Athira Pharma’s tumultuous journey to phase 2/3 Alzheimer’s disease data has ended in failure. The trial found fosgonimeton was no better than placebo on the primary and key secondary endpoints, driving investors to cut the cord holding up the biotech’s stock price.
Washington-based Athira burst onto the scene in 2020, raising an $85 million series B round and pulling off a $204 million in quick succession. The honeymoon was short-lived. In 2021, Leen Kawas, then the CEO of Athira, was accused of altering images in multiple papers. Kawas was gone later that year. In 2022 and 2023, the biotech reported phase 2 failures in Alzheimer’s and dementia.
The phase 2/3 study offered Athira a chance to radically improve perceptions of fosgonimeton. The trial didn’t deliver that boost. Rather, the results sent Athira’s share price down 73% to $0.76 in premarket trading, well below the slump following the Kawas scandal, let alone the post-IPO high of over $30.
Investors fled the stock after Athira failed to make the case that fosgonimeton can improve outcomes in Alzheimer’s by modulating HGF to promote neuron proliferation and survival. Athira designed the trial to compare the effect of 26 weeks of once-daily subcutaneous fosgonimeton injections to placebo in 312 people with mild to moderate Alzheimer’s who weren’t taking acetylcholinesterase inhibitors.
Fosgonimeton was no better than placebo on the Global Statistical Test, a measure that combined scores on assessments of cognition, ADAS-Cog11, and function, ADCS-ADL23. The result caused the trial to miss its primary endpoint. Fosgonimeton failed to beat placebo on ADAS-Cog11 or ADCS-ADL23.
However, Athira said ADAS-Cog11 and ADCS-ADL23 “directionally favored fosgonimeton treatment,” with a nonsignificant difference of 0.70 on the cognition scale and 0.67 on the function score. The divergence between the treatment and placebo groups was most pronounced in prespecified subgroups of patients who were expected to progress faster, namely those with moderate disease and APOE4 carriers.
Javier San Martin, M.D., chief medical officer at Athira, said in a statement that “the lack of clinical decline in the placebo group, combined with the short duration of the study, may have impacted the trial’s ability to translate the effect of fosgonimeton.” Talking on a webinar in June, Athira CEO Mark Litton said historically ADAS-Cog11 and ADCS-ADL23 scores decline about two points in six months.
The lack of that level of decline in the placebo cohort led Athira to run post hoc analyses in patients with worse cognition at baseline for signs of efficacy. Athira argued the totality of the data suggests positive modulation of HGF signaling may work in neurodegenerative diseases. The validity of that position has implications for ATH-1105, a HGF modulator Athira is developing in amyotrophic lateral sclerosis.