There were no statistically significant differences in infusion-related reactions among patients with multiple sclerosis who tested positive or negative for treatment-emergent antidrug antibodies.
Enrique Alvarez, MD, PhD
A post-hoc analysis of the phase 3 ULTIMATE 1 and 2 studies (NCT03277261; NCT03277248) showed that following treatment with ublituximab (TG Therapeutics) a low proportion of patients with relapsing multiple sclerosis (RMS) had treatment-emergent neutralizing antibodies (TE-NAbs) and a majority of patients developed treatment-emergent antidrug antibodies (TE-ADA).1
Ublituximab, an investigational glycoengineering anti-CD20 monoclonal antibody, is currently being reviewed by the FDA as a treatment for relapsing forms of MS. In December 2021, the agency announced it had accepted TG Therapeutics’ biologic license application for ublituxumab, with a Prescription Drug User Fee Act goal date of September 28, 2022. Positive results from the original ULTIMATE 1 and 2 studies were the basis for the application.2
The new results were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, held February 24-26, in West Palm Beach, Florida, by lead author Enrique Alvarez, MD, PhD, associate professor of neurology, University of Colorado School of Medicine. In this analysis of ULTIMATE 1 & 2, 549 and 545 patients with RMS, respectively, were randomized 1:1 to receive ublituximab 450-mg intravenous infusion every 24 weeks or teriflunomide (Aubagio; Sanofi) 14 mg once daily for 96 weeks.
At baseline, 2.4% and 17.8% of those receiving ublituximab tested positive for NAbs and ADAs. This increased to 6.4% and 86.5% at any time postbaseline, however, it was noted that testing positive at baseline did not necessarily correlate with testing positive at any postbaseline time points. At weeks 24, 48, 72, and 96, presence of TE-NAbs were found in 4.3%, 3.4%, 1.1%, and 1.1% of patients, respectively.1
Post-baseline, the annualized relapse rates (ARRs) were 0.03 in NAb-positive individuals (n = 30) and 0.11 in NAb-negative individuals (n = 500). Furthermore, the ARRs were 0.10 in TE-ADA-positive patients (n = 434) and 0.12 in TE-ADA-negative patients (n = 100). The investigators did note the small sample size of NAb-positive individuals.
TE-ADAs were generally transient and had no observable impact on the safety or efficacy of ublituximab. Among those who were TE-ADA-positive, 48.4% had all grade infusion-related reactions (IRRs) and 3.0% had at least a Grade 3 IRR. In comparison, 42.0% of the TE-ADA-negative group had an all-grade IRR occur, while 2.0% reported at least Grade 3 IRRs. Although not statistically significant, all grade IRR adverse events that occurred with greater than a 2% frequency in TE-ADA-positive vs TE-ADA-negative patients included pyrexia (10.1% vs 7.0%), chills (8.3% vs 6.0%), nausea (3.7% vs 1.0%), and lymphocyte decreases (3.2% vs 1.0%).
Original data from the ULTIMATE studies showed ublituximab reduced ARR and MRI parameters better than that of teriflunomide. Treatment with ublituximab resulted in an ARR of 0.076 in ULTIMATE 1 compared to 0.188 for the teriflunomide-treated group, a relative reduction of 60% (ARR ratio, 0.406; 95% CI, 0.268-0.615; P <.001). Similarly, in ULTIMATE 2, ARRs are 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).3
Global study chair Lawrence Steinman, MD, Zimmerman Professor of Neurology and Neurological Sciences, and Pediatrics, Stanford University, recently sat down with NeurologyLive® to discuss the initial data from the ULTIMATE studies and some of the biggest take-home messages. Watch below as he covers those findings, as well as the potential of ublituximab in an MS field crowded with other competing drugs.
For more coverage of ACTRIMS Forum 2022, click here.