Experts in neurology debate the utility of combination therapy in the management of multiple sclerosis and highlight current obstacles to this treatment approach both in clinical investigation and practice.
Ahmed Obeidat, MD, PhD: Other questions that come up is people talk about combination therapy and will you combine BTKIs with other existing medications? And this is a concept we're not used to in MS. I know in the past there have been some attempt to combine therapies and it didn't have good outcomes. What is your input on this, Dr Greenberg?
Benjamin Greenberg, MD: As a field, we have failed at studying combination therapy, the only true combination therapy trial we did, the CombiRx trial, an NIH-sponsored trial looking at injectable therapies, interferons and glatiramer acetate combination versus alone was born out of a time of necessity where we were using modestly effective drugs, and we were looking to see if you could have additive benefits, and we've moved from that era into an era of highly effective therapies even as monotherapy, they work extremely well across a broad array of patients. We've also have more complex and riskier adverse event profiles with the newer drugs, it makes it harder on multiple levels to do combination therapy studies. At times I'm pessimistic and when I'm in that pessimistic mode, I'll say I highly doubt we're going to see true combination trial therapies. I don't think we're going to have the infrastructure or the investments to do them in the way we'd want to do them in a scientifically rigorous fashion. We will see sequencing studies. What if you do drug X and then try a BTK inhibitor or vice versa? There are a lot of opportunities there. I'm not sure we're going to see the combination therapies. There is animal data looking at using a B cell depleting agent and then following up with a BTK inhibitor that showed promising results, and I know multiple groups are looking at this and considering this from a human trial perspective. Our current trials for relapsed/remitting are all single agent with an active comparator, and then on the progressive trials, the 2 drugs that are doing progressive trials are doing them differently. One is using an active comparator so using a B cell depleting ocrelizumab comparator. The other is using placebo as a comparator and even amongst the trials, we're not seeing anyone attempting combination therapy or sequencing. They're all very traditional, I'm not sure we're going to get that data.
Ahmed Obeidat, MD, PhD: Yes, and some of the trials you must wait 6 months or so before you start the medication from the other medication.
Benjamin Greenberg, MD: The wash out period, yes.
Ahmed Obeidat, MD, PhD: The wash out. And there's a wash out in clinical trials, and we just talked about we don't do this much in practice, but in the clinical trials we must do them sometimes for the actual criteria. I like the idea of sequencing. This is something that we may talk about later more and explore more as we learn more about this class of medication, and then maybe how to sequence them and what medications will be the ones before, and that will be kind of also part of our treatment algorithm when we meet our patients and say, "Well, maybe we start with this one andthen maybe we move to a BTK or maybe we start with a BTMI and then maybe move to something else, it's a very interesting concept to think about.
Transcript Edited for Clarity