Merck KGaA announced in December the top-line results of its failed phase III trials of evobrutinib, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, but few details were available at that time. Full results have now been presented by Dr. Xavier Montalban, Barcelona, Spain, at the ACTRIMS Forum conference, held February 29-March 2 in West Palm Beach, Florida.
The evolutionRMS 1 and 2 trials compared evobrutinib 45 mg BID (with food) with teriflunomide 14 mg/day for up to 156 weeks in 2290 patients with relapsing MS. The primary endpoint was annualized relapse rate (ARR). Secondary endpoints were the number of Gd+ lesions, number of new/enlarged T2 lesions, and change from baseline in neurofilament-light (NfL) at 12 weeks. In addition, there were prespecified pooled analyses of 12- and 24-week confirmed disability progression (CDP), 24-week confirmed disability improvement (CDI), Patient-Reported Outcome Measurement Information (PROMIS) for physical function and fatigue, and safety/tolerability.
Most patients (76%) were recruited from Eastern Europe; 42% were from Ukraine or Russia. Mean age of patients was 37 years and about 96% had RRMS. Mean time from MS symptom onset was 6.7 years, and mean EDSS score at entry was 2.7. About 63% of patients were treatment-naïve.
There were no significant differences in ARR between evobrutinib and teriflunomide in evolutionRMS 1 (0.15 vs. 0.14) or in evolutionRMS 2 (0.11 vs. 0.11). The proportion with 12-week CDP was 11.9% with evobrutinib vs. 13.0% with teriflunomide. The proportion with 24-week CDP was 7.7% and 7.1% respectively with the two treatments. The proportion with 24-week confirmed disability improvement was also similar (9.1% vs. 10.7%).
The mean number of Gd+ lesions was higher with evobrutinib compared to teriflunomide in both studies (0.5 vs. 0.35 and 0.5 vs. 0.31). However, the number of new/enlarging T2 lesions was lower with evobrutinib vs. teriflunomide in both trials (5.61 vs. 6.16 and 6.39 vs. 7.41). All comparisons were not significantly different.
Serum NfL at 12 weeks was comparable with the two treatments in evolutionRMS 1 (adjusted geometric mean 12.88 vs. 12.90 ng/L) and in evolutionRMS 2 (12.51 vs. 13.09 ng/L). sNfL was significantly lower with evobrutinib at several time points but showed no statistical difference at 96 weeks. Both treatments were associated with modest improvements in physical function and fatigue; differences were not significant.
Evobrutinib was associated with a slightly higher rate of serious adverse events (7.5% vs. 5.6%) and adverse events leading to discontinuation (12.0% vs. 10.6%). In the evobrutinib cohort there were three cases that met criteria for Hy’s Law (3x ULN for ALT or AST and 2 x ULN for bilirubin) (1 case with hepatitis C) compared to one case in the teriflunomide group. Liver enzymes normalized after drug discontinuation. The conclusion was that evobrutinib and teriflunomide have comparable efficacy, but evobrutinib has a less favourable safety profile.