Note: This story was updated May 27, 2020, to note a change in the protocol of the EVOLUTION trials, which are now comparing evobrutinib with Aubagio, rather than Avonex, along with updated NCT numbers.
The study, “Efficacy and Safety of the Bruton’s Tyrosine Kinase Inhibitor (BTKI) Evobrutinib in Relapsing Multiple Sclerosis Over 108 weeks: Open-label Extension to a Phase II Study,” was sponsored by Merck KGaA — known as EMD Serono in the U.S. and Canada — the company developing evobrutinib.
Evobrutinib works by blocking the activity of Bruton’s tyrosine kinase (BTK), a protein that is important for the activation of certain types of immune cells — like B-cells — that drive inflammation that damages the nervous system in MS.
Its efficacy and safety were evaluated in a Phase 2 clinical trial (NCT02975349) that enrolled 267 people with relapsing MS, which includes relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS).
In the initial trial, which lasted 48 weeks, participants were randomly assigned to one of five groups: three groups were given evobrutinib at different doses (25 mg once daily, 75 mg once daily, or 75 mg twice daily); a fourth was given a placebo; and the fifth was given Tecfidera (dimethyl fumarate), an approved oral therapy by Biogen.
Results from this part of the trial showed that evobrutinib, at 75 mg twice daily (highest dose tested), significantly reduced the annualized relapse rate compared to placebo — 0.11 vs. 0.37 relapses/year — with 79% of participants on this dose group remaining relapse-free after 48 weeks.
Participants were then invited to enroll in an open-label extension study (OLE), where all receive the active treatment at the dose determined to be the most effective and safe: in this case, evobrutinib at 75 mg twice daily.
Data presented at EAN come from an analysis of 213 patients who completed at least 60 weeks of treatment in the OLE study.
For those initially randomized to evobrutinib at 75 mg twice daily, this represents a total of 108 weeks (just over two years) of treatment. In these 44 patients, the annualized relapse rate observed after 48 weeks (0.11 relapses/year) was consistent with that seen at 108 weeks (0.12 relapses/year).
“These data demonstrate evobrutinib has a sustained and high impact on annualized relapse rate over 108 weeks,” Luciano Rossetti, head of global research and development for EMD Serono, said in a press release.
Notably, the relapse rate for this highest dose of evobrutinib was lower than for all other tested doses of evobrutinib, suggesting that this dosing schedule is best for preventing relapses.
Mathematical modeling suggested that the efficacy of this highest dose is likely attributable to the percentage of BTK molecules that are physically inhibited by evobrutinib, a process referred to as “BTK occupancy.”
“The largest and most sustained reduction in [annualized relapse rate] was achieved when BTK occupancy was [greater than] 95%, observed in nearly all [98%] patients receiving [75 mg evobrutinib twice daily],” the researchers wrote.
No new safety concerns were observed in the OLE study. The most common side effect of evobrutinib’s use was nasopharyngitis (more commonly known as a cold).
In the initial trial, some participants experienced an increase in blood markers of liver damage, but these increases were only observed in the main study, and were not found in the OLE.
“We are … encouraged by evobrutinib’s breadth of consistent safety data, including no increase of serious infections in more than 1,200 patients [treated across all clinical studies of evobrutinib in MS and other conditions] up to two years,” Rossetti said.
“The 108-week efficacy and safety data for evobrutinib through the double-blind and the OLE period are very robust,” added Xavier Montalban, MD, PhD, with Vall d’Hebron University Hospital in Spain, and a trial investigator. “This, combined with the high selectivity of evobrutinib, suggests that evobrutinib may offer a promising approach to MS treatment.”
Evobrutinib is being further evaluated in two Phase 3 clinical trials, EVOLUTION RMS 1 (NCT04338022) and EVOLUTION RMS 2 (NCT04338061). More than 1,800 people with relapsing MS will be enrolled and randomized to receive either evobrutinib or Sanofi‘s Aubagio (teriflunomide), or a placebo. This reflects a change to the trials’ original protocol, which called for evobrutinib to be compared with Biogen’s Avonex (interferon beta-1a).
These trials, which are not yet recruiting participants, are expected to conclude in 2023.
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