Safety Monitoring of Omaveloxolone in Friedreich Ataxia: Results from One Year of Clinical Treatment

Abstract

Introduction: Omaveloxolone, the only approved medication for Friedreich ataxia (FRDA), is an NRF2 activator available since July 2023. We examined safety monitoring of omaveloxolone administration over the first 12 months of administration.

Methods: We recorded baseline and follow-up serum transaminase, albumin, total bilirubin, cholesterol, and brain natriuretic peptide (BNP) values as well as adverse events over 1 year in patients initiating commercial omaveloxolone therapy.

Results: Access to omaveloxolone was obtained in 236 of individuals for whom it was prescribed. Side effects were noted in 23.8% of patient with the most common being gastrointestinal upset, headache, and fatigue baseline. Twenty-one patients (8.9%) permanently discontinued the drug during the first year. Over the first year, 56.6% of patients had at least one transaminase value above the upper limit of normal at some point. Elevations largely occurred over the first 3 months of therapy, and after 6 months of dosing, only 8.6% of patients had elevations in transaminases. Elevations were generally < 3 × the upper limit of normal and decreased with temporary pausing of the drug or dose reduction. Few changes were noted in albumin or bilirubin, and such changes did not parallel changes in transaminases, suggesting they are independent events. BNP values were generally unchanged throughout the year, and no systematic changes in blood counts were noted. Cholesterol and low-density lipoprotein (LDL) elevations were mild.

Conclusions: Most patients with FRDA eventually had access to omaveloxolone, and it was generally well tolerated. Side effects were modest, and, overall, most patients remained on the drug. Abnormalities in serum liver function tests were limited to transaminases, resolved with dose pausing or reduction, and diminished markedly over time. Thus, the safety features of omaveloxolone after administration largely resemble the favorable features noted during clinical trials.

Keywords: Brain natriuretic peptide; Mitochondria transaminase; Movement disorder; Omaveloxolone.

Fig. 1

Change in hepatic function testing over time. Alanine aminotransferase (ALT) levels (A) compared to the upper limit of normal (ULN) over time on omaveloxolone. ALT levels typically increased after starting omaveloxolone and leveled out after continuation or dose modification. Transaminase elevations (any value greater than the upper limit of normal) occurred in many subjects, with 56.6% of patients having an elevation in transaminases at some point over the 12-month period (p < 0.0001). At 1 month, 55.0% of patients had elevated ALT values with 12.1% above 3 × ULN (both p < 0.0001). At 2 months, 48.9% (p < 0.0001) of patients had elevations with 4.4% (p < 0.003) above 3 × ULN. At 3 months, 39.2% (p < 0.0001) had elevations with 4.4% (p < 0.003) above 3 × ULN. At 6 months, 35.2% (p < 0.0001) had elevations with 3.6% (p < 0.003) above 3 × ULN. At 12 months, 16.6% of patients had elevations (p < 0.0001), but none were > 3 × the ULN. B Aspartate aminotransferase (AST) levels were compared to the upper limit of normal (ULN) over time on omaveloxolone. Increases in AST levels correlated with increases in ALT levels but at lower magnitude. C Albumin levels over time on omaveloxolone. The low outlier (green line) is attributed to a comorbidity (pneumonia) while other outliers appear unrelated as they did not correlate to increases in transaminases. D Total bilirubin levels over time while on omaveloxolone. Two notable outliers had comorbidities that caused increases in bilirubin unrelated to omaveloxolone. One patient with biliary atresia (dark blue line) had increased bilirubin at baseline and discontinued the drug because of GI side effects. The other notable patient had Gilbert's syndrome (orange line) associated with increased indirect bilirubin. Gastrointestinal (GI)

Fig. 2

Change in a single subject excluded during MOXIe. Separate ALT graph of a single patient excluded from MOXIe because of persistent increased ALT. Multiple dose reductions with slowly increasing doses of commercial omaveloxolone allowed achieving the full dose. Alanine aminotransferase (ALT)

Fig. 3

Change in cholesterol, LDL, and BNP. A Total cholesterol (× ULN) at baseline and 12 months after 12 months of treatment. Patients had an average 0.07 (± 0.16) point increase relative to the ULN after 12 months of omaveloxolone. B LDL cholesterol (× ULN) at baseline and 12 months after 12 months of treatment. Patients had an average 0.24 (± 0.16) point increase relative to the ULN after 12 months of omaveloxolone. C BNP at baseline and at 12 months of treatment. BNP remained relatively unchanged. Outliers generally had pre-existing cardiac disease, potentially explaining fluctuations in BNP measurements. Upper limit of normal (ULN), brain natriuretic peptide (BNP), low-density lipoprotein (LDL)