Ublituximab Meets Primary End Point in Phase 3 ENHANCE Trial for Relapsing Multiple Sclerosis

In a recent company update, TG Therapeutics announced that its phase 3b ENHANCE trial (NCT05877963), evaluating a streamlined dosing regimen for ublituximab-xiiy (Briumvi; TG Therapeutics), met its primary end point in adults with relapsing forms of multiple sclerosis (RMS). All told, findings demonstrated bioequivalent systemic drug exposure between a single consolidated 600 mg infusion administered on Day 1 and the currently approved split initiation regimen of 150 mg on Day 1 followed by 450 mg on Day 15.¹

“We are very pleased to share these positive results from our ENHANCE Phase 3 trial. By eliminating the need for a second infusion visit two weeks after treatment initiation, this streamlined dosing regimen has the potential to accelerate time from prescription to treatment and reduce scheduling burdens at busy infusion centers,” Michael S. Weiss, chairman and chief executive officer at TG Therapeutics, said in a statement.¹ “If this consolidated dosing is approved, BRIUMVI would be the first and only IV anti-CD20 for which therapy can be initiated with a single infusion.”

“People living with RMS already manage significant complexity in their daily lives, and we believe treatment simplicity matters. These results reflect our broader commitment not only to developing effective therapies, but also to improving the treatment experience for patients and healthcare providers. We look forward to engaging with regulatory authorities regarding these data, with the goal of submitting a supplemental BLA in the second half of 2026,” Weiss added.¹

Trial Design and Primary Findings

The ENHANCE trial was a randomized, double-blind, placebo-controlled, multicenter phase 3b study designed to evaluate the pharmacokinetics, safety, and MRI outcomes of a consolidated first-infusion regimen of ublituximab in adults with RMS. Participants were assigned to 1 of 2 arms, the approved initiation schedule (150 mg on Day 1, 450 mg on Day 15) or a consolidated regimen consisting of a single 600 mg infusion on Day 1 paired with a placebo infusion on Day 15. Both arms received the same cumulative 600 mg dose through Day 15. Subsequent maintenance dosing followed the standard approved prescribing schedule in both groups.

Findings showed that the primary end point, bioequivalence of overall drug exposure as measured by area under the serum concentration–time curve from baseline through Week 16 (AUC 0–Wk16), was met in the trial. Results demonstrated that the geometric mean ratio (GMR) between arms was approximately 1.0, with a 90% confidence interval falling in the pre-specified bioequivalence bounds of 0.80 to 1.25.

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Secondary end points, including safety, B-cell depletion, and MRI outcomes, were reported to be consistent with prior ublituximab clinical data. Notably, no new safety signals were identified. Infusion-related reactions occurred at lower rates in both arms compared with rates reported in the pivotal ULTIMATE I and II trials (NCT03277261; NCT03277248), and no Grade 3 or higher infusion reactions were observed in either arm. The rate of infusion-related reactions was statistically indistinguishable between arms, with numerically fewer events in the consolidated single-infusion group.

Clinical Context and Disease Burden

RMS encompasses relapsing-remitting MS (RRMS), clinically isolated syndrome, and active secondary progressive MS. Approximately 1 million people in the United States are estimated to be living with MS, with roughly 85% initially diagnosed with RRMS. Globally, more than 2.3 million individuals carry an MS diagnosis.² The chronic, episodic nature of relapsing disease and its associated disability accrual create substantial and persistent burden for patients and health systems alike.

The IV anti-CD20 class has become central to high-efficacy disease-modifying therapy in RMS. Scheduling complexity, including split initiation regimens and biannual infusion center visits, represents a recognized barrier to timely treatment initiation and may affect patient retention. A regimen requiring only a single infusion to initiate therapy could have meaningful implications for care access and operational workflow in infusion settings, though the clinical significance of this logistical change will require real-world evaluation.

Drug and Mechanism Background

Ublituximab-xiiy is a glycoengineered, CD20-directed monoclonal antibody designed to target a distinct epitope on CD20-expressing B cells. Its glycoengineering, involving removal of specific sugar moieties from the Fc region, is intended to enhance antibody-dependent cellular cytotoxicity, enabling efficient B-cell depletion at relatively low doses.

The FDA granted approval for ublituximab-xiiy in December 2022, making it the third IV anti-CD20 agent approved for RMS in the United States, following ocrelizumab (Ocrevus; Genentech) and ofatumumab (Kesimpta Novartis).^3,4 Approval was based on results from the phase 3 ULTIMATE I and II trials, in which ublituximab demonstrated statistically significant reductions in annualized relapse rates compared with teriflunomide, 59% and 49% relative reductions, respectively, as well as marked suppression of gadolinium-enhancing and new or enlarging T2 lesions.

REFERENCES
1. TG Therapeutics Announces Positive Topline Results from Phase 3 ENHANCE Trial. News release. TG Therapeutics. May 27, 2026. Accessed July 7, 2026. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-positive-topline-results-phase-3
2. Nelson LM, Wallin MT, Marrie RA, et al. A new way to estimate neurologic disease prevalence in the United States: Illustrated with MS. Neurology. 2019;92(10):469-480. doi:10.1212/WNL.0000000000007044
3. Steinman L, Fox E, Hartung HP, et al. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. 2022;387(8):704-714. doi:10.1056/NEJMoa2201904
4. TG Therapeutics Announces FDA Approval of BRIUMVI™ (ublituximab-xiiy). News release. TG Therapeutics. December 28, 2022. Accessed July 7, 2026. https://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-announces-fda-approval-briumvitm-ublituximab