Application follows the results of 2 independent, identical phase 3 trials, ULTIMATE 1 and 2, which assessed the TG Therapeutics anti-CD20 antibody in more than 1000 patients.
A biologics license application (BLA) has been submitted to the FDA by TG Therapeutics for the use of ublituximab as treatment for patients with relapsing forms of multiple sclerosis (RMS). Ublituximab, an investigational glycoengineered anti-CD20 monoclonal antibody, was evaluated in 2 independent, identical, phase 3, randomized, global, multicenter, double-blinded, active-controlled trials, ULTIMATE 1 and 2 (NCT03277261; NCT03277248), which compared the efficacy of the treatment with teriflunomide (Aubagio; Sanofi).1
Results from both trials were announced earlier this year at the 7th Congress of the European Academy of Neurology, June 19-22, with investigators concluding that ublituximab met its primary end point in significantly reducing annualized relapse rate (ARR) and MRI parameters over a 96-week period, when compared to teriflunomide (P <.005 in each trial).1,2,3
“The submission of this BLA for ublituximab to treat patients with RMS marks a major milestone for us, being our first submission of a marketing application for an autoimmune indication and rounds out our near-term US regulatory submissions,” Michael S. Weiss, chairman and CEO, TG Therapeutics, said in a statement.1 “Multiple sclerosis is a chronic and potentially disabling disease that affects nearly 1 million Americans. We believe ublituximab has the potential to offer an important new treatment option for these patients, and we look forward to working closely with the FDA on this submission. We want to thank the patients and their families, as well as the physicians and their research teams, who participated in our ULTIMATE 1 and 2 trials.”
A special protocol agreement with the FDA allowed for both phase 3 ULTIMATE 1 and 2 trials to be conducted, enrolling a combined total of 1094 patients in 10 countries. In both studies, a 450-mg dose of ublituximab was administered via 1-hour intravenous infusion every 6 months. This followed an infusion on day 1 of the trial of 150 mg over the course of 4 hours and another infusion on day 15 of 450 mg over 1 hour. Teriflunomide was administered via 14-mg oral tablets that were taken once a day. Patients in both trials were randomized 1:1 to either agent and were then assessed on ARR at 96 weeks.
In ULTIMATE 1, treatment with ublituximab resulted in an ARR of 0.076, compared with 0.188 for those treated with teriflunomide, representing a relative reduction of 60% (ARR ratio, 0.406 [95% CI, 0.268-0.615]; P <.0001). In ULTIMATE 2, ARRs at 96 weeks were 0.091 and 0.178 in the ublituximab and teriflunomide groups, respectively, equating to a 49% relative reduction (ARR ratio, 0.509 [95% CI, 0.330-0.784]; P = .0022).
The total number of T1 gadolinium (Gd)-enhancing lesions were reduced when using ublituximab treatment by 97% and 96% relative to treatment with teriflunomide in ULTIMATE 1 and 2, respectively (P <.0001). Additionally, relative reductions of 92% and 90% for new or enlarging T2 lesions were observed by treatment with ublituximab in ULTIMATE 1 and 2, respectively (P <.0001).
Both trials reported similar numbers of adverse events, with the most common being infusion-related reaction (IRR), headache, nasopharyngitis, and lymphopenia. No patients treated with teriflunomide had grade 4 severity of IRRs, compared to 0.2% of those in the ublituximab group at weeks 1 and 3. Serious adverse events occurred in 6.2% of patients in the teriflunmide group and 9.5% in the ublituximab group, with the most common being infections and infestations, as well as nervous system disorders.
There were 3 deaths that occurred during the trial, which were all in the ublituximab group and the results of encephalitis, salpingitis, and pneumonia, all in the ublituximab group. Investigators noted the pneumonia case was potentially related to treatment and saw no cases of progressive multifocal leukoencephalopathy.
NeurologyLive sat down with global study chair, Lawrence Steinman, MD, Zimmerman Professor of Neurology and Neurological Sciences, and Pediatrics, Stanford University, who provided insight on the use of ublituximab in MS and reviewed results of the ULTIMATE 1 and 2 trials, which were originally presented at the American Academy of Neurology 2021 Annual Meeting. Watch what he had to say in the video below.