Targeting beta amyloid oligomers

Four compounds show promise against Alzheimer’s

November25th,2020
Ilene Schneider

FRAMINGHAM, Mass.—“The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials,” explained an article in Alzheimer’s Research & Therapy entitled “Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval.”

The article—authored by Alzheon Inc., a clinical-stage biopharmaceutical company focused on developing new medicines for patients suffering from Alzheimer’s disease (AD) and other neurodegenerative disorders—covered work that “evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles.” The four agents assessed in this study have the potential for near-term approval, according to the article. Aducanumab, gantenerumab and BAN2401 are injectable antibodies, while Alzheon’s ALZ-801 is a small-molecule oral agent.

These treatments have progressed to late-stage clinical trials for Alzheimer’s disease, in spite of clinical trial failures across the class of amyloid-targeted drugs in AD. The article discusses the clinical and biomarker evidence for each of the four agents, which engage neurotoxic amyloid oligomers to various degrees, a mechanism shown to be a key driver of AD pathology and clinical progression. The authors analyze the pharmacological properties of each treatment, including selectivity for amyloid oligomers, plasma half-life, brain penetration and time to peak brain exposure. They explain the clinical efficacy, biomarker effects, benefit and risk profile, and ease of administration for each of the agents.

Aducanumab, a human monoclonal antibody that has been studied for the treatment of Alzheimer’s disease, was developed by Biogen Inc., which licensed the drug candidate from Neurimmune. Aducanumab works to reduce the buildup of aggregated forms of beta-amyloid found in the brains of people with Alzheimer’s disease. The compound showed significant efficacy in the reanalysis of the EMERGE Phase 3 trial in early AD, while the ENGAGE Phase 3 trial was negative, according to the article in Alzheimer’s Research & Therapy. The article related that, “The highest dose of 10 mg/kg monthly IV infusions showed significant effects on the primary outcome, the cognitive and functional composite measure Clinical Dementia Rating—Sum of Boxes (CDR-SB), and on the cognitive endpoint Alzheimer’s Disease Assessment Scale—cognitive subscale (ADAS-cog). While both Phase 3 trials were stopped for futility after an interim analysis, the positive final analysis in the EMERGE trial was supported by significant biomarker effects on phosphorylated tau (p-tau) in CSF and on tau PET imaging.”

BAN2401, a potential immunotherapy for Alzheimer’s disease jointly developed by Biogen and Eisai, consists of a monoclonal antibody against a form of beta-amyloid protein that accumulates in the brain of people with Alzheimer’s disease. The article reported that, “In a large Phase 2 trial in early AD, BAN2401 demonstrated significant efficacy at the highest dose, 10 mg/kg IV infusion twice per month. BAN2401 showed significant and clinically meaningful effects on the primary outcome, the Alzheimer’s Disease Composite Score (ADCOMS) and the ADAS-cog, which were larger in APOE4 carriers. BAN2401 also showed significant effects on CSF p-tau and on downstream markers of neuronal injury (neurofilament light chain, NfL) and synaptic integrity (neurogranin).”

Gantenerumab, a monoclonal antibody for the treatment of Alzheimer’s disease being developed by Hoffmann-La Roche pharmaceuticals, binds to and clears aggregated beta-amyloid fibers. In Phase 3 studies in prodromal and early AD, the drug candidate showed no clinical efficacy at 225 mg and 1200 mg doses administered monthly by subcutaneous (SC) injection, while significant effects on CSF p-tau and total tau (t-tau, marker of neuronal injury) were reported.

“A recently completed study in familial AD, led by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), enrolled approximately 50 subjects into each of placebo, solanezumab, and gantenerumab arms for 4 years of treatment,” the authors explained. “This study used the higher dose of 1200 mg monthly SC injection of gantenerumab that has shown acceptable long-term safety [20]. At this dose, gantenerumab showed significant effects on CSF p-tau, t-tau, and NfL at 4 years in the familial AD population, but no clinical efficacy.”

ALZ-801, developed by Alzheon, received Fast Track designation from the U.S. Food and Drug Administration in 2017. It is an optimized prodrug of tramiprosate, which consists of tramiprosate conjugated to the essential amino acid valine, providing improved gastrointestinal tolerability and more consistent plasma levels that lead to increased brain penetration. According to the study authors, “Tramiprosate, the active agent in ALZ-801, was evaluated in a Phase 3 study of mild to moderate AD that enrolled all APOE genotypes and did not show efficacy in the overall study population. Subgroup analyses showed clinical efficacy in the high-risk APOE4 carriers. At the high dose, tramiprosate showed significant efficacy on both the ADAS-cog and CDR-SB co-primary outcomes in homozygous APOE4/4 subjects with mild AD [31]. In addition, a dose-dependent preservation of hippocampal volume was observed in the MRI sub-study [32], further supporting a disease-modifying effect of ALZ-801/tramiprosate treatment.”

Dr. Martin Tolar, founder, president and CEO of Alzheon, summarized, “We are entering a new era of drug development for Alzheimer’s disease, with high probability of meeting the goal of bringing effective treatments to patients before the United States NIH’s National Alzheimer’s Plan target date of 2025. The groundbreaking work by Biogen and BioArctic/Eisai to develop injectable anti-amyloid antibodies with enhanced specificity for neurotoxic soluble amyloid oligomers has resulted in late-stage clinical candidates with promising efficacy signals and potential for near-term approval. The research team at Alzheon has built upon this work to demonstrate that our lead oral drug candidate, ALZ-801, works by inhibiting the oligomerization of beta amyloid protein that drives the downstream pathology and cognitive decline in Alzheimer’s disease. This positions ALZ-801 to potentially become the first oral disease-modifying agent for patients and healthy people at high risk for Alzheimer’s disease.”

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