Can Cladribine Get FDA Approval in Multiple Sclerosis Now With Long-Term Data?

John Walsh, MD, the vice president of US Medical Affairs in Neurology and Immunology at EMD Serono

John Walsh, MD

Cladribine, an oral tablet under investigation for the treatment of relapsing multiple sclerosis (MS), has been a subject of discussion in the United States since before 2009, when it was first submitted to the FDA for approval.

Despite receiving a Complete Response Letter in 2010 requesting more data, the treatment was approved for use in Europe and has continued through the development pipeline. Now, with up to 10 years of follow-up data in some patients from 3 phase 3 clinical trials including CLARITY (NCT00213135), CLARITY-EXT (NCT00641537), and ORACLE-MS NCT00725985), as well as the PREMIERE study (NCT01013350), its manufacturer, EMD Serono, has resubmitted cladribine to the FDA.

At the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum in Dallas, Texas, a number of presentations were given to display some of the collected long-term data, including age-matched data which showed its efficacy and safety in older patients with MS.

To find out more about the data and what the next step for the treatment is, NeurologyLive spoke with John Walsh, MD, the vice president of US Medical Affairs in Neurology and Immunology at EMD Serono.

NeurologyLive: Were any of the findings presented surprising or unexpected in any way?

John Walsh, MD: The posters that we presented were, in most cases, on course for what we saw at ECTRIMS 2018, so nothing truly surprising. However, the thing that we do notice is that the impact of cladribine tablets was, on severe relapses, consistent on what we see on the impact of all relapses. That’s not what you would generally think, right? You would think that, obviously, the more severe the disease is, potentially, there are differences. We haven’t seen that.

In Europe, the labeling is actually for patients who have more severe, more aggressive disease, so this is actually consistent with that. But the data supports that irrespective of the relapse, we’re seeing a difference.

The other piece that I think is always very impressive when you think about cladribine is that this is a drug that is given in 2 short oral courses over 2 years. However, when you look at data across all of the trials that we’ve done, if you look at the No Evidence of Disease Activity-3 data, you see that we maintain that out to the 3- to 4-year mark. The fact that it’s only given for a short period of time but you’re seeing the durability of effect is a very intriguing piece to me when one looks at cladribine.

What does this add to the current understanding of cladribine’s use in MS?

The count is that we’ve approved in 49 countries as of the moment. We sent our file to the FDA this past summer and it was accepted in July of 2018 so we’re currently hopeful that we’ll have further discussion and eventual approval with the FDA in the first half of 2019.

With all that being said, the data that we have adds a few things. One is that it underscores this oral, short-course therapy and has data that of long-duration or extended-duration of effect. We’ve also demonstrated that this is a drug with which we haven’t seen any significant changes in the expected safety profile. If you look at the regulatory history of this drug, this was a drug that had a complete response back in 2010 from the FDA. The community, of course, will have appropriate questions around what the safety is for this drug. When we look at the continuing evolution of safety data that we’ve presented at these meetings and we see there are no significant differences in what we would expect, that, to me, adds some level of additional information, which helps people best understand the safety.

The major concern, of course, that people had in the past was that there was some concern about imbalance and malignancy. We saw that when we submitted with 1 clinical trial to the FDA in 2009, where there were no malignancies in the placebo group but there were malignancies in the active group. What we’ve seen now, based on the updated data cuts, is that the rate of malignancy continues to remain stable, and if you look at external reference populations like GLOBOCAN, there’s no change in instance over time. Things like this provide additional data for clinicians to make prescribing decisions and make evaluations on what to do with drugs based on this data. We’ve had followed up with some patients for up to 10 years. That’s not commonly seen at the time of approval.

What’s next for cladribine?

As I mentioned earlier, the FDA accepted our filing back in July of 2018, so we continue to work with the FDA on the submission, and there will be an answer in the first half of this year. Given that we really trust in the promise of the potential of cladribine, we’re excited to continue those interactions with the FDA. Those are our immediate steps. Like any drug that’s on the market, obviously we continue to look at what other data gaps would exist for this drug and, ultimately, we would look to better characterize those with future studies and investigations, pending the outcome of our FDA review and hopeful approval.

Is there anything you’d like to add?

Myself, I’m very excited about this, and we’re really excited about the potential to bring this to market. You know EMD Serono and Merck KGaA are very excited about adding future science in MS. We know that there are other products on the market, but we know that, as new products become available, it opens up new options for patients.

Moving forward with cladribine is the next step, and we continue to work on an exciting pipeline of MS innovation with the evobrutinib compound for the future. We’re really excited to be in the MS space and we’re excited to help patients and we really look forward to seeing how the FDA uses our application for cladribine.