Article In Brief
With the December approval of ublituximab, clinicians now have three approved and one off-label anti-CD20 therapies to choose from for treating relapsing multiple sclerosis (MS). MS specialists look at what the latest approved therapy offers and how it compares with other treatment options.
On Dec. 28, 2022, the Food and Drug Administration (FDA) approved ublituximab (Briumvi, TG Therapeutics), an infusion B-cell therapy administered every 24 weeks, for relapsing multiple sclerosis (MS). The approval was based on results from two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), published in August in the New England Journal of Medicine, which compared ublituximab with the once-daily pill teriflunomide. The trials found that patients taking ublituximab had lower annualized relapse rates (the primary endpoint) and fewer brain lesions on MRI than the teriflunomide group over a period of 96 weeks.
In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (p<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (p=0.002).
In the ULTIMATE 1 trial, the mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (p<0.001); in ULTIMATE II, it was 0.01 and 0.25, respectively (p<0.001).
But a pooled analysis of the two trials, which enrolled more than 1,000 total participants, found no significantly lowered risk of worsening of disability for the ublituximab group. At 12 weeks, 5.2 percent of the participants in the ublituximab group and 5.9 percent in the teriflunomide group had worsening of disability (p=0.51).
No new safety signals of concern emerged compared with those in phase 3 trials of other anti-CD20 monoclonal antibodies, and adverse events occurred at similar rates as those reported for those other agents. That said, the proportion of patients experiencing infusion-related or injection-related systemic reactions was higher with ublituximab (48 percent) than with ofatumumab (20 percent) and ocrelizumab (34 percent).
“Over the past several years, we have seen a dramatic shift in the MS treatment landscape towards the use of B-cell therapy, which has shown to be highly effective in reducing relapses in patients,” the trial's lead investigator, Lawrence Steinman, MD, FAAN, the Zimmermann Professor of Neurology & Neurological Sciences and of pediatrics at Stanford University, said in a news release from TG Therapeutics.
“Anti-CD20 therapies are widely used and among our highest-efficacy therapies, and ultimately, having more treatment options is always better for patients. Every patient is so different, with different lifestyles, comorbidities, and disease profiles. ... More choice allows more personalization of treatment, which is something we really need in the MS field.”—DR. JIWON OH
“The outcome of the ULTIMATE I and II trials evaluating ublituximab, a novel targeted anti-CD20 agent designed for efficient B-cell depletion that supported this approval, represents an important milestone in the history of MS research as the first phase 3 study of an anti-CD20 monoclonal antibody in patients with relapsing MS to produce an annualized relapse rate of less than 0.10, which translates to less than one relapse in 10 years. This approval is great news for patients living with MS and provides an appealing treatment alternative that can be administered in a one-hour infusion twice a year following the starting dose, which I believe is an added benefit to patients.”
With ublituximab's approval, clinicians can now select from three US FDA-approved anti-CD20 agents—including ocrelizumab and ofatumumab and one off-label, rituximab—for the management of patients with relapsing MS. Ocrelizumab was approved in March 2017 and ofatumumab in August 2020, and rituximab has been commonly used off-label for this indication, particularly since the phase 2 HERMES trial, published in the New England Journal of Medicine in 2008, demonstrated its efficacy in treating relapsing MS.
“The anti-CD20 agents have proved themselves as a class of highly effective therapies for MS,” said Ahmed Z. Obeidat, MD, PhD, associate professor of neurology and founding director of the neuroimmunology and MS fellowship program at the Medical College of Wisconsin. “We are very excited about having these options for our patients. These agents have also taught us more about the pathogenesis and immunology of MS and highlighted the role of B-cells in the disease process. For the longest time, we had thought of MS as primarily a CD4+ T-cell mediated disease, but the advent of these drugs has us thinking more about it as a disease driven by B-cells and the interaction between B-cells and T-cells, which is clearly important. Modulating or depleting the B-cells plays a key role in controlling relapses and, to some extent with some agents, slowing down progression.”
How Does Ublituximab Compare?
What makes ublituximab different, and why would a neurologist choose to prescribe one of the four available anti-CD20 agents over another? None of the anti-CD20 agents have been compared head to head with any of the others, and while ublituximab and ofatumumab were both compared to teriflunomide in their pivotal trials, ocrelizumab was studied in comparison with interferon-beta-1a (Rebif).
