New Treatment Landscape in MS — Preventing Long Term Disability Through High Efficacy Treatments in Early MS - Episode 11

High Efficacy Therapies in MS: Ocrelizumab, Ofatumumab, and Cladribine

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Thomas Leist, MD and Darin Okuda, MD discuss clinical trials supporting the use of high efficacy MS therapies: ocrelizumab, ofatumumab, and cladribine.

Neil Minkoff, MD: We have some of the newer therapies. We have the ASCLEPIOS trials and also the OPERA trials for ocrelizumab. Dr Leist, can you speak a little about those? We’ve been throwing around a lot of terms about these different therapies. Please provide a quick overview of what we know about ocrelizumab.

Thomas Leist, MD: Ocrelizumab had 3 clinical trials that led to its approval. Primary-progressive MS [multiple sclerosis] trials also led to the approval of ocrelizumab as the only medication formally approved for primary-progressive MS at this point. As Dr Okuda mentioned in the opening statements, it was marked by no relapses—just progression from the very beginning—in individuals who have appropriate lesions and no other conditions that could do this.

There were additional trials for ocrelizumab. Two OPERA trials led to the approval. They were large trials. The comparative was Rebif, and ocrelizumab beat Rebif in all outcomes in terms of disability, relapses, and MRI changes. From that point, we were assessing whether a patient has a relapse. These are protocol-defined relapses, which is slightly different from what we may consider a relapse in the community. These patients were observed to have less disability progression—not an insignificant number of patients had some improvement of disability—then also MRI changes, fewer new lesions, and less atrophy.

We mentioned that ofatumumab is a medication that’s self-administered by patients. Ocrelizumab is a medication that’s administered to the patient. Sometimes that may be a relative advantage in certain populations, when I actually know the patient had the treatment. I understand that there are site-of-care issues surrounding ocrelizumab. I also can note that I work in an area in Philadelphia that’s heavily penetrated by managed care with diligent work by both the hospitals or the provider organizations on the payers to ensure patients have access with the most appropriate site of care. Patients are infused in the physician office, in the same environments that they may be infused in the hospital environment, dependent on contractual basis. There are ways of managing that by the payer to prevent what Dr Okuda referred to from occurring.

I’ve been gratified to notice that that’s gone forward with significant success in our area. I was a little surprised when Dr Okuda said the infusion centers were frozen during the pandemic in Texas. In the state of Pennsylvania, a little more stout in every single axis, we were able to continue to serve our patients on an ongoing basis and nobody missed a beat. We’re both very concerned that adherence is as high as possible in patients. We’ve been able to continue to serve our patients, and we do that now. Sometimes, there are patient populations I perceive as less reliable in terms of adhering to medication. Obviously, that’s my judgment, and I always need to reanalyze that. It’s also good for me to know whether the patient had the product, had treatment. These are the relative characteristics I mentioned that may potentially swing 1 product over the other in a given patient.

Neil Minkoff, MD: Let me ask you a question. Could you compare and contrast that to cladribine? There was the CLARITY trial, I believe.

Thomas Leist, MD: Yes. Cladribine is a different approach. With all the medications we discussed, with perhaps the exemption of the mentioning of alemtuzumab, we’re looking at treatments where the patient needs relatively regular administration of a medication. Mavenclad, a brand name for cladribine, brings a different proposition to the table. Here we have the concept that a short-course treatment can potentially lead to long-term disease control in these patients. In the case of cladribine, these are short courses of 1 week followed by 1 week in month 2 in year 1, and 1 week plus followed with an additional week in month 2 in year 2. Essentially, the patient takes pills for 4 weeks out of 2 years, with the intent that this medication has a long-term reach in terms of reducing disease activity in these patients. This is a different approach in that respect.

You mentioned the CLARITY trial. This was a placebo-controlled trial where there was relatively long-term stability in patients who had completed 2 courses of cladribine, even after 4 years—so 2 years beyond the active treatment. There was a significant superiority of patients who had observed treatments. That’s a different approach, in which the patient is on medication for a very short period of time. Cladribine is essentially out of the system very quickly. It may afford the patient medication-free periods of time. That’s an additional treatment available to patients.

Neil Minkoff, MD: Dr Okuda, you already brought up ofatumumab. Could you expound on that a little to make sure we have a level playing field among some of these agents we’re discussing?

Darin Okuda, MD: In those 2 key pivotal trials, you saw an annualized relapse rate that was about half for the first trial, and then in excess of that for the second. It did hit the primary end point of reducing the annualized relapse rate. It was also very effective in suppressing new MRI changes and preventing disability. Ofatumumab was actually superior to teriflunomide in doing that. There are substudies that popped up that looked at discontinuation rates that ironically favored ofatumumab over an oral therapy once a day, teriflunomide. There are also studies that deal with NEDA [no evidence of disease activity]. Of course, if you have primary outcome measures in which the event rates are half, if not greater, you’re going to see stark differences in the measure of no evidence of disease activity between ofatumumab and teriflunomide, which is what you saw.

In fair balance, a lot of people in the medical economic circles will look at the number needed to treat. Is there an absolute difference between these 2 very effective therapies? Because you have other therapies at the precipice of being approved, like ublituximab, where they couldn’t show that it was superior to teriflunomide on the disability outcome measure, which may be related to a variety of issues. Ofatumumab is a therapy that’s effective. It showed to be more effective than teriflunomide in the pivotal trials. The interpretation of those data from an economic perspective may mean something different to others. But these are great treatments that allow for a different way for patients to get an anti-CD20. I agree that there are innate differences that are somewhat subtle but meaningful in certain circumstances. It’s a very attractive mechanism of action in MS because of its durable effect.

The other thing that’s important to mention, which Dr Leist was alluding to, was this induction form of effect. Lemtrada and Mavenclad fall into this class but less so the anti-CD20s. For those patients on Lemtrada or Mavenclad, there’s a potential of resetting the immune system, in part, that then yields a return of a system that’s more hospitable to that individual. That’s attractive, because then you have more of a durable effect that’s positive. From a payer standpoint, I’ve heard or had experiences where nobody likes to bury the piece of charcoal waiting for the diamond to come out. You want to see some benefit that year if not the year after. I get it. But from where we all sit as health care providers, it’s nice to know that an investment can lead to more positive gains in the future.

Transcript edited for clarity.