Oral ALS treatment lowers toxic protein levels, extends survival

Oral amyotrophic lateral sclerosis (ALS) treatment PrimeC significantly reduced levels of TDP-43, a protein that abnormally accumulates in nearly all ALS cases, in a Phase 2b clinical trial.

The PARADIGM study met its main efficacy goal of lowering TDP-43 levels in nerve cells relative to a placebo after six months. The reduction was sustained and became more pronounced over the full 18 months of the study, according to developer Neurosense Therapeutics.

The results add to previously reported PARADIGM data showing that PrimeC slowed declines in daily functioning and extended survival among people with ALS, while having a favorable safety profile.

“Achieving the primary endpoint of PARADIGM with a statistically significant reduction in TDP-43 marks a defining moment for NeuroSense and for ALS research,” Alon Ben-Noon, Neurosense’s CEO, said in a company press release. “We believe this growing dataset further validates our scientific approach and positions PrimeC as one of the most comprehensively supported therapeutic candidates in ALS today.”

In ALS, motor neurons (the nerve cells responsible for controlling voluntary movement) gradually become damaged and die. This leads to progressive muscle weakness and increasing difficulties with movement, speaking, swallowing, and breathing.

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TDP-43 is a protein involved in regulating RNA, the molecule that carries genetic instructions needed to make proteins. In most ALS cases, TDP-43 becomes misplaced and forms abnormal clumps inside nerve cells. This is believed to disrupt several essential cellular processes and contribute to nerve cell death.

PrimeC is an extended-release oral combination of two approved medications: the antibiotic ciprofloxacin and the anti-inflammatory medicine celecoxib. The therapy is designed to simultaneously target several mechanisms thought to contribute to ALS progression, including inflammation, abnormal iron accumulation, and disrupted RNA regulation.

The Phase 2b PARADIGM trial (NCT05357950) involved 68 adults with ALS who were randomly assigned to receive a placebo or PrimeC for six months, in addition to standard ALS treatments. Participants could then enter an open-label extension in which all received PrimeC for up to an additional year.

To assess whether PrimeC reduced TDP-43 accumulation, researchers measured TDP-43 in neuron-derived extracellular vesicles, small sacs released by nerve cells into the bloodstream. This allowed the researchers to distinguish nerve-derived TDP-43 from TDP-43 released by other cell types and tissues.

After 180 days, or about six months, TDP-43 levels were significantly lower among participants given PrimeC than in those receiving a placebo. Consistent with previous studies, TDP-43 levels increased in the placebo group.

These reductions were sustained and deepened over the full 18 months of PARADIGM. Participants who continuously received PrimeC throughout the study maintained lower TDP-43 levels than those who received a placebo for the first six months and then transitioned to PrimeC.

“One of the central questions in ALS drug development is whether a therapy is truly affecting the underlying biology of the disease,” said Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital and professor of neurology at Harvard Medical School.

The results are consistent with earlier findings from PARADIGM. PrimeC slowed declines on the ALS Functional Rating Scale-Revised, which assesses one’s ability to perform everyday activities, by 36.5% after one year and by 32.8% after 18 months.

Long-term data showed an approximately 15-month extension in median survival and a 65% reduction in the risk of death among participants who started PrimeC at the beginning of the study compared with those whose treatment was delayed by six months.

“For decades, TDP-43 has been recognized as the pathological signature of ALS, yet demonstrating a treatment-associated reduction in people with ALS has remained elusive,”  Ben-Noon said. “Combined with the clinically meaningful slowing of disease progression, significant survival benefit, and consistent biomarker findings previously reported from PARADIGM, these results provide a compelling and highly differentiated body of evidence supporting PrimeC’s potential as a disease-modifying therapy.”

PrimeC was generally well tolerated, with no new safety concerns identified over up to 18 months of treatment.

“These results provide compelling data supporting advancement into a confirmatory Phase 3 clinical trial,” Cudkowicz said.

To confirm PARADIGM’s findings, Neurosense is planning a global, pivotal Phase 3 clinical trial, called PARAGON, enrolling approximately 300 people with ALS across the U.S. and Europe. The trial has received U.S. Food and Drug Administration (FDA) clearance.

In the meantime, the company is in talks with regulators in several countries, including Canada, where it plans to request expedited conditional approval.