Athira Pharma has released topline data from the Phase II/III LIFT-AD trial of its lead Alzheimer’s disease therapy, fosgonimeton.

The results show that the study failed to meet its primary and key secondary endpoints, as well as to show a statistically significant improvement in both cognition and function compared to placebo.

Athira Pharma’s chief medical officer Javier San Martin, pointed to “the lack of clinical decline in the placebo group” and “short duration of the study” as the possible reasons for trial failure.

The news had a devastating impact on Athira’s stock; it was down by almost 72% in premarket trading today (4 September). The company, however, was not deterred and noted the “totality of the data continues to suggest that positive modulation of the HGF pathway has the potential to translate into improvement in parameters of neuronal health and may mitigate disease progression”.

Athira was particularly encouraged by the biomarker and subgroup data, which the trial’s principal investigator noted as “intriguing and remarkably consistent not only across endpoints but also with our understanding of fosgonimeton’s neuroprotective mechanism of action”. The two subgroups that showed improvement in cognition with fosgonimeton, compared to placebo at 26 weeks, were those with the highest baseline ADAS-Cog11 (>30) scores and those with moderate dementia.

Fosgonimeton is a prodrug formulation of a small molecule, fosgonimeton-active metabolite, which plays a part in the positive modulation of HGF/MET signalling. The therapy, therefore, may have neurotrophic and neuroprotective functions.

The therapy has been marred by controversy since 2021, when reports emerged that Athira’s then-CEO Leen Kawas “altered images” that were part of her doctoral thesis, and the company used the “tainted Western blot images” to obtain a US National Institutes of Health (NIH) grant to start a Phase II trial of fosgonimeton. The reports also resulted in a class action lawsuit against the company on behalf of the shareholders.

The proof-of-concept Phase II trial (NCT04491006) of fosgonimeton in patients with mild to moderate Alzheimer’s then failed to meet the study’s primary endpoint. After that, the company pointed to the therapy’s success in a subgroup analysis and started the Phase III trial.

The placebo-controlled Phase II/III LIFT-AD trial (NCT04488419) enrolled 312 participants with mild to moderate Alzheimer’s disease. The study’s primary endpoint was the change from baseline after 26 weeks of treatment using the Global Statistical Test (GST), a combination of results from measures of cognition (ADAS-Cog11) and function (ADCS-ADL23). Athira noted that detailed results will be presented at the 17th Annual Clinical Trials on Alzheimer’s Disease, which will take place in October in Spain.