MS: New Dosing, A New Withdrawal

Stephen Krieger, MD


March 29, 2018

Hello. I am Dr Stephen Krieger, a neurologist at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis (MS) at Mount Sinai Hospital in New York. I am reporting for Medscape about updates in MS therapeutics, particularly some that were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2018 in February.

Extended-Interval Natalizumab Dosing Cuts PML Risk

I'll begin with recent data presented by Dr Lana Ryerson and colleagues[1] from New York University on extended-interval dosing with natalizumab. Natalizumab is a highly effective therapy for relapsing MS, typically given intravenously every 4 weeks or every 28 days. But we know that the use of natalizumab is constrained by the risk for progressive multifocal leukoencephalopathy (PML). Several factors help us to personalize or stratify that risk, including positive JC (John Cunningham virus) antibodies, the duration of natalizumab treatment, history of immune suppressants, and also the JC antibody index.

Dr Ryerson and colleagues looked at extended-interval dosing as another potential factor that might help to minimize and assess PML risk in individual patients. They used the TOUCH registry of natalizumab-treated patients, which includes just over 90,000 people in total, and studied 35,000 patients for whom positive JC antibodies had been recorded.

They looked at those patients who had received extended-interval natalizumab dosing—every 5-12 weeks—and they found that the cumulative risk for PML in patients who had received extended-interval dosing was dramatically lower than in those who had received standard, every-4-week dosing.

Because these were real-world data, they used different definitions of extended intervals, including dosing intervals in the past 18 months of recorded infusion history, up to intervals of dosing extending out to the entire duration of treatment for individual patients. Regardless of how they defined it, extended-interval dosing, typically in the 5- to 8-week range, correlated with much lower rates of PML. Looking out at the full infusion history, the numbers were reduced by more than 90%.

The authors of this study commented that these are hypothesis-generating results, and indeed, the TOUCH Registry does not include data on efficacy or data on the JC antibody index. This comprised patients who were organized into simply being JC positive or negative. That said, I believe it raises intriguing questions about how we can use natalizumab in the safest possible way, particularly in our JC-positive patients. I look forward to seeing where this work continues to go.

Disability Outcomes Favor Ibudilast in Progressive MS

A second study presented at the ACTRIMS Forum 2018 in February reported the clinical results for the phase 2 trial of ibudilast in progressive MS.[2] We saw the top-line data at ECTRIMS in the fall of 2017; this data showed that ibudilast versus placebo reduced the rate of brain atrophy by around 50% in this cohort of patients with progressive MS. That was a terrific number. We have rarely seen other agents slow the rates of brain atrophy by 50%, particularly in progressive MS.

Thus, everyone was very interested to see what the clinical data would look like. At the ACTRIMS Forum 2018, Dr Naismith presented the clinical outcomes—the secondary endpoints from this SPRINT-MS study—showing that ibudilast versus placebo reduced the risk for sustained accumulation of disability by 26%.

To put that into context, the reduction of risk for disability in patients with progressive MS by 26% is a pretty decent number, particularly noting that ibudilast is not an immune suppressant as many of our other medicines in development for MS, and progressive MS in particular, have been. It raises the intriguing possibility that not only does this agent slow brain atrophy, but it may reduce the risk for sustained disability as well. We look forward to seeing this move into a phase 3 study where clinical disability endpoints will be the primary endpoint.

Daclizumab-Linked Encephalitis

Finally, some sobering news. Daclizumab is an agent that was approved for multiple sclerosis in the fall of 2016. This is a self-injected monoclonal antibody. Daclizumab was considered a high-potency agent and was typically used second- or third- line for patients who had a suboptimal response to other MS therapeutics. It was just pulled off the global market by Biogen at the request of the European Medicines Agency after several cases of encephalitis emerged in Europe.

We do not yet have many details on the nature of those encephalitis cases. Were they infectious? Were they autoimmune encephalitides? But the fact remains that daclizumab has been pulled off the global market, both in the United States and in Europe. We need to have conversations with any patients who have been treated with daclizumab about transitioning them to other therapies, and also being mindful of the possible emergence of encephalitis.

More broadly, this relates to the risks we take when using complex, immune-modulating therapies to treat patients with MS, and it circles back to the data we have just seen for natalizumab on-extended interval dosing. We obviously must continue to look for the most effective medications for our patients. But being aware of the risks, and making novel attempts to stratify those risks and to minimize them, will allow us to take the best possible care of our patients.

That is the news in MS therapeutics for March 2018. Reporting for Medscape, this is Stephen Krieger at Mount Sinai. Thank you.


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