ABSTRACT
BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 µg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. FUNDING: Minoryx Therapeutics.
Subject(s)
Adrenoleukodystrophy , Adult , Male , Humans , Treatment Outcome , Adrenoleukodystrophy/drug therapy , France , Double-Blind Method , Disease ProgressionABSTRACT
Background and Objectives: Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator-activated receptor γ agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study. Methods: In this double-blind, randomized controlled trial, eligible participants (age 12-60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2-6, inclusive. Key exclusion criteria were age at FRDA onset ≥25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and total N-acetylaspartate to myo-inositol (tNAA/mIns) ratio. Results: Overall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares [LS] mean change [standard error (SE)]: 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 (LS mean change [SE]: leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb; p = 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change [SE]: leriglitazone, 0.03 [0.02]; placebo, -0.02 [0.03]; p = 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%). Discussion: The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA. Trial Registration Information: ClinicalTrials.gov: NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019. clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1. Classification of Evidence: This study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.
ABSTRACT
Membrane fusion induced by the envelope glycoprotein enables the intracellular replication of HIV-1; hence, this process constitutes a major target for antiretroviral compounds. It has been proposed that peptides having propensity to interact with membrane interfaces might exert broad antiviral activity against enveloped viruses. To test this hypothesis, in this contribution we have analyzed the antiviral effects of peptides derived from the membrane-proximal external region and the transmembrane domain of the envelope glycoprotein subunit gp41, which display different degrees of interfacial hydrophobicity. Our data support the virucidal activity of a region that combines hydrophobic-at-interface membrane-proximal external region aromatics with hydrophobic residues of the transmembrane domain, and contains the absolutely conserved 679LWYIK/R683 sequence, proposed to embody a "cholesterol recognition/interaction amino acid consensus" motif. We further sought to correlate the antiviral activity of these peptides and their effects on membranes that mimic lipid composition and biophysical properties of the viral envelope. The data revealed that peptides endowed with virucidal activity were membrane active and induced permeabilization and fusion of virus-like lipid vesicles. In addition, they modulated lipid packing and miscibility of laterally segregated liquid domains, two properties that depend on the high cholesterol content of the viral membrane. Thus, the overall experimental evidence is consistent with a pattern of HIV inhibition that involves direct alteration of the physical chemistry of the virus membrane. Furthermore, the sequence-dependent effects observed might guide the development of new virucidal peptides.
