum, a validated immunoassay (ELISA or electrochemiluminescense assay) was performed. In addition, immunogenicity was assessed using a tiered approach that included screening, confirmatory, and neutralizing antibody assays to detect anti-drug antibodies. In the case of pharmacodynamics, amyloid tracer PET imaging was performed to quantify amyloid beta plaque changes in the brain, the surrogate endpoint used to approve the study. All of these were performed in accordance with the FDA bioanalytical method validation guidelines to maintain accuracy and reliability. Overall, these bioanalytical approaches confirmed that aducanumab reduced amyloid plaques in a dose- and time-dependent manner, supporting its accelerated approval.

5.3.2 Reports of studies on pharmacokinetics using human biomaterials

5.3.2.1 Plasma protein binding: Study reports and related information

According to FDA-reviewed pharmacokinetic studies, Aduhelm (aducanumab) is a human IgG1 monoclonal antibody with pharmacokinetics typical of this class of drugs. Unlike small-molecule drugs, it does not bind to plasma proteins such as albumin. Instead, it behaves like a natural IgG antibody and is broken down into amino acids and small peptides through normal body processes. In addition, Aduhelm binds specifically to aggregated forms of beta-amyloid, including soluble oligomers and insoluble fibrils, while showing very weak binding to amyloid monomers. From a pharmacokinetic perspective, the drug has a long half-life of about 24.8 days, which supports its monthly dosing schedule. It also has a volume of distribution of approximately 9.63 L at steady state, indicating that it is mainly distributed within the vascular and interstitial spaces. Overall, these features are consistent with the expected behavior of monoclonal antibodies.

5.3.2.2 Reports of hepatic metabolism and drug interaction studies

According to FDA-approved prescribing information and clinical pharmacology reviews, Aduhelm (aducanumab-avwa) is a human IgG1 monoclonal antibody that does not undergo hepatic metabolism. It is administered through intravenous infusion and is not expected to cause significant drug-drug interactions. Unlike small-molecule drugs, aducanumab is not metabolized by liver enzymes such as the cytochrome P450 system. Instead, it is broken down through normal catabolic processes into small peptides and amino acids, similar to natural IgG in the body. Because of this, the FDA did not require dedicated drug interaction studies, and the overall risk of interactions is considered low. In addition, immunogenicity was low, with anti-aducanumab antibodies developing in about 0.6% of patients. However, due to the small number of affected individuals, the impact of these antibodies on safety, effectiveness, or pharmacokinetics remains unclear.

5.3.2.3 Reports of studies using other human biomaterials

Aducanumab is a biologic drug that was approved through the accelerated pathway based on its ability to reduce amyloid plaques in the brain. This reduction was accepted by the FDA as a surrogate endpoint that is reasonably likely to demonstrate clinical benefits in individuals with Alzheimer’s disease. Aducanumab is a human immunoglobulin gamma 1 (IgG1) monoclonal antibody created through recombinant technology in Chinese hamster ovary (CHO) cells. It acts by binding to aggregated amyloid beta peptides, such as plaques, fibrils, protofibrils and oligomers. This binding makes the drug decrease the density of amyloid plaques in the brain. Notably, the FDA gave its approval after evidence indicated a definite dose- and time-dependent decrease in these plaques. This biomarker effect supported approval, even though the direct clinical benefit had not been fully confirmed at the time.

5.3.3 Reports of human pharmacokinetic (PK) studies

5.3.3.1 Healthy subject PK and initial tolerability Study reports and related

According to FDA documentation and clinical trial reviews, Phase 1 studies of Aduhelm (aducanumab) in healthy subjects and patients with mild-to-moderate Alzheimer’s disease showed a reasonable safety profile and predictable pharmacokinetics. The drug showed linear pharmacokinetics at doses up to 30mg/kg in healthy subjects, with systemic exposure, Cmax and AUC rising proportionally to dose, and a mean accumulation ratio of 1.7 when administered with a single dose every four weeks. Regarding safety, lower doses of aducanumab were generally well-tolerated. This was, however, more sensitive in higher doses. In the first-in-human study, with a dosage of 0.3-60 mg/kg, patients who received the highest dose suffered serious adverse events, namely, symptomatic amyloid-related imaging abnormalities (ARIA), and these resolved upon cessation of the treatment. Although early studies included healthy participants, the FDA-approved use of the drug is limited to patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease. No data support its use in individuals without cognitive impairment.

