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Ublituximab, an investigational monoclonal antibody targeting CD20, lowered relapse rates relative to teriflunomide (Aubagio) in two identical phase III trials of people with relapsing multiple sclerosis (MS).

At 96 weeks, ublituximab significantly reduced annualized relapse rate (ARR) by 59.4% (P<0.0001) over teriflunomide in , and by 49.1% (P=0.0022) over teriflunomide in , said Lawrence Steinman, MD, of Stanford University in Palo Alto, California, during a presentation at the 2021 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress.

Ublituximab is a glycoengineered drug that binds to B cells, triggering a series of immunologic reactions including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity leading to cell destruction. The drug is designed to lack certain sugar molecules normally expressed on the antibody, which may enhance its ADCC activity.

Currently, two other drugs targeting CD20 are approved for use in MS: intravenous ocrelizumab (Ocrevus) and subcutaneous ofatumumab (Kesimpta). Another anti-CD20 agent, rituximab (Rituxan), often is used off-label. Ublituximab's glycoengineering allows for shorter infusion times than ocrelizumab, Steinman said.

In the ULTIMATE trials, MS patients were randomized 1:1 to receive either 450-mg ublituximab by a 1-hour intravenous infusion every 24 weeks (after a day 1 infusion of 150 mg) or 14-mg oral teriflunomide once daily for 96 weeks.

Participants had a diagnosis of relapsing MS, an Expanded Disability Status Scale () score of 0 to 5.5, and were 18 to 55 years old. They were required to have two or more documented relapses in the 2 years before starting the study, or at least one relapse in the year prior, or at least one gadolinium-enhancing lesion before screening.

In each study, the primary endpoint was the ARR at 96 weeks. Secondary endpoints included the total number of gadolinium-enhancing T1 lesions and number of new or enlarging T2 hyperintense lesions by week 96, and the proportion of participants with no evidence of disease activity (NEDA) from week 24 to week 96.

Patients in 10 countries were infused from September 2017 to October 2018. In ULTIMATE I, 240 people completed ublituximab treatment and 252 completed teriflunomide treatment; in ULTIMATE II, those numbers were 254 and 239. Average ages ranged from 34.5 to 37 in the groups, and about two-thirds of all participants were women. Nearly all (98%) had relapsing-remitting disease; the remainder had secondary progressive MS. More than half of participants were previously untreated, and average baseline EDSS ranged from 2.8 to 2.96.

Treatment with ublituximab resulted in an ARR of 0.076 versus 0.188 for teriflunomide in ULTIMATE I (P<0.0001), and an ARR of 0.091 versus 0.178 for teriflunomide in ULTIMATE II (P=0.0022).

Total numbers of gadolinium-enhancing T1 lesions were 0.016 for ublituximab and 0.491 for teriflunomide in ULTIMATE I, and 0.009 for ublituximab and 0.250 for teriflunomide in ULTIMATE II. The number of new or enlarging T2 lesions was 0.213 for ublituximab and 2.789 for teriflunomide in ULTIMATE I, and 0.282 for ublituximab and 2.831 for teriflunomide in ULTIMATE II (all P<0.0001)

In ULTIMATE I, 44.6% of ublituximab-treated patients achieved NEDA, compared with 15.0% for teriflunomide (P<0.0001). In ULTIMATE II, 43% of people treated with ublituximab achieved NEDA, compared with 11.4% for teriflunomide (P<0.0001).

Disability progression was low across all treatment groups. In pooled results, 5.2% of ublituximab-treated patients showed 12-week confirmed disability progression (CDP) and 3.3% showed 24-week CDP, compared with 5.9% and 4.8% for teriflunomide, respectively. These differences were not significant.

In a prespecified pooled tertiary analysis, ublituximab significantly increased the proportion of patients with 12-week and 24-week confirmed disability improvement. Ublituximab treatment was also associated with significant improvement in Multiple Sclerosis Functional Composite ( scores versus teriflunomide in ULTIMATE I and II.

"Overall, the ULTIMATE studies reported a favorable safety and tolerability profile, with no unexpected safety signals," Steinman said in his presentation. The proportion of patients with adverse events was similar in the ublituximab and teriflunomide groups in pooled analyses, about 89% in each. The most common adverse event was infusion-related reactions, affecting 47.7% of people who received ublituximab. Headache was also common, affecting 30.3% of the ublituximab group.

Serious adverse events occurred in 9.5% of the pooled ublituximab group and 6.2% of the pooled teriflunomide group. Four percent of the ublituximab group developed infections or infestations. Two malignancies in the ublituximab group were reported (uterine and endometrial).

Three deaths occurred in the ublituximab group, due to pneumonia, post-measles encephalitis, and salpingitis. The death from pneumonia was deemed possibly related to treatment. No cases of progressive multifocal leukoencephalopathy were reported.

Based on the results of the ULTIMATE trials, drugmaker TG Therapeutics recently to the FDA, requesting approval of ublituximab as a treatment for relapsing MS. The ULTIMATE trials were conducted under a agreement with the FDA, the company said. Ublituximab is also being evaluated in trials of people with chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

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