Athira Pharma, Inc. announced an update to its plans for the ongoing LIFT-AD clinical trial of fosgonimeton (ATH-1017), a small-molecule positive modulator of the HGF/MET neurotrophic factor system, in patients with mild-to-moderate Alzheimer's disease (AD). The completed, exploratory ACT-AD study was designed to better understand fosgonimeton's effect on biomarkers, psychometric measures and safety over six months as well as to inform the larger ongoing LIFT-AD study in the same mild-to-moderate AD population. Study results from ACT-AD suggested positive effects on measures of cognition, function and neurodegeneration in patients taking fosgonimeton alone without background acetylcholinesterase inhibitors (AChEIs) during the study period.

Leveraging these results, the company will amend the LIFT-AD trial to investigate the effects of fosgonimeton compared with placebo, without background AChEIs. The overall design of LIFT-AD remains unchanged, including the Global Statistical Test as the primary endpoint. An independent, unblinded interim analysis will be conducted to inform the required sample size needed to appropriately power the primary endpoint in the target patient population.

ACT-AD was an exploratory, randomized, double-blind, placebo-controlled, parallel-group 26-week trial evaluating fosgonimeton compared to placebo in patients with mild-to-moderate Alzheimer's disease. The study enrolled 77 patients in the United States and Australia (age 55 to 85 years, Mini-Mental State Exam (MMSE) score of 14-24 and Clinical Dementia Rating (CDR) scale global score of 1 or 2). Patients were allowed to continue receiving AChEIs; 60% remained on stable doses of AChEIs and 40% were not receiving AChEIs during the study.

Patients were randomized 1:1:1 to receive placebo or fosgonimeton at either 40 mg/day or 70 mg/day. The primary endpoint for ACT-AD was Event-Related-Potential (ERP) P300 Latency, a functional measure of working memory processing speed. Secondary endpoints included ADAS-Cog11, a measure of cognition; ADCS-CGIC, a measure of global clinical change; and ADCS-ADL23, a measure of functional change.

Safety data were evaluated throughout. As previously reported, the ACT-AD study did not meet the primary endpoint of a statistically significant change in ERP P300 latency. However, the data showed a numerical improvement in the functional measure of ADCS-ADL23, which evaluates patients' activities of daily living as assessed by their caregivers, compared to placebo at 26 weeks (+2.12 points, n.s.).

Additional analyses of the data from patients treated with fosgonimeton alone suggested a potentially beneficial change in ERP P300 latency (-28 milliseconds, n.s.), as well as cognitive improvement, as measured by ADAS-Cog11 (-3.3 points, n.s.), compared with placebo at 26 weeks. Among patients treated with fosgonimeton alone, there was a statistically significant improvement of plasma Neurofilament light Chain (NfL), a validated fluid biomarker of neurodegeneration, (6.89 pg/ml, p=0.018). These encouraging findings further support the decision to focus the ongoing clinical evaluation on fosgonimeton alone without background AChEIs.

Athira reports that, to date, more than 90% of patients completing the ACT-AD and LIFT-AD studies have elected to participate in the ongoing open label extension study. The ACT-AD trial was supported by a grant from the National Institute on Aging of the National Institutes of Health under Award Number R01AG06268. LIFT-AD is a randomized, double-blind, placebo-controlled, parallel-group study of fosgonimeton for patients with mild-to-moderate Alzheimer's disease.

The study has enrolled more than 300 patients in the United States, with enrollment ongoing. Patients are randomized across two dose groups and one placebo group on a 1:1:1 basis to receive a subcutaneous injection of fosgonimeton or placebo once daily over a treatment course of 26 weeks. The primary endpoint for LIFT-AD will be measured by the Global Statistical Test, which is a mathematical algorithm combining the scores from cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog11]), and function (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL23]).

Additional information on the study can be found at: NCT04488419. Fosgonimeton is a small molecule designed to enhance the activity of hepatocyte growth factor (HGF) and its receptor, MET, to impact neurodegeneration and regenerate brain tissue. The function of the HGF/MET receptor system may be impaired in the brain under conditions of neurodegeneration.

In addition to Alzheimer's disease, fosgonimeton has the potential to address the broader dementia population, including Parkinson's disease dementia and Dementia with Lewy bodies, as the mode of action focuses on network recovery and synaptic signal transmission in the brain.