#ECTRIMS2018 – Ublituximab Markedly Reduces Lesions, Promotes B-cell Depletion, Halts Disability Progression in Phase 2 Trial

A 48-week treatment of relapsing multiple sclerosis (MS) with TG Therapeutics’ investigational compound ublituximab led to a marked reduction of brain and spinal cord lesions, massive depletion of relapse-associated immune B-cells, and significantly halted disability progression, according to results from a Phase 2 clinical trial.

The data also revealed a positive safety profile of ublituximab’s intravenous infusions.

The study, “Final results of a placebo controlled, Phase 2 multicenter study of ublituximab (UTX), a novel glycoengineered anti-CD20 monoclonal antibody (mAb), in patients with relapsing forms of multiple sclerosis (RMS),” was selected for an oral presentation at the upcoming 34^th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), which will be held Oct. 10-12, in Berlin, Germany.

TG Therapeutics’ presentation will be made Oct. 11 (at 16:51-17:03 CEST) as part of the “Free Communications 4 – Treatment” session. It is expected to include final data on all 48 enrolled patients in the study through 48 weeks of treatment. The presenter will be Edward Fox, MD, PhD, from Central Texas Neurology Consultants, in Round Rock, Texas, which is one of the trial sites.

Ublituximab (TG-1101) is an engineered monoclonal antibody that has a unique target on the CD20 antigen of mature B-cells, which depletes these cells from the blood and central nervous system. B-cells are activated during relapses and are found within acute spinal cord lesions. According to the company, ublituximab has superior potency over current anti-CD20 antibodies, which may enable lower doses and shorter infusion times.

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The multicenter, placebo-controlled Phase 2 trial (NCT02738775), sponsored by TG Therapeutics, intended to assess ublituximab’s optimal dose, infusion time, safety, and tolerability in relapsing MS patients, aged 18-55. All participants, including those on placebo for the first four weeks, received ublituximab infusions on days 1, 15, and week 24, and then were followed for 48 weeks.

To determine optimal dose and infusion time, the scientists compared B-cell depletion as well as safety and tolerability between six dosing groups — 450 mg or 600 mg at infusion times from one to four hours. Brain and spinal cord magnetic resonance imaging (MRI) scans, and clinical efficacy analyses also were conducted.

The available results, which include data from the first 22 patients treated through week 48, and 44 patients through week 24, showed an annualized relapse rate — the number of confirmed relapses per year — of 0.07, and a median B-cell depletion greater than 99% at weeks 4, 24 and 48 in all groups.

With MRI, researchers saw complete elimination of T1 gadolinium-enhancing lesions at weeks 24 and 48, and the mean T2 lesion volume showed an 8% decrease at week 24, and a 10% decrease at week 48, compared to baseline. Of note, T1 MRI offers information about current disease activity by highlighting areas of active inflammation, while a T2 MRI image provides information about disease burden or lesion load (the total amount of lesions, both old and new).

No participant showed sustained progression of disability.

The data further revealed that immune T-cells shifted toward naïve and regulatory phenotypes, which indicated less activation (of note, overactive T-cells are known to play a role in MS development).

Ublituximab treatment was well-tolerated, not inducing any treatment-related severe adverse side effects. The most common side effects reported were infusion-related reactions, and faster infusion times did not change the rate of infusion-related reactions.

Overall, the team concluded that patients receiving ublituximab “showed rapid and robust B-cell depletion, a profound reduction in MRI activity, suppression of relapses, and clinical stability. Moreover, [ublituximab] can be safely delivered in infusions as fast as 1 hour,” they wrote.

The data builds on the benefits of ublituximab presented at the 2018 CMSC Annual Meeting and “continue to demonstrate that ublituximab is an active treatment for patients with MS,” Michael S. Weiss, TG’s executive chairman and CEO, said in a press release.

“We have been impressed with the data presented to date and look forward to presenting the final Phase 2 data, which we believe should be representative of our ongoing ULTIMATE Phase 3 program,” Weiss added. The study is expected to end by February 2019.

TG Therapeutics is conducting two Phase 3 studies comparing ublituximab to Sanofi Genzyme’s Aubagio (teriflunomide) in this patient population.

The ongoing global, double-blind Phase 3 program includes the ULTIMATE 1 (NCT03277261) and ULTIMATE 2 (NCT03277248) trials, which compare the effectiveness and safety of ublituximab vs. Aubagio over 96 weeks of treatment in relapsing MS patients. TG recently announced that although patient recruitment would continue until mid-September, both trials already reached target enrollment at 440 participants each, and that results are expected as early as mid-2020.

The program is being led by Lawrence Steinman, MD, of Stanford University, and is being conducted under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA), which refers to a declaration that an unfinished Phase 3 trial’s design, clinical goals, and statistical analyses are acceptable for FDA approval.

Of note, five of the study’s authors are employed by TG Therapeutics, three received partial salary support, and another one received research support from the company.