Ublituximab Quite ‘Reassuring’ as Potential MS Therapy, Experts Say

In clinical trials, the investigational anti-CD20 therapy ublituximab was the first to push the annualized relapse rate (ARR) below the 0.1 threshold among patients with relapsing forms of multiple sclerosis (MS), while improving disability outcomes in a significant proportion of patients.

“The [relapse] rate was below a tenth of a relapse a year, and this had been a barrier that hadn’t been [crossed],” Lawrence Steinman, MD, a professor of neurology at Stanford University, said in an interview with MS News Today. While stressing that this rate is just an average, meaning more or less relapses are possible in any given patient over the course of this disease, Steinman called the result “a very big deal.”

“It sure would feel good to tell a patient you’re going to have a tenth of a relapse a year,” he added. “They’ll say, ‘Doctor, what’s a tenth of a relapse?’ [and I’d say,] ‘Think about it as that, in a decade, you might only have one event similar to what you went through with [a previous relapse].’ That’s pretty reassuring.”

To Michael Weiss, the president and CEO of TG Therapeutics — ublituximab’s developer — the very low ARR seen in trials means people treated with ublituximab “can hopefully sleep a little bit better, knowing [they] don’t have to worry about waking up the next day with some sort of relapse and then have some disability disadvantage caused from that relapse.”

These findings come from ULTIMATE 1 (NCT03277261) and ULTIMATE 2 (NCT03277248), two identical Phase 3 clinical trials in which ublituximab outperformed Aubagio (teriflunomide) across annualized relapse rates and a range of other measures over two years of treatment.

Ublituximab-treated patients had 0.076 and 0.091 relapses per year in ULTIMATE I and II, respectively — rates 50-60% lower than with Aubagio — allowing both trials to meet their primary goal.

The proportion of patients with a confirmed disability improvement was also significantly higher with ublituximab than Aubagio — 12% vs. 6% for improvements lasting at least 12 weeks, and 9.6% vs. 5.1% for improvements sustained over 24 weeks or more. Rates of confirmed disability progression were similar, and low, with both medications.

While these results are not likely to allow someone in a wheelchair to walk around after treatment, “it is exceptionally good news to be able to tell somebody that, in this clinical trial, there was really an impressive and statistically meaningful increase in the number of people who improved [in terms of disability],” said Steinman, the global chair for the ULTIMATE studies.

Weiss considered these positive relapse and disability outcomes as fundamentally linked, since relapses tend to accompany worsening disability in people with relapsing forms of MS.

“If you can reduce the amount of relapses, it should translate to less progression of disability,” he said. “I think the confirmed disability improvement numbers are pretty exciting. Certainly, not everyone is going to have disability improvement, but there is a small percentage of patients that can get some disability improvement.”

Potential new kid on the block

Supported by data from the ULTIMATE trials, TG Therapeutics is planning to ask the U.S. Food and Drug Administration (FDA) to approve ublituximab as a treatment for relapsing forms of MS in the third quarter of this year.

If it gets FDA approval, ublituximab would become the third anti-CD20 antibody open to relapsing MS patients in the U.S. — joining Roche’s Ocrevus (ocrelizumab) and Novartis’ Kesimpta (ofatumumab). All three work through the same general mechanism: by targeting the CD20 protein, they lead to the destruction of B-cells, immune cells that drive inflammation in MS.

Ublituximab has been glycoengineered — meaning that certain sugar molecules attached to the protein have been modified — to give it very high potency for antibody-dependent cellular cytotoxicity (ADCC). Put more simply, the medicine is designed to be very powerful at triggering other immune cells, such as natural killer cells, to kill the target B-cells.

A notable consequence of this potency is that lower doses of ublituximab are required to achieve the same effect as with other medications. Since ublituximab is delivered by intravenous infusion — a steady drip into the bloodstream over time — its lower dose equates to shorter infusion times.

“[Ublituximab] has a stronger ability to kill a B-cell in assays that are done in a test tube. But the important difference is that, because of this glycoengineering, ublituximab can be infused in a much shorter period of time than the comparator, which would be ocrelizumab [Ocrevus],” Steinman said.

Ocrevus is also administered by infusion, with infusions that take a minimum of two hours given every six months (once patients are established on treatment). Ublituximab, which is also administered every six months, is reportedly able to be infused in about an hour.

“A one-hour infusion, ideally, is short enough that it doesn’t ruin [patients’] day and they can have their physicians visit, they can get their infusion, and they can get home or get back to work as seamlessly as possible,” Weiss said.

Kesimpta is taken subcutaneously, as an under-the-skin injection that can be done at home, every month. According to Weiss and Steinman, some patients may find at-home injections more convenient than infusions, but others won’t, so it’s good to have both options available.

“I think the [subcutaneous] monthly for some patients is a reminder that they have a disease and they have to deal with it on a semi-regular basis … whereas the nice part of an every-six-month infusion is that it should pretty much approximate the time in which patients are going back to visit with their physicians,” Weiss said.

In clinical trials, all three of these medications have had similar safety profiles: rates of serious adverse events were under 10%, with the most common serious safety issues being infections. Experts don’t think this surprising, given that the medicines work by effectively wiping out a part of the immune system.

Despite their similarities, adding ublituximab to the list MS approved therapies “makes for a menu of very good drugs that can really put [the disease] in check,” Steinman said.

“They all have strengths. I don’t think any of them have weaknesses, but there are points that can differentiate one product from another a little bit,” he said of the three anti-CD20 medications.

Steinman also favored having another competing therapy on the market, as it could help to drive down cost, which “is not as important to an individual patient [with insurance] as it is to a broader view of the economics of healthcare.” Currently, the U.S. list price for Ocrevus is about $67,000 a year, and for Kesimpta about $83,000 a year.

TG has previously said that, if approved, ublituximab would be made available at a competitive cost. Weiss reaffirmed in the interview that TG is looking to price ublituximab lower than both Ocrevus and Kesimpta, with specifics still under consideration.

“We’re working with payers and doing research right now, and our goal with price is to identify a price that will make access as available as possible to patients,” he said.

Possibilities for progressive MS

Collectively, the ULTIMATE trials enrolled 1,094 adults with relapsing forms of MS: about 98% had relapsing-remitting MS (RRMS) and the remaining 2% had active secondary progressive MS (SPMS). TG is requesting FDA approval of ublituximab as a treatment for relapsing forms of MS, a broad category that generally includes RRMS, active SPMS, as well as clinically isolated syndrome (CIS).

Both Weiss and Steinman agreed that, although most enrolled in the ULTIMATE trials had RRMS, the results could support a broad relapsing MS label.

“These disease categories that you’re talking about — CIS, secondary progressive, relapsing remitting — in some ways, they’re well-intentioned inventions of us neurologists,” Steinman said, noting that all three types share fundamental similarities in terms of their underlying biology.

TG would consider additional clinical studies if regulatory agencies decide the trials’ data do not support a relapsing MS approval, Weiss said.

He also said that the company is considering running clinical trials in primary progressive MS. To date, Ocrevus is the only approved treatment for this MS form in the U.S. and European Union.

“We’re definitely exploring additional studies for ublituximab in MS, including exploring the potential of a PPMS study,” Weiss said.

Ocrevus has been shown to substantially reduce the rate of disability progression among people with PPMS. Since they work through similar mechanisms, an anti-CD20 therapy like ublituximab may also be effective in PPMS, But, so far, only Ocrevus has been tested in clinical trials.

“I’d like to see a trial, particularly in the primary progressive area, just to see how it [ublituximab] stacks up with the exciting results from ocrelizumab [Ocrevus] that really broke a barrier,” Steinman said.