ObjectivePrevious studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF‐kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose‐ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).MethodsSixty‐nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5–300 mg/day.ResultsOmaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (P = 0.0001) and by 2.3 points versus placebo (P = 0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (P < 0.0001) and by 4.4 points versus placebo (P = 0.01) at the 160 mg/day.InterpretationTreatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.
ObjectiveTo investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.MethodsIn cohorts of 8–13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).ResultsNo differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.ConclusionsOmaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.Clinicaltrials.gov identifierNCT02255422.Classification of evidenceThis study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.
BackgroundTopical application of the synthetic triterpenoid RTA 408 to rodents elicits a potent dermal cytoprotective phenotype through activation of the transcription factor Nrf2. Therefore, studies were conducted to investigate if such cytoprotective properties translate to human dermal cells, and a topical lotion formulation was developed and evaluated clinically.MethodsIn vitro, RTA 408 (3–1000 nM) was incubated with primary human keratinocytes for 16 h. Ex vivo, RTA 408 (0.03, 0.3, or 3 %) was applied to healthy human skin explants twice daily for 3 days. A Phase 1 healthy volunteer clinical study with RTA 408 Lotion (NCT02029716) consisted of 3 sequential parts. In Part A, RTA 408 Lotion (0.5 %, 1 %, and 3 %) and lotion vehicle were applied to individual 4-cm2 sites twice daily for 14 days. In Parts B and C, separate groups of subjects had 3 % RTA 408 Lotion applied twice daily to a 100-cm2 site for 14 days or a 500-cm2 site for 28 days.ResultsRTA 408 was well-tolerated in both in vitro and ex vivo settings up to the highest concentrations tested. Further, RTA 408 significantly and dose-dependently induced a variety of Nrf2 target genes. Clinically, RTA 408 Lotion was also well-tolerated up to the highest concentration, largest surface area, and longest duration tested. Moreover, significant increases in expression of the prototypical Nrf2 target gene NQO1 were observed in skin biopsies, suggesting robust activation of the pharmacological target.ConclusionsOverall, these data suggest RTA 408 Lotion is well-tolerated, activates Nrf2 in human skin, and appears suitable for continued clinical development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12895-015-0029-7) contains supplementary material, which is available to authorized users.
Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and-most criticallypatients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.
Background: Omaveloxolone (Omav) reduces production of reactive oxygen and nitrogen species by myeloid derived suppressor cells (MDSCs) and restores immune surveillance in preclinical cancer models. Administration of Omav with checkpoint inhibitors (CI) may enhance the anti-tumor immune response of immunotherapies. A Phase 1b/2 study was designed to evaluate the safety and efficacy of Omav in combination with ipilimumab (Ipi) or nivolumab (Nivo) for treatment of patients with unresectable or metastatic melanoma. Data from the ongoing Phase 1b study are reported. Methods: Patients with or without prior exposure to CI, and with >5% of tumor cells from a screening biopsy positive for inducible nitric oxide synthase (iNOS) were enrolled. Serial biopsies were also collected at Weeks 2 and 13. Omav monotherapy (5, 10, 20, 100, or 150 mg PO QD) was dosed continuously starting one week prior to CI initiation (Ipi x 4 doses or Nivo q 2 weeks). Primary objectives were safety, MTD, and ORR measured via RECIST v1.1. Results: At data cutoff, 39 patients were enrolled (Omav þ Ipi: n ¼ 12; Omav þ Nivo: n ¼ 27) with median treatment duration of 13 weeks. Of 30 patients with evaluable tumor restaging, 7/30 (23%) of patients were CI-naïve, while 23/30 (77%) of patients were refractory to prior CI therapy. The ORR (confirmed þ unconfirmed) observed in all evaluable patients was 8/30 (27%, 6 partial response (PR) and 2 complete response (CR)) and 4/7 (57%) in CI-naïve patients, including 1 CR. 3/18 (17%) patients treated with Omav þ Nivo who were refractory to prior CI therapies had objective responses including 1 CR. Omav was associated with decreases in tumor iNOS, PD-L1, and IDO-1 expression. The MTD for Omav has not been established since no dose-limiting toxicities were observed. No serious AEs considered related to Omav have been reported to date. Commonly reported treatment-related adverse events included fatigue, nausea, pruritus, transaminase increases and decreased appetite. Conclusions: Omav was well tolerated at doses up to 150 mg in combination with CI and initial efficacy data suggest that Omav may overcome CI resistance. The Phase 2 portion of the trial will study the effects of Omav with Nivo in patients refractory to prior anti-PD-1/PD-L1 therapies.
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