Athira Pharma's Phase II/III LIFT-AD trial evaluating fosgonimeton in patients with mild-to-moderate Alzheimer's disease has failed to meet its primary endpoint. The study, which enrolled 312 participants, did not demonstrate a statistically significant improvement in cognition and function compared to placebo after 26 weeks of treatment. The results have led to a significant drop in Athira's stock price.
Trial Details and Results
The Phase II/III LIFT-AD trial (NCT04488419) was a randomized, placebo-controlled, double-blind study assessing the efficacy and safety of fosgonimeton, administered via subcutaneous injection at a dose of 40 mg daily. The primary endpoint was the change from baseline in the Global Statistical Test (GST), a composite measure of cognition (ADAS-Cog11) and function (ADCS-ADL23) at 26 weeks. Key secondary endpoints included individual assessments of cognition (ADAS-Cog11) and function (ADCS-ADL23).
The topline results indicated a -0.08 change in GST favoring fosgonimeton, which was not statistically significant (p=0.70). Similarly, while the fosgonimeton group showed a -1.09 change in ADAS-Cog11 compared to -0.39 in the placebo group (p=0.35), and a 0.65 increase in ADCS-ADL23 versus a -0.02 decline in the placebo group (p=0.61), these differences were not statistically significant.
Subgroup Analysis and Biomarker Data
Despite the overall negative outcome, pre-specified subgroup analyses revealed some encouraging trends. Patients with moderate Alzheimer's disease showed a greater numerical treatment effect in clinical outcomes in the fosgonimeton group compared to placebo, with a delta of -1.16 (p=0.39) in ADAS-Cog11. Additionally, APOE4 carriers in the fosgonimeton group remained stable in cognition, while the placebo group declined, with a delta of -1.07 (p=0.33).
Biomarker data showed consistent directional improvements favoring fosgonimeton over placebo in markers of neurodegeneration (NfL), inflammation (GFAP), and protein pathology (p-Tau181, p-Tau217, and amyloid beta 42/40 ratio). Notably, fosgonimeton treatment reduced plasma levels of pTau217 by -0.12 pg/mL compared to placebo (p<0.01).
Company Perspective
Athira's Chief Medical Officer, Dr. Javier San Martin, suggested that the lack of clinical decline in the placebo group and the short duration of the study may have impacted the trial's ability to demonstrate a meaningful clinical benefit. However, he emphasized that the totality of the data continues to suggest that positive modulation of the HGF pathway has the potential to improve neuronal health and mitigate disease progression.
Athira plans to present the full analyses of the LIFT-AD data at the upcoming Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain.
Fosgonimeton's Mechanism of Action
Fosgonimeton is a prodrug formulation of a small molecule designed to positively modulate the hepatocyte growth factor (HGF)/MET signaling pathway. This mechanism is believed to have neurotrophic and neuroprotective functions, potentially improving neuronal health and slowing neurodegeneration.
Previous Trials and Controversy
This is not the first time fosgonimeton has failed to meet its primary endpoint in clinical trials. A previous Phase II trial also did not meet its primary endpoint. Additionally, Athira has faced controversy regarding data manipulation allegations against its former CEO, which led to a class action lawsuit.
Future Directions
Despite the setback, Athira is continuing to develop other compounds, including ATH-1105, an orally administered HGF modulator currently in Phase 1 trials for ALS and other neurodegenerative diseases. The company remains committed to exploring the potential of HGF modulation in treating neurological disorders.
