An update on combination therapies for multiple sclerosis: where are we now?

ABSTRACT

Introduction

In theory, combination of two agents, which are suboptimal when given individually, may result in a significant increase in therapeutic effect. Combination therapies have proven particularly effective against infections such as HIV, cancer, and also chronic autoimmune diseases such as rheumatoid arthritis.

Areas covered

The authors review the literature, searching for randomized placebo-controlled or comparative, double-blind or investigator-blinded clinical trials, not including open label clinical trials, of treatment of multiple sclerosis (MS) with combination therapy or add-on therapy, including trials of induction therapy, trials for prevention of disease activity or worsening, amelioration of adverse effects, and treatment of relapses, and trials to increase remyelination.

Expert opinion

Combination of two platform therapies (Interferon-beta or glatiramer acetate) was without additional effect. Clinical trials with add-on, often applying repurposed drugs (e.g. simvastatin, atorvastatin, minocycline, estriol, cyclophosphamide, azathioprine, albuterol, vitamin D), have been negative, apart from monthly methylprednisolone that, however, had low tolerability. Combination therapy for neuroprotection/remyelination showed some interesting results, though we are still awaiting results of phase III trials. The results of combination of anti-inflammatory therapies have in general been disappointing. In the future, combination of new effective neuroprotective/remyelinating drugs and highly effective anti-inflammatory treatments may benefit people with MS.

KEYWORDS:

• (5-8) Multiple sclerosis
• disease-modifying therapy
• combination therapy
• add-on therapy
• treatment of disease activity
• treatment of relapses
• neuroprotective therapy
• remyelinating therapy

Article highlights

• Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS).

• To date, combination trials of two approved disease-modifying treatments in multiple sclerosis or the add-on of a new drug or a repurposed drug (e.g. simvastatin, atorvastatin, minocycline, estriol, cyclophosphamide, azathioprine, albuterol, vitamin D) to an approved disease-modifying treatment have been disappointing as no additive therapeutic efficacy has been demonstrated apart from monthly methylprednisolone that had often unacceptable adverse effects.

• One explanation of the lack of positive results of combination therapy in multiple sclerosis may be that almost all trials have combined two anti-inflammatory medications as it seems that anti-inflammatory treatments do not show any additive effects, even when the mechanism of action by which the two combined treatments exert their anti-inflammatory properties has been different.

• Relapsing-remitting and progressive multiple sclerosis may require different treatment regimens to control the disease activity.

• In the future, combination therapy will be needed to control disease activity and progression, consisting of an effective neuroprotective or remyelinating treatments and a highly effective anti-inflammatory disease-modifying treatment that is capable of controlling inflammation, both the systemic inflammation as well as the compartmentalized inflammation within the CNS.

Declaration of interest

PS Sørensen has received personal compensation for serving on scientific advisory boards, steering committees, independent data monitoring committees or have received honoraria as speaker from Biogen, Merck and Co, Novartis, Teva, GlaxoSmithKline, Sanofi/Genzyme, and Bristol-Myers Squibb/Celgene. M Magyari has served on the scientific advisory boards for Sanofi, Novartis and Merck and Co., and has received honoraria for lecturing from Biogen, Merck & Co., Novartis, Roche, Genzyme and Bristol-Myers Squibb. F Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol-Myers Squibb, Merck and Co, Novartis, Roche and Sanofi Genzyme. Furthermore, his laboratory has received research support from Biogen, Merck & Co, Novartis, Roche and Sanofi Genzyme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.