ATH-1017, as Fosgonimeton, Seen to Aid Neurons and Motor Function

Early studies in nerve cells and a rat model of Parkinson’s disease support the potential of fosgonimeton, also known as ATH-1017, to be neuroprotective and possibly disease modifying, Athira Pharma, the therapy’s developer, reported.

Data from preclinical work showed that the therapy increased cell survival in the presence of neurotoxic insults, lowered alpha-synuclein protein accumulation — a key event in Parkinson’s — and improved the rats’ motor function and coordination, the company said in a press release.

Kevin Church, PhD, executive vice president of research at Athira, shared the results in the presentation “Fosgonimeton, a Small-Molecule Positive Modulator of HGF/MET, Protects Against Neuronal Damage and Motor Deficits in Preclinical Models of Parkinson’s Disease” at the Neuroscience 2022 conference held in San Diego, Nov. 12–16.

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ATH-1017 targets a pathway critical to central nervous system health

Fosgonimeton, given as an under-the-skin (subcutaneous) injection, is a small molecule designed to boost the activity of hepatocyte growth factor (HGF) and its receptor, MET.

The signaling pathway controlled by HGF and MET is critical to the normal function of the central nervous system, which comprises the brain and spinal cord. MET receptors are found in several nerve cells, including the dopaminergic (dopamine-producing) neurons that are gradually lost in Parkinson’s disease.

Activating the HGF/MET pathway with fosgonimeton is believed to have neuroprotective effects, including promoting nerve cell survival when exposed to neurotoxic insults that damage and kill these cells. Such insults include excessive levels of glutamate (an excitatory chemical messenger), neuroinflammation, and oxidative stress (a condition marked by high levels of molecules that can damage cells).

Under the name ATH-1017, the investigative therapy is now in an enrolling Phase 2 clinical trial in people with Parkinson’s disease dementia or dementia with Lewy bodies.

In the preclinical studies, scientists first assessed fosgonimeton’s neuroprotective effects in lab-grown primary neurons from the cortical, or outer, region of the rats’ brain.

Treatment with fosgo-AM — the active metabolite of fosgonimeton — significantly improved cell survival after exposure to different neurotoxic insults when compared with untreated control cells.

The therapy’s neuroprotective effects were maintained when rat dopaminergic neurons were exposed to two neurotoxins, 6-hydroxydopamine (6-OHDA) or rotenone. Neuronal degeneration induced by both 6-OHDA and rotenone lessened upon treatment.

Importantly, treatment also lowered the alpha-synuclein aggregation that these toxins provoke in neurons.

Researchers then assessed whether these benefits would be maintained in a Parkinson’s rat model. A group of rats were injected with 6-OHDA directly into the striatum  — a brain region involved in voluntary movement control — to induce typical Parkinson’s motor symptoms, while others were given a sham injection as a control group. After about two weeks, the animals received daily injections of fosgonimeton for eight weeks.

Treatment significantly improved motor function and coordination in the disease model, as assessed by three behavioral measures: the use of an impaired forelimb, grip strength, and time to fall from a rotarod, a test of animals’ strength and coordination.

The Phase 2 trial, called SHAPE (NCT04831281) is investigating the efficacy of ATH-1017 against a placebo in up to 75 adults, ages 40-85, with Parkinson’s disease dementia or Lewy body dementia. Recruitment is ongoing at sites across the U.S.; contact and site information are available.

Its primary goal is changes with 26 weeks of treatment (about six months) in the Global Statistical Test, a formula that combines a cognitive assessment with a test for functional working memory processing speed. Changes in activities of daily living and motor function also will be evaluated. SHAPE is due to conclude in November 2023.

ATH-1017 is also in clinical trials as a potential treatment of mild-to-moderate Alzheimer’s disease.

“Our studies continue to show that enhancing the HGF/MET pathway may have significant therapeutic benefit in various neuropathologies,” Church said.