“It's hard to draw conclusions when the active comparator wasn't the same,” said Jiwon Oh, MD, a staff neurologist, associate professor, and medical director of the Barlo Multiple Sclerosis Program at St. Michael's Hospital of the University of Toronto.
As is often the case, the decision comes down to multiple factors, including efficacy, adverse events, convenience, insurance formularies, and out-of-pocket cost to the patient, experts told Neurology Today.
One of the biggest differences between ublituximab and the other anti-CD20 agents is the shorter infusion time. The first infusion is four hours, and the second, given two weeks after the first, is one hour followed by a required one-hour observation period. Each subsequent infusion is an hour, and monitoring is at the discretion of the treating physician, so patients who have not had any adverse reactions can expect a one-hour infusion time. Ocrelizumab begins with either a 3.5- to four-hour infusion protocol, and later doses can be shortened to a two-hour infusion protocol if the patient has not had a serious infusion reaction. (Ofatumumab is a once-monthly injection, delivered subcutaneously.)
“I won't say that it's a therapeutic game-changer, but for a young, generally healthy patient who's busy with work and family, having more sense of control over their schedule with a shorter infusion time is compelling,” said Dina Jacobs, MD, associate professor of neurology and clinical director of the Multiple Sclerosis and Related Disorders Center at the University of Pennsylvania.
“Shorter infusion times also open up more availability in infusion centers. This will make it easier for patients to get appointments, which is especially important when we know that prompt initiation of highly effective therapy improves clinical outcomes.”
Ocrelizumab also contains a label warning about malignancy risk, as there was a small signal of increased risk of breast cancer in the trials that led to its approval. (Breast cancer occurred in six of 781 females treated with ocrelizumab and in none of 668 the females treated with interferon-beta-1a or placebo.) Neither ublituximab nor ofatumumab has this label warning.
There are other mechanistic differences between all of the anti-CD20 agents, Dr. Oh noted. “These antibodies all target slightly different epitopes and have different molecular attributes and pharmacokinetics, which could have implications in the longer run for efficacy and safety,” she said. “Within the existing trials, we just don't know what those differences are.”
Ublituximab does have unique properties compared with the other anti-CD20 agents. It not only targets a unique epitope but also is glycoengineered for enhanced B-cell depletion, noted Bruce A. Cohen, MD, FAAN, professor of neurology and chief of multiple sclerosis and neuroimmunology at the Northwestern University Feinberg School of Medicine.
“It causes a very rapid breakdown of the B-cell, literally within 24 hours, and we saw that the frequency of infusion reactions in this trial was just under 50 percent,” he said. “As this drug gets into more widespread use, there is the potential that we may start to see rare but more severe infusion reactions because of the rapid breakdown of the cells. I don't know that that will be the case, but it is something that one needs to be alert for.”
“In an individual patient where you really want to deplete B-cells as fast as possible, a drug like this may be more suitable,” Dr. Oh said.
Unlike the other two FDA-approved anti-CD20 antibodies, ublituximab is chimeric, about two-third human and the rest murine. “By contrast, ofatumumab is a fully human antibody with no murine components, while ocrelizumab is humanized, 90 percent human and the rest murine,” said Dr. Obeidat. “We know that rituximab is also chimeric, and so far we have not seen any major issues with that drug related to this. As with so many other questions about the differences between these agents, long-term pharmacovigilance studies will be essential.”
Dr. Oh agreed. In a Lancet Neurology editorial in December she coauthored with Amit Bar-Or, MD, Melissa and Paul Anderson President's Distinguished Professor of Neurology, chief of the Multiple Sclerosis Division, and director of the Center for Neuroinflammation and Neurotherapeutics at the University of Pennsylvania, she wrote, “Whether the distinguishing attributes of ublituximab warrant choosing it over other anti-CD20 agents should be informed by long-term assessments in extension, real-world, and discontinuation studies.”
