Alzheimer’s LIFT-AD Trial OK’d to Continue by Monitoring Committee

The decision to continue study was reached following an analysis of 100 patients

Teresa Carvalho, MS avatar

by Teresa Carvalho, MS |

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Note: The headline of this story was updated Dec. 1, 2022, to correct that the decision to continue the Phase 2/3 clinical trial of fosgonimeton was recommended by an independent data monitoring committee.

A Phase 2/3 clinical trial evaluating Athira Pharma’s experimental therapy fosgonimeton (formerly ATH-1017) in people with mild to moderate Alzheimer’s disease should continue as planned.

That’s the recommendation of an independent data monitoring committee following an interim analysis on 100 participants not on standard acetylcholinesterase (AChE) inhibitors to assess whether fosgonimeton was indicating superior effectiveness over a placebo, as well as favorable safety.

AChE inhibitors approved for Alzheimer’s include Aricept (donepezil), Exelon (rivastigmine), and Razadyne (galantamine).

The analysis also allowed the committee to establish that adding up to 150 patients not taking AChE inhibitors — for up to a total of 300 people — would be enough to power the trial to assess its primary goal.

The trial, called LIFT-AD (NCT04488419), is recruiting patients, ages 55 to 85, who aren’t on AChE inhibitors at more than 40 U.S. sites. Athira anticipates completing its target enrollment by the middle of next year and expects top-line data in early 2024.

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“Our goal with fosgonimeton is to demonstrate its ability to improve cognition and function, and to ultimately provide neuroprotection,” said Mark Litton, PhD, Athira’s president and CEO, in a company press release. “We are very excited by the results of this independent review as we believe they mitigate the risk of the fosgonimeton development plan, support the potential clinical benefit of fosgonimeton, and inform the sample size needed to achieve success with LIFT-AD.”

Hans Moebius, MD, PhD, Athira’s chief medical officer, said the “analysis supports the potential clinical benefits of fosgonimeton treatment and underscores the rationale for continued development of this promising new therapy.”

A detailed discussion on LIFT-AD’s interim analysis was held in a company webcast.

What is fosgonimeton?

Fosgonimeton is a small molecule designed to promote the interaction between HGF, a signaling molecule that promotes nerve cell growth and survival, and its receptor protein, MET, at the cell surface.

By increasing HGF-MET interaction in nerve cells — which is thought to be reduced in Alzheimer’s — fosgonimeton is expected to improve brain health and function in people with the neurodegenerative condition.

In a previous Phase 1 trial (NCT03298672), it was found to be generally safe and well tolerated, at all doses tested, in older, healthy volunteers.

Athira also tested two doses (40 and 70 mg) against a placebo in 77 adults with mild to moderate Alzheimer’s in the now-completed Phase 2 ACT-AD trial (NCT04491006).

Its main goal was to assess changes on event-related potential (ERP) P300 latency, a functional measure of working memory processing speed, after six months. Other goals included changes in cognitive function, and global and daily functioning assessments.

Top-line results from this exploratory trial showed the therapy was generally safe and was associated with positive trends on cognitive function and overall functioning that failed to reach statistical significance.

The levels of a nerve damage biomarker called neurofilament light chain (NfL) were significantly reduced in fosgonimeton-treated patients relative to a placebo.

Our goal with fosgonimeton is to demonstrate its ability to improve cognition and function, and to ultimately provide neuroprotection.

While this meant the trial failed to meet its main and key secondary goals, a subsequent subgroup analysis of patients not on standard AChE inhibitors suggested a positive effect for fosgonimeton on ERP P300 latency, cognitive function, and daily functioning.

Amending LIFT-AD trial’s protocol

Guided by these results, Athira amended LIFT-AD’s protocol in September to enroll only patients not on background therapy. The recent interim analysis of 100 participants not on AChE inhibitors was conducted to confirm ACT-AD’s findings and ensure the new trial is powered to detect the therapy’s effects.

These stringent criteria are expected to increase the probability that fosgonimeton will show a clinically meaningful effect on cognitive function and daily functioning in patients.

In the LIFT-AD trial, patients are being randomly assigned to receive an under-the-skin injection of either one of two fosgonimeton doses (40 and 70 mg) or a placebo, once daily for 26 weeks (about six months).

The study’s main goals are assessing its safety profile and changes in a composite score of measures of cognitive function (Alzheimer’s Disease Assessment Scale-Cognitive Subscale) and daily functioning (Alzheimer’s Disease Cooperative Study-Activities of Daily Living).

Secondary goals include changes in each of the measures independently and on global disease, as assessed with the Alzheimer’s Disease Study Cooperative Study-Clinical Global Impression of Change. Changes in the levels of fluid biomarkers such as NfL will also be investigated.

“We believe any drug that can demonstrate neuroprotection could become a treatment of choice for mild-to-moderate Alzheimer’s patients,” Litton said, adding “the ACT-AD study suggested these benefits and the results of the LIFT-AD interim analysis corroborate those findings.”

These findings “give us confidence in a potentially positive outcome for LIFT-AD, as stringent evaluation criteria were applied based on validated and clinically meaningful cognitive and functional outcomes,” Moebius said.

Participants completing either ACT-AD or LIFT-AD may choose to enter an open-label extension study (NCT04886063) wherein all will receive the therapy for 1.5 years.

“Moving forward, we remain keenly focused on advancing this novel investigational therapy with the hope of positively impacting the lives of millions of Alzheimer’s patients,” Litton added.