Athira Pharma’s stock plunged by 75% after the company announced that its Phase 2/3 LIFT-AD clinical trial for its experimental Alzheimer’s drug, fosgonimeton, failed to meet primary and key secondary endpoints. This significant drop reflects investor concern over the future of the company’s approach to treating neurodegenerative diseases, particularly Alzheimer’s. The trial aimed to demonstrate the efficacy of fosgonimeton, a hepatocyte growth factor (HGF) modulator, in slowing cognitive decline in patients with mild to moderate Alzheimer’s disease. However, the results showed no statistically significant improvement in patients compared to those who received a placebo.

Trial results disappoint investors

The LIFT-AD trial, which lasted 26 weeks, was designed to assess changes in cognition and daily functioning using the Global Statistical Test (GST), which combines measures of cognition (ADAS-Cog11) and function (ADCS-ADL23). The results of the trial showed that neither the primary endpoint nor the secondary endpoints reached statistical significance. This outcome has raised doubts about the drug’s effectiveness and led to a sharp decline in Athira Pharma’s stock, reflecting widespread investor disappointment.

Athira Pharma’s management indicated that the trial’s inability to meet its endpoints might have been influenced by the use of acetylcholinesterase inhibitors (AChEIs) by some patients in the trial. These drugs, which are the standard treatment for Alzheimer’s, may have interfered with the action of fosgonimeton. Athira Pharma CEO Mark Litton suggested that fosgonimeton might be more effective as a monotherapy, without the interference of standard Alzheimer’s treatments.

Potential for phase 3 adjustments

Despite the setback, the trial data did show some promising results in certain patient subgroups. Patients with more advanced Alzheimer’s disease and carriers of the APOE4 gene showed signs of cognitive stability or improvement when treated with fosgonimeton. This has led Athira Pharma to consider adjustments to their ongoing Phase 3 trial, potentially focusing on fosgonimeton as a monotherapy. The company plans to consult with the U.S. Food and Drug Administration (FDA), clinical trial investigators, and scientific advisors to determine the best path forward.

The biomarker data from the LIFT-AD trial also pointed to potential benefits, as changes in neurodegeneration markers like p-Tau217 were consistent with fosgonimeton’s proposed neuroprotective mechanism. This data provides some hope that the drug could still play a role in treating Alzheimer’s if the right patient population and treatment conditions are identified.

Expert opinion on trial failure and future prospects

Experts believe that while the failure to meet primary and secondary endpoints is a setback, it is not uncommon in Alzheimer’s drug development due to the complex nature of the disease and the challenges of designing effective clinical trials. The failure underscores the difficulties of developing new treatments for Alzheimer’s and the importance of tailoring trials to identify the most responsive patient populations.

Athira Pharma’s unique approach to targeting the HGF/MET pathway distinguishes it from other Alzheimer’s drugs that primarily focus on beta-amyloid or tau protein buildup. This method, which aims to stimulate neuronal repair and improve brain function, continues to be a compelling area of research. With $301 million in cash reserves as of early 2024, Athira Pharma is well-positioned financially to continue its development efforts and potentially pivot its trial strategy to focus on the drug’s potential as a monotherapy.

What’s next for Athira pharma

Looking ahead, Athira Pharma will need to analyze the LIFT-AD trial data thoroughly and decide whether to modify its ongoing Phase 3 study, which is currently enrolling patients. Potential changes could include focusing exclusively on fosgonimeton as a monotherapy to avoid the confounding effects of AChEIs. The company remains committed to its broader pipeline, including the development of ATH-1105 for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. The outcome of these efforts will be crucial for rebuilding investor confidence and determining the future of Athira’s innovative approach to neurodegenerative disease treatment.

  Alzheimer’s Disease, amyotrophic lateral sclerosis, APOE4 gene, Athira Pharma, beta-amyloid, Fosgonimeton, hepatocyte growth factor, Javier San Martin, Mark Litton, tau protein, U.S. Food and Drug Administration