5.3.3.2 Patient PK and initial tolerability Study reports and related information

Aduhelm is given as a 1-hour intravenous infusion after every four weeks, with an FDA-approved titration regimen to enhance tolerability. The dosing begins at 1 mg/kg for the first two infusions, increases to 3 mg/kg for infusions three and four, then 6 mg/kg for infusions five and six, and reaches a maintenance dose of 10 mg/kg from the seventh infusion onward. According to clinical pharmacology data, the drug decreases amyloid-beta dose-dependently, with the greatest effect being on the highest dose, and the drug is cleared via catabolism with no dose modifications depending on demographics or clinical characteristics. But there is a boxed warning of Amyluid Relevant Imaging Abnormalities (ARIA), especially ARIA-E, occurring most frequently during the first eight doses and necessitating MRI surveillance at certain intervals. Even though the drug has the capacity to clear amyloid plaques, the U.S. Food and Drug Administration approved it on an expedited basis, and its clinical efficacy remains under assessment.

5.3.3.3 Intrinsic factor PK Study reports and related information

According to the clinical pharmacology review of Aduhelm by the U.S. Food and Drug Administration, intrinsic patient factors such as age, sex, race, body weight, and renal or hepatic function do not significantly affect the drug’s pharmacokinetics. Aducanumab is a human monoclonal antibody which exhibits a consistent behavior within the body in various groups of patients. The FDA determined that there should be no dosage or therapeutic individualization in accordance with these inherent properties. Also, since the drug is given at 10 mg/kg depending on body weight, a weight-related variation is well controlled.

5.3.3.4 Extrinsic factor Study reports and related information

As indicated in the clinical pharmacology review and abelling of Aduhelm by the U.S. Food and Drug Administration, extrinsic factors do not necessitate dose adjustments with this treatment. Since Aduhelm is given as an intravenous infusion, food does not affect drug pharmacokinetics or the total drug exposure. The FDA also evaluated broader contextual extrinsic factors, including protocol amendments in clinical trials, noting that mid-study changes allowing higher dosing in the EMERGE trial compared to ENGAGE may explain differences in outcomes. Although the FDA did not specify any extrinsic factors that might require dose adjustments, it emphasized that the safety has not yet been completely established in patients with some high-risk conditions, yet those are considered intrinsic rather than extrinsic.

5.3.3.5 Population PK Study reports and related information

According to a clinical pharmacology review and labeling of Aduhelm by the U.S. Food and Drug Administration, population pharmacokinetics is linear and time-invariant. The 1 to 10 mg/kg range of Alzheimer’s disease dose proportionality was predictably linear across a sample size of over 2,900. Steady-state concentrations are achieved after approximately 16 weeks of once-every-4-week intravenous dosing, with a systemic accumulation of about 1.7-fold. These results, in general, suggest reliable and reproducible exposure to drugs throughout the approved dosing regimen.

5.3.4 Reports of human pharmacodynamic (PD) studies

5.3.4.1 Healthy subject PD and PK/PD Study reports and related information

According to the U.S. Food and Drug Administration pharmacology review (BLA 761178), initial experiments of Aduhelm in healthy subjects defined its basic pharmacological profile by single-ascending-dose and multiple-ascending-dose studies. Pharmacodynamically, aducanumab is a human IgG1 monoclonal antibody which specifically attaches to aggregated amyloid-beta, which activates microglial activity and leads to the elimination of amyloid plaques. The pharmacokinetic results were linear and dose proportional both in healthy volunteers and patients with Alzheimer’s disease in a large dose of 0.3 to 60 mg/kg. Additionally, PK/PD modeling played a central role in development, confirming that the drug crosses the blood-brain barrier at low levels and achieves sufficient brain exposure to interact with amyloid plaques.

5.3.4.2 Patient PD and PK/PD Study reports and related information

According to the U.S. Food and Drug Administration, Aduhelm was granted accelerated approval based on pharmacodynamic evidence showing a dose- and time-dependent reduction of amyloid-beta plaques, a surrogate biomarker considered reasonably likely to predict clinical benefit in Alzheimer’s disease. Pharmacodynamic experiments with amyloid PET imaging revealed that increased doses, specifically 10 mg/kg, resulted in higher and prolonged plaque reduction with time, but there were inconsistent clinical results across Phase 3 trials. The pharmacokinetic characteristics of the drug include complete bioavailability with intravenous administration, a volume of distribution of about 9.6 litres and dose proportionality over the 1 to 10 mg/kg dose range. Moreover, PK/PD modeling with a two-compartment model indicated the high-dose regimen was required to reach maximum plaque clearance, even though the FDA recognized that amyloid plaque reductions did not always correlate with significant cognitive benefit, necessitating a confirmatory Phase 4 trial.

