Alzheimer’s clinical trial for fosgonimeton completes enrollment
Top-line data is expected in second half of 2024, company says
The Phase 2/3 study (NCT04488419) enrolled about 315 participants, who received either 40 mg fosgonimeton or a placebo for 26 weeks (about six months). Top-line data is expected in the second half of this year, the company announced in a press release.
“The new year is off to a strong start with the completion of enrollment in our Phase 2/3 LIFT-AD clinical trial of fosgonimeton as a potential treatment for mild-to-moderate Alzheimer’s disease (AD), which we expect will enable topline data readout from the study in the second half of 2024,” said Mark Litton, PhD, president and CEO of Athira.
In the brains of Alzheimer’s patients, an interaction between a signaling molecule called hepatocyte growth factor (HGF), which promotes nerve cell growth and survival, and its cell surface receptor protein, MET, is thought to be impaired.
Fosgonimeton (formerly ATH-1017), administered once daily by subcutaneous, or under-the-skin injection, is a small molecule designed to enhance the HGF-MET interaction and improve brain health and function in people with the cognitive disorder.
After an early Phase 1 trial (NCT03298672) found that fosgonimeton was generally safe and well tolerated at all doses tested in older healthy volunteers, the treatment was tested in people with Alzheimer’s in the now-complete Phase 2 ACT-AD study (NCT04491006).
The trial enrolled 77 adults with mild to moderate disease and assessed 40 and 70 mg doses of fosgonimeton against a placebo. Top-line results from this exploratory trial failed to show fosgonimeton’s ability to statistically improve cognitive function and overall functioning over a placebo.
However, a subgroup analysis of participants not taking standard acetylcholinesterase (AChE) inhibitors indicated a positive effect for the therapy on working memory processing speed, cognitive function, and daily functioning. AChE inhibitors approved for Alzheimer’s include Razadyne (galantamine), Exelon (rivastigmine), and Aricept (donepezil).
Moreover, levels of neurofilament light chain (NfL), a nerve damage biomarker, were significantly reduced in fosgonimeton-treated patients.
Based on these findings, LIFT-AD’s protocol was amended by Athira to enroll only patients who were not on background therapy.
An unblinded interim efficacy and futility analysis of the study’s first 100 participants not on AChE inhibitors was conducted to confirm ACT-AD’s findings and determine if the trial was powered to detect a significant effect from fosgonimeton. Guided by these results, an independent data monitoring committee recommended the study should continue as planned.
“The potential of fosgonimeton as a treatment for AD is supported by the independent, unblinded interim efficacy and futility analysis of the first 100 subjects in the Phase 2/3 LIFT-AD study and the results from the exploratory Phase 2 ACT-AD clinical trial,” Litton said.
Altogether, data showed “potential congruent improvements in biomarkers of neurodegeneration, inflammation and Alzheimer’s disease protein pathologies as well as measures of cognition and function,” Litton said.
Full enrollment reached in primary analysis population
LIFT-AD has now completed full enrollment with about 315 participants in the primary analysis population. The trial’s primary goal is to measure changes in composite score assessments of daily functioning (Alzheimer’s Disease Cooperative Study-Activities of Daily Living) and cognitive function (Alzheimer’s Disease Assessment Scale-Cognitive Subscale).
Secondary measures include changes in each of the assessments independently, as well as on biomarkers of disease-related processes, such as neurodegeneration, protein abnormalities, and neuroinflammation.
Eligible participants who complete the LIFT-AD or ACT-AD trials can participate in OLEX, a long-term, open-label extension study (NCT04886063) wherein all will receive 40 mg of daily fosgonimeton for up to 30 months, or 2.5 years. So far, more than 85% of those who completed either study have enrolled in OLEX, with 60 patients continuing treatment beyond 18 months.
“We are also encouraged that more than 85% of participants who completed the LIFT-AD and ACT-AD clinical trials elected to participate in the open label extension trial (OLEX),” Litton said in a separate press release. “Notably, there are currently more than 60 patients in this open label trial who are continuing fosgonimeton treatment beyond 18 months, which is unexpected in a progressive mild-to-moderate Alzheimer’s disease population.”
Fosgonimeton also has shown potential in an Athira-sponsored Phase 2 study as a potential treatment for Parkinson’s disease dementia and Lewy body dementia. The company also is developing a next-generation, orally administered drug candidate called ATH-1105 for amyotrophic lateral sclerosis.
“The totality of data shared to date strengthens our confidence in and supports the potential of our small molecule approach to targeting the neurotrophic hepatocyte growth factor (HGF) system for diseases including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS),” Litton added.