By Mary Vo, MD, PharmD
Assistant Professor of Neurology, Weill Cornell Medicine
SYNOPSIS: Friedreich ataxia (FRDA) is an autosomal, recessive, multisystemic disease characterized by progressive weakness, ataxia, and dysarthria starting in childhood and resulting in severe morbidity and premature death. There are no approved treatments for FRDA. With recent preclinical studies suggesting potential benefit of PPARPγ agonists in motor function and reduced radiographic disease activity, the current study explores the effect of leriglitazone, a PPARPγ agonist, in patients with moderate to severe FRDA.
SOURCE: Pandolfo M, Reetz K, Darling A, et al. Efficacy and safety of leriglitazone in patients with Friedreich ataxia: A phase 2 double-blind, randomized controlled trial (FRAMES). Neurol Genet 2022;8:e200034.
Friedreich ataxia (FRDA) is caused by a GAA expansion in intron 1 of the FXN gene, resulting in reduced frataxin protein. Frataxin is essential for mitochondrial iron-sulfur cluster molecule assembly, and deficiency results in mitochondrial dysfunction, oxidative stress, and abnormal iron metabolism. Affected patients experience progressive weakness, ataxia, speech disturbance, sensory loss, cardiomyopathy, skeletal deformities, and impaired glucose tolerance. The majority of cases are childhood- or adolescent-onset, with patients requiring use of a wheelchair within 15 years of diagnosis. Hypertrophic cardiomyopathy is a common cause of morbidity and mortality in FRDA patients. To date, there are no approved treatments for FRDA.
Dorsal root ganglia (DRG) and cerebellum are particularly vulnerable to the effects of frataxin depletion, reflected in magnetic resonance imaging (MRI) cervical cord volume loss and iron accumulation noted on magnetic resonance spectroscopy (MRS), respectively.
Leriglitazone is a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist that crosses the blood-brain barrier. PPARγ is an important regulator of mitochondrial biogenesis and function. Evidence of PPARγ and PPARγ coactivator pathway dysregulation has been found in lymphoblasts and fibroblasts of FRDA patients, and also in tissues of FRDA mouse models. Recent preclinical studies of leriglitazone suggest neuroprotection of DRG neurons, reduced cerebellar iron accumulation, and improved motor function in murine models. This Phase II, multicenter, double-blinded, proof-of-concept trial enrolled 22 men and 17 women with genetically confirmed FRDA. The mean age was 24 ± 10.7 years, with disease duration 10.5 ± 6.3 years and Scale for the Assessment and Rating of Ataxia score 12.6 ± 4.6.
Patients with late-onset disease or a history of cardiac disease were excluded. No significant differences were noted between the treatment and placebo groups.
Subjects were randomly assigned in a 2:1 ratio to receive oral leriglitazone or placebo for 48 weeks. MRI and MRS were performed in addition to clinical assessments and patient questionnaires. The primary endpoint was the change in spinal cord area at the level C2-C3 measured by T1-weighted MRI. Secondary endpoints were change in dentate iron deposition and cervical spinal cord total N-acetylaspartate (tNAA) to myo-inositol (mIns) ratio using the cerebellar composite functional scale score.
Twenty-six patients received leriglitazone and 13 received placebo, with six patients from the treatment group and one patient from the placebo group withdrawing from the study. Leriglitazone generally was well tolerated, with peripheral edema being the most commonly reported side effect in 73% of the treatment group. There was no significant difference between the two groups in change of spinal cord area from baseline to week 48 (leriglitazone, -0.39 [0.55] mm2; placebo, 0.08 [0.72] mm2; P = 0.61). Iron accumulation in the dentate nucleus was greater with placebo (leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb; P = 0.05). However, no significant differences in dentate iron concentration or tNAA/mIns ratio were observed in either group.
Limitations of the study included a small sample size and the inclusion of severely affected patients. The absence of measurable cervical cord volume change may be a result of the notion that cervical cord volume plateaus early in the disease course.
COMMENTARY
FRDA is a progressive neurological disease resulting in severe disability and early death. The current study explores the effect of leriglitazone, a selective PPARγ agonist, on FRDA disease activity.
Although primary and secondary measures were not met, the findings offer important insights into FRDA pathogenesis and the potential for targeted disease-modifying treatment. The current work highlights an important unmet clinical care gap.
Further long-term studies including patients with milder disease are needed to determine the efficacy of leriglitazone.
