Alzheimer’s disease (AD) is the most common dementia of the elderly. After two decades without a new drug and hundreds of flops in AD therapy, the US Food and Drug Administration (FDA) announced the approval of Aducanumab on June 7, 2021. Here, we examine whether skepticism regarding Aducanumab immunotherapy for AD to see whether it is a ray of hope or lowering of standards of drug approval.
By Dr Jamshed
Alzheimer’s disease (AD) Pharmacology
AD has no known cause and only a tiny minority has genetic predisposition from trisomy 21 or ε4 allele of apolipoprotein E (APOE). AD neuropathology includes two forms of protein aggregates: extracellular amyloid beta plaques, and intracellular neurofibrillary tau tangles. Most of the drugs in clinical trials rely on amyloid beta hypothesis of AD, according to which restoration of deficient cholinergic transmission in AD brain would improve cognition, with or without reducing amyloid plaques or tau tangles.
From 1993 to 2001, FDA approved four cholinesterase inhibitors – Tacrine, Donepezil, Rivastigmine and Galanthamine – that increase the acetylcholine reservoir in the brain to improve behavioral symptoms in early to mild AD. Memantine, a partial N-methyl-D-aspartate (NMDA) receptor antagonist approved in 2003, provides only mild symptomatic relief. None of these medications reverse the actual AD pathology. This changes with the arrival of Aducanumab, which attacks the amyloid plaques directly to reverse AD pathology.
Non-pharmacological options to supplement AD therapies include lifestyle changes and consuming nuts such as walnuts and almonds, natural antioxidants and so on.
Aducanumab: Pharmacokinetics and Pharmacodynamics
Aducanumab is a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody, developed by Massachusetts-based biotechnology company Biogen, in collaboration with Japan’s pharmaceutical company, Eisai. Aducanumab is marketed as preservative-free intravenous infusion, called Adulhelm, in single-dose vials in various concentrations, including 170 mg/1.7 mL (100 mg/mL) and 300 mg/3 mL (100 mg/mL). It is a prescription-only drug that will be administered once a month as an hour-long intravenous infusion. The best candidates for Adulhelm are people in the prodromal phase of AD, called mild cognitive impairment (MCI), and early stages of AD.
Aducanumab reaches the brain in low concentrations. It binds to the aggregated amyloid beta, and stimulates the immune system (especially microglia) to help breakup the plaques and clear the disease.
Since Aducanumab is an intravenously infused antibody, it is not surprising that it does not undergo renal or hepatic elimination, and gets degraded by pathways for endogenous IgG.
Aducanumab removes amyloids from the blood vessels as well, especially in the APOE4 carriers, which leads to leakiness. This can occur early in the treatment, but most of the time, there are no outward symptoms of these micro-hemorrhages. Another side effect is brain swelling, which usually rescinds on its own without headaches or confusions.
Why FDA Approval Sparked Controversy?
The idea of immunotherapy or immune-based vaccine-like treatments, is not new. The bases for approval of Aducanumab are three phase III trials involving 3482 participants of median age 71 years. The results of these randomized, double-blind, placebo-controlled, dose-ranging studies did not look promising at first, but then, Biogen analyzed a bigger dataset of a 2019 trial and showed slowing of cognitive decline with the highest dose (10 mg/kg) in early stage of AD. Aducanumab did reduce the amyloid plaques in a dose- and time-dependent manner as evident from MRI and PET scans.
In November 2020, none of the 11 experts in the FDA advisory committee supported the biologics license application (BLA) 761178 for Aducanumab. FDA almost always follows the recommendations of its advisory committee, but this time, FDA went ahead with the approval under FDA’s accelerated approval program. The FDA advisory committee acknowledged a 22% reduction in clinical decline of early stage AD and MCI with 18 months of treatment.Since amyloid reduction was not necessarily followed by improvement in cognition, it is debatable whether a partial positive result (reduction in amyloid plaques) is the same as a negative result (no real improvement in AD).
The evidence supporting Aducanumab was primarily in the early stage AD, but FDA has implicitly approved it for all stages. FDA’s accelerated approval does mandate phase 4 trial within the next 9 years, but European Union and other countries can now approve Aducanumab based on FDA’s current verdict. So, there is a fear of lowering of standards for drug approvals in the coming future.
Use of surrogate endpoint of reducing amyloid plaques in clinical trials has annoyed many experts since FDA’s move favors amyloid hypothesis of AD over other underlying causes. Manufacturers of anti-amyloid antibodies and drugs with molecular structure similar to a Aducanumab, such as Donanemab by Eli Lilly, may just need to show the reduction in amyloids without demonstrating concrete effect on cognition to get FDA approval. In other words, companies will seek accelerated approval rather than regular approval, thereby lowering of standards that experts are complaining about. Comparative trials of Aducanumab with other monoclonal antibodies like Donanemab are also warranted.
The interaction of Aducanumab with COVID-19 is unknown. It is important since SARS-CoV-2 infection is especially dangerous for the elderly and recently, COVID-19 has been associated with increased likelihood of AD-like dementia.
On the positive side, reducing disease progression, even without cognition, may be the first step towards AD pharmacotherapy. The FDA-approval is bound to trigger funding and innovation in AD therapeutics. It must be noted that PET scans and CSF analysis showed a decreased tau pathophysiology as well, which may be related to Aducanumab-induced reduction in amyloid plaques.
This means that for the millions of people afflicted with AD, Aducanumab provides a ray of hope. Preserving the quality of life at early AD or MCI is worth the risk, especially for those who can afford the yearly bill of US$56,000 and PET scans or lumbar punctures to check amyloid plaques.
In sum, Aducanumab with healthy lifestyle is reasonably likely to reduce the horrors associated with AD and related dementias.