From September 14th-17th, over 9,000 clinicians, scientists, and industry professionals—another record—convened in London for the 32nd Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). DRG was on site, as always; this year, the conference brought the buzz of another positive Phase III trial in progressive MS patients amidst the usual barrage of data ranging from real-world use of marketed drugs to preclinical studies of pipeline hopefuls. What follows is a (small) selection of the key themes and data presentations that most caught our attention:

Novartis’s Siponimod delays disease progression in secondary-progressive MS (SP-MS)
In front of a packed house at the late-breaking news session, detailed results from the Phase III SP-MS study (EXPAND) of Novartis’s second-generation S1P receptor modulator siponimod took center stage. The drug reduced the risk of three-month confirmed disability progression (CDP) by 21% versus placebo (26% for six-month CDP) in a trial that randomized 1,651 SP-MS patients in more than 30 countries. This statistically significant, albeit relatively modestly-sized, treatment effect puts siponimod on track to become an approved treatment option for underserved SP-MS patients. Among commonly-prescribed DMTs, only Betaferon has SP-MS label claims, but only in Europe, and only for relapsing SP-MS patients—and follow-up data from the positive European trial of Betaferon in SP-MS suggest that long-term benefits with that drug may be limited (Kuhle J., et al. Multiple Sclerosis Journal 2016, Vol. 22(4) 533–543). Mitoxantrone also carries label claims for SP-MS, but safety issues preclude meaningful use of the drug in MS.

Preplanned subgroup analyses in EXPAND suggest that siponimod’s impact on 3-month CDP was more pronounced in younger patients, patients experiencing relapses in the two years prior to enrollment, patients with Gd-enhancing lesions, patients with lower baseline scores on the Expanded Disability Status Scale (EDSS), and those with rapidly evolving or moderate to severe disease course. The greater benefit evident in younger patients with active inflammation is unsurprising, based on the drug’s anti-inflammatory mechanism of action (MOA), and is qualitatively similar to subgroup analyses from the ORATORIO trial of Roche/Genentech’s Ocrevus in primary-progressive MS (PP-MS) patients. Siponimod separated from placebo on most secondary end points, including brain atrophy, but failed to demonstrate a significant benefit on the Timed 25-Foot Walk test. The drug’s safety profile generally aligned with clinical data for other S1P-targeting agents.

What now?: Scientifically, questions remain as to whether particular mechanistic underpinnings of drug action, or simply differences in the enrolled population and trial design, explain why siponimod succeeded in EXPAND, while Gilenya, the first-generation S1P modulator, failed in the INFORMS trial in PP-MS—a question that was raised during the meeting. Data presented separately at the meeting suggest that siponimod may directly influence oligodendrocyte function/myelination, perhaps through S1P5 receptors—a mechanistic link we’re likely to hear more about in the future, although it’s unclear whether such a mechanism would be unique to/more potent with siponimod than Gilenya. Novartis intends to continue analysis of data from EXPAND, and discuss next steps for the program with regulators.

Biogen’s opicinumab (anti-LINGO-1) lives on
ECTRIMS brought the first look at full results from the trail-blazing Phase II SYNERGY trial of Biogen’s putative remyelinating anti-LINGO-1 monoclonal antibody, which was tested as adjunctive therapy to Avonex in relapsing MS patients. The trial employed an ambitious composite primary end point that assessed the percentage of patients with confirmed improvement in disability and neurophysical and/or cognitive function at 72 weeks of treatment. None of the four doses tested (3mg/kg to 100 mg/kg) separated from placebo on the composite end point or individual components of it. The drug’s “inverted u” dose response curve belied its linear serum pharmacokinetic profile; however, Phase I studies of the drug indicate that blood-brain barrier penetration, which is necessary for target engagement, is highly variable between patients (Tran J., et al, Neurol Neuroimmunol Neuroinflamm. 2014 Aug; 1(2): e18).

What now?: Despite the negative top-line results, preplanned subgroup analyses uncovered signs of a positive effect in patients younger than 40, patients with relapsing-remitting MS, and patients with a disease duration less than eight years, among others. Ultimately, the data are enticing enough for Biogen to commit to additional studies of the drug, which will likely enroll a population with characteristics informed by the subgroup analyses presented, and test doses in the range of 10-30 mg/kg.

B-cells, Roche/Genentech’s Ocrevus, remain in the spotlight
The role(s) of B-cells in the pathophysiology of MS and the potential therapeutic utility of B-cell-directed therapies were explored at ECTRIMS in more than 30 abstracts, including posters and presentations at the European Charcot Foundation Symposium, a Hot Topic session, and other satellite symposia. Post-hoc analyses of the Phase III program for Roche/Genentech’s anti-CD20-targeting Ocrevus highlighted the drug’s positive impact on brain atrophy measures, on freedom from disease activity in relapsing MS or disease progression in PP-MS, and on a composite measure of disability serving as a potential alternative to the imperfect, but well-entrenched EDSS. In addition, real-world outcomes from a sizable Swedish registry demonstrated a high degree of clinical success—measured by drug survival—in patients treated off-label with first-generation anti-CD20 agent rituximab, further fueling the optimism for an approved B-cell-targeting agent.

