Fosgonimeton Shows Safety in Early Trial, Phase 3 Study Enrolling in US

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by Marisa Wexler MS |

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Fosgonimeton, an experimental therapy Athira Pharma is developing to treat Alzheimer’s disease, was well-tolerated overall in a Phase 1 clinical trial that included Alzheimer’s patients as well as healthy volunteers.

“These encouraging results showed a positive safety and tolerability profile of fosgonimeton across a wide dose range,” Hans Moebius, MD, PhD, Athira’s chief medical officer, said in a press release.

The potential therapy is now in a fully enrolled Phase 2 trial in Alzheimer’s patients due to conclude around mid-year. A Phase 3 study called LIFT-AD (NCT04488419) is also underway and currently enrolling up to 300 people with mild-to-moderate disease at sites across the U.S.

Phase 1 trial results were detailed in the study, “Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer’s Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial,” published in the Journal of Alzheimer’s Disease.

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Fosgonimeton is designed to modulate HGF/MET signaling in the brain. HGF is a signaling molecule that binds to the MET protein receptor on neurons (nerve cells), helping to promote their growth. HGF/MET signaling is thought to be impaired in the brains of Alzheimer’s patients.

Fosgonimeton (also known as ATH-1017), contains an inactive molecule, or prodrug, that is administered by subcutaneous (under-the-skin) injection. Once inside the body, the prodrug gets converted into its active form, called ATH-1001, which works to increase the interaction between HGF and MET in the brain. Ultimately, the aim is to enhance healthy neuronal growth by increasing HGF/MET signaling.

Athira sponsored a Phase 1 clinical trial (NCT03298672) to evaluate the medication’s safety, tolerability, and pharmacological properties.

In the first part of the study, 48 healthy male volunteers, ages 18 to 45, were given a single dose of fosgonimeton at 2, 6, 20, 40, 60, or 90 mg.

Its second part included older healthy volunteers of any sex, ages 60 to 85. These 29 adults were given injections of fosgonimeton (20  to 80 mg) or a placebo daily for nine days. Pharmacological, clinical, and safety assessments were regularly conducted throughout the treatment period.

Eleven adults with Alzheimer’s disease were also assigned to fosgonimeton at 40 mg or a placebo daily for nine days.

At all doses tested, fosgonimeton was found to be generally safe and well tolerated. No serious adverse events were reported, and no noteworthy anomalies on seen on clinical tests.

The most common side effects attributed to fosgonimeton were pain and itching at the injection site. These generally were mild and resolved on their own without intervention.

Two study participants, both healthy elderly adults, withdrew due to adverse events. One given fosgonimeton at 40 mg withdrew due to neutropenia — low levels of a type of white blood cell called neutrophils — that was deemed likely to be unrelated to the experimental therapy. The other, assigned to 80 mg fosgonimeton, had an allergic skin reaction that was seen as likely to be connected to the treatment.

Pharmacological data was generally in line with expectations: levels of ATH-1001 increased rapidly after dosing, and the medication cleared from the body within a day of the last dose.

“The safety and [pharmacological] results clearly support continued development of fosgonimeton,” the researchers concluded.

Notably, assessment of electrical activity in participants’ brains showed a notable increase in event-related potential (ERP) P300 latency in the Alzheimer’s patients with fosgonimeton treatment compared to healthy individuals. ERP P300 latency is basically a measure of the delay between a person physically hearing a sound, and electrical activity in the brain as the organ registers the sound.

“As expected, healthy elderly subjects receiving active doses of fosgonimeton (20, 40, 60 mg) did not show a change in ERP P300 latency [from the study’s start], since there was no impairment in neuronal connectivity,” the researchers wrote.

In treated Alzheimer’s patients, in contrast, fosgonimeton led to a “gradual normalization of ERP P300 latency with repeat dosing,” the researchers reported. This effect was seen in all seven Alzheimer’s patients given fosgonimeton, but in none of the four patients given a placebo.

“We believe the significant reduction of ERP P300 latency levels seen in the Alzheimer’s disease patient cohort on active treatment may be suggestive of enhanced synaptic function and, ultimately, the potential procognitive properties of fosgonimeton,” Moebius said.

Athira is currently sponsoring a Phase 2 trial called ACT-AD (NCT04491006), in which 77 people with Alzheimer’s are being given fosgonimeton or a placebo for 26 weeks (about half a year). The goal of the study, which is due to conclude in May, is to assess the effects of treatment on ERP P300 latency as well as standardized measures of cognition.

The Phase 3 LIFT-AD study is comparing fosgonimeton against placebo and assessing its effect on cognition. About 300 people with mild-to-moderate Alzheimer’s will be randomized to receive a high or low dose of fosgonimeton or placebo, both injected daily for 26 weeks.

LIFT-AD is enrolling at 48 sites across the U.S.

Results from the Phase 1 study “support our ongoing Phase 2 ACT-AD and Phase 3 LIFT-AD trials evaluating fosgonimeton’s potential as a treatment for Alzheimer’s disease,” Moebius said. “We look forward to sharing the Phase 2 ACT-AD top-line data in the second quarter of 2022.”