New Developments in Alzheimer’s Disease Therapeutics
R. Scott Turner, PhD, MD Memory Disorders Program, MedStar Georgetown University Hospital
Nov. 18, 2021
On June 7, 2021 the FDA granted accelerated approval of the anti-amyloid antibody aducanumab (Aduhelm, Biogen). This approval was based on reduction of amyloid load in the brains of treated individuals with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s disease (AD). Almost 20 years have passed since thelast new drug was FDA-approved for the treatment of AD (memantine, Namenda®).
While controversial, Aduhelm’s approval represents a milestone in AD therapeutics – the first disease-modifying treatment available for prescription use. The initial approval was for individuals with AD (a very broad indication). However, this was revised July 8 to more closely match the population in the two phase 3 studies (EMERGE and ENGAGE) leading to its approval – namely, individuals with MCI or mild dementia due to AD (a much narrower indication).
According to the amyloid hypothesis of AD, plaque reduction is considered likely to predict clinical benefits. Actual benefits, however, have been inconclusive, with conflicting results from EMERGE and ENGAGE. Therefore, the question of clinical benefits of Aduhelm remains unanswered. This controversy – in combination with the significant risk of side effects and the lack of third-party coverage by Medicare and otherhealth insurance carriers – has resulted in less than enthusiastic utilization of this newly-available treatment. Major medical centers including MedStar Georgetown University Hospital declined adding Aduhelm to their pharmacy formularies.
Aduhelm has significant risks including excessive inflammation and swelling of the brain (ARIA-E, or amyloid-related imaging abnormality-edema) and hemorrhages – typically microhemorrhages (ARIA-H or amyloid-related imaging abnormality-hemorrhagic). While usually asymptomatic and detected only by MRI, these side effectsmay lead to new symptoms such as headache, worsening confusion, dizziness, visual disturbances, nausea, seizure(s), and in one case, death due to ARIA-E. Symptomatic ARIA requires either temporary or permanent discontinuation of treatment, with resolution of ARIA-E requiring several weeks to months. ARIA-E may also be recurrent, with one individual having six distinct episodes (separated in time and brain region affected). The risk of ARIA increases with dosage and is decreased by slowly ramping up the monthly dose (as approved).
Recommendations regarding what characteristics make a patient appropriate to receive Aduhelm include:
- A diagnosis of MCI or mild dementia due to AD
- Cognitive tests with performance scores of 21-30 on the Mini Mental State Examination (MMSE) or 17-30 on the Montreal Cognitive Assessment (MoCA).
- Amyloid positive by cerebrospinal fluid (CSF) testing or by a PET scan of the brain (within 1 year)
- Medically and psychiatrically stable, no organ failure, and no active cancer (low grade basal and squamous cell carcinomas excepted)
- Not on blood thinners (anticoagulants) and no blood clotting disorders
- Testing for ApoE genotype is optional but recommended. The risk of ARIA is higher in ApoE4 carriers.
- Brain MRI (within 1 year) with no large hemorrhage(s) or ischemic stroke(s) and a maximum of 4 microhemorrhages
- Patient and care partner recognize the requirement of monthly intravenous infusions and understand expectations (not improvement but slowing of decline)
- Willing to obtain regular MRI scans
Biogen is collecting additional data in an ongoing open-label (no placebo) study of Aduhelm (EMBARK) for individuals who were enrolled in prior trials. A new study announced by Biogen will collect real-world experience with Aduhelm post-approval (iCARE AD) and a Phase 4 study (mandatory for accelerated FDA-approval) is in the planning stages. The next question is whether Medicare will cover Aduhelm – a decisionanticipated January 2022 (becoming effective in April). In the meantime, competing anti-amyloid antibodies to treat AD are now following the same regulatory pathway.
In June the FDA granted donanemab (Lilly) breakthrough therapy designation. This designation is intended to expedite the development and review of medicines for serious or life-threatening conditions when preliminary clinical evidence indicates that the drug (or biologic in this case) may demonstrate substantial improvement on clinical endpoints over available therapies. In October Lilly announced the initiation of a rolling submission for a biologics license application (BLA) for donanemab under the accelerated approval pathway based on promising data from TRAILBLAZER-ALZ – including results demonstrating that donanemab may be the most potent in removal of brain amyloid. A rolling submission allows completed portions of the application to be submitted to the FDA for review on an ongoing basis. The safety and efficacy of donanemab are being evaluated in a phase 3 trial in progress (TRAILBLAZER-2). Lilly also launched two new studies – TRAILBLAZER-3, a prevention trial, and TRAILBLAZER-4 – a phase 3 head-to-head comparison of donanemab versus aducanumab in early AD.
Also in June, lecanumab (previously BAN2401, Eisai and Biogen) was granted breakthrough therapy designation. In September, Eisai initiated a rolling submission for a BLA for lecanumab for the treatment of early AD. The application is supported by datafrom a phase 2 trial demonstrating a reduction in brain amyloid accompanied by a consistent reduction of decline across several clinical and biomarker endpoints in patients with MCI or dementia due to AD. Lecanemab may also have a better safety profile than aducanumab – a lower risk of ARIA. A lecanumab phase 3 study (CLARITY)in early AD is in progress.
In October the FDA granted gantenerumab (Genentech/Roche) breakthrough therapy designation. This designation is based on results of two studies (SCarlet RoAD and Marguerite RoAD) and a study of individuals with familial AD all showing clearance of brain amyloid. Gantenerumab is now being studied in two phase 3 trials (GRADUATE1 and 2). In contrast to the other three antibodies requiring monthly intravenous infusion, gantenerumab is administered by biweekly subcutaneous injection.
FDA approval of Aduhelm in June energized the field of AD therapeutics – prompting other companies to seek approval for competing treatments on the accelerated pathway, and promoting investment and research interest by biotech and pharmaceutical firms around the world. By the end of 2022 there may be three or four FDA-approved disease-modifying treatments for AD. Since the phase 3 studies for the latter three antibodies are in progress and unlikely to be stopped prematurely (as was the case with the Aduhelm studies) we anticipate more robust results – finally answeringthe question regarding clinical benefits of amyloid removal. However, since treated patients are still declining in their cognitive and functional abilities, albeit more slowly, additional treatments with different molecular targets are clearly essential to halt or perhaps even reverse the progressive dementia of AD. Similar to other life-threatening disorders including heart disease, cancer, and HIV, a treatment “cocktail’ may be required for real progress. An anti-amyloid antibody, a form of passive immunization, may be the first component of this cocktail.
We thank the many study subjects and partners, including all who enrolled in trials at Georgetown University, for their many contributions. Studies of all four anti-amyloid antibodies are ongoing at the Memory Disorders Program – namely, EMBARK, TRAILBLAZER-2, CLARITY, and GRADUATE but all are closed to new enrollment. In parallel, a prevention trial with lecanumab is now recruiting cognitively-normal older volunteers at risk for AD, and their study partners (A3/45, AHEAD). Another prevention study (A4) with solanezumab (Lilly) is ongoing but closed to recruitment – with results anticipated 2023.
To learn more about Aduhelm, including patient support services, see aduhelm.com. To learn more about the Memory Disorders Program and opportunities toparticipate in research, see memory.georgetown.edu.