aducanumab-avwa (Aduhelm)

Introduction

Biogen will stop developing & selling aducanumab

Indications

• treatment of mild cognitive impairment or early Alzheimer's disease
  • for use only in patients with the earliest stages of disease

* 2 trials discontinued due to futility

• Biogen later reversed its position of futility on one of 2 trials

* FDA approval using the accelerated approval pathway June 7, 2021

* accelerated approval includes an FDA mandate for a phase 4 study to verify clinical benefit of aducanumab

Contraindications

• patients on anticoagulants were excluded from clinical trials*
  • 19% of patients treated with Aduhelm developed ARIA-hemorrhage

* 91% of patients with Alzheimer's disease & 85% of patients with mild cognitive impairment met at least 1 exclusion criteria from the EMERGE & ENGAGE clinical trials stopped prematurely based on prespecified futility thresholds; most patients with multiple exclusion criteria

• the most common exclusion criteria include cardiovascular disease, anticoagulation, anti-platelet therapy (except low-dose aspirin), chronic kidney disease, age > 85 years

Dosage

• 1-10 mg/kg monthly administered as IV infusion over 1 hour
  • dose titration of infusion is required over the initial 6 infusions
    • infusions 1 & 2 -> 1 mg/kg
    • infusions 3 & 4 -> 3 mg/kg
    • infusions 5 & 6 -> 6 mg/kg
  • treatment dose of 10mg/kg begins on infusion 7

Vials: 170 mg/1.7 mL, 100 mg/mL single dose vials

(must be diluted prior to indfusion)

Adverse effects

• cerebral edema (vasogenic), seen on PET, occurred in 3-41% (higher at higher doses) with resolution within 4-12 weeks
  • no new cases of cerebral edema in those who continued on the same dose of aducanumab
  • case report of 6 amyloid-related imaging abnormality (ARIA) episodes
    • over 44 months recurrent episodes of asymptomatic mild-moderate ARIA-edema including 1 episode with mild ARIA-hemorrhage
  • ARIA-related edema (35%) 26% symptomatic
    • apolipoprotein E4 carriers may be more likely to have ARIA-related edema
• cerebral microhemorrhage 19%
• ARIA siderosis (15%)
• headache
• falls
• diarrhea
• confusion/delirium

• drug adverse effects of anti-Alzheimer monoclonal antibody
• drug adverse effects of pharmaceutical monoclonal antibodies

Drug interactions

• antiplatelet drugs increase risk intracerebral hemorrhage
• anticoagulants increase risk of intracerebral hemorrhage
• thrombolytic agents increase risk of intracerebral hemorrhage

Mechanism of action

• monoclonal IgG1 directed against aggregated soluble & insoluble forms of beta-amyloid
• removes amyloid plaques (PET scan confirmed in 100%)
  • dose-dependent reductions in amyloid plaques through 36 months of treatment
• slows cognitive decline in some, but not all studies

Radiology

• may require amyloid PET scan for eligibility & CMS does not cover amyloid PET unless performed as part of a CMS-approved clinical trial
• 3 screening MRI of brain*
  • prior to beginning infusion (within the past year)
  • prior to infusion 7
  • prior to infusion 12

* looking for Amyloid Related Imaging Abnormalities edema or hemorrhage (ARIA-E, ARIA-H)

Notes

• industry-funded investigators report
• advisory committee concludes that study 302 EMERGE does not support strong evidence of aducanumab effectiveness in treatment of Alzheimer's disease
• many scientists disagree with FDA approval
• 3 FDA advisors resign over FDA's approval of Aduhelm
• Public Citizen's Health Research Group calls for removal of FDA's acting commissioner & 2 other FDA officials for reckless approval of Aduhelm
• 87% of US-based physicians & 89% of neurologists disagree with the FDA's approval of aducanumab
• ex-FDA advisor calls decision to approve Aduhelm probably the worst decision in U.S. history
• no net benefit
• FDA acting commissioner calls for investigation into FDA approval of Aduhelm
• CMS opened a National Coverage Determination analysis to review & determine whether Medicare will establish a national coverage policy for monoclonal Ab targeting beta-amyloid for treatment of Alzheimer's Disease
• FDA-defends decision of accelerated approval of Aduhelm
• Biogen pulled Aduhelm paper after JAMA demanded edits
• Biogen launches controversial infomercial campaign directed at consumers
• Veterans Administration decides not to add Aduhelm to its formulary & recommends against using it
• FDA broke with its own protocols in reviewing & subsequently approving aducanumab (Aduhelm), by inappropriately collaborating with drugmaker Biogen on briefing documents, holding unreported meetings, & failing to obtain internal consensus before engaging in such collaborations

• average annual cost of aducanumab treatment is > $75,000
• annual cost of Aduhelm will be $56,000/year with no cost increase for 4 years
• Biogen has reduced the price of Aduhelm to 28,200/year as the drug has sold poorly since its approval in June 2021 due to concerns about its safety, effectiveness & cost
• Medicare copayments for Aduhelm may be ~$11,500
• Aduhelm coverage & cost
• public & private payers may check on the FDA's decision, by refusing to cover the drug
• CMS has upheld its proposed plan to cover aducanumab (Aduhelm) only for people in randomized controlled trials

More general terms

• anti-Alzheimer monoclonal antibody

Additional terms

• investigational therapies for treatment of Alzheimer's disease

Patient information

aducanumab (Aduhelm) patient information