Anti-CD20 Therapy Ublituximab Gains FDA Approval for Relapsing Multiple Sclerosis

Marketed as Briumvi, the TG Therapeutics treatment becomes the third anti-CD20 agent approved for relapsing multiple sclerosis and is expected to become available in the first quarter of 2023.

Michael S. Weiss, chairman and CEO of TG Therapeutics

Michael S. Weiss

The FDA has approved TG Therapeutics’ investigational glycoengineered monoclonal antibody ublituximab, marketed as Briumvi, for the treatment of patients with relapsing forms of multiple sclerosis (MS), further expanding the treatment toolbox for this patient population.1 The therapy is administered in a 1-hour infusion, twice yearly following the starting dose, and is anticipated to become commercially available in the first quarter of 2023.

"Today’s FDA approval marks an exciting day for everyone touched by MS and everyone that has worked on the development of Briumvi. We believe in the importance of treatment alternatives for patients and believe the profile of Briumvi offers unique attributes to patients and physicians alike. We have built a strong commercial team with deep knowledge of the MS landscape and look forward to launching in Q1 2023.” Michael S. Weiss, chairman and CEO of TG Therapeutics, said in a statement.1 “We want to thank the patients and their families, the clinical investigators and their teams, and our advisors for their support and participation in our trials, and for helping us get to this point. We remain committed to the patients we serve and providing seamless access to Briumvi once launched.”

Ublituximab, an agent 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, which featured 1094 patients with relapsing MS across 10 countries, showed the superior efficacy and safety of ublituximab in comparison with teriflunomide (Aubagio; Sanofi), a relatively newer agent that received FDA approval in 2012. Both trials were conducted under a special protocol assessment established with the FDA.

When ublituximab binds to the B-cell it triggers a series of immunological reactions, including antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, leading to the destruction of the cell. Additionally, the agent is uniquely designed to lack certain sugar molecules normally expressed on the antibody. After having an original PDUFA date of September 28, 2022, the FDA announced in May that it was extending the review period to December 28, 2022, to allow more time to evaluate the new drug application submission.

In ULTIMATE 1 and 2, patients 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) or oral teriflunomide (14 mg once daily), with annualized relapse rate (ARR) as the primary end. All told, treatment with ublituximab resulted in ARRs 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 group 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.

Change in gadolinium-enhancing lesions, a secondary end point, showed a mean number of 0.02 for those on ublituximab vs 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. In terms of safety, adverse events (AEs) were found in 89.2% of those on ublituximab vs 91.4% of those on teriflunomide, with grade 3 or higher AEs slightly more frequent in the ublituximab group (21.3% vs 14.1%). Additionally, serious infections were also higher in the ublituximab group (5.0% vs 2.9%).

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; = .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 a 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).

Lawrence Steinman, MD, Zimmermann Professor of Neurology & Neurological Sciences, and Pediatrics at Stanford University, said in a statement,1 “Over the past several years we have seen a dramatic shift in the MS treatment landscape towards the use of B-cell therapy, which has shown to be highly effective in reducing relapses in patients. The outcome of the ULTIMATE I & II trials evaluating ublituximab, a novel targeted anti-CD20 agent designed for efficient B-cell depletion that supported this approval, represents an important milestone in the history of MS research as the first Phase 3 study of an anti-CD20 monoclonal antibody in patients with relapsing MS to produce an annualized relapse rate of less than 0.10, which translates to less than 1 relapse in 10 years. This approval is great news for patients living with MS and provides an appealing treatment alternative that can be administered in a one-hour infusion twice-a-year following the starting dose, which I believe is an added benefit to patients.”

Earlier this year, at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, a post hoc analysis from the ULTIMATE trials showed a low proportion of patients developing treatment-emergent neutralizing antibodies (TE-NAbs) and a majority of patients developing treatment-emergent antidrug antibodies (TE-ADA). 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.

Post-baseline, the 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%).

Then, in April, at the 2022 American Academy of Neurology (AAN) Annual Meeting, in Seattle, Washington, data on the TG Therapeutics drug were presented by Bruce Cree, MD, PhD, MAS, FAAN, professor of clinical neurology, University of California, San Francisco (USCF) Weill Institute for Neuroscience, and clinical research director, UCSF Multiple Sclerosis Center. Cree sat down with NeurologyLive® at AAN 2022 to offer his thoughts on the findings and the importance of developing therapies for MS that not only control relapses but improve the quality of life for patients. See what he had to say in the video below (WATCH TIME: 4 minutes).

REFERENCES
1. TG Therapeutics Announces FDA Approval of BRIUMVI™ (ublituximab-xiiy). News release. TG Therapeutics. December 28, 2022. Accessed December 28, 2022. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-fda-approval-briumvitm-ublituximab
2. TG Therapeutics announces FDA extension of BLA PDUFA date for ublituximab to treat patients with RMS. News release. TG Therapeutics. May 31, 2022. Accessed December 21, 2022. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-fda-extension-bla-pdufa-date#:~:text=(NASDAQ%3A%20TGTX)%2C%20today,of%20multiple%20sclerosis%20(RMS).
3. Steinman L, Fox E, Hartung HP, et al. Ublituximab versus teriflunomide in relapsing multiple sclerosis. N Engl J Med. 2022;387:704-714. doi:10.1056/NEJMoa2201904.
4. Alvarez E, Steinman L, Fox E, et al. Neutralizing antibodies and antidrug antidodies in the ublituximab phase 3 ULTIMATE 1 and 2 studies in relapsing multiple sclerosis. Presented at ACTRIMS Forum 2022; February 24-26; West Palm Beach, FL. Abstract P103
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