Athira Pharma’s experimental Alzheimer’s drug Phase 2 clinical trial failed and a working theory of why small molecules do not work well with broadly prescribed standards of care therapy. Company executives say the results suggest their drug fosgonimeton may work better as a monotherapy. They need to decide how soon, because a key test is already underway.
The primary goal of the 77-patient Phase 2 test was to show improvement according to P300, a measure of neural electrical activity used to assess how quickly the brain processes information from external stimuli. This is an atypical way of evaluating Alzheimer’s drugs. Bothell, Wash.-based Athira described the 26-week test as a “learning study” to evaluate P300 as a biomarker for Alzheimer’s in a larger patient population and more. for a long time. The Phase 1 study included only 11 Alzheimer’s patients who were evaluated within 8 days.
Phase 2 testing also aims to evaluate fosgonimeton in a way that is closer to the real situation. To achieve this, the trial included some patients already receiving standard Alzheimer’s treatments, such as docepin. The drug and others in its class are acetylcholinease inhibitors (AChEi), which block an enzyme responsible for breaking down a key neurotransmitter whose low levels are linked to Alzheimer’s disease worsening symptoms.
Although the trial failed to meet its primary goal, preliminary data showed encouraging signs compared with placebo in a subgroup of patients who received only fosgonimeton. In addition to the P300 improvement, the results also showed an improvement in the score measured by ADAS-Cog11, a widely used assessment of the severity of cognitive symptoms in people with dementia. The assessment is a more traditional clinical trial measure for Alzheimer’s.
Chief executive Mark Litton said on Wednesday’s conference call that Athira had no reason to think AChEis would affect fosgonimeton. But with encouraging signs in the fosgonimeton-only group, Litton said the company now believes what happened is that AChEis weakened the Athira drug’s effect.
The subgroup of patients that showed improvement was not sufficient to assess statistical significance, but the company believes the improvement shows the potential of Athira’s drug as a monotherapy. When asked why the standard of care affects the investigational drug, Litton acknowledged that the company is still looking for answers.
“It’s a fair question,” Litton said. “We’ve been thinking about it, and it’s a small number. We just don’t know. We’ll take a look at it and hopefully have a better answer the next time we speak.”
Many of the Alzheimer’s drugs in development are antibodies that block amyloid beta, or tau, proteins that build up in patients’ brains. Athira took a different approach to fosgonimeton, A small molecule that can cross the blood-brain barrier and activate hepatocyte growth factor and its receptor MET. These proteins are expressed in the central nervous system. Activating them is designed to spark a repair mechanism that, hopefully, restores neurons and improves overall brain health and function.
Hans Moebius, chief medical officer of Athira, said the analysis of the Phase 2 results is ongoing and will inform the ongoing Phase 3 study if modifications are required. The goal of this pivotal study is to enroll 420 patients with mild to moderate Alzheimer’s disease. So far, with the exception of fosgonimeton, those who received standard-of-care AChEis and those who received only the study drug had evenly split enrollment, Moebius said.
P300 is not a primary or secondary objective of the Phase 3 study. The primary endpoint was to show a change in the composite score of ADAS-Cog11 and another Alzheimer’s assessment. Possible changes in late-stage clinical trials include evaluating fosgonimeton as a monotherapy and comparing it to a placebo, Litton said. He added that Athira will speak with the FDA, clinical trial investigators and the company’s scientific advisors before making any decisions on the trial. The company will try to learn everything from the Phase 2 study before determining if it needs to unravel the blind spots of the clinical trial. Litton said he expected Athira to say more in the coming weeks.
“All options are open and we’re going to explore everything because we really need to figure this out,” he said.
Shares of Athira were hit by the news, falling more than 64% Wednesday morning to $3 a share. Results of fosgonimeton clinical trials are more important than Alzheimer’s disease. Athira’s approach to HGF and MET has potential applications in other neurological diseases. Fosgonimeton is in mid-stage clinical development for Parkinson’s disease, dementia and dementia with Lewy bodies. At the end of the first quarter of this year, Athira reported that it had $301 million in cash, cash equivalents and investments.
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