5.3.5 Results of efficacy and safety studies

5.3.5.1 Study reports and related information of controlled clinical studies

The U.S. Food and Drug Administration approved Aduhelm on the basis of controlled clinical trials that indicated its capacity to decrease amyloid-beta plaques in the brain, a surrogate biomarker that was meant to predict clinical benefit in early Alzheimer disease. This approval was made under accelerated approval pathway since the drug was expected to fill a medical need not met before, even though it was unclear whether the drug would actually have a clinical effect or not. Two Phase 3 trials, EMERGE and ENGAGE, were randomized, double-blind, placebo-controlled studies involving over 3,200 patients, but both were initially terminated early after a futility analysis suggested they would not meet primary endpoints. Later re-evaluations revealed that the high-dose arm in EMERGE had a lower rate of clinical deterioration and ENGAGE had none, and the FDA based its approval mostly on the surrogate endpoint of amyloid plaque reduction.

5.3.5.2 Study reports and related information of uncontrolled clinical studies

The U.S. Food and Drug Administration reported that the expedited approval of Aduhelm was based on the results of two randomized, placebo-controlled Phase 3 trials (EMERGE and ENGAGE) and the previous PRIME (Study 103) trial. Although the Phase 3 studies were halted early for futility, the FDA placed significant weight on long-term extension and post-hoc analyses, particularly from the PRIME study, which showed consistent, time- and dose-dependent reductions in amyloid plaques. These results supported the agency in concluding that amyloid reduction is a strong surrogate endpoint that is sufficiently likely to be a predictor of clinical benefit, on which accelerated approval is based. However, this approach was controversial, as the FDA advisory committee strongly opposed approval, citing concerns about insufficient evidence and potential bias introduced by reliance on post-hoc analyses.

5.3.5.3 Reports of analysis of data from more than one study

The U.S. Food and Drug Administration analyzed two identical Phase 3 trials, EMERGE and ENGAGE, with inconsistent outcomes in terms of clinical benefit. EMERGE showed a reduction in clinical decline with high-dose treatment, while ENGAGE did not show significant benefit. The FDA used post-hoc analysis and discovered that the inconsistent results can be attributed to differences in dose exposures. Although the FDA had reservations about the drug, it granted approval to the drug on the basis of the totality of evidence, which included its capacity to lower amyloid beta plaques and its possible utility in some patient groups.

5.3.5.4 Other Study reports and related information

The U.S. Food and Drug Administration approved Aduhelm (aducanumab) in June 2021 based on a “totality of evidence” showing that it reduces amyloid beta plaques, which are reasonably likely to predict clinical benefit, although the evidence was highly controversial. The decision drew on conflicting Phase 3 results from EMERGE and ENGAGE, early trial termination due to futility, supportive findings from the PRIME study showing dose- and time-dependent plaque reduction with possible cognitive benefit, and additional preclinical and pharmacology data linking amyloid reduction to clinical outcomes.

5.3.6 Reports on postmarketing experience

The U.S. Food and Drug Administration reported that the postmarketing experience for Aduhelm (aducanumab-avwa) was marked by significant safety concerns, particularly Amyloid Related Imaging Abnormalities (ARIA), including brain swelling (ARIA-E) and hemorrhages (ARIA-H). These events were frequently reported and often resulted in serious outcomes such as hospitalization. Surveillance data from FAERS confirmed high adverse event rates, while additional risks like hypersensitivity reactions were also noted, requiring close monitoring. Although the drug received accelerated approval in June 2021 based on amyloid plaque reduction, its clinical benefit remained unconfirmed, and low adoption led Biogen to discontinue its development and halt required confirmatory trials in January 2024.

5.4 Literature reference

Gandy, S., Knopman, D. S., & Sano, M. (2021). Talking points for physicians, patients and caregivers considering Aduhelm® infusion and the accelerated pathway for its approval by the FDA. Molecular Neurodegeneration, 16(1), 74. https://doi.org/10.1186/s13024-021-00490-z

Liu, K. Y., & Howard, R. (2021). Can we learn lessons from the FDA’s approval of aducanumab?. Nature Reviews Neurology, 17(11), 715-722.

Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., Ames, D., Banerjee, S., Burns, A., Brayne, C., Fox, N. C., Ferri, C. P., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Nakasujja, N., Rockwood, K., . . . Mukadam, N. (2024). Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The Lancet, 404(10452), 572–628. https://doi.org/10.1016/s0140-6736(24)01296-0

Michener, J. (2022). Health justice through the lens of power. The Journal of Law Medicine & Ethics, 50(4), 656–662. https://doi.org/10.1017/jme.2023.5

Wang, B. (2021). Biogen’s Sandrock Defends Aduhelm Data, Responds To ‘Misinformation’. InsideHealthPolicy. com’s FDA Week, 27(30), 9-11.

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HCR 577 CTD Module 1 2 3 4 and 5

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