Progressive MS trials – design and interpretation


Part 2

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Part 1 of this article examined how the definitions of secondary-progressive and primary-progressive MS (SPMS, PPMS) have evolved and the contentious role that focal inflammatory activity has played (See Secondary-progressive MS: conceptual and practical challenges, NeuroSens, April 17, 2019). One shift has been to view the phenotypes of SPMS and PPMS as virtually indistinguishable with respect to their pathophysiology and clinical course, so both SPMS and PPMS trials will be considered here.

How progressive MS should be conceptualized and defined has practical implications with respect to the design and interpretation of progressive MS trials. Two early studies set the stage. The first was the European SPMS trial, in which interferon-beta-1b was superior to placebo in time to disability progression (European Study Group. Lancet 1998;352:1491-1497). Interest in interferons waned when no effect on disability progression was seen in the North American SPMS trial of interferon-beta-1b (Panitch et al. Neurology 2004;63:1788-1795) or the SPECTRIMS trial of interferon-beta-1a (SPECTRIMS Study Group. Neurology 2001;56:1496-1504). However, a noteworthy development was when a combined analysis of the European and North American interferon studies noted that patient selection could influence trial outcomes: the European trial enrolled SPMS patients who were younger (mean age 41 years), at an earlier stage of SPMS (mean duration of SPMS was 2.2 years) and with more active disease at baseline and throughout the study compared to the North American trial (Kappos et al. Neurology 2004;63:1779-1787).

The second positive study was MIMS, which showed that potent immunosuppression with mitoxantrone was beneficial with respect to the composite endpoint (EDSS, ambulation, relapses, neurological status) in patients with “progressive” MS (which included worsening RRMS) (Hartung et al. Lancet 2002;360:2018-2025). Inflammation may not have been the principal driver of neurodegeneration but anti-inflammatory agents could slow disability accrual.

The importance of these two factors – age and inflammatory activity – would be supported by the OLYMPUS trial of rituximab (Hawker et al. Ann Neurol 2009;66:460-471). While the results were negative, subgroup analyses showed that time to disability progression was delayed in younger patients (< 51 years) and those with gadolinium-enhancing lesions.

Age has emerged as an important factor in trial recruitment. Among the phase III progressive MS trials, the youngest cohorts are found in two positive trials – the European SPMS study of interferon (mean age 40.9 years) and the ORATORIO trial of ocrelizumab (mean age 44.7 years) (reviewed in Mills et al. Mult Scler 2018;24:1795-1807). Indeed, every trial (e.g. PROMISE [glatiramer], OLYMPUS [rituximab], ASCEND [natalizumab], INFORMS [fingolimod]) in which the mean patient age at entry was >46 years has produced negative results; the sole exception is the EXPAND trial of siponimod (mean age 48.0 years). This is consistent with the observation that patient age is a good predictor of DMT efficacy in slowing disability progression (Weideman et al. Front Neurol 2017;8:57). That analysis also found that the average patient will obtain little treatment benefit after age 53, which was, the authors noted, close to the upper age limit for eligibility in the ORATORIO trial.

Other baseline values, such as duration of MS or time since diagnosis of SPMS/PPMS, likely function as surrogates of patient age but may be less reliable. Duration of MS/progressive MS is hampered by diagnostic uncertainty in earlier studies using the Poser criteria (Leary et al. J Neurol 1999;246:562-568), and diagnostic delay in more recent studies. A Swiss MS Registry analysis found that PPMS patients were five-fold more likely to have a delayed diagnosis (Kaufmann et al. Mult Scler J Exp Transl Clin 2018;4:2055217318814562). A Canadian analysis also reported delays in diagnosis and referral among PPMS patients (Kingwell et al. J Neurol Sci 2010;292:57-62).

