8-K: Athira Pharma's LIFT-AD Trial Fails Primary Endpoint, Shows Promise in Subgroups

Athira Pharma's Phase 2/3 LIFT-AD trial for fosgonimeton in Alzheimer's disease did not meet its primary endpoint, but showed positive trends in certain patient subgroups and biomarkers.

Summary

• Athira Pharma announced topline results from its Phase 2/3 LIFT-AD clinical trial of fosgonimeton for mild-to-moderate Alzheimer's disease.
• The trial did not meet its primary endpoint, the Global Statistical Test (GST), which combines measures of cognition and function.
• Key secondary endpoints, including cognition (ADAS-Cog11) and function (ADCS-ADL23), also did not reach statistical significance.
• However, both cognition and function components of the GST showed directional improvements favoring fosgonimeton.
• In pre-specified subgroups of patients with moderate Alzheimer's or who are APOE4 carriers, fosgonimeton showed a numerically greater treatment effect.
• Biomarkers associated with Alzheimer's disease pathology showed changes with fosgonimeton treatment consistent with the neuroprotective mechanism of HGF modulation.
• The company's cash resources are estimated to be approximately $75.1 million as of August 31, 2024.
• The company is also developing ATH-1105, a next-generation, orally administered drug candidate for neurodegenerative diseases, with a Phase 1 trial expected to complete by year-end 2024.

Sentiment

Score: 4

Explanation: The document presents mixed results. While the primary endpoint was missed, there are positive signals in subgroups and biomarkers. The overall sentiment is cautiously optimistic but tempered by the trial's failure to meet its main goal.

Positives

• Fosgonimeton showed a numerically greater treatment effect in pre-specified subgroups of patients with moderate Alzheimer's disease or who are APOE4 carriers.
• Biomarkers of protein pathology, inflammation, and neurodegeneration showed directional improvements with fosgonimeton treatment.
• Fosgonimeton treatment reduced plasma levels of pTau217, a hallmark of AD, by -0.12 pg/mL compared to placebo (p<0.01).
• Fosgonimeton was generally well tolerated with a favorable safety profile.
• The company is advancing ATH-1105, a next-generation, orally administered drug candidate for neurodegenerative diseases.

Negatives

• The LIFT-AD trial did not meet its primary endpoint of the Global Statistical Test (GST).
• Key secondary endpoints of cognition (ADAS-Cog11) and function (ADCS-ADL23) also did not reach statistical significance.
• The study had a 22 percent early termination rate.
• Participants treated with fosgonimeton showed a higher incidence of treatment emergent adverse events compared to placebo, mainly driven by injection site reactions.

Risks

• The LIFT-AD trial failed to meet its primary endpoint, raising questions about the efficacy of fosgonimeton in the broader Alzheimer's population.
• The higher incidence of treatment emergent adverse events, particularly injection site reactions, could impact patient compliance and acceptance.
• The 22% early termination rate could indicate issues with the treatment or trial design.
• The company's cash resources of $75.1 million may not be sufficient to fund further development of fosgonimeton and other pipeline candidates.
• The forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially.

Future Outlook

Athira plans to continue evaluating ATH-1105 in neurodegenerative diseases, with a goal to be in ALS patients in 2025. The company will also present a full analysis of the LIFT-AD results at the CTAD conference in late October/early November 2024.

Management Comments

• Javier San Martin, M.D., Chief Medical Officer of Athira, stated that the lack of clinical decline in the placebo group and the short duration of the study may have impacted the trial's ability to show meaningful clinical benefit.
• Anton P. Porsteinsson, M.D., a LIFT-AD investigator, noted that the biomarker and subgroup data are intriguing and consistent with the understanding of fosgonimeton's neuroprotective mechanism of action.
• Mark Litton, Ph.D., President and Chief Executive Officer of Athira, stated that the company has a pipeline of next-generation, orally delivered HGF modulators and expressed appreciation for the patients, caregivers, and healthcare professionals who participated in the LIFT-AD trial.

Industry Context

The results of the LIFT-AD trial are being released in a competitive landscape for Alzheimer's treatments, where many companies are pursuing different approaches. While the primary endpoint was not met, the positive trends in subgroups and biomarkers may provide a basis for further research and development of HGF modulators.

Comparison to Industry Standards

• The failure to meet the primary endpoint is a setback compared to some recent successes in Alzheimer's drug development, such as lecanemab (Leqembi) which showed a statistically significant slowing of cognitive decline.
• However, the positive biomarker data and subgroup analysis are similar to other trials that have shown promise in specific patient populations, such as those with early-stage disease or specific genetic markers.
• The safety profile of fosgonimeton appears to be generally favorable, which is important given the safety concerns associated with some other Alzheimer's treatments.
• The company's focus on HGF modulation is a unique approach compared to the more common amyloid-targeting strategies, and the results may provide valuable insights into alternative treatment pathways.

Stakeholder Impact

• Shareholders may react negatively to the failure of the LIFT-AD trial to meet its primary endpoint.
• Patients and caregivers may be disappointed by the lack of significant clinical benefit in the overall study population.
• Employees may be affected by the uncertainty surrounding the future of fosgonimeton development.
• The positive trends in subgroups and biomarkers may provide some hope for future development of HGF modulators.

Next Steps

• Athira will present a full analysis of the LIFT-AD results at the CTAD conference.
• The company will continue to evaluate ATH-1105 in neurodegenerative diseases.
• Athira plans to advance ATH-1105 into ALS patients in 2025.

Key Dates

Keywords

Alzheimer's disease, fosgonimeton, clinical trial, LIFT-AD, neurodegeneration, biomarkers, HGF modulation, ATH-1105, cognition, APOE4, pTau217