Between the 2 trials, patients showed significantly lower annualized relapse rates and mean number of gadolinium-enhancing lesions when treated with ublituximab relative to teriflunomide.
TG Therapeutics has announced the publication of the phase 3 ULTIMATE 1 & 2 trials (NCT03277261; NCT03277248) in the New England Journal of Medicine, describing the safety and efficacy of ublituximab, its investigational agent for multiple sclerosis (MS) that is currently under FDA review, and its comparison with the disease-modifying therapy teriflunomide (Aubagio; Sanofi).1,2
All told, treatment with ublituximab in patients with relapsing MS resulted in annualized relapse rates (AAR) of 0.08 and 0.09 in ULTIMATE 1 and 2 at week 96, compared with rates of 0.19 and 0.18 for the teriflunomide-treated groups in the respective studies (P <.001; P = .002). Ublituximab was associated with infusion-related reactions, though, which occurred in 47.7% of the treated participants compared with 12.2% of those on teriflunomide. Serious infections were also higher in the ublituximab group (5.0% vs 2.9%).
"The ULTIMATE trials found ublituximab treatment, compared to teriflunomide, produced significantly lower annualized relapse rates, reduction in the total number of MRI-detectable lesions, as well as improved rates of patients achieving no evidence of disease activity [NEDA]," Lawrence Steinman, MD, Zimmerman Professor of Neurology & Neurological Sciences, and Pediatrics, Stanford University, and global study chair for the trials, said in a statement.1 "If approved, the unique attributes of ublituximab, particularly its ability to be infused in a one-hour infusion every six months following the first dose, may offer benefits to patients with relapsing forms of multiple sclerosis."
Ublituximab, an investigational glycoengineering anti-CD20 monoclonal antibody, had its biologics license application (BLA) accepted by the FDA in December 2021, months after the company submitted it.3 In it included the positive results from ULTIMATE 1 and 2, which were both conducted under a special protocol assessment established with the FDA and originally announced at the 7th Congress of the European Academy of Neurology, June 19-22, 2021. When the BLA was accepted by the FDA, the agency noted it did not plan to hold an advisory committee meeting to discuss the application, and thus set a prescription drug user fee goal date of September 28, 2022.
ULTIMATE 1 and 2 included 1094 patients with relapsing MS across 10 countries who were randomly assigned to either intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was change in ARR, while secondary end points included number of gadolinium-enhancing lesions on MRI and worsening of disability.1,2
At the conclusion of the analysis, the mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio [RR], 0.03; 95% CI, 0.02-0.06; P <.001) in the ULTIMATE 1 trial and 0.01 and 0.25 (RR, 0.04; 95% CI, 0.02-0.06; P <.001), respectively, in the ULTIMATE 2 trial. When comparing safety for the treatments, 89.2% of those on ublituximab had at least 1 adverse event (AE) vs 91.4% of those on teriflunomide. Grade 3 or higher AEs were slightly more frequent in the ublituximab group (21.3% vs 14.1%)
In the prespecified pooled analysis, 5.2% of those on ublituximab had worsening of disability confirmed at 12 weeks, compared with 5.9% of those in the teriflunomide group (hazard ratio [HR], 0.84; 95% CI, 0.50-1.41; P = .51). Worsening of disability confirmed at 24 weeks was found in 3.3% of ublituximab-treated patients vs 4.8% of teriflunomide-treated patients, but was not considered significant. In the prespecified pooled tertiary analysis that was not included in the hierarchical analysis and from which no conclusions can be drawn, 12.0% of the participants who received ublituximab had lessening of disability confirmed at 12 weeks, as compared with 6.0% of the participants who received teriflunomide (hazard ratio, 2.16; 95% CI, 1.41 to 3.31).
"We are extremely pleased that the results from the ULTIMATE I & II trials have been published in the New England Journal of Medicine. We believe ublituximab’s novel mechanism of action, coupled with the convenience of a one-hour infusion represents a potential advance for patients with RMS and we are pleased that this publication will share the ULTIMATE I and II data with a broad audience," Michael S. Weiss, chairman and chief executive officer, TG Therapeutics, said in a statement.1 "We continue to be singularly focused on working toward the potential approval of ublituximab by the December 28, 2022, PDUFA goal date, and if successful, being prepared to launch early next year."