PRISMS: the story of a pivotal clinical trial series in multiple sclerosis

Abstract

Background:

The PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study was initiated in 1994, at which time there were few disease-modifying drugs for multiple sclerosis (MS). The PRISMS series of studies has since provided up to 8 years of clinical, magnetic resonance imaging (MRI), safety, and immunogenicity data on the use of subcutaneous (sc) interferon (IFN) beta-1a in patients with relapsing–remitting MS. This review is the first collation of all these data in one article, with a look ahead to the next generation of studies involving the new formulation of sc IFN beta-1a.

Methods:

Published efficacy, safety, and immunogenicity data, in terms of prospectively defined endpoints and later post hoc analyses, from years 1–8 of the PRISMS series are summarized and collated for the first time. Some of the studies of sc IFN beta-1a that evolved from the PRISMS studies are also discussed.

Findings:

In the 2-year, double-blind, randomized, placebo-controlled study, IFN beta-1a (22 or 44 mcg three times weekly [tiw]) was associated with significantly lower relapse rates, disability progression, and MRI burden of disease compared with placebo (p ≤ 0.05). Subsequently, in the 2-year extension, patients previously receiving placebo were re-randomized to active treatment, and a further 2 years of open-label treatment confirmed good long-term safety and therapeutic efficacy. Follow-up visits at years 7 or 8 (68.2% of initial population) demonstrated a continued benefit for patients originally randomized to the 44-mcg dose compared with those receiving the 22-mcg dose or whose treatment had been delayed by 2 years. Neutralizing antibodies were more common in patients receiving the 22-mcg dose and attenuated treatment efficacy during years 1–4.

Conclusion:

Class I and long-term data from PRISMS support the use of sc IFN beta-1a tiw as a first-line treatment for MS, as evidenced by sustained efficacy rates, acceptable safety profiles, and high patient retention rates.

Key words::

• Disability
• Interferon beta-1a
• Magnetic resonance imaging
• Neutralizing antibody
• Relapse
• Relapsing
• remitting multiple sclerosis
• Safety

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Declaration of funding

Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany, initiated the preparation of this review, and funded medical writing/editing assistance for the manuscript. The authors received no compensation for this project.

Declaration of financial/other relationships

B.C. has disclosed receiving funding from Biogen-Idec, BMS Medical/Lilly, EMD Serono, Inc., the National Institutes of Health, Novartis, Sanofi-Aventis and Teva Neuroscience; he has carried out consultancy work for Accorda, Bayer, Biogen-Idec, EMD Serono, Inc., Sanofi-Aventis and Teva Neuroscience and has received honoraria for speaking from Bayer, Biogen-Idec, EMD Serono, Inc., Novartis and Teva Neuroscience; he holds common stock in Abbott Laboratories and CVS Caremark. V.R. has disclosed receiving funding and honoraria from Biogen-Idec, Bayer Healthcare, EMD Serono, Inc., Teva Neuroscience, NMSS, Consortium of MS Centers and Stendhal Neurosciences; he has also carried out consultancy work for Novartis.

Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed receiving research grant funding from Genzyme, Genentech, Alexion and acting as a consultant/adviser to Novartis. Peer Reviewer 2 has disclosed no relevant financial relationships.

Acknowledgements

The authors take responsibility for the content of the paper but thank Polly Field, DPhil, and Joanna Brown, DPhil (Caudex Medical; supported by Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany), for their assistance in preparation of the manuscript and collating the comments of authors. Thanks also go to Jason Gardner, PhD (Medical Communication and Information, Neurodegenerative Diseases, Merck Serono S.A. – Geneva), for full cooperation in providing access to company data where required. Relevant parties at Merck Serono S.A. – Geneva were allowed the opportunity to review the manuscript prior to submission for publication.

Notes

* Betaferon is a registered trade name of Bayer Schering Pharma AG, Berlin, Germany.

† Betaseron is a registered trade name of Bayer HealthCare Pharmaceuticals, Wayne, New Jersey, USA.

‡ Avonex is a registered trade name of Biogen Idec Limited, Berkshire, UK.

§ Rebif is a registered trade name of Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.