Collaboration to study PrimeC’s impacts on ALS disease mechanisms

Therapy combines antibiotic ciprofloxacin, anti-inflammatory celecoxib

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by Andrea Lobo |

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NeuroSense Therapeutics has joined researchers at Massachusetts General Hospital to study the impact of its investigational therapy PrimeC on key amyotrophic lateral sclerosis (ALS) processes.

The collaboration will the headed by Ghazaleh Sadri-Vakili, director of the Neuroepigenetics laboratory at the MassGeneral Institute for Neurodegenerative Disease. Using a new laboratory model generated from post-mortem brain tissue samples, the researchers seek to know more about PrimeC’s mechanisms of action in ALS.

“We are excited to join NeuroSense in its mission to advance PrimeC for people living with ALS,” Sadri-Vakili said in a company press release. “Our in vitro model may serve as an effective tool to increase our understanding of PrimeC’s neurotherapeutic mechanism of action.”

PrimeC is an extended-release oral formulation that combines a fixed dose of the antibiotic ciprofloxacin and the anti-inflammatory celecoxib. Both are individually approved by the U.S. Food and Drug Administration and have established safety profiles.

The combination therapy is thought to target multiple disease processes in ALS, including iron accumulation, faulty RNA processing, inflammation, and motor nerve cell degeneration.

In a previous Phase 2a trial (NCT04165850), the original formulation of PrimeC markedly reduced levels of ALS biomarkers and showed trends toward lower disease progression rates and lung function declines compared with historical controls.

In particular, it reduced the amount of TDP-43, a protein that’s abnormal in most ALS cases, in neuron-derived exosomes (NDEs) — packets of cellular cargo released by nerve cells into the extracellular space.

As part of the new collaboration, Sadri-Vakili and her team will explore how PrimeC affects TDP-43 accumulation in patients. The scientists will also try to unravel how it works to reduce other disease mechanisms, including defects in autophagy (the process by which cells recycle faulty or unwanted molecules) and abnormalities in mitochondria, the cells energy-producing factories.

Its impact on oxidative stress, another ALS-related process caused by an imbalance between reactive oxygen-containing molecule production and the body’s ability to clear them, will also be investigated.

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 Study to explore PrimeC’s effects on oxidative stress, mitochondrial defects

To address that, the researchers will use vesicles derived from nerve tissue from ALS patients and control subjects after death. The team has shown these vesicles can induce oxidative stress and mitochondrial defects in cell cultures.

They aim now to see how much these processes are impaired when cells are treated with the vesicles in the presence of PrimeC. They’ll also compare the effects of the individual components of PrimeC, celecoxib and ciprofloxacin, with those seen with the combination therapy.

“We are pleased to formally establish this important collaboration with Dr. Sadri-Vakili’s team, where we hope to elucidate PrimeC’s efficacy via key measurements that correlate with our Phase 2b ALS study endpoints,” said Shiran Zimri, PhD, vice president of research and development at NeuroSense.

PrimeC was granted orphan drug status in the U.S. in 2020 and in Europe the following year. The designation is given to potential treatments for rare diseases to accelerate their development and possible regulatory review.

The extended-release formulation of PrimeC is being investigated in the Phase 2b PARADIGM trial (NCT05357950). The trial is enrolling about 69 patients, ages 18-75, at multiple sites in Israel, Canada, Germany, and Italy.

In addition to standard ALS therapies, participants will be randomly assigned to receive PrimeC — two oral tablets twice daily for a total of 1,496 mg a day — or a placebo for six months.

The trial’s main goals are to determine the therapy’s safety and impact on disease biomarkers. Other, secondary measures include changes in the rate of disease progression, lung function and quality of life declines, and survival. Top-line data are expected later this year.