First human trial begins in Europe for ALS, Parkinson’s drug NRG5051

The first participants have been dosed in an early Phase 1 clinical study that’s testing NRG5051, a first-in-class treatment candidate for amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, in healthy volunteers.

Developed by NRG Therapeutics, the experimental therapy is designed to restore the health of mitochondria, known as the powerhouses of cells. Mitochondria, which provide a cell’s energy, are often dysregulated in neurodegenerative conditions.

The first-in-human Phase 1 trial (2025-523872-22-00) is enrolling about 110 healthy adults at the Centre for Human Drug Research (CHDR) in the Netherlands. Participants will receive single or multiple ascending doses of the oral medication to assess its safety, tolerability, and pharmacological properties.

The study is expected to be completed by year’s end, and the results will help researchers select the therapy’s optimal dose for future trials involving people with ALS and Parkinson’s, according to a company press release.

“The start of our first clinical trial marks a proud moment for NRG as we transition into a clinical stage company,” said Neil Miller, PhD, cofounder and CEO of NRG Therapeutics.

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ALS is a neurodegenerative disease marked by the progressive dysfunction and loss of motor neurons, the nerve cells that control voluntary movements. While the exact mechanisms that drive ALS are not fully known, abnormalities in mitochondria are thought to play a role. Mitochondrial impairments are also believed to underlie Parkinson’s disease.

Trial now testing NRG5051 in healthy volunteers

Mitochondrial dysfunction leads to energy deficits and a form of cell damage known as oxidative stress. Because the nerve cells involved in ALS and Parkinson’s have high energy demands, they are particularly vulnerable to these mitochondrial abnormalities.

It’s thought that the abnormal accumulation of toxic protein clumps in both ALS and Parkinson’s may trigger mitochondrial dysfunction by opening a protein channel called mitochondrial permeability transition pore, or mPTP. This can trigger the release of DNA from mitochondria, which abnormally activates the immune system, causing mitochondria to swell and rupture, and contributing to neuronal death.

NRG identified a protein, which it dubbed Protein A, that is essential for the opening of the mPTP. NRG5051 is a first-in-class small molecule designed to target that undisclosed protein and potently inhibit the mPTP. The candidate was designed to be administered orally and to cross the blood-brain barrier, which normally prevents foreign substances from entering the brain and spinal cord.

Our ultimate objective is to establish the therapeutic efficacy of our novel mPTP inhibitors as disease-modifying medicines that are designed to slow or prevent the progression of neurodegenerative diseases, and this first-in-human trial is a significant step toward that goal.

In preclinical models of both ALS and Parkinson’s, NRG5051 reduced mPTP opening, prevented neuroinflammation and neuronal death, and improved motor function. The treatment also reduced levels of neurofilament light (NfL) chain, a marker of nerve cell death, according to the company.

Following the completion of the ongoing Phase 1 trial in healthy volunteers, NRG plans to advance NRG5051 into a proof-of-concept Phase 2 clinical trial in ALS, while also generating clinical data in Parkinson’s.

“Our ultimate objective is to establish the therapeutic efficacy of our novel mPTP inhibitors as disease-modifying medicines that are designed to slow or prevent the progression of neurodegenerative diseases, and this first-in-human trial is a significant step toward that goal,” Miller said.

On its website, NRG states: “NRG5051 has the potential to be the first disease-modifying therapeutic for sporadic ALS/MND [motor neuron disease] and for Parkinson’s.”