Immunomodulatory agents in multiple sclerosis: clinical trials and therapy

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By Luca Durelli MD, Elisabetta Versino MD, and Marinella Clerico MD

In the 2012 update, Drs. Berkovich and Kantor review current data on FDA-approved multiple sclerosis relapse treatment options; disease-modifying treatments for long-term management of multiple sclerosis; new data on previously approved disease-modifying treatments, including updated information concerning natalizumab and risk stratification for progressive multifocal leukoencephalopathy; clinical trials leading to FDA approval of fingolimod in 2010 and subsequent changes to the FDA package labeling; and recently published phase III trial which led to the FDA approval of teriflunomide in 2012. There is a practical monitoring section for the busy clinician to ensure that patients are being monitored per FDA recommendations.

Key points:

  • Chronologically, treatment options for multiple sclerosis relapse preceded the disease-modifying treatments introduction.
  • There are still 2 FDA-approved methods for treating multiple sclerosis relapses: intravenous methylprednisolone (IVMP) and intramuscular adrenocorticotropic hormone (ACTH), approved in 1979 and 1978 respectively.
  • In 1992 there was no FDA-approved disease-modifying treatment for multiple sclerosis.
  • As of the end of 2012, there are 9 branded disease-modifying treatments for multiple sclerosis--5 self-injectable, 2 intravenous, and 2 oral.
  • In the near future, we expect the approval of 2 more disease-modifying treatments for multiple sclerosis.

Prior to 1993, there were no FDA-approved disease-modifying treatments for the reduction of multiple sclerosis activity and for delaying physical disability. Twenty years later, patients and neurologists are entering 2013 with 9 branded FDA-approved disease-modifying agents.

It is widely accepted that clinical trials should fulfill standard criteria for methodological quality, assuring an objective estimate of treatment effects. The quality of clinical trials is now frequently evaluated according to the CONSORT statement (Altman et al 2001). Adequate randomization eliminates selection bias; blinding prevents ascertainment bias. Randomization is the crucial component of high quality clinical trials (Altman et al 2001), particularly when testing drugs, such as interferons or immunosuppressants, with well-known side effects that can bias reliability of blinding (Rice et al 2001). Recent trials have also heightened the need to ensure matching (which is not assured by randomization or blinding); treatment arms with unmatched baseline demographics or disease characteristics may lead to skewed and uninterpretable results.

As the best known biomarker for multiple sclerosis disease activity (Filippi and Miller 1996), MRI has proven crucial in clinical trial design, albeit not as a surrogate primary endpoint in pivotal phase III trials. The vast majority of pivotal clinical trials on multiple sclerosis are designed with annualized relapse rate or other relapse-related metrics as primary outcome. This approach leads to a wide acceptance of relapse prevention as a drug efficacy marker. However, disability progression seems to be at least just as important yet frequently gets overlooked as clinical trials rarely accept disability progression prevention as primary outcome, reserving disability metrics (EDSS – Expanded Disability Status Score) for secondary clinical outcomes. For this reason, past and current clinical trials on multiple sclerosis tend to be rather short (1 to 2 years). Long-term outcomes are becoming increasingly important in terms of collecting both disability progression and safety data.

Despite cautions against comparing results among clinical trials, evidence-based medicine principles allow clinically meaningful conclusions to be drawn from clinical trials and simplified comparison of results from different trials (Sackett et al 1997). The relative effectiveness of a drug can be compared using both the risk ratio and risk reduction relative to the control group as well as the number needed to treat. Evidence-based medicine compares risks of the disease event (adverse outcome, side effects) in the actively treated group to that in the placebo-treated group, which is considered to be the reference population. Risk ratio measures how large (or small) the risk of the adverse outcome is in the treated group relative to the control group. Risk reduction measures to what extent the active drug reduced the risk of the adverse outcome compared to the control, whereas the number needed to treat is the number of patients that must be treated to prevent 1 additional adverse outcome if patients are treated with the placebo instead of the active drug. Importantly, evidence-based medicine measures are all calculated as proportion of the risk of the disease event in the control population of each trial, so they can be compared between trials.

In this review, we evaluate the quality of published randomized clinical trials in multiple sclerosis. We will evaluate trial internal validity to allow physicians to decide for themselves the reliability of a published trial. A different issue is that of the external validity, or generalizability, of trial results--that is, the applicability of the results of a study to “real life” multiple sclerosis population, settings, or treatment variables (Juni et al 2001). External validity is a matter of judgment of each individual physician facing a single specific clinical case. Special circumstances, such as highly aggressive cases, pregnancy, coexistent (comorbid) medical conditions, adverse effects necessitating a change in treatment, long-term remissions, and unrelenting progression despite treatment are not discussed in this review and must be individually evaluated.

The treatment of multiple sclerosis, like that of other autoimmune diseases, is focused on 3 different pathways: (1) disease modification; (2) symptom management; and (3) rescue therapy for acute exacerbation (relapse). For a detailed discussion on symptomatic therapy of multiple sclerosis, please consult the relevant MedLink clinical summary, Multiple sclerosis: treatment of its symptoms. For this summary, we will start with multiple sclerosis relapse therapy options, as this was the first approved and widely accepted treatment concept for multiple sclerosis.

In This Article

Treatment of acute relapses
Treatment of disease activity and progression of relapsing multiple sclerosis
Treatment of the first clinical event suggestive of multiple sclerosis
Treatment of secondary progressive multiple sclerosis
An overview on the future of multiple sclerosis treatment
References cited