“This approval is great news for patients living with MS and provides an appealing treatment alternative that can be administered in a one-hour infusion twice- a- year following the starting dose, which I believe is an added benefit to patients.”—DR. LAWRENCE STEINMAN
“As this drug gets into more widespread use, there is the potential that we may start to see rare but more severe infusion reactions because of the rapid breakdown of the cells. I don't know that that will be the case, but it is something that one needs to be alert for.”—DR. BRUCE A. COHEN
Pricing and Formulary Placement
In terms of the novelty of the drug itself, ublituximab may not change much about the treatment landscape, but it could have a significant impact on access to medication, Dr. Cohen said.
According to the National Multiple Sclerosis Society, the wholesale acquisition cost for ublituximab (medication alone) will be $59,000 per year. “That's about 20 percent less than ocrelizumab,” Dr. Cohen observed. “Of course, then it will be up to every pharmacy benefit manager to negotiate their own rebate, determining their resultant net cost, which is not transparent.”
TG Therapeutics has said that ublituximab may be available for prescription in February, but it will take some time after that before anyone knows how it will be placed on insurance companies' formularies and whether any savings will be passed along to patients, Dr. Cohen said. “The formularies don't change quickly, and it's going to take some time before we really see the results,” he added.
The introduction of another drug into an already crowded space also could potentially impact pricing among these agents in general. “If the negotiations that typically take place between payers and producers result in savings that are actually passed on to the patient—and that is a very big if—that could improve access to this class of drugs in general,” Dr. Cohen said.
“And we'd like to think that the more therapies in a class that compete with each other, that this would translate into a reduction in cost,” he continued. “Although it's likely to do so at the wholesale level, that savings may just get eaten up by the middlemen in the distribution chain rather than being passed on to the people who use the drugs. Look at what happened with dimethyl fumarate; this is the cheapest MS disease-modifying therapy out there, yet when people get switched to a generic dimethyl fumarate, their out-of-pocket costs go up. The same thing happened with glatiramer acetate. More competition is good for the suppliers, but that doesn't necessarily translate into good for the patients.”
If patients are already stable and happy with another anti-CD20 agent, it would be hard to make the case to switch to a new agent in the same class, Dr. Jacobs said. “I don't anticipate that we will see a large percentage of our patients switching drugs unless insurance companies require it. But for patients who are new to therapy, ublituximab may have some advantage in terms of convenience and cost. It is certainly beneficial to have another highly effective treatment with durable efficacy; one that may even be considered around family planning given its long therapeutic effect after the drug is cleared.”
Overall, ublituximab is highly effective, and all clinical and MRI measures are in keeping with what has been seen in other drugs in the class, said Dr. Obeidat. “The best medication is the one a patient takes, and each of these therapies adds a benefit to the landscape of MS treatment,” he said. “This is why shared decision-making and discussion of the differences between these molecules with the patient is so important.”
“I won't say that it's a therapeutic game-changer, but for a young, generally healthy patient who's busy with work and family, having more sense of control over their schedule with a shorter infusion time is compelling. Shorter infusion times also open up more availability in infusion centers. This will make it easier for patients to get appointments, which is especially important when we know that prompt initiation of highly effective therapy improves clinical outcomes.”—DR. DINA JACOBS
“Anti-CD20 therapies are widely used and among our highest-efficacy therapies, and ultimately, having more treatment options is always better for patients,” Dr. Oh agreed. “Every patient is so different, with different lifestyles, comorbidities, and disease profiles. Most people with MS will cycle through a few different therapies over the course of their lives, and the type of therapy you want at one point in your life may be very different from what you want at another point. More choice allows more personalization of treatment, which is something we really need in the MS field.”
Dr. Obeidat received personal compensation for participation in scientific advisory boards, steering committees, and/or for speaking engagements from Alexion pharmaceuticals, Banner life sciences, BD sciences, Biogen, Biologix, Bristol Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharma, Horizon therapeutics, Jazz Pharma, Novartis, Sandoz pharmaceuticals, Sanofi/Genzyme, TG therapeutics, Viela Bio. Honoraria from Medscape, WebMD, and MJH Life Sciences. Dr. Jacobs has received research support from Biogen, Genentech, and Novartis; consulting and scientific advisory board fees from Biogen, Genentech, Novartis, EMD Serono, Banner Life Sciences, Bristol Myers Squibb, Horizon, and Sanofi Genzyme.