Synaptic Agent Fosgonimeton Falls Short in Phase 2/3 LIFT-AD Trial of Mild-to-Moderate Alzheimer Disease

Newly announced topline data from the phase 2/3 LIFT-AD trial (NCT04488419), a study assessing Athira Pharma’s fosgonimeton, showed that the agent failed to meet its primary end point of change on the Global Statistical Test (GST) in patients with mild-to-moderate Alzheimer disease (AD); however, it did show numerically greater treatment effect in patients who were apolipoprotein e4 (APOE) carriers.¹

The company plans to present the full analyses of these data at the upcoming Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29-November 1, in Madrid, Span. All told, treatment with once-daily subcutaneous injections of fosgonimeton (40 mg) led to a –0.08 change in GST over a 26-week period favoring active drug; however, this did not reach statistical significance (P = .70). Overall, fosgonimeton was considered generally well tolerated, with a favorable safety profile and an incidence of serious adverse events (AEs) that was similar to those on placebo.

"These are not the results we hoped for, as 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 treatment into meaningful clinical benefit," Javier San Martin, MD, chief medical officer at Athira, said in a statement.¹ "However, we believe the totality of the data continues to suggest that positive modulation of the HGF pathway has the potential to translate into improvement in parameters of neuronal health and may mitigate disease progression."

Fosgonimeton is a prodrug formulation of a small molecule originally identified in a screen for positive modulators of human growth factor (HGF)/MET signaling. LIFT-AD, which began originally as a phase 2 study and was reclassified to phase 2/3, included 312 patients with mild-to-moderate AD not on acetylcholinesterase inhibitors (AChEIs). The primary end point, the GST, is a combination of results from measures of cognition like the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) and function, like the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL23).

After 26 weeks of treatment, patients on fosgonimeton demonstrated a –1.09 change in ADAS-Cog11, an assessment of cognition, compared with changes of –0.39 for those on placebo (P = .35). In addition, fosgonimeton-treated patients showed an improvement of 0.65 points on ADCS-ADL23 vs a decline of –0.02 observed in placebo, although this difference was not statistically significant (P = .61).

In terms of biomarkers, investigators observed nonsignificant, but consistent directional improvements in markers of neurodegeneration (neurofilament light), inflammation (glial fibrillary acidic protein), and protein pathology (phosphorylated tau181 [p-tau], p-tau217, and amyloid-ß 42/40 ratio) over the 26-week treatment period. Of note, those on active drug showed reductions in p-tau217 by –0.12 pg/mL relative to placebo (P <.01).

Lead investigator Anton P. Porsteinsson, MD, director of the University of Rochester Alzheimer’s Disease Care, Research, and Education Program, said in a statement that, "While the trial did not meet its primary endpoint, the biomarker and subgroup data are intriguing and remarkably consistent not only across endpoints but also with our understanding of fosgonimeton’s neuroprotective mechanism of action."

READ MORE: FDA Grants Fast Track Designation to PI-2620 Tau-PET Diagnostic Scan for Neurodegenerative Diseases

In the study, greater effects on clinical outcomes were observed in a subgroup of patients with more advanced AD. In patients with moderate AD, fosgonimeton-treated participants (n = 16) demonstrated improvements in ADAS-Cog11 relative to those on placebo (n = 70), indicated by a delta of –1.16 (P = .39). Furthermore, over the 26-week treatment period, APOE e4 carriers on fosgonimeton (n = 74) showed stable cognitive status on the ADAS-Cog11 whereas those on placebo (n = 74) declined (delta, –1.07; P = .33).

In a post hoc analyses by disease severity as defined by baseline ADAS-Cog11 (>30) and Clinical Dementia Rating (CDR) 2, fosgonimeton showed a larger effect size mainly driven by an improvement in cognition at week 26. Those with the highest baseline ADAS-Cog11 (>30) who were treated with fosgonimeton (n = 42) compared with placebo (n = 52) showed a –2.51 improvement in cognition as assessment by ADAS-Cog11 (P = .16), with lower numbers representing improvement. In a smaller group of participants with a CDR score of 2, considered moderate dementia, investigators recorded a –3.74-point difference between patients treated with fosgonimeton (n = 20) vs placebo (n = 19; P = .21).

This was not the first time fosgonimeton failed to meet its primary end point in a clinical trial while showing other promising effects on cognitive measures. In December 2023, data from an exploratory phase 2 study dubbed SHAPE (NCT04831281) showed that the agent produced positive effects on cognitive outcomes in patients with Parkinson disease dementia (PDD) and Dementia with Lewy bodies (DLB).²

SHAPE, a double-blind, placebo-controlled, parallel-group study, included 28 patients who were randomly assigned 1:1:1 to either 2 dosed groups of ATH-1017 or placebo for a 26-week treatment period. The primary end point, change in event-related potential (ERP) P300 latency, a functional measure of working memory processing speed, was not met; however, all 5 patients in the modified intent-to-treat population treated with fosgonimeton 40 mg once daily demonstrated statistically significant improvements (–7.2 points) in ADAS-Cog13 compared with placebo (n = 7; P = .0321).

In the previously concluded phase 2 ACT-AD study (NCT04491006), an exploratory study, fosgonimeton demonstrated mechanistic potential to treat AD. Topline findings announced in June 2022 showed that the agent did not meet its primary or secondary end points when used with standard-of-care AChEIs; however, it did show meaningful differences when used as a monotherapy. After 26 weeks, treatment with fosgonimeton monotherapy resulted in a potentially beneficial change of –28 milliseconds in ERP P300 latency, the primary end point. Additionally, over that time period, the treated group demonstrated a –3.3-point change in ADAS-Cog11.³

REFERENCES
1. Athira Pharma Announces Topline Results from Phase 2/3 LIFT-AD Clinical Trial of Fosgonimeton for Mild-to-Moderate Alzheimer’s Disease. News release. September 3, 2024. https://www.globenewswire.com/news-release/2024/09/03/2940069/0/en/Athira-Pharma-Announces-Topline-Results-from-Phase-2-3-LIFT-AD-Clinical-Trial-of-Fosgonimeton-for-Mild-to-Moderate-Alzheimer-s-Disease.html
2. Athira Pharma announces encouraging results from SHAPE phase 2 clinical trial of fosgonimenton for the treatment of Parkinson’s disease dementia and dementia with Lewy bodies. News release. Athira Pharma. December 12, 2023. Accessed September 4, 2024. https://finance.yahoo.com/news/athira-pharma-announces-encouraging-results-120000969.html
3. Athira Pharma announces topline results from ACT-AD phase 2 proof-of-concept study of fosgonimeton in mild-to-moderate Alzheimer disease. News release. Athira Pharma. June 22, 2022. Accessed September 4, 2024. https://www.globenewswire.com/news-release/2022/06/22/2466956/0/en/Athira-Pharma-Announces-Topline-Results-from-ACT-AD-Phase-2-Proof-of-Concept-Study-of-Fosgonimeton-in-Mild-to-Moderate-Alzheimer-s-Disease.html