Fosgonimeton trial in Parkinson’s dementia to have fewer participants

Exploratory Phase 2 SHAPE study enrolled 28 of anticipated 75 patients

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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Athira Pharma is completing its Phase 2 clinical trial of the experimental therapy fosgonimeton in people with Parkinson’s disease dementia or dementia with Lewy bodies with fewer participants than its initial target enrollment.

According to a recent corporate update, the company has closed recruitment with 28 of the initially estimated 75 participants, aged 40-85. The reasons for the decision haven’t been disclosed.

The exploratory trial, called SHAPE (NCT04831281), is likely expected to be completed this year, and Athira plans to use its results to determine the next steps of its Parkinson’s program.

“The progress we made throughout 2022 and in recent months continues to support our strategy to advance our small molecule therapeutic candidates, such as fosgonimeton, to impact neurodegenerative diseases,” Mark Litton, PhD, Athira’s president and CEO, said in the update.

Parkinson’s is marked by the progressive loss of neurons responsible for releasing a major brain signaling molecule called dopamine. The death of these neurons, called dopaminergic neurons, results in coordination and movement impairments.

Also called ATH-1017, fosgonimeton is a small molecule designed to boost the activity of hepatocyte growth factor (HGF) and its receptor, MET, which are involved in several processes critical for the normal function of the central nervous system (brain and spinal cord). By activating the HGF/MET pathway, fosgonimeton, administered under the skin, should offer neuroprotective effects and improve brain health and function.

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SHAPE trial testing fosgonimeton‘s safety, effectiveness

The U.S.-based SHAPE trial is evaluating the therapy’s safety and effectiveness in 28 adults with mild to moderate Parkinson’s disease dementia or dementia with Lewy bodies, which form in both conditions and are toxic aggregates of the alpha-synuclein protein with other proteins.

Dosing was initiated in January 2022 and participants were randomly assigned to receive either one of two doses of fosgonimeton (40 or 70 mg) or a placebo for 26 weeks, or about six months.

The study’s goals include changes in cognitive function, clinician-reported overall disease change, ability to perform daily activities, and motor function. Preclinical results have also supported the broader potential of fosgonimeton to improve motor function with Parkinson’s.

Data presented at the Neuroscience 2022 conference showed it significantly improved motor function and coordination in a mouse model of Parkinson’s. Athira “will seek to evaluate study designs to further explore its potential in this complex disease,” according to the update.

The company recently presented more fosgonimeton preclinical data at the AD/PD 2023-International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, March 28-April 1 in Gothenburg, Sweden and virtually.

Fosgo-AM — the active metabolite of fosgonimeton — was shown to significantly improve cell survival, prevent neurite degeneration, and reduce alpha-synuclein clumps in lab-grown dopaminergic neurons exposed to neurotoxic insults that promote Parkinson’s-like features. Neurites are cell body extensions that nerve cells normally use to communicate with each other.

Similar benefits were seen in a cellular model of Alzheimer’s disease, for which the therapy is also being evaluated in clinical trials.

Fosgonimeton also lessened cognitive deficits in a mouse model of neuroinflammation-induced cognitive impairment. This effect was found to be mediated by a reduction in pro-inflammatory molecules and protection against neurotoxicity.

“New therapeutic strategies for neurodegenerative diseases are urgently needed. Our presentations at AD/PD highlight a wide range of preclinical evaluations demonstrating the ability of fosgonimeton, or its active metabolite fosgo-AM, acting through the HGF/MET system, to address multiple aspects of neurodegeneration,” Kevin Church, PhD, chief scientific officer of Athira, said in a separate press release. “These findings include notable neuroprotective, neurotrophic, and anti-inflammatory effects, as well as reduction of disease-related protein [damage] following multiple and varied challenges in models of Alzheimer’s and Parkinson’s.”