A daily injection intended to protect and regenerate brain cells has failed to slow the progression of Alzheimer’s disease in a Phase 2/3 clinical trial run by Athira Pharma, the company announced Tuesday.
The drug, fosgonimeton, didn’t meet any of the company’s primary or secondary endpoints in a 26-week study of 549 patients with mild-to-moderate dementia. Plans for a larger follow-up study have been scrapped.
Mark Litton“We’re just assessing what is the best way to move forward with this biology,” CEO Mark Litton told Endpoints News in an interview.
The Bothell, WA-based biotech had about $75 million at the end of August, enough to keep it running until the end of 2025 “under certain scenarios,” Litton said. The company had a valuation of about $108 million at market close on Tuesday, but its stock $ATHA fell 75% after hours.
While most Alzheimer’s drugs have focused on reducing amyloid or tau, the two proteins most strongly linked to dementia, Athira was working on a different protein called hepatocyte growth factor, or HGF. The protein was discovered in the liver but was later found to be vital for neuronal development and survival.
Athira’s drug binds to HGF receptors and enhances the growth factor’s activity. In preclinical studies, fosgonimeton showed that it helps neurons make more connections and may even protect brain cells from injury. It also shuts down inflammation and enhances autophagy, a cellular housecleaning process that removes bad proteins like amyloid and tau.
Replicating those benefits in people has proven more challenging. The drug already failed a previous clinical test, which the company blamed on the fact that many patients were taking existing Alzheimer’s drugs called acetylcholinesterase inhibitors, even though most doctors believe the drugs only have marginal effects on symptoms of the disease.
While Athira enrolled nearly 550 patients in its new study, Tuesday’s results are based on data from just 287 participants. The company excluded people who were on the other Alzheimer’s drugs that foiled its earlier study. It also excluded patients who got the larger of two doses, which it stopped testing due to more frequent injection site reactions — the drug’s most prevalent side effect.
The drug was no better than placebo at slowing the disease, as measured by a cognitive test called the ADAS-Cog11 and a functional test called ADCS-ADL23. The drug also failed to significantly change most key biomarkers including neurofilament and amyloid beta, but did lower a form of tau increasingly linked to Alzheimer’s disease.
The company said that the drug had slightly bigger effects in subgroups of people with moderate dementia and in people carrying at least one copy of the APOE4 gene linked to the disease. But in all cases, the outcomes between those who got the drug and those who got a placebo were not statistically significant.
Despite the trial’s failure, the company isn’t ready to give up on targeting HGF just yet. It’s already testing an oral alternative to fosgonimeton, ATH-1105, in healthy volunteers, with plans to test the compound in ALS patients in 2025. Litton said that it could potentially be tested in Alzheimer’s patients too.
“This is the first proof of concept with enhancing HGF, and we truly believe that it’s neuroprotective and should play a role in helping diseases with neurodegeneration,” Litton said.