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In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics.This analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (30 or ≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (9 or ≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS.In the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P0.0001) and MS (2005 McDonald criteria; HR=0.485; P0.0001) versus placebo. Similar effects of cladribine tablets on risk of conversion were observed in post hoc analyses of subgroups defined by various baseline characteristics. In both the ITT population and across subgroups, cladribine tablets 3.5 mg/kg reduced the numbers of cumulative T1 Gd+ (range of rate ratios: 0.106-0.399), new or enlarging T2 (range of rate ratios: 0.178-0.485), and CUA (range of rate ratios: 0.154-0.384) lesions versus placebo (all nominal P0.03). Multivariate Cox proportional hazards models revealed that age (HR=0.577, nominal P0.0001), FCDE classification (HR=0.738, nominal P=0.0043), presence of T1 Gd+ lesions (HR=0.554, nominal P0.0001), and number of T2 lesions (HR=0.417, nominal P0.0001) at baseline were factors associated with risk of conversion to MS (2005 McDonald criteria), whereas no baseline factors examined were associated with risk of conversion to CDMS.In this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics.

The objective of the Therapy Optimization in MS (TOP MS) Study was to prospectively assess the relationship between MS disease-modifying therapy (DMT) adherence and MS relapse risk over 2 years.Potential participants were recruited for TOP MS by specialty pharmacies who dispensed glatiramer acetate and beta interferons for MS nationwide. Signed IRB-approved informed consents were returned to the pharmacies. TOP MS used electronic data capture with monthly patient entries. Adherence, measured by medication possession ratio (MPR), was derived from pharmacy shipment records. Logistic regression examined the association between protocol-defined relapses and DMT MPR (0.5;0.5-0.9;0.9).TOP MS enrolled 3151 persons with MS, and 2410 completed the full 2 years. Across all therapies, the mean MPR for the 2-year completer cohort of 2049 who maintained the same DMT was 0.9+0.2 (range: 0.1-1.0), with 63.8% reaching a 2-year MPR0.9. Evaluated by categories of MPR, the proportion of participants remaining relapse-free for 24 months increased with increasing MPR, and the proportion with1 relapses declined with increasing levels of MPR (p0.0008). Regression analysis revealed the odds of relapse for a patient in the MPR0.9 MPR group was 64% that of a patient in the MPR0.5 category (p=0.02). Use of1 DMT prior to the current one was an independent predictor of relapse.The study provides class III evidence that improvement in adherence to DMT for MS is associated with improved clinical outcomes as measured by relapse reduction.

Dimethyl fumarate (DMF), fingolimod, and teriflunomide are oral disease-modifying therapies (DMTs) indicated for the treatment of relapsing-remitting multiple sclerosis. Despite well-established limitations of cross-trial comparisons, DMTs are still frequently compared in terms of relative reductions in specific endpoints, most commonly annualized relapse rate. Consideration of absolute risk reduction and number needed to treat (NNT) provides an alternative approach to assess the magnitude of treatment effect and can provide valuable additional information on therapeutic gain. Using data from pivotal studies of DMF (DEFINE, NCT00420212; CONFIRM, NCT00451451), fingolimod (FREEDOMS, NCT00289978; FREEDOMS II, NCT00355134), and teriflunomide (TEMSO, NCT00134563; TOWER, NCT00751881), we calculated NNTs to prevent any relapse, more severe relapses (such as those leading to hospitalization or requiring intravenous corticosteroids), and disability worsening. Higher relative reductions were reported for DMF and fingolimod vs placebo on overall relapse and relapses requiring intravenous corticosteroids in both individual and pooled studies (pooled data unavailable for fingolimod). However, NNTs for each outcome were similar for DMF and teriflunomide, with marginally lower NNTs observed with fingolimod. By contrast, for relapses requiring hospitalization, relative reductions were higher and NNTs were substantially lower for teriflunomide compared with DMF. For fingolimod, there were inconsistent outcomes between the two studies for relapses requiring hospitalization; thus, comparative conclusions against DMF or teriflunomide cannot be clearly established. The risk of disability worsening was significantly reduced in both teriflunomide studies, but only in a single study for DMF (DEFINE) and fingolimod (FREEDOMS). NNTs to prevent one patient from experiencing disability worsening were similar in DEFINE, FREEDOMS, and TEMSO and TOWER but were higher in CONFIRM and FREEDOMS II. This NNT analysis demonstrates broadly comparable effects for DMF, fingolimod, and teriflunomide across key clinical outcomes. These observations are clinically relevant and may help to inform treatment decisions by providing additional information on therapeutic gain beyond informal assessments of relative reductions alone.