Ublituximab (TGTX-1101)

Ublituximab (TGTX-1101) is an investigational anti-CD20 monoclonal antibody being developed by TG Therapeutics. Originally developed to treat blood cancers like non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, ublituximab is also being studied as a potential infusion therapy for relapsing forms of MS.

Based on data from the ULTIMATE clinical trials, TG is planning to submit a request for regulatory approval of ublituximab to treat relapsing forms of the disease in the U.S.

How does ublituximab work?

Ublituximab is a monoclonal antibody that targets CD20, a protein found on the surface of immune cells called B-cells. Evidence shows that B-cells contribute to MS in various ways, producing antibodies and activating other cells of the immune system. B-cells are found within acute lesions of the spinal cord, which suggests a role in MS flares.

By targeting CD20, ublituximab is designed to deplete the number of inflammatory B-cells that drive MS. The antibody has been glycoengineered — meaning that certain sugar molecules attached to the antibody have been altered in order to increase its potency.

When antibodies like ublituximab bind to target proteins on cells, they can kill the cell through one of two main mechanisms: in antibody-dependent cellular cytotoxicity (ADCC), or in complement-dependent cytotoxicity (CDC).

In ADCC, the antibody, by binding to its target cell, signals other immune cells like natural killer (NK) cells to destroy that target cell.

In CDC, the antibody activates a group of immunological proteins, called the complement cascade, which kill the target cell. However, the complement system also participates in autoimmune processes, and its activation may result in side effects.

According to TG, ublituximab’s design makes it substantially more potent at triggering ADCC, relative to other anti-CD20 antibodies used in MS. The therapy is reportedly a less potent trigger of CDC.

Ublituximab in clinical trials

TG Therapeutics sponsored a Phase 2 clinical trial (NCT02738775) assessing ublituximab’s safety and efficacy in 48 people with relapsing-remitting MS (RRMS) or active secondary progressive MS (SPMS).

Initial doses were administered to all as a 150 mg infusion on day 1, followed by 450 mg or 600 mg on day 15, and then by either 450 mg or 600 mg at week 24. There were six groups, each receiving infusions at a higher dose or faster rate than the other; including a one-hour infusion of 600 mg in the sixth group.

Ublituximab was well-tolerated with no serious adverse events reported, with a median B-cell depletion of 99% within four weeks. All trial participants had at least 95% B-cell depletion.

The therapy also reduced relapse rates (from 1.45 to 0.07 relapses per year) and reduced the size of brain lesions. Overall, 74% of trial participants had no evidence of disease activity — NEDA, a composite measure meaning no relapses, no confirmed disability progression, and no new or enlarging brain lesions — at week 48.

Ublituximab was further evaluated in two twin Phase 3 trials — ULTIMATE I (NCT03277261) and II (NCT03277248) — which collectively enrolled 1,094 patients across 106 sites in 10 countries. About 98% of participants had RRMS, and the rest had active SPMS.

Patients in the ULTIMATE trials were randomly assigned to treatment with ublituximab — as a 150 mg infusion delivered over four hours on the first day of treatment, followed by a one-hour 450 mg infusion on day 15, then 450 mg infusions every six months — or with Aubagio (teriflunomide), a widely approved oral MS medication marketed by Sanofi Genzyme. These trials ran for 96 weeks, or about two years.

Compared with Aubagio, ublituximab reduced the mean annual relapse rate by over 50% in both trials: 0.188 vs. 0.076 relapses per year in ULTIMATE I, and 0.178 vs. 0.091 relapses per year in ULTIMATE II.

Rates of NEDA were also significantly higher for ublituximab than Aubagio: 44.6% vs. 15% in ULTIMATE I, and 43% vs. 11.4% in ULTIMATE II. Statistically, participants given ublituximab were more than five times as likely to achieve NEDA, compared to those on Aubagio.

While rates of confirmed disability progression (worsening) were similar for ublituximab and Aubagio at 12 weeks and at 24 weeks, rates of confirmed disability improvement — meaning less severe disability — were substantially higher with ublituximab.

Ublituximab also lowered the number of T1 lesions (areas of active, ongoing inflammation in the brain) by more than 95% in both trials. The number of new or enlarging T2 lesions (regions of brain damage, regardless of whether there is ongoing inflammation at the time of the scan) was reduced by more than 90%.

In both treatment groups, about 90% of participants reported  adverse events. The most common side effects associated with ublituximab included infusion-related reactions, nasopharyngitis (the common cold), and headaches. Serious adverse events occurred in 9.5% of participants on ublituximab, and 6.2% of those on Aubagio; about half were infections.

 

Last Updated: June 22, 2021

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