Drugs in Development for MS, Including Ofatumumab

Fred D. Lublin, MD: We have several phase 3 trials that have reported out as successful. Let’s start with ofatumumab. Amit?

Amit Bar-Or, MD, FRCP: You’re referring to the ASCLEPIOS I and ASCLEPIOS II trials. As Stephen has mentioned, these were randomized active comparator trials with teriflunomide as the comparator and ofatumumab at 20 mg monthly, subcutaneous injection dose. This is a fully humanized anti-CD20 to distinguish it from rituximab as a chimeric and ocrelizumab as a humanized antibody. The studies were both quite positive with a 50% and 57% reduction in annualized relapse rate as the primary outcome measures in each of these 2 identically designed trials and hitting on multiple imaging metrics, again of focal inflammatory disease as well.

The safety and tolerability profiles are really quite good. There had been a question from the phase 2 studies as to whether this drug dosed at much lower milligram doses than the currently approved ocrelizumab would indeed have as high an efficacy, and of course not head-to-head with ocrelizumab. But the magnitude of difference with teriflunomide was overall quite impressive, and the relatively boring safety profile appears quite attractive as well.

Fred D. Lublin, MD: We’ve alluded to 2 other S1P1s [sphingosine 1-phosphate receptor 1 modulators], ozanimod and ponesimod. Peter?

Peter A. Calabresi, MD: Yes. As we discussed, there typically are not head-to-head studies with these, but they have shown efficacy in phase 3 trials and will be moving forward. They are each slightly different molecules that are, as we mentioned, somewhat shorter acting. I think we will see as we move forward whether that will lead to more rapid rebound. That’s something that we might have to consider when patients are coming off of them. The efficacy part of the equation looks very similar to siponimod and the older generation, fingolimod, with probably subtle differences in terms of their engagement of other targets and CNS [central nervous system]. So we’ll wait and see how those evolve.

Fred D. Lublin, MD: Then we have an entirely different type of agent that will report out data very soon, and that’s high-dose biotin. The idea there being that it’s theoretically restoring or enhancing mitochondrial function, and therefore allowing them to preserve neuronal integrity. Interesting study. They had 1 small study that was positive, but what’s interesting about the biotin development pathway is that their primary outcome measure is improvement. And they will report out for AAN [the American Academy of Neurology], although we may hear an announcement sooner; they are putting their data together. Other agents anyone wants to mention?

Amit Bar-Or, MD, FRCP: Since we talked about siponimod in SPMS [secondary progressive multiple sclerosis], it may be worth mentioning the 1 drug approved for primary progressive MS [multiple sclerosis,] which is ocrelizumab. This was a trial that was a fairly large primary progressive trial with ocrelizumab anti-CD20 against placebo. Patients entering have to have primary progressive MS clinically and also a positive CSF [cerebrospinal fluid] profile, at least at the level of the antibodies. And there was a modest but a statistically significant benefit in terms of confirmed disability progression with the anti-CD20 versus the placebo. This study was on the coattails of the OLYMPUS trial with rituximab, which was a negative trial in primary progressive MS with this other anti-CD20. And some of the lessons learned in terms of potentially a patient profile that’s more likely to benefit were implemented in the design of the ORATORIO ocrelizumab trial.

Fred D. Lublin, MD: It bucked the trend of trying to do subset analysis of failed studies; usually that gives you a failed study. And in fact, rituximab, the OLYMPUS trial, was just the opposite, that they took the subset analysis and turned it into a good phase 3 trial.

Patricia K. Coyle, MD: There are several groups that are looking at BTK [Bruton tyrosine kinase] inhibitors, which affect B cells and innate immunity. There’s a very interesting gold nanoparticle study that’s looking at trying to boost remylinization in CNS repair in chronic optic neuropathy. It’s kind of interesting, different.