Fosgonimeton Fails to Reach End Points, but Shows Mechanistic Potential in Alzheimer Disease

After 26 weeks of treatment, those on fosgonimeton alone without acetylcholinesterase inhibitors showed a potentially beneficial change in event-related potential P300 latency, an outcome of working memory processing speed.

Topline results from the exploratory phase 2 ACT-AD study (NCT04491006) showed that fosgonimeton (Athira Pharmaceuticals), a small molecule Hepatocyte Growth Factor (HGF) and MET enhancer previously known as ATH-1017, did not meet its primary or secondary end points in patients with mild-to-moderate Alzheimer disease (AD) when used with standard-of-care acetylcholinesterase inhibitors (AChEIs); however, the agent did show meaningful differences when used as a monotherapy.1

After 26 weeks, treatment with fosgonimeton monotherapy showed a potentially beneficial change of –28 milliseconds in event-related potential (ERP) P300 latency, the primary end point assessing working memory processing speed. Additionally, this group also demonstrated cognitive improvements, as represented by changes of –3.3 points on the Alzheimer’s Disease Assessment Scale-Cognitive 11 (ADAS-Cog-11), a secondary end point. Athira plans to present the full results at the upcoming Alzheimer’s Association International Conference, held July 31 to August 4.

"These data points are very encouraging as they indicate the expected pharmacological activity of fosgonimeton by parallel improvement on ERP P300 latency and ADAS-Cog11 and show a favorable safety profile over 6 months. This is the first-time monotherapy fosgonimeton has shown an effect on ADAS-Cog11, suggesting a potential cognitive benefit,” Hans Moebius, MD, PhD, chief medical officer, Athira, said in a statement.1 "We will use these insights for a rational optimization of the ongoing LIFT-AD trial. We plan to seek advice from our scientific advisors, investigators, and ultimately regulators, on how to expeditiously analyze and potentially adapt the LIFT-AD study."

The double-blind, placebo-controlled, parallel-group trial enrolled 77 patients with mild-to-moderate AD, with 60% of the cohort who continued on stable doses of AChEIs with fosgonimeton. Eligible participants aged 55 to 85 years with Clinical Dementia Rating scale scores of 1 or 2, were randomly assigned 1:1:1 to receive placebo or fosgonimeton at either 40 mg/day or 70 mg/day. The study was only powered to show statistical significance for change in ERP P300 latency, the primary end point.

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In the modified intent-to-treat population, mixed model repeated measures analysis of the pooled 40 mg and 70 mg dose groups showed a change of –6.02 milliseconds in ERP P300 latency, which was not significant. Secondary end points, including ADAS-Cog11, Alzheimer’s Disease Cooperative Study-Clinical Impression of Change (ADCS-CGIC), and ADCS-Activities of Daily Living (ADL23), were not significant in fosgonimeton-treated individuals compared with placebo at 26 weeks.

"The data from the fosgonimeton monotherapy analysis are encouraging and show biologic activity that may support the potential role of the HGF/MET pathway in neurodegenerative diseases," Marwan Sabbagh, MD, FAAN, professor of neurology, Barrow Neurological Institute, said in a statement.1 "ACT-AD adds to the body of literature suggesting ERP P300 latency as an important biomarker for cognitive status."

Fosgonimeton showed a safe profile, with no treatment-related serious adverse events (AEs) or deaths observed. There was a higher incidence of treatment-emergent AEs observed in the active drug compared with placebo throughout the study period. The most frequent AE was injection site reaction, sometimes associated with transient and asymptomatic increases in absolute eosinophil count.

The safety and tolerability of fosgonimeton was previously demonstrated in a phase 1 clinical trial (NCT03298672) of 88 patients, including 48 healthy young men in a single ascending dose cohort, 29 healthy elderly volunteers in a multiple ascending dose cohort, and 11 patients with AD in a fixed-dose cohort. Across all doses, the therapeutic was safe and well-tolerated, and pharmacokinetic results were dose-proportional, with no sex effect or accumulation over 9 days. Compared with placebo, fosgonimeton demonstrated a statistically significant effect toward ERP P300 latency normalization (40-mg fosgonimeton: n = 7; placebo: n = 4; P = .027).2

"As planned, the ACT-AD study results have provided us with important insights that we will use to inform our ongoing LIFT-AD study, which is enrolling mild-to-moderate AD patients. We are encouraged by these data as they show more than just biologic activity; although a small sample size, they suggest a potentially beneficial treatment effect as a monotherapy that in the ACT-AD study was similar to standard-of-care with a favorable safety profile," Mark Litton, PhD, president and chief executive officer, Athira, said in a statement.1

REFERENCES
1. Athira Pharma announces topline results from ACT-AD phase 2 proof-of-concept study of fosgonimeton in mild-to-moderate Alzheimer disease. News release. Athira Pharma. June 22, 2022. Accessed June 22, 2022. https://www.globenewswire.com/news-release/2022/06/22/2466956/0/en/Athira-Pharma-Announces-Topline-Results-from-ACT-AD-Phase-2-Proof-of-Concept-Study-of-Fosgonimeton-in-Mild-to-Moderate-Alzheimer-s-Disease.html
2. Athira Pharma announces publication of phase 1 results for fosgonimeton (ATH-1017) in the Journal of Alzheimer’s Disease. News release. Athira Pharma. February 22, 2022. Accessed June 22, 2022. https://finance.yahoo.com/news/athira-pharma-announces-publication-phase-120000034.html