Expanded Data, Future Implications for Ublituximab in Relapsing Multiple Sclerosis

Lawrence Steinman, MD

Expanded data from the 2 independent, identical, phase 3, randomized, global, multicenter, double-blinded, active-controlled trials, ULTIMATE 1 and 2 (NCT03277261; NCT03277248) of ublituximab (TG Therapeutics) in patients with relapsing forms of multiple sclerosis (MS) were recently presented at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 13-15, 2021.

The principal investigator for both trials, Lawrence Steinman, MD, Zimmermann Professor of Neurology and Neurological Sciences, and Pediatrics at Stanford University, presented findings at the virtual conference, summarizing investigators’ conclusion that ublituximab, an investigational glycoengineered anti-CD20 monoclonal antibody, met both studies' primary end point in significantly reducing annualized relapse rate (ARR) and MRI parameters over a 96-week period, when compared to teriflunomide (Aubagio; Sanofi).^1,2,3 

Steinman sat down with NeurologyLive to discuss the data presented at ECTRIMS 2021, following the submission of a biologics license application by TG Therapeutics to the FDA earlier this month. Steinman highlighted key findings from both phase 3 trials, sharing his thoughts on surprising aspects and promising results, as well as on the future implications for ublituximab in treating patients with relapsing MS. 

NeurologyLive: Can you provide an overview of the data/findings that are being presented on ublituximab from the ULTIMATE 1 and 2 phase 3 trials?

Lawrence Steinman, MD: We achieved our primary end point—we reduced the relapse rate compared to the comparative group, which was an approved drug, teriflunomide—the annualized relapse rate was below one-tenth of a relapse per year in both trials. Each trial had approximately 500 patients, and it was a global trial, [and] the results were identical. There were a number of other features of the trial that were very much in concordance with the reduction in the annualized relapse rate. Another prespecified endpoint was MRI activity, and there was a 96% or higher reduction in new lesions being formed. 

The safety was impressive. There were the usual infusion reactions, often on the first dose, but nothing out of line with other anti-CD20s. One of the remarkable features of the trial results was that we actually were able to see improvement on the disability scales, compared to the comparator. I think that's good news to all the individuals who I see with MS—to be able to say that not only did we have an impact on the relapse rate, but there's an improvement in functional activity. So, it's a very good trial. 

The antibody, ublitixumab, is glycoengineered, the sugars have been engineered so that the infusion time can be reduced. Essentially, after the first infusion, individuals come in every 6 months, and it's a 1-hour process. Assuming the parking is good where you come in to get your infusion, you can get back to school or get back to work or get back to your life [in a timely manner], and I think this will be a very attractive advantage compared to other infusion-based therapies for multiple sclerosis.

Were any of the findings surprising in any way?

It doesn't sound very dramatic, but based on the early studies—the phase 2 studies—this isn't surprising. What is gratifying is that when you put [ublituximab] to a test in a real clinical trial, [with] the magnitude of these 2 trials, [and] you get virtually identical results, there is a certain satisfaction in penetrating the .1 relapse a year. One way of telling it to patients is that if you look at that fraction, it means you might have 1 relapse every 10 years, again, that's good news. I don't know if that's a fair way of translating results, and I would speak about it while wearing my white coat to a patient—I am saying affirmatively that I would. I don't know whether I would have the license to say that outside of 1 to 1 with a patient, but it is a very satisfying result, in my opinion.

If successful, how will this treatment benefit patients with relapsing multiple sclerosis?

I think it's 1 of the most powerful drugs. The profile for safety and the convenience is attractive, and I think that having competing drugs in this space that have many of these characteristics, might improve the economics from the perspective of the patient. 

It's a little beyond my role as a global investigator to talk about price points, but I think that having grown up in my father's neighborhood pharmacy, competition is usually a good sign. We'll see what happens, as they say, but I think it will be a benefit to individuals with MS.

What are the next steps for this treatment—are there plans in place for future trials? What further research is needed?

The next step is to see how it’s evaluated by the regulatory authorities, and to get it out there and see that it's available to individuals after the approval process runs its course. Then there are any number of scientific studies to do in a post-marketing sense to learn about what it's doing to the immune system—how resilient the immune system is. I look forward to potentially participating in those types of trials, because there's still a lot to learn.

Although, I have to say that the magnitude of the trial and the magnitude of the effect is very encouraging, but there's still things to learn. For instance, with the pandemic in the front or back of everyone's mind, how well do people do following immunization? Do they have to be more watchful? These are real world issues that the people who I take care of will face. It's good to know how they'll fare out in the real world. But again, based on what we know from other studies, things should go reasonably well, even with a pandemic, facing the virus.

Is there anything else you would like to add?

Again, I think it's a good time. If an individual has MS, there's a lot coming out that shows that we can get reasonably good control of the disease early on. I certainly come from the school of thought that for serious diseases like MS, earlier intervention is going to be more effective intervention. Again, this is my opinion—it's nothing that came out of the trial results, but it's really good to have in the armamentarium of effective pharmaceuticals that we can use, drugs like ublituximab. I look forward to working with the TG Therapeutics team as the process evolves and to get involved with further studies of this exceptionally effective and very interesting glycoengineered antibody.

Is there an overarching theme you've taken away or anything you’re looking forward to learning about at ECTRIMS 2021?

I'm always keeping my eye out on anything that looks promising for individuals who have the other form—the much rarer form of primary progressive multiple sclerosis—to see what else we can offer. There's a large distance to cover until we have treatments that are as effective as what I've been talking about with you with ublituximab. I'd like to see that degree of improvement and that degree of positive signal when we get to PPMS. There's a start with anti-CD20s, but I think we have to get to the next level for that phase of the disease.

Transcript edited for clarity. For more coverage of ECTRIMS 2021, click here.

REFERENCES

1. TG Therapeutics submits biologics license application to the US Food and Drug Administration for ublituximab as a treatment for patients with relapsing forms of multiple sclerosis. News release. TG Therapeutics, Inc. September 30, 2021. Accessed October 4, 2021. https://www.globenewswire.com/news-release/2021/09/30/2306091/8790/en/TG-Therapeutics-Submits-Biologics-License-Application-to-the-U-S-Food-and-Drug-Administration-for-Ublituximab-as-a-Treatment-for-Patients-with-Relapsing-Forms-of-Multiple-Sclerosis.html
2. TG Therapeutics announces presentation of data from the ULTIMATE 1 & 2 phase 3 trials of ublituximab in multiple sclerosis at 7th Congress of the European Academy of Neurology. News release. TG Therapeutics. June 18, 2021. Accessed October 4, 2021. https://www.biospace.com/article/releases/tg-therapeutics-announces-presentation-of-data-from-the-ultimate-i-and-ii-phase-3-trials-of-ublituximab-in-multiple-sclerosis-at-7th-congress-of-the-european-academy-of-neurology/
3. Steinman L, Fox E, Hartung HP, et al. Ublituximab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ULTIMATE 1 and 2 trials. Presented at the 7th Congress of the European Academy of Neurology; June 19-22. Abstract A-21-00763
4. Steinman L, Alvarez E, Fox E, et al. Ublitiximab is associated with significant improvement in the multiple sclerosis functional composite (MSFC): results from the phase 3 ULTIMATE 1 & 2 studies. Presented at ECTRIMS 2021; October 13-15; Virtual. Poster P932.