What now?: Although escalation currently prevails in MS treatment, several experts in attendance voiced an expectation to reach for Ocrevus early in MS treatment, because of the strong efficacy and generally favorable safety/tolerability profile evident in the Phase III program; however, some experts we interviewed harbor lingering concerns over the drug’s safety profile, and expect any early-line use of Ocrevus in MS to evolve slowly. In addition, thought leaders in attendance expect future research to explore alternative B-cell-targeting MOAs in the treatment of MS.

New data for Merck KGaA’s oral cladribine presented on the heels of its MAA resubmission
As the European Medicines Agency takes a second look at the regulatory application for oral cladribine in relapsing MS, Merck KGaA presented data highlighting the durability of the drug’s efficacy after two short courses of administration over two years. In the uniquely-designed, blinded CLARITY extension study, one arm comprised patients who received oral cladribine during CLARITY and were switched to placebo for the extension, to begin to assess the utility of the drug as an induction treatment; notably, patients in this arm did not exhibit a significant increase in relapse rate or decrease in the proportion of relapse-free patients over two years of follow-up after their initial treatment courses, although there were signs of new MRI activity for a subset of patients.

What now?: Although these data are compelling, and oral cladribine appears to present another solid option for the treatment of relapsing MS, experts we interviewed expect the drug’s uptake to be somewhat limited in the highly competitive market it may enter in 2017.

Evidence accumulates for serum neurofilament light chain (NFL) as an MS biomarker
Several ECTRIMS presentations explored the case for serum NFL as a biomarker for neuronal damage in MS; the data presented highlighted the correlation between serum NFL levels and the (more invasively collected) CSF NFL levels, as well as correlations between serum NFL levels and clinical/paraclinical measures of disease activity in MS. The late-breaking session kicked-off with proof-of-concept data from 149 patients participating in the Phase III FREEDOMS trial of Gilenya in RR-MS patients. Notably, serum NFL levels in that (relatively small) cohort increased proportionally with the number of Gd-enhancing lesions, number of relapses, and EDSS score; furthermore, higher serum NFL levels at six months were correlated with higher annualized rates of brain atrophy at 24 months. In addition, Gilenya-treated patients had lower serum NFL levels than placebo patients at multiple time points over a two-year period, as early as month six.

What now?:Although preliminary, these data are compelling, and future ECTRIMS meetings will likely see increasing effort devoted to development of this potential MS biomarker.

Investigators harnessing the potential of real-world data from MSBase
More than a dozen abstracts at ECTRIMS presented insights from analyses of real-world data from the MSBase registry (, including propensity-matched comparisons of treatment outcomes between drugs or alternative choices at clinical decision points (e.g., to escalate to Tysabri, or remain on a platform therapy).

What now?: Although much of the presented outcomes data generally confirms the perceptions of neurologists we interview, formed from their extensive clinical experience (e.g., Lemtrada and Tysabri likely offer comparable efficacy), robust real-world data breed confidence for neurologists weighing treatment decisions with their MS patients.

Early- to mid-stage industry-sponsored programs with novel MOAs were on display, including:

  • Phase II data for Coherus Biosciences’ CHS-131: The oral, CNS-penetrant PPARγ agonist delivered a statistically significant reduction in mean cumulative Gd-enhancing lesions at six months versus placebo (4.2 versus 7.8, respectively), in a 227-patient RR-MS trial completed at 21 centers in Russia.
  • Phase IIb trial design for GeNeuro/Servier’s GnBAC-1: This novel monoclonal antibody targets the envelope protein of an MS-associated retrovirus; thus, it’s designed to act on a putative trigger of MS, rather than causing generalized suppression or modulation of immune function. Some experts we interviewed, however, question the strength of the evidence base underlying the approach.
  • Phase I data for AbbVie’s ABT-555: Data from a double-blind, single ascending dose study of this monoclonal antibody raised against repulsive guidance molecule A (RGMa) suggest it is generally safe and well-tolerated, and is likely amenable to once-monthly intravenous delivery. As a putative neurorestorative agent—RGMa is thought to inhibit axon regeneration—this agent may see development in indications beyond MS, as well.

Wrap Up
ECTRIMS grows larger every year, in proportion to the size of the MS treatment armamentarium—which is set to surpass 15 approved immunomodulatory DMTs in the coming months. Neither ECTRIMS attendance nor the MS pipeline itself show signs of slowing down, as—after Ocrevus—a series of late-stage, second-generation therapies are beating a path to market and novel MOAs advance through early clinical development. Each year brings a new company booth/smiling barista to the exhibitor area, and a steady uptick in abstracts to peruse as neurologists wander the floor, grappling with how best to use all available treatment options in the care of their MS patients. ECTRIMS 2016 saw a continued focus on the “next frontier” in treatment—remyelination/neuroprotection—with sessions devoted to new therapeutic targets, pilot studies, and MRI or other techniques that will advance those fields. “Induction” versus “escalation” was debated (again), and will continue to be—likely more vigorously than ever after Ocrevus comes online in 2017. Thought leaders in attendance continued to impress upon the audience the importance of early treatment initiation and confident escalation, backed by a mounting real-world evidence base. Sessions devoted to comorbidities, gaps in care around the world, rehabilitation (the 21st Annual Conference of Rehabilitation in MS ran in parallel), and emerging science rounded out another exhilarating/exhausting year. Circle your calendars for October 25-28 2017, as we do it all again in Paris.

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