MS therapies: analyses and re-analyses of phase III studies


Highlights of the 29th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Copenhagen, DK, October 2-5, 2013 – ECTRIMS 2013 featured data from a number of new treatment studies. The following is a summary of new studies in CIS and RRMS.

TOPIC phase III trial: This study assessed the efficacy of teriflunomide 7 mg or 14 mg once-daily versus placebo in 618 patients with CIS (Miller et al. ECTRIMS 2013; abstract 99). The probability of conversion to MS at 108 weeks was 24% and 27.6% with teriflunomide 14 mg and  7 mg, respectively, versus 35.9% with placebo. Risk reductions were 37-46% with active treatment, which is similar to what has been seen in CIS trials of injectable drugs. Teriflunomide also reduced the risk of a new relapse by 31-35%. Adverse effects associated with teriflunomide were elevated liver enzymes, headache, hair thinning, diarrhea and paresthesiae.

ADVANCE phase III trial: The new interferon formulation, pegylated interferon-beta-1a, has an extended half-life, which may enable less frequent dosing. The ADVANCE study randomized 1,512 patients to one of two dose schedules (q2weeks or q4weeks) of peg-IFN 125 mcg administered subcutaneously or placebo for two years (Calabresi et al. ECTRIMS 2013; abstract P514). Data from year 1 were presented. At one year, the annualized relapse rate (ARR) was reduced 36% and 27% with Q2W and Q4W, respectively, versus placebo. Risk of 12-week disability progression was reduced 38% with both dose schedules (Kieseier et al. ECTRIMS 2013; abstract P540). Q2W dosing had a more pronounced effect on MRI measures.

Disease activity-free rates: The proportion of patients who were disease activity-free (no relapses, EDSS progression or new MRI lesions) was reported for three studies. In the ADVANCE study (above), DAF rates at 12 months were 34% with peg-IFN Q2W and 22% with Q4W.

DAF rates for natalizumab were determined in a retrospective analysis of the AFFIRM trial (Havrdova et al. Lancet Neurol 2009;8:254-260). The DAF rate at two years was 37%. A subgroup analysis now reports that DAF was less likely to be achieved in patients aged 35 or older (33.6%), >2 years’ duration of MS (35.3%), EDSS 3 or higher (28.1%), or those with two or more relapses in the year prior to therapy (30.6%) (Havrdova et al. ECTRIMS 2013; abstract P519).

A post hoc analysis has been performed for the DEFINE and CONFIRM phase III studies of BG-12 (Gold et al. N Engl J Med 2012;367:1098-1107; Fox et al. N Engl J Med 2012;367:1087-1097). The pooled analysis found that the overall DAF rate at two years was 23% with either 240 BID or TID dosing versus 11% for placebo (Havrdova et al. ECTRIMS 2013; abstract P521).

Brain atrophy: Patient-level data from the FREEDOMS trial of fingolimod (Kappos et al. N Engl J Med 2010 Feb 4;362:387-401) were analysed to determine if the impact of treatment on disability progression was due in part to a reduction in brain atrophy (Sormani et al. ECTRIMS 2013; abstract P611). Results were pooled for the 0.5 mg and 1.25 mg treatment groups. Progression was defined as a 1-point change in EDSS confirmed at six months. A multivariate stepwise procedure was used to select variables independently associated with disability progression after adjusting for treatment. First year relapse rate, first year number of active T2 lesions and brain atrophy accumulation all met Prentice criteria for surrogacy. The impact of fingolimod on disability progression was a result of its effect on relapses (66% of effect), active T2 lesions (45%) and brain atrophy (24%). On multivariate analysis, 80% of the drug’s effect on disability was explained by its effects on relapses and brain atrophy.

Guest Reviewer: Dr. Paul S. Giacomini, Associate Director, MS Clinic, Montreal Neurological Hospital and Institute, Assistant Professor, Department of Neurology and Neurosurgery, McGill University, Montréal, Québec.


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