InTORduction
B (as in billion) cells
Novel therapies, new chapters
SDMT revisited

The year 2019 saw important changes in how multiple sclerosis is being managed in an a increasingly complex therapeutic landscape (reviewed in Cree et al. Curr Opin Neurol 2019;32:365-377). The tectonics of that landscape are also shifting as new drugs are approved, generic formulations become available and the hothouse regulatory environment cools.

It was a year of consensus. The Canadian MS Working Group laboured to develop its new consensus recommendations on MS treatment, which are expected to be published soon. There was a growing acceptance of the need for earlier use of higher-efficacy disease-modifying therapies (DMT), supported by two papers published early in the year. An MSBase analysis found a lower rate of conversion to secondary-progressive MS if treatment was initiated with a higher-efficacy DMT compared to an injectable, or if a patient on an injectable was escalated within the first five years (Brown et al. JAMA 2019;321:175-187). In that same issue of JAMA, a preliminary head-to-head study reported improved outcomes with nonmyeloablative hematopoietic stem cell transplantation versus DMTs (Burt et al. JAMA 2019;321:165-174). These and other findings prompted some to suggest that resetting the immune system early in the clinical course may alter the disease trajectory in MS (Bose et al. Can J Neurol Sci 2019; epublished September 12, 2019).

Two of the current DMTs purport to be immune reconstitution therapies. A report on lymphocyte kinetics supported the suggestion that intermittent dosing with oral cladribine may result in a less pathogenic immune profile (Comi et al. Mult Scler Relat Disord 2019;29:168-174). The results were similar to those in a study previously reported by Baker and colleagues, which found that both cladribine and alemtuzumab appear to act primarily through B cell suppression (Baker et al. Neurol Neuroimmunol Neuroinflamm 2017;4:e360).

B (as in billion) cells
B cell suppression fuelled the remarkable growth of ocrelizumab through 2019, aided by a first-ever indication in primary-progressive MS and clinicians’ familiarity with its fraternal twin rituximab. Roche has described the ocrelizumab launch as the most successful one in its history. The biological racked up over CDN$3 billion in global sales in 2018 and was expected to earn over $4 billion in 2019 (www.roche.com/investors.htm).

But it has not been all sunny days. A number of safety concerns have emerged with higher-efficacy DMTs. The FDA required a label change to Lemtrada in January following case reports of intracerebral hemorrhage (Rare cases of stroke reported with alemtuzumab, NeuroSens, December 14, 2018). Hypogammaglobulinemia has been reported in a subset of patients treated with anti-CD20 agents and appears to be associated with an increased risk of infections (Zoehner et al., P407. Derfuss et al., 65. Chang et al., P1387 at ECTRIMS 2019). The year also saw the first reported case of progressive multifocal leukoencephalopathy (PML) in a previously-untreated patient receiving ocrelizumab (PML reported in patient newly-treated with ocrelizumab. NeuroSens, October 30, 2019).

The PML case occurred in a 78-year-old patient, raising questions about how immunosenescence may change the benefit-risk assessment of treatment and whether DMTs should be de-escalated or discontinued in patients older than 60 years (Salavisa et al. ECTRIMS 2019; P703).

Novel therapies, new chapters
The year 2019 was also noteworthy for a trio of MS drugs receiving FDA approval, with regulators continuing with two recent trends. Since 2011, MS drug labels have not included the indication “to slow progression of disability” (or similar wording). Instead they are now approved for “relapsing forms of MS”, which may or may not include CIS. Thus, the U.S. labels often include indications for which the drugs were not formally studied. In March, the FDA approved Mayzent (siponimod; not available in Canada), a sphingosine 1-phosphate receptor-1,5 modulator for all relapsing forms of MS, including CIS and SPMS. Approval was based on the EXPAND study in SPMS (Kappos et al. Lancet 2018;391:1263-1273). Three days later, the FDA greenlit Mavenclad (oral cladribine, previously approved in Canada) for the treatment of relapsing MS, including active SPMS but not CIS (despite the phase III ORACLE-MS trial). Then in October the FDA signed off on Vumerity (diroximel fumarate, not available in Canada), a second-generation fumarate, for relapsing forms of MS, including CIS, RRMS and SPMS. Approval was based on the EVOLVE-MS-1 trial (Naismith et al. Mult Scler 2019; epublished November 4, 2019). Diroximel fumarate has the same metabolite as dimethyl fumarate and a curiosity of the U.S. monograph for Vumerity is that the safety data used are actually for DMF. Preliminary data suggest that diroximel may be better tolerated (Palte et al. Adv Ther 2019;36:3154-3165). The two fumarates will be directly compared in the EVOLVE-MS-2 study. These new entries will need to compete with generic formulations of dimethyl fumarate and fingolimod that have been submitted for approval in Canada and other countries.

One other DMT recently filed with the FDA and at least three others are in development. After an initial rebuff last year, ozanimod successfully filed with the FDA and the European Medicines agency for an RRMS indication. The two trials – SUNBEAM and RADIANCE – suggest that sunny days are indeed returning, but it will be challenging for the S1PR-1,5 modulator to differentiate itself from siponimod. The two late-phase studies were published in November (Comi et al. Lancet Neurol 2019;18:1009-1020. Cohen et al. Lancet Neurol 2019;18:1021-1033).

In the wings are evobrutinib, a novel Bruton’s tyrosine kinase (BTK) inhibitor, which published phase II results in June (Montalban et al. N Engl J Med 2019;380:2406-2417); ponesimod, an S1P1R-1 modulator that presented phase II results at ECTRIMS (Kappos et al., abstract 93); and ofatumumab, an anti-CD20 MAb administered subcutaneously, which unveiled results from two phase III trials at ECTRIMS (Hauser et al., abstract 336). The ponesimod and ofatumumab studies were also noteworthy for using teriflunomide as the active comparator rather than one of the interferons.

SDMT revisited
This past 12 months also saw the first full year of legal cannabis in Canada. Just before legalization, a University of British Columbia survey found that 29% of MS patients regularly used cannabis (Schabas et al. Mult Scler J Exp Transl Clin 2019;5:2055217319869360). That number is likely higher now, adding further doodles to the MS treatment canvas. Perhaps even less surprising than the high rate of cannabis use in B.C. were the findings from a joint study by the University of Toronto and Waterloo University. The researchers found that neurocognitive test scores improved if MS patients were weed-free for a month (Feinstein et al. ECTRIMS 2019; P542). So 2020 may see patient sheets including the instruction: SDMT – Stop Doing Marijuana Today, or Sorry Dude, Marijuana’s Taboo.