Leriglitazone for Friedreich’s ataxia
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What is leriglitazone Friedreich’s ataxia?
Leriglitazone (MIN-102) is an investigational oral medication being developed by Minoryx Therapeutics for Friedreich’s ataxia (FA) and other diseases of the brain and spinal cord. It has reported antioxidant and anti-inflammatory properties, and helps to restore the functioning of mitochondria, the so-called “power plants” of cells.
The therapy has received orphan drug status in the U.S. and Europe for treating FA patients. It’s also received orphan drug and fast-track designations for treating adrenoleukodystrophy, a rare genetic disorder of the nervous system and the adrenal glands, which sit on top of each kidney.
Therapy Snapshot
| Treatment name: | Leriglitazone |
| Administration: | Being tested in FA as an oral liquid |
| Clinical testing: | Phase 2 trial for FA completed |
How does leriglitazone work in FA?
In FA, mutations in the FXN gene lead to a deficiency in the frataxin protein. Frataxin is important for mitochondria’s proper functioning, so its loss in FA is associated with a lack of cellular energy and a type of cellular damage called oxidative stress that drives neurodegeneration.
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a type of protein, called a transcription factor, that regulates the synthesis of other proteins. One of its roles is to work together with a protein called PGC-1-alpha to manage the generation of mitochondrial proteins.
Leriglitazone belongs to a class of molecules called PPAR-gamma agonists, which work to induce PPAR-gamma signaling. It was designed to have better entry into the brain and spinal cord than related compounds.
In doing this, it’s believed the treatment would restore mitochondrial function and energy production, boosting nerve cell survival and improving motor function in FA, as demonstrated in preclinical studies.
How will leriglitazone be administered in FA?
In a clinical trial involving FA patients, leriglitazone was given as a liquid oral suspension once a day.
The specific starting dose was individualized based on sex and age — 150 mg for adult men, 130 mg for adult women, and 2.2 mg/kg of body weight for adolescents, ages 12-17. Maintenance doses were modified based on pharmacological properties and tolerability.
Leriglitazone in clinical trials
A Phase 1 clinical trial was conducted in 33 healthy male volunteers to assess the safety, tolerability, and pharmacological properties of single and multiple doses of leriglitazone.
Leriglitazone was found to be safe and well tolerated. No serious side effects were reported and biomarker assessments indicated successful PPAR-gamma receptor activation. Leriglitazone reached its target in the brain, results showed.
FRAMES trial
The Phase 2 FRAMES clinical trial (NCT03917225) evaluated the safety and efficacy of leriglitazone against a placebo in 39 FA patients, ages 12-60, at five sites in Europe.
Participants were randomly assigned to receive an oral suspension of leriglitazone at an individualized dose or a placebo once daily for about a year.
The main goal was to assess the treatment’s effects on spinal cord atrophy (wasting) after a year of treatment, which is generally thought to correlate with clinical disease progression. The change in cervical spinal cord area on a MRI from the study’s start didn’t significantly differ between the leriglitazone and placebo groups, failing to meet the trial’s main goal. However, little evidence of disease progression was observed in either group throughout the trial.
Most other MRI measures in the brain and spinal cord also failed to show a significant effect of leriglitazone, and no significant differences were observed in other patient- and clinician-reported measures of disease severity and quality of life.
Some secondary endpoints suggested a potential benefit of leriglitazone regarding metabolic improvements, including reduced iron accumulation in the brain. It was also found to prevent a decline in upper limb ataxia compared with a placebo.
Common side effects of leriglitazone
The most common side effects associated with leriglitazone in the FRAMES trial include:
- Peripheral edema (swelling that usually occurs in the legs)
- Face swelling
- Increases in cardiac biomarkers
- Weight gain.
Swelling events are consistent with the known safety profile of PPAR-gamma agonists used in people with diabetes. Most cases of swelling or edema occurred during the first three months of treatment and were managed by dose reductions and diuretics to reduce fluid retention.
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FAQs about Leriglitazone
A Phase 2 clinical trial testing leriglitazone in people with Friedreich’s ataxia has been completed, but it didn’t meet its main efficacy goal. Because the safety and efficacy of leriglitazone haven’t been fully established, it’s not known if or when the treatment will be approved in the U.S.
An experimental therapy not yet approved for Friedreich’s ataxia (FA), leriglitazone is designed to increase cellular energy production, which is deficient in FA, thereby easing symptoms of the disease.
Existing clinical trial data don’t mention an interaction between leriglitazone and alcohol, however, the treatment is still in early stages of development. More information is needed about leriglitazone’s potential interactions with other substances.
Leriglitazone is still in the early stages of clinical development, but existing clinical trial data didn’t find a benefit of the therapy in Friedreich’s ataxia (FA) patients over a year of treatment with respect to spinal cord atrophy (wasting), a measure that’s thought to correlate with clinical disease progression. Data on secondary measures, however, suggested a potential benefit of leriglitazone regarding metabolic biomarkers and in preventing a decline in upper limb ataxia after 48 weeks of treatment. Additional clinical trial data will be needed to further establish the potential benefits of leriglitazone in FA.
The most common side effects associated so far with leriglitazone in clinical trials include swelling (edema) in the legs, face, or other areas, along with weight gain and increases in certain cardiac markers. These side effects are consistent with the known safety profile of PPAR-gamma agonists, the family of molecules to which leriglitazone belongs.
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