A Less Expensive, More Convenient Treatment Option for MS?

Pauline Anderson

June 30, 2021

Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.

Results from two new phase 3 trials show that the investigational drug ublituximab (TG Therapeutics), a novel glycoengineered anti-CD20 monoclonal antibody, significantly reduced the annualized relapse rate (ARR) and MRI parameters compared with teriflunomide in patients with relapsing forms of MS.

Dr Lawrence Steinman

The positive results suggest "another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients," lead author Lawrence Steinman, MD, professor of neurology, Stanford University, Stanford, California, told Medscape Medical News. "These are delightful data in my opinion," he added.

The findings were presented at the virtual Congress of the European Academy of Neurology (EAN) 2021.

"Glycoengineered" Anitbody

If approved by the US Food and Drug Administration (FDA), ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.

There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means "at least half their day is shot," Steinman said. "A lot of people don't want to or can't miss a half day of work." Ublituximab can be infused more rapidly, he noted.

For the study, the investigators analyzed data from the ULTIMATE 1 and ULTIMATE II studies, which included a total of 1089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.

Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.

The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Steinman.

Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 month over the course of the 96-week study.

Primary Outcomes Met

For ULTIMATE I, the primary outcome was AAR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted AAR ratio, 0.406; 95% CI, 0.268 – 0.615; P < .0001).

In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330 – 0.784; P = .0022).

One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Steinman. "So that was very good news."

It is not clear why relative reductions for ARR differeed between the two studies; "probably the real number is somewhere between 60% and 49%," Steinman said.

From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.

Another "piece of really good news" from the studies is that the drug led to a significant improvement in disability, rather than "just slowing it down," Steinman noted.

There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab vs teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).

The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).

A Life Changer?

Steinman said the "robust" findings suggest that patients with MS "won't have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease."

The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.

The ublituximab group had more infections (4.0% vs 2.6%), which Steinman said is not surprising because the drug is a potent immune suppressant.

"It's an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent," he said.

If approved, "it will be interesting to see how regulatory agencies handle this in terms of risk mitigation," said Steinman. He added that a warning label might be a consideration.

However, the safety of this drug "is certainly acceptable," said Steinman. "In general, this drug is not that different from the other drugs in the class of anti-CD20s."

Steinman noted that he understands why some patients prefer an oral drug and may have an "aversion to getting stuck with a needle," but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.

"For people who have had relapses, people who are unable to do what they want to in life ― attend school, hold down jobs, exercise ― this new drug could really be life changing," he said.

He added that he would "strongly urge" his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.

Ublituximab also has a number of advantages over the others agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be be less costly, Steinman noted. "The company has said it intends to come in at a lower price point," he said.

The company is now planning to prepare a biological licence application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.

Striking Improvement

When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Steinman to elaborate on the "very strong effect" of the drug with regard to improving disability, Steinman said the improvement was "striking."

Being able to talk to patients about possible improvement rather than about delaying disability "is really gratifying" and provides a "much more constructive and optimistic outlook," he said.

He noted that as physicians improve their management of patients with MS "and are paying attention to things that we haven't over the years, like vitamin D and even mental health," disability progression management "is getting better."

Steinman is a consultant for TG Therapeutics.

Congress of the European Academy of Neurology (EAN) 2021: Oral Session 1006. Presented June 19, 2021.

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