Ublituximab’s Benefits Over Aubagio Seen in ULTIMATE Clinical Trials
The US FDA is expected to decide by Dec. 28 whether to approve ublituximab
Treatment with the experimental B-cell depleting therapy ublituximab significantly outperformed Aubagio (teriflunomide) at reducing relapse rates and the number of lesions in people with relapsing forms of multiple sclerosis (MS), according to updated data from the Phase 3 ULTIMATE clinical trials.
The two medications had comparable effects on disability progression over approximately two years of treatment, but there were more patients on ublituximab who experienced disability improvement, meaning a lessening in their disability.
Full results from the twin trials have been published in The New England Journal of Medicine, in the study “Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis.” The work was funded by ublituximab’s developer TG Therapeutics.
“We are extremely pleased that the results from the ULTIMATE I & II trials have been published in The New England Journal of Medicine,” Michael Weiss, chairman and CEO of TG Therapeutics, said in a company press release. “We believe ublituximab’s novel mechanism of action, coupled with the convenience of a one-hour infusion represents a potential advance for patients with [relapsing] MS and we are pleased that this publication will share the ULTIMATE I and II data with a broad audience.”
What is ulituximab?
Ublituximab is an anti-CD20 monoclonal antibody that is designed to destroy B-cells, a type of immune cell that plays a central role in MS-driving inflammation. The experimental medication is under review by the U.S. Food and Drug Administration, with a decision expected by year’s end.
“We continue to be singularly focused on working toward the potential approval of ublituximab by the December 28, 2022 … goal date, and if successful, being prepared to launch early next year,” Weiss said.
The identically designed Phase 3 trials ULTIMATE I (NCT03277261) and ULTIMATE II (NCT03277248) collectively enrolled 1,094 adults, ages 18 to 55, with relapsing forms of MS.
All participants had experienced at least two relapses in the two years prior to the study’s start, or at least one relapse or one inflammatory lesion in the prior year, and all had a score of 5.5 or lower on the expanded disability status scale, meaning they could walk at least short distances without an aid.
Half of the trial participants were randomly assigned to Aubagio, an approved oral MS therapy by Sanofi Genzyme. The other half were treated with ublituximab — which involved a four-hour infusion of 150 mg on the first day, then hour-long infusions of 450 mg on day 15 and every six months thereafter for about two years.
What were the results of the ULTIMATE trials?
The study’s main goal was to compare the two treatments’ effects on relapse rates. Results showed that average annual relapse rates were significantly lower on ublituximab than Aubagio: 0.08 vs. 0.19 relapses/year in ULTIMATE 1, and 0.09 vs. 0.18 relapses/year in ULTIMATE 2, representing a reduction in relapse rates of 59% and 49%, respectively.
Data from MRI scans showed that ublituximab also significantly reduced the average number of actively inflamed lesions: 0.02 vs. 0.49 lesions per scan in ULTIMATE 1, which represented a 97% reduction, and 0.01 vs. 0.25 in ULTIMATE 2, a 96% reduction.
The total number of new or enlarging lesions — with or without inflammation — were also reduced by at least 90% in both trials. But brain atrophy rates were not significantly different in the two groups.
Rates of 12-week confirmed disability progression, as assessed by changes in Expanded Disability Status Scale scores lasting at least 12 weeks, also were overall similar for both ublituximab and Aubagio: 5.2% and 5.9% in pooled analyses. Disability progression lasting at least 24 weeks also showed no significant difference between the therapies.
“The percentage of participants with worsening of disability was similar in the two treatment groups,” the researchers wrote. They noted the overall low rate of relapses likely contributed to low rates of disability progression for both therapies, which may help explain the lack of significant difference.
More patients on ublituximab experienced confirmed disability improvements, both lasting 12 weeks or more (12% vs. 6%) and lasting at least 24 weeks (9.6% vs. 5.1%). But statistical analyses were not conducted and therefore “no conclusions can be drawn,” the team wrote.
Trial data also showed that ublituximab substantially reduced B-cell counts, by about 96% after 24 hours and 97% through the end of the trial, whereas Aubagio lowered levels of these cells by 53% or less in the two trials.
Adverse events — side effects and other safety-related occurrences — were reported in about nine in 10 participants in both treatment groups. Serious adverse events occurred in 10.8% of patients on ublituximab and 7.3% of those on Aubagio.
Rates of infections were similar in both groups, with serious infections reported in 5.0% of patients on ublituximab and 2.9% of those on Aubagio. No cases of progressive multifocal leukoencephalopathy, a dangerous neurological infection that can occur with other MS therapies, were reported.
Among participants given ublituximab, the most common side effects were infusion-related reactions (47.7%) — most commonly flu-like symptoms, headache, chills, and fever — headache (34.3%), the common cold (18.3%), fever (13.9%), and nausea (10.6%). Six participants discontinued treatment due to infusion reactions, including one case of severe allergic reaction.
“We once again want to thank the patients that participated in ULTIMATE I and II and the healthcare providers at the sites that worked so hard on these trials,” Weiss said.
A limitation of this study is that it does not allow comparisons between ublituximab and other MS therapies that are generally more potent than Aubagio, including other anti-CD20 monoclonal antibody therapies.
“Larger and longer trials are required to determine the efficacy and safety of ublituximab in patients with relapsing multiple sclerosis, including comparison with other disease-modifying treatments such as existing anti-CD20 monoclonal antibodies,” the scientists wrote.
About the Author
