Leriglitazone, an oral treatment candidate for Friedreich’s ataxia (FA), is well-tolerated and can significantly prevent ataxia worsening and iron buildup in the brain, according to top-line data from a Phase 2 trial.
The proof-of-concept study, called FRAMES (NCT03917225), also demonstrated that the therapy was able to improve a series of metabolic disease biomarkers. Yet, data on its effects on disease progression in the spinal cord, the study’s primary goal, were inconclusive.
According to Minoryx Therapeutics, the company developing leriglitazone, these findings confirm the treatment’s mechanism of action and support its further development as a therapy for FA.
“We believe that the Phase 2 FRAMES trial data shows promising proof of concept as a therapy for Friedreich’s ataxia, despite the inconclusive results of the primary endpoint, and provide a clear demonstration of the mechanism of action of leriglitazone,” Marc Martinell, PhD, CEO of Minoryx, said in a press release.
“We intend to initiate discussions with regulatory agencies to define the clinical development path forward to deliver this therapy to Friedreich’s ataxia patients as quickly as possible,” Martinell added.
FA is a progressive genetic disease in which the lack of frataxin — a protein normally found in mitochondria — causes defects in iron metabolism and abnormalities in mitochondria. This may lead to heart disease, nerve cell degeneration, and loss of muscle strength and coordination (ataxia). Mitochondria are the small cell compartments responsible for producing energy.
Leriglitazone (MIN-102) is a selective activator of PPAR gamma, a molecule needed for proper mitochondrial function, which is able to cross the blood-brain-barrier — the semi-permeable barrier separating the brain from harmful substances circulating in the blood — and reach the central nervous system (CNS, comprising brain and spinal cord).
Studies in animal models have shown that leriglitazone can interfere with signaling cascades that lead to mitochondrial abnormalities to restore energy production. Moreover, the experimental therapy has also been found to counteract brain inflammation, myelin loss, and nerve cell degeneration, making it a promising treatment candidate for several diseases affecting the CNS, including FA.
FRAMES was a proof-of-concept, double-blind, placebo-controlled trial that assessed the safety, tolerability, and preliminary efficacy of leriglitazone in a small group of FA patients.
Last year, the study completed participant recruitment, with 39 FA patients, ages 12–60, enrolled. From these, 32 completed the one-year study, in which they were randomly assigned to receive a daily oral suspension containing leriglitazone at a dose of 15 mg/ml, or a matched placebo.
The study’s primary goal was to assess whether leriglitazone is superior to a placebo at slowing FA progression, which was evaluated by analyzing changes in the spinal cord area on MRI scans.
Secondary goals included leriglitazone’s safety and tolerability, as well as its effects on certain disease biomarkers and functional disability scores.
Top-line data from the study now show that leriglitazone was able to interact and activate PPAR gamma, its intended target, in all treated patients.
The therapy also directly modulated signaling cascades involving frataxin, demonstrated by its ability to lower iron accumulation in the patients’ brains. Leriglitazone improved mitochondrial function and energy metabolism as well, which was measured by changes in a series of metabolic disease biomarkers.
Altogether, these findings demonstrated that leriglitazone elicited a series of effects that were consistent with its recently described mechanism of action in cellular and animal models of FA.
Moreover, compared with a placebo, treatment with leriglitazone also prevented patients from seeing their upper limb ataxia worsen. This beneficial effect was associated with consistent improvements in metabolic disease biomarkers and reductions in brain iron buildup.
“Clinical results from the Minoryx Phase 2 FRAMES clinical trial are promising,” said Alexandra Durr, MD, PhD, principal investigator and coordinator of FRAMES. “Specifically, the reduction in decline in upper limb ataxia in Friedreich’s ataxia patients demonstrate the potential of meaningful benefit in tackling this neurodegenerative condition.”
Durr is also professor at the Brain and Spine Institute of La Pitié-Salpêtrière University Hospital.
Despite these beneficial effects, leriglitazone’s effects on FA progression — assessed by changes in spinal cord area — were inconclusive, since no signs of disease progression were observed in patients treated with the placebo.
In general, leriglitazone was found to be safe and well-tolerated. The most common side effects, which were expected based on the therapy’s mechanism of action, were weight gain and swelling. Importantly, none of the patients were found to be at an increased risk of heart disease as a result of treatment.
Minoryx is planning to present full detailed data from FRAMES, which is also being used to inform the design of an upcoming confirmatory study, in the coming months. The company is also planning to discuss details of the new study with U.S. and European regulatory health authorities in the future.
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