Phase 2 SHAPE Trial Results Showcase Fosgonimenton’s Benefit in Neurodegenerative Disorders
Also known as ATH-1017, fosgonimenton demonstrated a safe profile, with directional improvements in cognitive, functional, and biomarker assessments.
Hans Moebius, MD, PhD
Newly announced findings from the exploratory phase 2 SHAPE clinical trial (NCT04831281) showed that fosgonimenton, an investigational small molecule, produced positive effects on cognitive measures among patients with Parkinson disease dementia (PDD) and Dementia with Lewy bodies (DLB) despite not meeting its primary end point. Designed to positively modulate the hepatocyte growth factor (HGF) system, fosgonimenton represents a potentially beneficial treatment for patients with neurodegenerative disorders.1
SHAPRE, 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 (mITT) treated with fosgonimenton 40 mg once daily demonstrated statistically significant improvements (–7.2 points) in ADAS-Cog13 compared with placebo (n = 7; P = .0321).
"In this small exploratory trial, once daily treatment with fosgonimeton 40 mg showed positive effects in cognitive measures compared to placebo, with an observed statistically significant difference in ADAS-Cog13, and numeric positive differences in MMSE and COWAT over the 6-month double-blind treatment period,” Hans Moebius, MD, PhD, chief medical officer of Athira, said in a statement.1 "These findings support the potential of targeting HGF system positive modulation as a broadly applicable strategy for treating neurodegenerative diseases."
SHAPRE was originally designed to enroll approximately 75 individuals, but Athira elected to end enrollment in October 2022 because of subsequently identified study design limitations and a prioritization of resources toward the ongoing LIFT-AD trial (NCT04886063) in Alzheimer disease (AD). Of the cohort, 29% of patients were on background therapy with acetylcholinesterase inhibitors. Additional findings from the study showed directional improvements in other cognitive, functional, and biomarker measurements in the fosgonimention 40 mg group.
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In terms of safety, the therapy was shown to have a favorable treatment profile, with no treatment-related serious adverse events (AE) or deaths observed in the study. Injection site reactions were the most commonly reported AE. Athira noted that the efficacy results for the 70 mg dose of fosgonimention were inconsistent, potentially because of a higher dropout rate (50%) than both the 40-mg (22%) and placebo (22%) groups. The company plans to present additional data from the study at an upcoming medical conference.
"These encouraging findings from the SHAPE trial further bolster our confidence in the ongoing Phase 2/3 LIFT-AD trial of fosgonimeton as a potential treatment for Alzheimer’s disease and support our May 2023 amendment to the LIFT-AD protocol to pursue the 40 mg dose versus placebo and discontinue the 70 mg dose. We expect to complete enrollment of the LIFT-AD trial early in 2024 and to report topline results in the second half of 2024," Mark Litton, PhD, president and chief executive officer of Athira, said in a statement.1 "More broadly, we are encouraged by the clinical and preclinical evidence that support the potential therapeutic effects of HGF system positive modulation across a wide range of neurodegenerative diseases."
LIFT-AD, an ongoing phase 2/3 trial (NCT04488419), began to recruit participants with clinically diagnosed mild to moderate AD in September 2020. The 6-month study uses Global Statistical Text, a combination of scores from the ADAS-Cog11 and the ADCS-Clinical Global Impression of Change, as the primary end point. In early 2022, the company increased enrollment to 420, and reclassified the trial to phase 3. Earlier this year, enrollment was further increased to 475.2
In the previously concluded phase 2 ACT-AD study (NCT04491006), an exploratory study, fosgonimenton 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 fosgonimenton 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
