The FDA has approved TG Therapeutics’ investigational glycoengineered monoclonal antibody ublituximab (marketed as Briumvi) for the treatment of patients with relapsing multiple sclerosis (MS), further expanding the therapeutic toolbox for this patient population.1 The treatment is given as a one-hour infusion twice a year following the starting dose and is expected to be commercially available in the first quarter of 2023.
“Today’s FDA approval is an exciting day for everyone involved with multiple sclerosis and everyone involved in the development of Briumvi. We believe in the importance of alternative therapies for patients. We believe Briumvi’s profile offers a unique set of attributes for both patients and physicians.We are building a strong commercial team with deep knowledge of the MS landscape and look forward to launching in Q1 2023. said Michael S. Weiss, Chairman and CEO of TG Therapeutics.1 “We would like to thank our patients and their families, our clinical investigators and their teams, and our advisors for their support and participation in our clinical trials and for helping us get to this point. We remain committed to the patients we serve and will continue to provide seamless access to Briumvi post-launch.”
Ubrituximab, a drug designed to target a unique epitope on CD20-expressing B cells, was approved based on results from the Phase 3 ULTIMATE 1 and 2 trials (NCT03277261; NCT03277248). These trials, involving 1,094 patients with relapsed MS in 10 countries, demonstrated superior efficacy of ubrituximab compared to teriflunomide (Aubagio; Sanofi), a relatively new agent that received FDA approval in 2009. demonstrated efficacy and safety. Protocol evaluation established by FDA.
When ubrituximab binds to B cells, it triggers a series of immune responses, including antibody-dependent cytotoxicity and complement-dependent cytotoxicity, that destroy the cells. Additionally, this drug is uniquely designed to lack specific sugar molecules that are normally expressed on antibodies. After his original PDUFA date was September 28, 2022, the FDA announced that in May he would extend the review period to allow more time to evaluate the submission of new drug applications. announced that it will be extended until December 28, 2022.
In ULTIMATE 1 and 2, patients received intravenous ubrituximab (150 mg on day 1, then 450 mg on day 15 and weeks 24, 48, and 72) or oral teriflunomide (14 mg once daily). ) were randomly assigned to one of the Recurrence rate (ARR) as primary end. Overall, treatment with ubrituximab resulted in ARRs of 0.08 and 0.09 in ULTIMATE 1 and 2 at 96 weeks compared to rates of 0.19 and 0.18 in the teriflunomide-treated arm in the respective studies (P. <.001; P. = .002). Ubrituximab was associated with infusion-related reactions, which occurred in 47.7% of treated participants compared with 12.2% in the teriflunomide group.
The secondary endpoint, change in gadolinium-enhancing lesions, showed a mean number of 0.02 in the ubrituximab group compared to 0.49 in the teriflunomide group (rate ratio [RR]0.03; 95% CI, 0.02–0.06; P. <.001), 0.01 and 0.25 in the ULTIMATE 1 trial (RR, 0.04; 95% CI, 0.02–0.06; P. <.001), respectively, in the ULTIMATE 2 trial. Regarding safety, adverse events (AEs) were found in 91.4% of teriflunomide groups compared to 89.2% of ubrituximab groups, with grade 3 or higher AEs being slightly more common in the ubrituximab group (21.3% 14.1%). In addition, serious infections were also higher in the ubrituximab group (5.0% vs. 2.9%).
A pre-specified pooled analysis confirmed worsening of disability at week 12 in 5.2% of patients in the ubrituximab group compared to 5.9% in the teriflunomide group (hazard ratio). [HR]0.84; 95% confidence interval, 0.50 to 1.41. P. = .51). Confirmed worsening of disability at 24 weeks was seen in 3.3% of ubrituximab-treated patients versus 4.8% of teriflunomide-treated patients, but was not considered significant. In a prespecified, pooled tertiary analysis from which no conclusions can be drawn, 12.0% of participants who received ubrituximab confirmed disability reduction at 12 weeks. received teriflunomide (hazard ratio 2.16; 95% CI 1.41 to 3.31).
Lawrence Steinman, MD, Zimmerman Professor of Neurology and Neuroscience and Pediatrics at Stanford University, said in a statement:1 “Over the past few years, the MS treatment landscape has changed dramatically to the use of B-cell therapies, which have been shown to be highly effective in reducing patient relapse. Efficient B-cell depletion Results from the ULTIMATE I and II trials evaluating ublituximab, a novel targeted anti-CD20 agent designed for and supported this approval, mark a milestone in the history of MS research as the first Phase 3 trial of an anti-CD20 antibody. Represents a significant milestone: – CD20 monoclonal antibodies in patients with relapsing MS produce an annualized relapse rate of less than 0.10, which equates to less than 1 relapse in 10 years. “This is good news for patients with multiple sclerosis and we believe it will further benefit patients by providing an attractive alternative treatment that can be administered as a one-hour infusion twice a year following their starting dose.”
Earlier this year, at the Americas Committee for Multiple Sclerosis Treatment and Research (ACTRIMS) Forum 2022, a post-hoc analysis from the ULTIMATE trial found that the proportion of patients who developed therapeutic emergent neutralizing antibody (TE-NAb) was Patients with low, majority of patients developing treatment-emergent anti-drug antibodies (TE-ADA). At baseline, his 2.4% and 17.8% of patients receiving ubrituximab were positive for his NAb and ADA. This increased to 6.4% and 86.5% at any time after baseline, although it was noted that positive tests at baseline did not necessarily correlate with positive tests at any time after baseline. rice field. At 24, 48, 72, and 96 weeks, the presence of TE-NAb was found in 4.3%, 3.4%, 1.1%, and 1.1% of patients, respectively.
Post-baseline ARR was 0.03 in NAb-positive individuals (n = 30) and 0.11 in NAb-negative individuals (n = 500). Furthermore, ARR was 0.10 in TE-ADA positive patients (n = 434) and 0.12 in TE-ADA negative patients (n = 100). The researchers noted the small sample size of NAb-positive individuals. TE-ADA was generally transient and had no appreciable impact on the safety or efficacy of ubrituximab. Among TE-ADA-positive patients, 48.4% had all grades of infusion-related reactions (IRRs) and 3.0% had at least grade 3 her IRRs. In contrast, 42.0% of the TE-ADA-negative group experienced all grades of her IRR and 2.0% reported at least grade 3 IRR. Although not statistically significant, all grade IRR adverse events occurring with a frequency of ≥2% in TE-ADA-positive and TE-ADA-negative patients included fever (10.1% vs. 7.0%), chills (8.3%). 6.0%) were included. , nausea (3.7% vs. 1.0%), and lymphocyte depletion (3.2% vs. 1.0%).
Then, in April, at the 2022 American Academy of Neurology (AAN) Annual Meeting in Seattle, Wash., data on TG therapeutics were shared with Bruce, MD, MAS, FAAN, and Professor of Clinical Neurology. Presented by Lee, M.D. Director of Clinical Research, UCSF Multiple Sclerosis Center, Weill Institute for Neuroscience, San Francisco, CA (USCF).Cree sat together neurology live® At AAN 2022, he will offer his thoughts on the discovery and importance of developing treatments for MS that not only control relapses, but improve patients’ quality of life. Watch the video below to see what he had to say (Watching time: 4 minutes).