Drs Neil Cashman and Larry Altstiel of ProMIS Neurosciences weigh in on recent progress towards an effective therapy for Alzheimer’s disease, potentially representing a break from three decades of scientific stagnation.
Are we there yet with Alzheimer’s immunotherapies? No. But we have a map, and it’s a good one.
In late September 2022, Eisai and Biogen announced topline results for CLARITY-AD, the phase three study for lecanemab, an investigational monoclonal antibody for the treatment of Alzheimer’s disease (AD). The study met its primary and secondary endpoints with lecanumab slowing the rate of cognitive decline for patients with early stage Alzheimer’s disease by 27 percent. The news was a powerful shot in the arm for a beleaguered community of researchers, clinicians, patients and families who have waited an excruciatingly long time for positive news. Reverberations from Biogen and Eisai’s momentous achievement will extend far beyond their study results because they affirm—at long last—a critical revision to the amyloid beta (Aβ) hypothesis, a decades-old, controversial view of how to halt AD progression.
Amyloid beta is a peptide fragment of the amyloid precursor protein (APP) that occurs naturally in the brain and has an important physiologic function. However, numerous studies support its role in familial and sporadic AD, which led researchers to propose the original Aβ hypothesis in the early 1990s. The hypothesis posited that, in susceptible individuals, high levels of Aβ monomers can form aggregates that combine to form fibrils, which ultimately led to plaque deposits. This view guided drug development accordingly, but the years ahead saw every candidate aimed at plaque fail to show cognitive benefit.
Revising the amyloid hypothesis
As data emerged showing that amyloid plaque density is not directly proportional to cognitive decline, a subset of researchers began advocating for a revision to the hypothesis. Data over the past decade demonstrate that amyloid beta oligomers (AβOs) likely contribute to the fundamental pathologies in AD: including neuronal death, synapse loss and tau pathology. Major studies designed to target amyloid were well underway, but in recent years, one drug candidate—Biogen’s Aduhelm—inched closer to neutralizing AβOs, though not completely and with serious treatment-limiting side effects. In 2020, I (Neil Cashman) offered perspective on how Aduhelm achieved its modest treatment benefit, explaining that while it targeted amyloid plaque it also managed to neutralize some oligomers at high doses. Regrettably, this high dosage resulted in 35% of study subjects experiencing adverse ARIA-E (brain swelling) despite attempts to minimize it with drug up-titration. I predicted that Aduhelm’s most important contribution to AD would be its impact on future therapy development, specifically therapies with more precise targeting for amyloid-beta toxicity without ARIA-E.
Lecanemab, which targets the toxic oligomeric forms of the Aβ peptide while also binding amyloid plaque, gets us closer. The recent press release from Eisai/Biogen presented top-line data from a phase three, 18-month study that enrolled 1,795 participants with early-stage disease. Patients treated biweekly with 10 mg/kg lecanemab had a 27% slower rate of decline than placebo patients as measured by the rigorous Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale, which measures cognitive and functional outcomes. This result allowed lecanemab to meet its primary endpoint with statistical significance. Additionally, key secondary outcomes—ADAS-Cog14, ADCOMS, and ADCS MCI-ADL, which are human cognition and daily function assessments —all favored lecanemab with robust statistical significance. Significantly, and aligned with its predecessor, Aduhelm, lecanemab binds to amyloid plaque, which caused a 21.1 percent incidence of ARIA-E and ARIA-H in treated patients. This safety concern may limit dose levels and in general practice, especially for patients with cardiovascular co-morbidities.
The Good Map: Selective targeting without distraction
The results of CLARITY-AD support the hypothesis that AβOs play a significant role in AD pathology and raise the possibility of optimizing efficacy and safety. Three antibodies have shown some clinical benefit: lecanemab, Aduhelm, and Eli Lilly’s donanemab. Each of these treatment candidates retain strong binding signal to low-molecular-weight AD brain extracts (enriched in AβOs) after monomer pre-exposure. It is thought that Aβ monomers makes a minimal contribution to AD pathology, but intravenously infused antibodies encounter abundant amyloid monomer within blood vessels. When an antibody can’t avoid monomer binding in the peripheral vasculature, the antibody is effectively neutralized outside the brain, such that any residual antibody that enters the brain is effectively diluted. This “target distraction” may leave inadequate therapeutic ammunition to neutralize the toxic amyloid oligomers. In the case of two antibodies that showed no benefit in the clinic, Roche’s crenezumab and Eli Lilly’s solanezumab, both had a binding signal to low-molecular weight brain extract in isolation, but when pre-exposed to monomer, that AβO binding disappeared. In contrast, In a recent poster presented at Alzheimer’s Association International Conference (AAIC) in July 2022, a pre-clinical candidate (PMN310) in a head-to-head comparison, showed strong binding to AβOs and no binding to plaque while simultaneously avoiding monomer target distraction. Thus, it appears PMN310 can avoid effective dose dilution by negating monomer distraction and may also reduce ARIA liability due to lack of plaque binding.
Reversing failure: a brighter path ahead
Alzheimer’s disease is one of the largest, most expensive and most vexing drug development challenges of the past three decades. After years of disappointment, lecanemab’s data offers a turning point in AD therapy. The next nine months will bring phase three data readouts from additional promising candidates: Roche’s gantenerumab and Eli Lilly’s donanemab. Based on the data presented, donanemab targets amyloid plaque but appears to reach some oligomers while avoiding monomers. Gantenerumab may be less effective than donanemab and lecanemab because a significant portion of its activity is directed at monomers. However, each should rise and fall on their own merit without casting a shadow over the momentum gained by lecanemab’s success. The CLARITY-AD data is assuredly positive and strongly supports a revised drug development approach that compels development of highly specific monoclonal antibodies that selectively target AβO while avoiding both Aβ monomer and plaque. A drug candidate that does this could support adequate dose levels, avoiding ARIA, and improved efficacy not only through selective targeting of AβO but also by reducing off target binding. Lecanemab has credibly defined the developmental path ahead, and we have good reason to feel optimism about the way forward.