The Clinical Challenges of Slowing Disability Progression in Patients With Primary Progressive Multiple Sclerosis
During 2014 to 2016, encouraging results were reported from 2 drugs (simvastatin and biotin) evaluated in phase 2 trials and 2 drugs (ocrelizumab and siponimod) evaluated in phase 3 trials. In the MS-STAT trial, simvastatin, which has neuroprotective and immunomodulatory properties, reduced the rate of whole-brain atrophy and delayed the progression of disability in patients with secondary progressive multiple sclerosis (MS). Biotin, which supports myelin repair and protects against hypoxia-induced axonal degeneration, was shown to improve MS-related disability in a 2016 double-blind, placebo-controlled study. In the ORATORIO trial, ocrelizumab, an anti-CD20 monoclonal antibody, delayed the accrual of disability in patients with primary progressive MS. And, finally, the results of the EXPAND trial indicated that siponimod, which has been shown to have anti-inflammatory effects, may also have neuroprotective effects in patients with secondary progressive MS. The findings reported in these trials are encouraging, and have highlighted the importance of targeting the pathogenic mechanisms that characterize progressive MS. An important challenge will be obtaining positive results when these drugs are used to treat a broader, more heterogenous population of patients with progressive MS in the real-world clinical setting. Our featured experts in the field discuss the clinical challenges of slowing disability progression in individuals with primary progressive MS.
Q: What are the clinical challenges of slowing disability progression in patients with primary progressive MS?
Chairman, Department of Neurology
Well, I think that the main issue is that we do not know how to do it. I think that the data with ocrelizumab, as impressive as they were with relapsing disease, were much less impressive with primary progressive disease. The difference in the rate of disability was statistically significant, but modestly at best. Further, the patients who had active magnetic resonance imaging (MRI) lesions seemed to do better, although it did not reach statistical significance. That suggests to me that the beneficial effect of ocrelizumab in primary progressive disease was because of the overlap between the patients with early or late secondary progressive disease with inflammation, and it is such a strong, effective way of treating MS that it spilled over to the wobble diagnosis of primary progressive MS. From clinical experience, you can treat patients with primary progressive disease for years with rituximab, which is similar to ocrelizumab, with an intensive use of cyclophosphamide, and see virtually no beneficial effects. Of course, in a randomized, double-blind trial you will see things that you will not see from the clinical impression, but, as of now, I do not see any really effective way of stopping primary progressive disease. I do not think that we understand the disease the same way we understand relapsing-remitting MS.
Professor of Neurology
“Siponimod, reputed to be effective in secondary progressive disease, is a very interesting compound, but I am not sure why the sphingosine-1-phosphate
selectivity of this molecule would make it more effective than its sister molecule, fingolimod, in progressive disease.”
Well, Dr Hafler is right. We really do not have anything, because even though ocrelizumab (a fully humanized monoclonal antibody against the CD20 determinant) reached its endpoint of an absolute difference in clinical disability of 6.5% in the ORATORIO trial, rituximab (a chimeric murine human monoclonal antibody against the CD20 determinant) actually showed a greater difference (8.1%) and showed a trend for those patients under 50 years of age with active MRIs in the previous large primary progressive trial, the OLYMPUS trial. The ocrelizumab trial showed no effect in women at all and there is a precedent for that. The very first large primary progressive trial, the PROMISE trial with glatiramer acetate, was stopped after 2 years because the placebo group was not progressing adequately. There was a futility analysis, but, when they tweaked the data, they found out that men actually had a beneficial effect that was not shown in women. Now we are faced with the problem of seeing women over 50 years of age and saying to them, “We can we try ocrelizumab, but I’m not sure that it’s going to work.” With regard to some of the other trials that have been completed—the statin trials and the biotin trials—they are just too small to say that much about them. One very interesting trial showed that siponimod reduced the risk of disability progression in patients with secondary progressive MS. The odd thing is that fingolimod did not seem to work at all in patients with primary progressive MS in the INFORMS trial. Progressive disease, whether it is secondary progressive after years of relapse or primary progressive, is probably similar. Siponimod, reputed to be effective in secondary progressive disease, is a very interesting compound, but I am not sure why the sphingosine-1-phosphate selectivity of this molecule would make it more effective than its sister molecule, fingolimod, in progressive disease. Regardless, it is a very interesting molecule, and we will see if it gets through the agency for secondary progressive MS.
Chairman, Department of Neurology
“I would argue that we have a reasonably good working model for relapsing-remitting MS based on the genetics, the immunology, the animal models, and the clinical trials, which point to an underlying autoimmune mechanism. But when we look at primary progressive disease or secondary progressive disease, we do not understand the underlying mechanism.”
I totally agree. I would argue that we have a reasonably good working model for relapsing-remitting MS based on the genetics, the immunology, the animal models, and the clinical trials, which point to an underlying autoimmune mechanism. But when we look at primary progressive disease or secondary progressive disease, we do not understand the underlying mechanism. The possibility exists that the B-cell follicle in the brain and the spinal cord are driving the disease and, so, we want to try methods that eliminate those follicles, potentially using chimeric antigen receptor T cells.
Professor and Chair
“Treatments that we are using, including ocrelizumab, may be having a small effect on patients with primary progressive MS through inflammatory mechanisms, but we do not yet know how much of an impact we are having, if any, on the neurodegenerative mechanisms that are of overriding importance.”
Primary progressive MS is an uncommon form of the disease but the most challenging to treat because the phenotype of most of these people is one of a gradually worsening walking problem, and at the root of that seems to be loss of axons, a neurodegenerative type of process. We know that there is still inflammation that is active in many of these patients. Some patients will have an occasional relapse, there might be some MRI activity, but at the base of things is a degenerative process and it is driving why they gradually get worse. That makes it a challenge because virtually all of the agents that we have right now primarily work on inflammatory mechanisms. Studies have shown recently that drugs such as ocrelizumab can slow down established primary progressive MS, but looking at those data, we can see that the patients who tended to benefit or drove most of the benefit were younger and had a greater amount of inflammatory disease detected at the onset of the study. So, that means that the treatments that we are using, including ocrelizumab, may be having a small effect on patients with primary progressive MS through inflammatory mechanisms, but we do not yet know how much of an impact we are having, if any, on the neurodegenerative mechanisms that are of overriding importance.
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014;383(9936):2213-2221.
Dutta R, Trapp BD. Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr Opin Neurol. 2014;27(3):271-278.
Kappos L, Bar-Or A, Cree BAC, et al; EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273.
Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220.
Tourbah A, Lebrun-Frenay C, Edan G, et al; MS-SPI study group. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study. Mult Scler. 2016;22(13):1719-1731.
Tur C, Montalban X. Progressive MS trials: lessons learned. Mult Scler. 2017;23(12):1583-1592.