お知らせ • Sep 04
Athira Pharma, Inc. Announces Topline Results from Phase 2/3 Lift-AD Clinical Trial of Fosgonimeton for Mild-to-Moderate Alzheimer's Disease
Athira Pharma, Inc. announced topline results from its Phase 2/3 LIFT-AD clinical trial of fosgonimeton, a hepatocyte growth factor (HGF) positive modulator, in patients with mild-to-moderate Alzheimer's disease (AD). The topline results showed that neither the trial's primary endpoint (the Global Statistical Test (GST), a combination of results from measures of cognition (ADAS-Cog11) and function (ADCS-ADL23)) nor its key secondary endpoints of ADAS-Cog11 and ADCS-ADL23 reached statistical significance compared with placebo at 26 weeks. However, both components of GST, cognition (ADAS-Cog11) and function (ADCS-ADL23), directionally favored fosgonimeton treatment, and in pre-specified subgroups characterized by more rapid disease progression (moderate AD and APOE4 carriers), cognition and function improved or stabilized in the fosgonimeton treated group. In addition, data across biomarkers of protein pathology (Aß42/40, p-Tau181, and p-Tau217), inflammation (GFAP) and neurodegeneration (NfL) showed directional improvements with fosgonimeton treatment that are consistent with the broad neuroprotective mechanism of HGF modulation. LIFT-AD (NCT04488419) was a randomized, placebo-controlled, double-blind study that evaluated the efficacy and safety of once-daily subcutaneous injections of fosgonimeton (40 mg) in 312 mild-to-moderate AD patients not on acetylcholinesterase inhibitors (AChEIs) compared to placebo over a 26-week treatment period.?The primary endpoint of LIFT-AD was the change from baseline after 26 weeks of treatment using the Global Statistical Test (GST), a combination of results from measures of cognition (ADAS-Cog11) and function (ADCS-ADL23). Secondary endpoints included cognition (ADAS-Cog11), function (ADCS-ADL23), and a plasma biomarker of neurodegeneration, neurofilament light chain (NfL). The trial explored additional plasma biomarkers including glial fibrillary acidic protein (GFAP), a marker of neuroinflammation, and both amyloid beta and phosphorylated tau (pTau), hallmark measures of AD pathology. Primary Analysis Population Topline results from the LIFT-AD study of fosgonimeton in mild-to-moderate AD patients after 26 weeks showed: A -0.08 change in GST favoring fosgonimeton that did not reach statistical significance (p=0.70) The change in cognition from baseline as assessed by ADAS-Cog11, for which a decrease from baseline represents improvement, was -0.39 for the placebo group and -1.09 for the fosgonimeton treated group, a difference of -0.70 (p=0.35) favoring fosgonimeton; In the fosgonimeton treated group, there was an increase (improvement) of 0.65 in function as measured by ADCS-ADL23 versus a decline of -0.02 in placebo, although this difference did not meet statistical significance (p=0.61). Prespecified Biomarker Analyses: Data from the plasma biomarkers of neurodegeneration (NfL), inflammation (GFAP), and protein pathology (p-Tau181, p-Tau217, and amyloid beta 42/40 ratio) showed consistent directional improvements favoring fosgonimeton versus placebo after 26 weeks. Notably, fosgonimeton treatment reduced plasma levels of pTau217, a hallmark of AD, by -0.12 pg/mL compared to placebo (p<0.01). Prespecified Subgroup Analyses: In a prespecified subgroup analyses of more advanced AD patients, a greater numerical treatment effect in clinical outcomes was observed in the fosgonimeton treatment group compared to placebo after 26 weeks: The change in cognition from baseline as assessed by ADAS-Cog11 in moderate AD patients, for which a decrease from baseline represents improvement, showed the fosgonimeton treatment group (n=61) improved compared to placebo (n=70), with a delta of -1.16 (p=0.39); For AD patients who are carriers of the APOE4 gene, the placebo group (n=74) declined in cognition as assessed by ADAS-Cog11 over the 26-week period as expected, whereas the fosgonimeton treatment group (n=74) remained stable, with a delta of -1.07 (p=0.33). Post Hoc Subgroup Analyses: 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. Patients with the highest baseline ADAS-Cog11 (>30) who were treated with fosgonimeton (n=42) compared to placebo (n=52) showed a -2.51 improvement in cognition as assessed by ADAS-Cog11 (p=0.16), for which a lower number represents improvement; A small subset of patients with a CDR 2 (moderate dementia) who were treated with fosgonimeton (n=20) compared to placebo (n=19) showed a -3.74 improvement in cognition as assessed by ADAS-Cog11 (p=0.21). Full analysis of these results is scheduled to be reviewed at the 17th Annual Clinical Trials on Alzheimer’s Disease (CTAD) taking place October 29 - November 1, 2024, in Madrid, Spain. Athira continues to evaluate ATH-1105, a next-generation, orally administered, small molecule drug candidate in development for the potential treatment of amyotrophic lateral sclerosis (ALS), AD, and other neurodegenerative diseases. Athira is currently conducting a first-in-human, dose escalation Phase 1 clinical trial evaluating safety, tolerability and pharmacokinetics of ATH-1105 in up to 80 healthy volunteers. Athira completed the first cohort of healthy volunteers in June 2024 and expects trial completion by year-end 2024, with a goal to be in ALS patients in 2025. ATH-1105’s potential is supported by a growing body of preclinical evidence demonstrating improvements in nerve and motor function, biomarkers of inflammation and neurodegeneration, and survival in various models of ALS.