Fosgonimeton fails to meet goal in Alzheimer’s clinical trial: Data
Therapy safe, but no significant gains seen in cognition, daily function
Fosgonimeton, an investigational medication from Athira Pharma, failed to significantly improve cognitive and daily functioning in adults with mild to moderate Alzheimer’s disease who took part in a Phase 2/3 clinical trial, despite being safe and well tolerated, top-line data show.
“These are not the results we hoped for,” Javier San Martin, MD, Athira’s chief medical officer, said in a company press release announcing the new clinical data from its LIFT-AD trial (NCT04488419).
LIFT-AD had tested the safety and efficacy of a 40 mg dose of fosgonimeton versus a placebo, when given as daily injections for 26 weeks, or about six months. It enrolled 312 patients who were not taking standard acetylcholinesterase (AChE) inhibitors.
While the trial’s main goal of improving both cognitive skills and the ability to perform daily activities wasn’t met, fosgonimeton was, however, numerically superior, although still not significantly, to the placebo in pre-specified groups of patients. These included individuals with more advanced Alzheimer’s or those who carried the APOE4 gene variant, which increases the risk of Alzheimer’s.
As a possible explanation, San Martin said the short treatment course and lack of clinical decline in the placebo group “may have impacted the trial’s ability to translate the effect of fosgonimeton treatment into meaningful clinical benefit.”
According to Athira, both cognition and daily functioning “directionally favored fosgonimeton treatment.”
Clinical trial data show some positive results, but none are significant
Given via subcutaneous, or under-the-skin, injections, fosgonimeton is designed to activate signaling via the hepatocyte growth factor (HGF) protein — which is thought to be impaired in Alzheimer’s. Activating HGF signaling is expected to protect brain cells from death and modify the course of the neurodegenerative disease.
The LIFT-AD trial’s main goal, called the primary endpoint, was to determine changes in the Global Statistical Test (GST), which combines two measures. One, the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), is designed to assess cognitive skills, while the other, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL23), evaluates a person’s ability to perform daily activities.
After 26 weeks of treatment, there was a small difference in the GST scores favoring fosgonimeton over the placebo — a difference of 0.08 points — but it did not reach statistical significance.
Similar observations were made when separately watching for changes in ADAS-Cog11 or ADCS-ADL23 scores, two of the secondary endpoints of the trial. While participants on the placebo showed a 0.39-point decline in ADAS-Cog11, indicating improvement, and a 0.02-point decline in ADCS-ADL23, suggesting stable scores, those on fosgonimeton experienced a 1.09-point decline in ADAS-Cog11 and an increase in ADCS-ADL23 scores by 0.65 points, suggesting greater benefits.
Treatment with fosgonimeton resulted in a significant reduction in the blood levels of a form of tau, a protein that builds up as toxic tangles in Alzheimer’s, causing damage to brain cells and loss of cognitive skills. Other biomarkers of Alzheimer’s and damage to brain cells also were reduced, but not significantly.
In a subgroup analysis, patients with moderate Alzheimer’s showed even greater cognitive improvements with fosgonimeton compared with the placebo, but the difference also did not reach statistical significance. In addition, those carrying the APOE4 gene variant did not show cognitive decline, while those on the placebo did.
We believe the totality of the data continues to suggest that positive modulation of the HGF pathway [with fosgonimeton] has the potential to translate into improvement in parameters of neuronal health and may mitigate disease progression.
“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,” said Anton P. Porsteinsson, MD, a LIFT-AD investigator and the director of the University of Rochester Alzheimer’s Disease Care, Research, and Education Program.
Fosgonimeton was generally well tolerated over the 26-week treatment course. Patients on fosgonimeton experienced more treatment-emergent side effects, which were mostly driven by injection site reactions. Serious side effects were evenly distributed between groups, with no deaths reported. However, about 22% of participants ended the trial early.
While fosgonimeton did not meet the trial’s primary and secondary endpoints, “positive modulation of HGF signaling may have potential beneficial effects in neurodegenerative diseases,” the company wrote in a presentation shown during a recent webcast for investors.
“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,” San Martin said.
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