Assessment of Hepatic Safety in Patients with Friedreich’s Ataxia in the MOXIe Trial of Omaveloxolone

S.H. Subramony, MD, University of Florida Health System, David Lynch, MD, PhD, Children's Hospital of Philadelphia, Martin Delatycki, MD, PhD, Murdoch Children’s Research Institute, Deborah Ferguson, PhD, Reata Pharmaceuticals, Angie Goldsberry, MS, Reata Pharmaceuticals, Seemi Khan, MD, Reata Pharmaceuticals, Caterina Mariotti, MD, Istituto Neurologico Carlo Besta, Katherine Mathews, MD, FAAN, University of Iowa, Colin Meyer, MD, Reata Pharmaceuticals, Masako Murai, 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, Isaac Trevino, Reata Pharmaceuticals, Christian Wigley, PhD, Reata Pharmaceuticals, George Wilmot, MD, PhD, Emory University School of Medicine, Theresa Zesiewicz, MD, University of South Florida Ataxia Research Center. Muscular Dystrophy Association, conference posters 2023. Here, we present analyses of laboratory parameters associated with hepatic functio (MOXIe Part 2 (NCT02255435)). 

The majority of AEs were mild to moderate in severity. There were no deaths. The distribution of hepatobiliary disorder AEs was similar between treatment groups, with 2 events in the omav group (n=51) and 1 in the placebo group (n=52). ALT increases were reported as AEs in 37.3% of patients in the omav group versus 1.9% of patients in the placebo group. AST increases were reported as AEs in 21.6% of patients in the omav group versus 1.9% of patients in the placebo group. GGT increases were reported in 5.9% of patients in the omav group versus no patients in the placebo group. Discontinuations due to ALT or AST elevation occurred in one patient in the omav group (2%) and no patients in the placebo group. Among omav-treated patients, most (68.6%) had maximum ALT and AST increases of ≤ 3 times the upper limit of normal (ULN). None had ALT and AST increases of ≥10 times the ULN. ALT and AST elevations were mild to moderate, transient, and reversible after drug discontinuation. Maximal values occurred within the first 12 weeks of treatment. No aminotransferase increase was associated with concurrent increases in total bilirubin, and no Hy’s Law cases were observed. Nonclinical data show omav modulates aminotransferase gene expression. No new safety signals were observed in the OLE, at the last data-cut (March 24th, 2022). 

Conclusions Omav was well tolerated and had a manageable hepatic safety profile in clinical studies in patients with FA.

Assessment of Cardiac Safety in Patients with Friedreich’s Ataxia in the MOXIe Trial of Omaveloxolone

S.H. Subramony, MD, University of Florida Health System, David Lynch, MD, PhD, Children's Hospital of Philadelphia, Martin Delatycki, MD, PhD, Murdoch Children’s Research Institute, Angie Goldsberry, MS, Reata Pharmaceuticals, Seemi Khan, MD, Reata Pharmaceuticals, Caterina Mariotti, MD, Istituto Neurologico Carlo Besta, Katherine Mathews, MD, FAAN, University of Iowa, Colin Meyer, MD, Reata Pharmaceuticals, Masako Murai, 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, George Wilmot, MD, PhD, Emory University School of Medicine, Theresa Zesiewicz, MD, University of South Florida Ataxia Research Center. Muscular Dystrophy Association, conference posters 2023. 

Here, we present post-hoc analyses of cardiac safety assessments performed during MOXIe Part 2. Cardiac adverse events (AEs) occurred in 9.8% of patients receiving omav (n=51) as compared to 13.5% of those receiving placebo (n=52). A standardized medical query revealed no imbalances for arrhythmia-related AEs (5 in omav group and 5 in placebo group). In patients with a medical history of cardiomyopathy, no imbalances in cardiovascular AEs were observed (12% in omav group and 13.3% in placebo group). Only one cardiac serious AE (SAE), atrial fibrillation, was reported in more than one patient, and it was reported in one patient each in placebo and omav groups. Two additional patients in the omav group reported cardiac SAEs. No clinically significant changes were observed between groups in echocardiogram, electrocardiogram, heart rate and blood pressure assessments. Slight increases in BNP and NT-Pro-BNP were observed only in the omav-treatment group but occurred without signs or symptoms of fluid retention. Mean values remained below the ULN of 100 pg/mL. Although mean cholesterol values were higher in the omav group than in the placebo group, the values remained within normal limits. The OLE trial is ongoing, with data in MOXIe accrued up to 4.3 years, as of the last data-cut of March 24th, 2022. No new cardiac safety signals have been observed. There were no deaths in the study and the majority of all adverse events were mild to moderate in severity. 

Conclusions Omav was well tolerated and had a manageable cardiac safety profile in MOXIe Part 2.