Mean EDSS scores are remarkably similar across progressive MS trials, ranging from 4.7 (ORATORIO, INFORMS) to 5.4 (EXPAND). What may be more important is the rate of EDSS progression. The 2001 McDonald criteria introduced the requirement of one year of disease progression for a diagnosis of PPMS. While this (and subsequent criteria in 2005 and 2010) was intended to increase diagnostic certainty (Wolinsky et al. J Neurol Sci 2003;206:145-152), it also specified a rate of disability worsening that may have contributed to more positive trials. A problem in short-term studies is the slow rate of progression: a mean EDSS change of 0.35 points/year has been reported for PPMS (Stellmann et al. PLoS One 2014;9:e92761). So in a two-year study, roughly 35-40% of patients in the placebo group would be expected to meet the progression criterion of a 1-point change. This was seen in the placebo group of the ORATORIO trial of ocrelizumab (39.3% progressed) and the OLYMPUS trial of rituximab (38.5% progressed). In contrast, a higher proportion of placebo patients progressed in two negative studies: the ASCEND trial of natalizumab (48% progressed) (Kapoor et al. Lancet Neurol 2018;17:405-415), and the INFORMS trial of fingolimod (80% progressed) (Lublin et al. Lancet 2016;387:1075-1084). This suggests that while a high progression is needed in short-term studies, too high a rate may indicate a different stage in the disease process that is less responsive to therapy.

The negative results of the PROMISE trial of glatiramer acetate have been attributed to a low rate of progression but this does not appear to be the case: 45.2% of placebo patients progressed over the three-year period, which is in the range of what would be expected. A more likely explanation was the low proportion of patients with Gd+ lesions (14.1%) in PROMISE, which was similar to what was reported in the INFORMS trial (14.0%).

In contrast, the proportion of Gd+ patients was two-fold higher in the ORATORIO trial of ocrelizumab (27.5%) (Montalban et al. N Engl J Med 2017;376:209-220).  This supports the suggestion that the success of ORATORIO was largely attributable to an enriched study population of younger patients (mean age 44.7 years) with a more inflammatory phenotype, which may limit the generalizability of the findings (Tur & Montalban. Mult Scler 2017;23:1583-1159). The progression rate in ORATORIO was slightly higher than predicted for the ocrelizumab arm (32.9% rather than 30.0%) and slightly lower than predicted for the placebo arm (39.3% rather than 43.0%), resulting in a somewhat modest 24% relative risk reduction.

The EXPAND trial of siponimod did not enrol an enriched study population (Kappos et al. Lancet 2018;391:1263-1273). Patients were older than those in ORATORIO (48.0 vs. 44.7 years), with less active disease (Gd+ lesions 21.4% vs. 27.5%) and higher baseline disability (EDSS 5.4 vs. 4.7). The rate of progression in EXPAND (siponimod 26.3% vs. placebo 31.7%) was lower compared to what was seen in ORATORIO (ocrelizumab 32.9% vs. placebo 39.3%). Both trials were event-driven to offset this effect. EXPAND used a substantially larger sample size (n=1651 vs. 732 in ORATORIO), which allowed for a shorter trial. The median time on drug to demonstrate a treatment effect was 18 months with siponimod versus 35 months with ocrelizumab. The relative risk reduction for three-month confirmed disability was 21% with siponimod. An analysis of the two studies that adjusted for differences in how the primary endpoints were defined found that the benefits seen with siponimod and ocrelizumab were similar (Gold R. ECTRIMS 2017; abstract P1239).

While siponimod was associated with a significant 86.6% reduction in Gd+ lesion count in the first 12 months of treatment (Fox RJ. ECTRIMS 2017; abstract 129), its clinical benefit does not appear to be solely attributable to an anti-inflammatory effect. A post-hoc analysis of EXPAND reported that siponimod reduced the risk of six-month confirmed disability progression by 19% in patients with on-study relapses compared to 22% in patients without on-study relapses (Kappos L. ECTRIMS 2017; abstract P782). (This issue will be explored further by Ralf Gold at ECTRIMS 2019 [abstract P750]). So part of the clinical benefit with siponimod may be due to effects within the CNS (recently reviewed in Behrangi et al. Cells 2019;8:E24; free full text at This suggestion of a putative neuroprotective effect is supported by the early and significant reduction in brain atrophy reported with siponimod in EXPAND. Additional data on the effects of siponimod in the CNS and on grey-matter atrophy will be presented at ECTRIMS 2019 (abstracts P382, P512, P844, P1008 and P1376).

Other potential neuroprotective strategies are currently being explored. Ibudilast showed a modest effect on brain atrophy in a phase II trial of progressive MS (Fox et al. N Engl J Med 2018;379:846-855), but no additional studies are listed on The MS-SPI study of high-dose biotin appeared promising (Tourbah et al. Mult Scler 2016;22:1719-1731), however, two subsequent studies have reported no benefit (Birnbaum & Stulc. Mult Scler Relat Disord 2017;18:141-143) or worsening inflammatory activity with biotin (Granella et al. ECTRIMS 2017; abstract P750). Additional studies will be required.

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