By Annette M. Boyle
While treatment options have continued to expand for patients with the most common type of multiple sclerosis—relapsing-remitting—that has not been the case for those with a less-common variety—primary progressive. That changed this spring with FDA approval of the first therapy specifically for that condition.
WASHINGTON—The great majority of multiple sclerosis (MS) patients have the relapsing-remitting type (RRMS), which is characterized by symptoms that develop quickly, remain for a few weeks or months and then largely resolve.
The small percentage of MS patients with the primary progressive type do not have relapses, however. Instead, their disability continues to progress from diagnosis without any intervals of improvement or episodes of notable deterioration.
Secondary-progressive patients start out with RRMS, but over a decade or two gradually have fewer relapses but continue to lose function between relapses. They also have a continuous loss of function and also have intermittent, well-defined relapses from which they may or may not have some recovery.
Furthermore, few clinical trials have included them and no therapies had been approved for their treatment, even as the options available for other MS patients continued to expand.
That changed this spring when the U.S. Food and Drug Administration approved the first therapy for primary progressive multiple sclerosis (PPMS), ocrelizumab.
“Because PPMS makes up a small proportion of the total MS population (10-15%) and because they tend to present at an older age, it is challenging to get adequate numbers for a clinical trial,” explained Mitchell T. Wallin, MD, MPH, director of the VA Multiple Sclerosis Center of Excellence-East in Washington. That difficulty is compounded by the more variable rate of progression and the longer follow-up periods required to measure meaningful change compared to the time between and number of relapses used for patients with relapsed-remitting MS (RRMS).
Consequently, treatments have focused on RRMS.
“Until ocrelizumab, there had been no successful phase 3 trials for PPMS,” Wallin told U.S. Medicine. “This leaves one MS disease-modifying therapy for PPMS. That said, there are 14 FDA-approved disease-modifying therapy choices for RRMS.” Ocrelizumab received approval for both subtypes.
In the phase 3 studies on which its approval was based, fewer patients on ocrelizumab showed confirmed disability at each checkpoint compared to placebo. At 12 weeks, progression was confirmed in 32.9% of those on the therapy compared to 39.3% of those receiving placebo, but 24 weeks the progressing percentages were 29.6% to 35.7% for the drug and placebo, respectively.
At week 120, 38.9% of patients on ocrelizumab had deteriorated performance on the timed 25-foot walk, while 55.1% of those receiving placebo had worsened. Total volume of brain lesions decreased 3.4% with the DMT compared to an increase of 7.4% for those receiving placebo. Brain-volume loss was also reduced on the therapy. The percentage of patients who developed neoplasms was higher at 2.3% to 0.8%. 1
The categorization of MS most commonly used divides patients into four subtypes—relapsing-remitting, secondary-progressive, primary-progressive and progressive-relapsing. A simplified bifurcated classification for MS has been discussed since 2014, which divides patients into relapsing-remitting and progressive types. Under either categorization, 85% of patients have the relapsed-remitting subtype.
That proportion holds true from patients in the general population as well as among veterans. “Based on recent population-based assessments of the VA MS population, the proportion of PPMS and RRMS are similar compared to other large US MS registries,” Wallin said. “Additionally, with the exception of the male bias due to the US military background, the age of MS onset, diagnosis and most prevalent symptoms were very similar across the VA and other US MS registry cohorts.2
While the subtypes have different courses, they have similar prognoses, though it may not seem that way initially. “In terms of time from onset of first symptoms, PPMS progresses more quickly than RRMS to standard Kurtzke Expanded Disability Status Scale (EDSS) outcomes,” Wallin said.
But research by Confavreax and Vukusic showed that disability corresponds most closely with age, he noted.
In that study, the researchers looked at the age at which 1844 MS patients reached three thresholds on the Kurtzke Disability Status Scale (DSS): DSS 4, limited walking but without assistance; DSS 6, walking with unilateral aid; and DSS 7, wheelchair required. They found patients reached DSS 4 at a median age of 44.3 years and DSS 6 at 54.7 years. The median for DSS 7 was 63.1 years.3
“These results were essentially similar whether the initial course of multiple sclerosis was exacerbating-remitting [relapsing-remitting] or progressive and whatever the initial symptomatology,” Confavreax and Vukusic found. “The most influential clinical factor was age at clinical onset of multiple sclerosis: the younger the onset, the younger the age at assignment of disability milestones.”
More therapies for PPMS may be on the way soon. Wallin noted that the Progressive MS Alliance and other groups are increasing the attention given to primary-progressive MS. As a result, “more resources are being pooled to study mechanisms and treatment options.
Two phase 2 studies are currently evaluating idebenone for PPMS. Both are expected to conclude next year. Idebenone is a synthetic form of the antioxidant coenzyme Q10 initially developed to treat Alzheimer’s disease. It may be able to reduce demyelination and brain cell death, slowing the neurological deterioration associated with MS.
The options for patients with RRMS appear likely to continue to grow more quickly, however. Just within the VA’s MS Centers of Excellence Wallin noted that three disease-modifying therapies are in trials: siponimod, ozanimod and lipoic acid.
- Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIO Clinical Investigators. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21.
- Culpepper WJ, Wallin MT, Magder LS, Perencevich E, Royal W, Bradham DD, Cutter G, Bever CT. VHA Multiple Sclerosis Surveillance Registry and its similarities to other contemporary multiple sclerosis cohorts. J Rehabil Res Dev. 2015;52(3):263-72. doi: 10.1682/JRRD.2014.07.0172.
- Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain. 2006 Mar;129(Pt 3):595-605. Epub 2006 Jan 16.
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