New Drug Overview: Aducanumab-Avwa (Aduhelm) for Alzheimer Disease

On June 7, 2021, the FDA granted aducanumab-avwa (Aduhelm) accelerated approval as a new treatment for Alzheimer disease (AD).¹ Aducanumab-avwa is a monoclonal antibody that is the first treatment of its class designed to target the amyloid β protein, a biomarker of AD and other dementias.²

The monoclonal antibody binds to both soluble and insoluble forms of amyloid beta to reduce the number of plaques in the brain. Confirmatory trials are needed to achieve continuous approval for this agent as a disease-modifying therapy for AD.²

It is currently only available as an injection for intravenous usage. On January 4, 2011, President Barack Obama enacted the National Alzheimer's Project Act.³ The act required the US Department of Health and Human Services (HHS) to establish the project to:

• Create and maintain an integrated national plan to overcome AD.
• Coordinate AD research and services across all federal agencies.
• Accelerate the development of treatments that would prevent, halt, or reverse the course of AD.
• Improve early diagnosis and coordination of care and treatment of AD.
• Improve outcomes for ethnic and racial minority populations that are at higher risk for AD.
• Coordinate with international bodies to fight AD globally.

The law also establishes the Advisory Council on Alzheimer's Research, Care, and Services and requires the Secretary of HHS, in collaboration with the advisory council, to create and maintain a national plan to overcome AD.³

Pharmacology and Pharmacokinetics

Aducanumab-avwa is an immunoglobulin gamma 1 (IgG1) human monoclonal antibody that targets an agglomeration of soluble and insoluble forms of amyloid beta. According to the amyloid cascade hypothesis, amyloid beta accumulation results in neurotoxicity that leads to AD. In clinical studies, aducanumab-avwa was found to reduce amyloid beta plaques.²

Aducanumab-avwa reaches steady-state concentrations by the fourth infusion, with infusions administered every 4 weeks. The steady state C-max increased the dose proportionally in the dosage range of 1 mg-10 mg/kg every 4 weeks, as did the steady state AUC. The elimination half-life is 24.8 days.

Dosing and Administration

For the treatment of AD, aducanumab-avwa is dosed based on actual body weight and the number of infusions received. The dose should be titrated upward for the first 6 infusions. Following dose 6, continue with the maintenance dosing. There are no renal or hepatic adjustments indicated.²

Dosing: Give infusions every 4 weeks and at least 21 days apart.

Maintenance dosage: Infusions every 4 weeks and at least 21 days apart at 10 mg/kg IV over 1 hour.

Aducanumab-avwa is supplied in single-dose vials containing 170 mg/1.7 mL and 300 mg/3 mL. It is only compatible with 0.9% saline and should not be mixed with any other diluent.

Contraindications, Warnings, and Precautions

Currently, there are no drug interactions or contraindications for aducanumab-avwa.

A neurologic precaution is that this medication can cause amyloid-related imaging abnormalities-edema (ARIA-E) and amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H), including brain edema, microhemorrhage, and superficial siderosis when observed during a brain magnetic resonance imaging (MRI). Obtain a recent (within 1 year) brain MRI before initiation of treatment.

The safety of aducanumab-avwa in patients with any pre-treatment localized superficial siderosis, 10 or more brain microhemorrhages, and/or with a brain hemorrhage greater than 1 cm within 1 year of treatment initiation has not been established.

Immunologic precautions include the occurrence of angioedema and urticaria. If hypersensitive reactions occur (observance of first symptoms), stop treatment immediately.²

The most common adverse events are hemosiderosis, falls, microhemorrhage, brain edema, and headache.²

Clinical Trials

The EMERGE and ENGAGE trials are twin phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group studies to evaluate the efficacy and safety of aducanumab-avwa (BIIB037) in subjects with early AD. The primary objective was to assess Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores in patients with early AD compared to a placebo. Mini-Mental State Examination, AD Assessment Scale-Cognitive Subscale, and AD Cooperative Study-Activities of Daily Living Inventory were compared to placebo as secondary objectives of the study.

In the ENGAGE trial, aducanumab did not reduce clinical decline. In the EMERGE trial, high dose aducanumab (10mg/kg) reduced clinical decline as measured by the primary and secondary endpoint. In the EMERGE trial, the recorded CDR-SB difference in the placebo vs the high dose aducanumab was -0.39 (-22%, P=0.0120) found to be clinically significant.

Clinical Relevance

The difference between the 2 studies is the baseline characteristics in the study samples. Between the 2 studies at baseline, the EMERGE trial had fewer Asian participants, fewer participants taking AD medication, fewer carriers of the ApoE ε4 allele, fewer cases of mild AD, a higher CDR-SB score, and a slightly (0.01) lower amyloid PET SUVR composite.²

Aducanumab-avwa is not included in the current practice guidelines, American Psychiatric Association (2007, updated 2014)^4,5 and the American College of Physicians (2008).⁶ However, the data from the EMERGE trial² may help determine whether a patient may be a good candidate for the $56,000 per year therapy.

One must consider the annual cost of the drug as a tier 5 specialty drug under Medicare. The co-payment would be $11,500 annually and other costs include monthly infusions, 3 MRIs, initial PET scan, and additional visits.

Differential diagnosis should be used to rule out ApoE ε4 allele pathology as a contributing factor. EMERGE sheds light that high dose aducanumab-avwa may reduce cognitive decline if used at the earliest stages of AD and if the patient is a non-carrier of the ApoE ε4 allele.²

References

1. Food and Drug Administration. FDA Grants Accelerated Approval for Alzheimer’s Drug.; 2021. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
2. Aducanumab [ADUHELM]. Package insert. Biogen; 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf
3. U.S. Department of Health and Human Services. National Plan to Address Alzheimer's Disease. U.S. Department of Health and Human Services; 2011. https://aspe.hhs.gov/collaborations-committees-advisory-groups/napa/napa-documents/napa-national-plans/national-plan-address-alzheimers-disease
4. Rabins P, Blacker D, Rovner B et al. Practice Guideline for the Treatment of Patients with Alzheimer’s Disease and Other Dementias. american psychiatric association. 2021;2.
5. Rabins P, Rovner B, Rummans T, Schneider L, Tariot P. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients with Alzheimer's Disease and Other Dementias. FOCUS. 2017;15(1):110-128. doi: 10.1176/appi.focus.15106.
6. Qaseem A. Current Pharmacologic Treatment of Dementia: A Clinical Practice Guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148(5):370. doi:10.7326/0003-4819-148-5-200803040-00008.