Journal of Alzheimer's disease reports · 2025
Fosgonimeton in mild-to-moderate Alzheimer's disease.
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Porsteinsson Anton P, Sabbagh Marwan, Tariot Pierre N, Church Kevin J, San Martin Javier, Ooi Kai-Bin C, Daggett Simon, Hale Michael D, Holub Richard, Moebius Hans J
Аннотация
BACKGROUND: Fosgonimeton, a small-molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, was studied in participants with Alzheimer's disease (AD).
OBJECTIVE: To assess the efficacy and safety of fosgonimeton in AD.
METHODS: LIFT-AD was a randomized, placebo-controlled, Phase 2/3 trial (NCT04488419; 23Jun2020), the primary analysis (N = 287) included participants with mild-to-moderate AD not receiving concomitant acetylcholinesterase inhibitors (AChEIs) randomized 1:1 to daily subcutaneous fosgonimeton 40 mg or placebo. The primary endpoint, the Global Statistical Test (GST) score, combined ADAS-Cog11 and ADCS-ADL23. Secondary endpoints included ADAS-Cog11, ADCS-ADL23, and NfL. Exploratory endpoints included plasma biomarkers of AD. Safety included all dosed participants, including those receiving and not receiving AChEIs or randomized to fosgonimeton 70 mg (N = 549).
RESULTS: The trial did not achieve its primary or secondary endpoints; between-group difference in the least-square mean change (SE) from baseline to Week 26 in the GST score was -0.08 (0.10) (p = 0.70), -0.70 (0.77) (p = 0.35) in ADAS-Cog11, and +0.67 (0.92) (p = 0.61) in ADCS-ADL23. This showed small differences favoring fosgonimeton versus placebo. Nominally significant changes in plasma biomarkers were observed in p-τ217 only. Fosgonimeton had an acceptable safety profile. Serious AEs were balanced between groups (4.2% fosgonimeton, 6.9% placebo). More participants in the fosgonimeton group (14.2%) discontinued due to AEs versus placebo (4.6%), mostly from injection site reactions.
CONCLUSIONS: Fosgonimeton did not significantly improve ADAS-Cog11 or ADCS-ADL23 versus placebo. However, the consistently observed non-significant improvements favoring fosgonimeton suggests potentially relevant biological activity with fosgonimeton and that positive modulation of HGF signaling may impact components of the pathophysiologic processes of neurodegenerative diseases.
OBJECTIVE: To assess the efficacy and safety of fosgonimeton in AD.
METHODS: LIFT-AD was a randomized, placebo-controlled, Phase 2/3 trial (NCT04488419; 23Jun2020), the primary analysis (N = 287) included participants with mild-to-moderate AD not receiving concomitant acetylcholinesterase inhibitors (AChEIs) randomized 1:1 to daily subcutaneous fosgonimeton 40 mg or placebo. The primary endpoint, the Global Statistical Test (GST) score, combined ADAS-Cog11 and ADCS-ADL23. Secondary endpoints included ADAS-Cog11, ADCS-ADL23, and NfL. Exploratory endpoints included plasma biomarkers of AD. Safety included all dosed participants, including those receiving and not receiving AChEIs or randomized to fosgonimeton 70 mg (N = 549).
RESULTS: The trial did not achieve its primary or secondary endpoints; between-group difference in the least-square mean change (SE) from baseline to Week 26 in the GST score was -0.08 (0.10) (p = 0.70), -0.70 (0.77) (p = 0.35) in ADAS-Cog11, and +0.67 (0.92) (p = 0.61) in ADCS-ADL23. This showed small differences favoring fosgonimeton versus placebo. Nominally significant changes in plasma biomarkers were observed in p-τ217 only. Fosgonimeton had an acceptable safety profile. Serious AEs were balanced between groups (4.2% fosgonimeton, 6.9% placebo). More participants in the fosgonimeton group (14.2%) discontinued due to AEs versus placebo (4.6%), mostly from injection site reactions.
CONCLUSIONS: Fosgonimeton did not significantly improve ADAS-Cog11 or ADCS-ADL23 versus placebo. However, the consistently observed non-significant improvements favoring fosgonimeton suggests potentially relevant biological activity with fosgonimeton and that positive modulation of HGF signaling may impact components of the pathophysiologic processes of neurodegenerative diseases.