Athira Pharma’s Phase 2/3 Alzheimer’s disease trial has ended in failure. The trial revealed that fosgonimeton performed no better than a placebo for the primary and several key secondary outcomes.
Athira, a Washington-based company, entered the market in 2020, raising $85 million in a Series B round followed by $204 million in quick succession. In 2021, Athira’s former CEO, Leen Kawas, was convicted of manipulating images in several scientific papers. Kawas left the company later that year amidst allegations of drug trafficking, which were linked to his death. In both 2022 and 2023, Athira experienced phase 2 failures in Alzheimer’s and dementia trials.
The Phase 2/3 study was supposed to reshape perceptions of fosgonimeton, but the much-needed positive results never materialized. Instead, the failure led to a 73% drop in the company’s share price, which fell to $0.76 in premarket trading—well below the lowest level seen after the Kawas scandal and far from the IPO peak of over $30.
Investors reacted by selling off shares after Athira failed to demonstrate that fosgonimeton could improve Alzheimer’s symptoms through hepatocyte growth factor (HGF) signaling, which is thought to promote neuron production and survival. The trial involved 312 outpatients with mild to moderate Alzheimer’s who were not receiving acetylcholinesterase inhibitors, and it compared 26 once-daily subcutaneous fosgonimeton injections to a placebo.
Fosgonimeton did not outperform the placebo on another key measure, the Global Statistical Test, which sums the scores from the ADAS-Cog11 (cognitive function) and the ADCS-ADL23 (daily living function). This meant that the trial failed to meet its primary endpoint, as fosgonimeton showed no significant improvement over the placebo on either the ADAS-Cog11 or ADCS-ADL23 scales.
However, Athira noted that ADAS-Cog11 and ADCS-ADL23 results “directionally favored fosgonimeton treatment,” though the differences were not statistically significant. Fosgonimeton had an impact of 0.70 on the cognition scale, while another score showed a 0.67 impact on function. The gap between the treatment and placebo groups was more pronounced in a prespecified subgroup of patients who were expected to progress more rapidly—those with moderate disease and carriers of the APOE4 gene.
Athira’s Chief Medical Officer, Javier San Martin, commented that the lack of clinical decline in the placebo group and the short duration of the trial may have hindered the ability to demonstrate fosgonimeton’s effect on the two parameters, which typically worsen by two points over six months, based on ADAS-Cog11 and ADCS-ADL23 scores.
The absence of decline in the placebo group led Athira to conduct post-hoc analyses in patients with worse baseline cognition for potential signs of efficacy. Athira suggested that positive modulation of HGF signaling could benefit neurodegenerative diseases cumulatively. This finding holds relevance for ATH-1105, an HGF modulator Athira is developing for the treatment of amyotrophic lateral sclerosis (ALS).
