Efficacy of Omaveloxolone in Patients with Friedreich’s Ataxia: Update of the Delayed-Start Analysis

Topic:

Clinical Trials

Poster Number: 121

Author(s):

David Lynch, MD, PhD, Children's Hospital of Philadelphia, Martin Delatycki, MD, PhD, Murdoch Children’s Research Institute, Angie Goldsberry, MS, Reata Pharmaceuticals, Caterina Mariotti, MD, Istituto Neurologico Carlo Besta Katherine Mathews, MD, FAAN, The University of Iowa Colin Meyer, MD, Reata Pharmaceuticals, Wolfgang Nachbauer, MD, PhD, Medical University Innsbruck, Lorenzo Nanetti, MD, Istituto Neurologico Carlo Besta, Susan Perlman, MD, University of California Los Angeles, S.H. Subramony, MD, University of Florida Health System George Wilmot, MD, PhD, Emory University School of Medicine, Theresa Zesiewicz, MD, University of South Florida Ataxia Research Center

Background and Objective Friedreich’s ataxia (FA) is a rare, degenerative neuromuscular disease with no available therapies. Omaveloxolone (Omav), an investigational drug, is an activator of the transcription factor, Nrf2. MOXIe (NCT02255435) was a 2-part study of the safety and efficacy of Omav in patients with FA that included an open-label extension (OLE). MOXIe Part 2 showed that Omav significantly improved modified FA Rating Scale (mFARS) scores by -2.40 points relative to placebo after 48 weeks of treatment (p=0.014; n=82). Methods Patients in both MOXIe study parts were eligible to receive Omav in the OLE; only patients who participated in Part 2 were included in the Delayed-start analysis. In MOXIe Part 2, the full analysis set (FAS) included patients without severe pes cavus. In the FAS, a post-hoc, non-inferiority test was performed to assess if the difference in mFARS change from baseline between the Omav and placebo groups at the end of the 48-week placebo-controlled period (MOXIe Part 2) was sustained in the delayed-start period (defined as Week 72 in the OLE for the primary endpoint) using a single mixed model repeated measures model with all available data from the MOXIe Part 2 and data through Week 144 in the OLE. Results Seventy-three patients from MOXIe Part 2 FAS went on to receive Omav in the OLE. This included 34 patients who were originally randomized to Omav (i.e, Early-Start group) and 39 patients who were originally randomized to placebo (i.e., Delayed-Start group). The noninferiority testing demonstrated that the difference in mFARS scores between the Early-Start and Delayed-Start groups observed at the end of MOXIe Part 2 (-2.17 ± 1.09 points) was preserved at the end of the delayed-start period (-2.91 ± 1.44 points). Additionally, patients in the Delayed-Start group had an annualized mFARS slope (0.76 ± 0.28 points/year) that was not convergent with the slope for the Early-Start group (0.45 ± 0.63 points/year); both slopes were less than the expected 1 to 2 points per year observed in natural history data. Conclusions The results of this post-hoc delayed-start analysis showed a persistent effect of early treatment on the disease course that could not be recovered by patients who only received omaveloxolone in the OLE. While treatment benefit was observed in both the Early-Start and Delayed-Start groups, compared with published natural history data, patients who started treatment earlier had a greater ben