Evobrutinib may reduce lesions in relapsing MS
The oral BTK* inhibitor evobrutinib at a dose of 75 mg/day reduced the number of gadolinium-enhancing lesions in patients with relapsing multiple sclerosis (MS), according to a phase II trial presented at AAN 2019.
The multicentre, double-blind trial population comprised 261 adults (mean age 42.4 years, 69 percent female) with active relapsing-remitting or secondary progressive MS with superimposed relapses (87 and 13 percent, respectively) and EDSS** score of ≤6 (mean score, 3.3). They received oral evobrutinib at doses of 25 or 75 mg QD or 75 mg BID, open-label dimethyl fumarate (DMF; 120 mg BID for the first week followed by 240 mg BID), or placebo. After 24 weeks, placebo recipients received evobrutinib 25 mg QD (double-blinded) for another 24 weeks, while evobrutinib and DMF recipients continued with their assigned doses. The mean number of gadolinium-enhancing lesions at baseline was 1.54.
The mean number of MRI***-detected gadolinium-enhancing lesions between weeks 12 and 24 was lower among evobrutinib 75 mg QD or BID recipients (1.69 and 1.15, respectively) compared with evobrutinib 25 mg (4.06), DMF (4.78), or placebo recipients (3.85). [AAN 2019, program number S56.004; N Engl J Med 2019;doi:10.1056/NEJMoa1901981]
The high number of lesions among DMF recipients could be due to a single patient with a high lesion count at baseline and post-treatment, said the researchers.
The rate ratios (RR) of total number of lesions over time showed that only evobrutinib 75 mg QD significantly reduced the number of gadolinium-enhancing lesions compared with placebo (adjusted [adj] RR, 0.30, 95 percent confidence interval [CI], 0.14–0.63; p=0.005), with the effects of evobrutinib 25mg (adjRR, 1.45, 95 percent CI, 0.72–2.91; p=0.32) and 75 mg BID (adjRR, 0.44, 95 percent CI, 0.21–0.93; p=0.06) not significantly different from that of placebo.
The effect of evobrutinib on the number of gadolinium-enhancing lesions between weeks 24 and 48 was comparable among doses.
At 24 weeks, there were 13 relapses among evobrutinib 25 mg QD recipients, three and two relapses among evobrutinib 75 mg QD and BID, respectively, and nine and five relapses among placebo and DMF recipients, respectively. Annualized relapse rates did not significantly differ between placebo (0.37), evobrutinib 25 mg (0.57), and evobrutinib 75 mg QD or BID (0.13 and 0.08, respectively) recipients.
At 24 weeks, 77, 74, 88, 87, and 89 percent of placebo, evobrutinib 25 mg, 75 mg QD, 75 mg BID, and DMF recipients were relapse-free, with similar results at 48 weeks. There was no change in median EDSS score from baseline to weeks 24 and 48 in all groups.
The lesion rate ratio for new or enlarging lesions of 0.42 in the evobrutinib 75 mg BID group at week 24 suggested that patients who received this dose had better responses than those receiving other evobrutinib doses, the researchers noted.
At 52 weeks, grade 3–4 adverse events (AEs) occurred most frequently in evobrutinib 75 mg QD and BID and DMF recipients (13, 15, and 13 percent, respectively), while serious AEs were most common in evobrutinib 75 mg BID recipients (7 percent). Infections affected more patients on evobrutinib 25 mg and placebo–evobrutinib 25 mg (30–33 percent) than other doses or treatments. The most frequent evobrutinib-related AEs were nasopharyngitis and ALT, AST, and lipase level elevations. In the first 24 weeks, reductions in lymphocyte counts were comparable between evobrutinib and placebo recipients, with a greater proportion of DMF recipients experiencing lymphocyte decreases. AE-related discontinuations were most common in evobrutinib 75 mg QD and BID recipients, primarily due to ALT, AST, and lipase elevations.
“[I]n patients with relapsing MS, the inhibition of BTK with evobrutinib at a dose of 75 mg once daily, but not at doses of 75 mg twice daily or 25 mg once daily reduced the total number of enhancing MRI lesions, as compared with placebo, at weeks 12 through 24 [of the trial],” said the researchers.
They suggested that “hepatic risk-mitigation strategies and stopping rules” could be incorporated in future trials, seeing as how most evobrutinib-related discontinuations were liver-related.