Acumen Pharmaceuticals (NASDAQ:ABOS) Chief Executive Officer Daniel O’Connell said the company remains focused on advancing its lead Alzheimer’s disease candidate, sabirnetug, as it prepares for a key Phase 2 readout later this year.
Speaking at Bank of America’s Annual Healthcare Conference in Las Vegas, O’Connell described Acumen as a clinical-stage company developing treatments for Alzheimer’s disease. He said sabirnetug is a humanized monoclonal antibody designed to selectively target soluble toxic amyloid beta, or Aβ, oligomers.
Sabirnetug Targets Amyloid Oligomers
Asked by Bank of America analyst Jason Zemansky to explain the rationale for targeting oligomers rather than other amyloid species, O’Connell said amyloid “is not monolithic” and appears in multiple forms and aggregated states.
O’Connell said Aβ monomer is a normal physiological peptide, while aggregated amyloid beta is associated with Alzheimer’s disease pathology. He said soluble aggregates, or oligomers, have been shown over decades to be toxic to synapses and neurons.
According to O’Connell, oligomer toxicity is associated with circuit disruption, synaptic loss, tau hyperphosphorylation and calcium induction into cells, processes he said are involved in initiating and propagating neurodegeneration in Alzheimer’s disease.
By contrast, he said strategies targeting monomer have generally been “safe, but ineffective.” He added that current plaque-directed approaches have generated attention in the field, but Acumen believes an oligomer-directed approach may offer a different path that could improve efficacy and safety relative to plaque-directed therapies.
Company Points to Phase 1 Biomarker Data
O’Connell said Acumen’s INTERCEPT-AD study, a Phase 1 single-ascending-dose and multiple-ascending-dose trial in early Alzheimer’s patients, was designed to evaluate sabirnetug’s safety profile, target engagement and impact on imaging and fluid biomarkers.
He said the study showed robust target engagement and dose-proportional evidence of oligomer engagement, measured by an assay assessing sabirnetug bound to oligomers in patients’ cerebrospinal fluid.
O’Connell said Acumen also observed effects on amyloid PET imaging biomarkers at higher dose levels that were consistent with results shown for lecanemab at a three-month time point. He added that the company saw movement in fluid biomarkers, including the Aβ 42/40 ratio, p-tau181 and p-tau217 in plasma.
He also said the study showed nominal statistical significance at some higher dose levels on synaptic markers neurogranin and VAMP2. O’Connell said the totality of those Phase 1 findings supported Acumen’s decision to advance sabirnetug into Phase 2.
ALTITUDE-AD Readout Expected Later This Year
O’Connell described ALTITUDE-AD as a robust Phase 2 study testing two active doses of sabirnetug against placebo. The doses are 35 mg/kg and 50 mg/kg, administered intravenously every four weeks.
He said the study enrolled 542 patients across five countries and fewer than 80 sites in as little as 10 months. Each cohort includes about 180 subjects.
The trial includes an 18-month placebo-controlled period. O’Connell said the primary outcome is the integrated Alzheimer’s Disease Rating Scale, or iADRS, a composite that includes measures of cognition and function through components of ADAS-Cog and ADCS-ADL.
O’Connell said a “clear win” on the primary endpoint would be around 30% slowing over 18 months in the early Alzheimer’s population being studied. He added that Acumen will also assess Clinical Dementia Rating Sum of Boxes, imaging biomarkers and fluid biomarkers, and said the full dataset will inform next steps for sabirnetug.
He said study conduct has been strong and early terminations have been consistent with company expectations. O’Connell also noted that an open-label extension began enrolling its first patient last November and has seen high conversion from placebo into the extension, with participation in the “upper 90 percentile.”
Enhanced Brain Delivery Program Advances
O’Connell also discussed Acumen’s enhanced brain delivery work, which uses receptor-mediated transcytosis to deliver therapeutic payloads into the brain. He said the program includes sabirnetug and sabirnetug-like antibodies, and is aimed at increasing exposure in the brain and interstitial space.
Acumen is working with JCR Pharmaceuticals, a Japanese company O’Connell described as a pioneer in the field. He said JCR has an approved product using a transferrin-directed enzyme replacement therapy for Hunter syndrome.
O’Connell said Acumen was attracted to the potential for enhanced delivery approaches to improve product profiles through greater efficacy, lower dose requirements, and potentially improved safety and convenience. He said Acumen’s non-human primate work showed 14- to 40-fold elevated drug levels in the cortex compared with an unmodified antibody.
He added that the company is evaluating sabirnetug and another Acumen antibody, ACU-234, as potential payloads. O’Connell said Acumen is close to designating two candidates under its JCR agreement and aims to advance toward a single clinical candidate for an IND filing.
Combination Treatment May Shape Alzheimer’s Field
Addressing broader Alzheimer’s treatment strategy, O’Connell said Acumen believes amyloid beta approaches are likely to remain a cornerstone of treatment for the foreseeable future, including in early Alzheimer’s disease and potentially preclinical populations.
He said the opportunity is expanding due to novel diagnostic technologies, including plasma-based diagnostics. O’Connell also said Alzheimer’s is unlikely to be treated most effectively with monotherapy and that combination strategies may ultimately provide the greatest patient benefit.
Asked about news involving a Biogen tau program, O’Connell said the update sounded potentially encouraging, though he emphasized that more data would be needed. He said clinical validation of a tau strategy has not yet occurred, but evidence that such an approach is on the right path would be a positive development for the field.
About Acumen Pharmaceuticals (NASDAQ:ABOS)
Acumen Pharmaceuticals, Inc is a clinical-stage biopharmaceutical company focused on the discovery and development of oral small molecule therapies for neurodegenerative diseases. Leveraging a proprietary drug discovery platform that integrates chemoproteomics, high-throughput screening and computational chemistry, the company seeks to identify and optimize compounds that selectively modulate pathological protein aggregation. Its approach is designed to address the underlying biology of conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and related proteinopathies.
The company’s pipeline comprises multiple lead candidates at various stages of preclinical and early clinical development.
