Study led by St. Michael’s Hospital scientist shows promise for treating progressive multiple sclerosis
Dr. Jiwon Oh
New research led by a St. Michael’s Hospital clinician-scientist and published in the prestigious New England Journal of Medicine suggests that a therapy called Tolebrutinib could reduce disability progression in people with non-relapsing progressive multiple sclerosis (MS) – a subtype of MS that doesn’t respond well to current disease-modifying therapies.
Tolebrutinib belongs to a new class of medication for anti-inflammatory diseases, called Bruton’s tyrosine kinase (BTK) inhibitors. The drug works by inhibiting the BTK enzyme to reduce activation of B cells that contribute to brain and spinal cord inflammation in MS. It’s also thought to modulate a specific immune cell called microglia, which is linked to MS progression.
The new research, led by scientist and staff neurologist Dr. Jiwon Oh, evaluated the safety and efficacy of Tolebrutinib compared to a different type of medication, called Teriflunomide, in people with relapsing MS – the most common subtype of MS. While both medications showed similar effects on the rate of relapses, Tolebrutinib showed a clear difference in disability progression, suggesting that it targets the mechanisms responsible for progressive disease.
We sat down with Oh, who’s also the Medical Director of the BARLO MS Program at St. Michael’s, a site of Unity Health Toronto health care network, to learn more about this research, what it means for people with progressive MS and how it could change the treatment landscape.
What was the impetus for this study?
The most common type of MS is relapsing MS, where people present with relapses or attacks – sudden onset of neurological symptoms that tend to get better over time. With progressive (or non-relapsing) MS, people have very slow neurological progression over time and no clear relapses. The greatest clinical unmet need in MS care is a meaningful treatment for progressive MS. There are so many treatments available for relapsing MS but they don’t seem to have a profound effect on progressive disease. We really wanted to find a treatment that gets into the brain and targets some of the unique processes responsible for progressive disease.
What were your findings?
We conducted two phase-three trials (GEMINI I and II) [the final stage of testing before a drug can be used in humans] of people with relapsing MS, and found that Tolebrutinib didn’t meet its primary endpoint, meaning that compared to Teriflunomide, there wasn’t a difference in annualized relapse rate (ARR) – the average number of relapses experienced by patients in a year. Compared to baseline, both drugs reduced ARR. However, despite not showing a difference in reducing ARR, there was a clear difference in reducing disability progression.
These results emphasize what we saw in the HERCULES clinical trial, which evaluated Tolebrutinib in non-relapsing secondary progressive MS, and found that it clearly reduced the risk of disability progression versus a placebo. Even in relapsing MS, there’s disease progression. We usually think that most of the progression in relapsing MS is related to relapses but when you compare two drugs that have a similar reduction in relapse rate, yet one of them very clearly reduces disability compared to the other, it further highlights the point that it’s targeting progressive disease processes.
What was your reaction to the findings?
Right before this study, there were phase three-trials reported on another BTK inhibitor that showed absolutely no effect on relapses or disability progression compared to Teriflunomide. The whole field was so depressed. I was optimistic going into this study, given what we know about Tolebrutinib and how easily it gets into the brain, but because of the recent failure and some of the similarities in drugs of the same class, we were a bit worried. I’m not surprised by the results, but I’m relieved that it showed an effect in both non-relapsing secondary progressive MS and on disability progression, even in relapsing MS. We’ve been talking about this class of therapy with patients with progressive MS for so long, and to be able to tell them that there’s something coming forward that will hopefully help, it’s such a wonderful thing.
What does this mean for people with progressive MS?
It’s really a new era for people with non-relapsing, secondary progressive MS. This population’s almost purely progressive, so to find a drug that’s shown an effect is exciting. More importantly though, this study showed that even many people with relapsing MS are having progressive disease unrelated to relapses. We would’ve loved to see more than a 30 per cent reduction but it’s still exciting to have a treatment that gets into the brain and targets some of the processes that cause progressive disease, which our existing therapies don’t do. I always say that the first treatments for relapsing MS became available only 30 years ago, and at the time, they reduced relapses by about 30 per cent. Today, the efficacy is closer to 70 to 90 per cent; that’s how far we’ve come in 30 years. In a way, this is the same beginning for progressive MS as it was 30 years ago for relapsing MS. Seeing that Tolebrutinib has a 30 per cent effect on progressive disease processes is incredible. For nearly 10 years, we’ve recognized that the greatest unmet clinical need in MS is a targeted treatment for progressive disease, so it’s exciting. I’m really hopeful.
What are the next steps for this treatment?
The next step is regulatory approval. We’re trying to get approval from the FDA, Health Canada and the European Medicines Agency. Once we have that, we’ll figure out which patients should receive the drug. Progression happens across the spectrum of MS, so there may be patients with other types of MS who benefit from this treatment too. Once patients are on it, there will be frequent monitoring in the first couple of months. Very rarely, people receiving this drug can experience significant liver enzyme elevation, but we’ll keep a close eye on that through regular blood testing.
* Dr. Oh has received research funding from Biogen Idec, Brain Canada, EMD Serono, Roche, the MS Society of Canada, the National MS Society and NIH. She has received consulting and/or speaking fees from Biogen-Idec, EMD Serono, Horizon Therapeutics, Novartis, Roche and Sanofi Genzyme.
By: Anna Wassermann
Share this Article
