Monthly Archives: October 2015

Progression of Modern Therapeutics for Rheumatoid Arthritis

Introduction

Since 1985, a total of 13 drugs have been approved for rheumatoid arthritis, in 8 different pharmacologic classes. The 1998 approval of Enbrel (etanercept), the first of 5 TNF inhibitor, ushered in the biologic DMARDs (disease-modifying antirheumatic drugs), representing the most significant progress in this therapeutic class; in fact, a total of 9 biologic DMARDs have been approved, the last, Actemra (tocilizumab), in 2010. Five small-molecule DMARDs had been approved between 1950 and 1970. In addition to the DMARDs for rheumatoid arthritis, NSAIDs (nonsteroidal anti-inflammatory drugs) and corticosteroids are sometimes used (not covered here).

Drug Approvals (1)

Excluding the 5 older, small-molecule DMARDs for rheumatoid arthritis, Azulfidine (sulfasalazine, 1950), Methotrexate (methotrexate, 1953), Plaquenil (hydroxychloroquine, 1955), Imuran (azathioprine, 1968), and Cuprimine (penicillamine, 1970), the 13 new drugs approved for rheumatoid arthritis, sorted by the 8 pharmacologic classes, are shown in the accompanying chart (click for a larger chart), and summarized below:

accompanying chart

  • Gold Preparation: 1 new drug; Ridaura (auranofin); in 1985.
  • T-cell Activation Inhibitor: 1 new drug; Neoral (cyclosporine); in 1995.
  • TNF Inhibitors: 5 new drugs; Enbrel (etanercept), Remicade (infliximab), Humira (adalimumab), Cimzia (certolizumab), and Simponi (golimumab); over 10 years and 6 months; between 1998 and 2009.
  • Anti-metabolite: 1 new drug; Arava (leflunomide); in 1998.
  • IL-1/IL-6 Receptor Antagonists: 2 new drugs; Kineret (anakinra) and Actemra (tocilizumab); over 8 years and 2 months; between 2001 and 2010.
  • T-cell Activation Inhibitor: 1 new drug; Orencia (abatacept); in 2005.
  • Anti-CD20/B Cell Depletor: 1 new drug; Rituxan (rituximab); in 2006.
  • JAK Inhibitor: 1 new drug; Xeljanz (tofacitinib) in 2012.

Comments

Over the past more than half a century, there has been development, albeit discontinuous, in new drug introductions for rheumatoid arthritis, characterized by two periods. First, the period between 1950 and 1970, when 5 new small-molecule DMARDs were introduced, and second, the period from the late 1990’s to the present, when 12 biologic and small-molecule DMARDs have been introduced.

  • The single most significant advance in the treatment of rheumatoid arthritis involves the introduction of the TNF inhibitors, a total of 5 new drugs.
  • The time from the discovery of TNF (in the 1960s) and from the determination of its structure (in the mid 1980s) until the approval of the first TNF inhibitor, Enbrel, was over three decades and over one decade, respectively.
  • The regulatory requirements for approval of agents for rheumatoid arthritis involve appropriate responses based on the American College of Rheumatology’s treatment assessment criteria ACR(20), ACR(50) and ACR(70), representing >20%, >50%, and >70% improvement, respectively.
  • Recently approved DMARDs have had patient responder rates in the approx. 40-60% range; responder rate typically defined as the proportion of subjects achieving a ACR(20) response at 3 months.
  • Based on a recently proposed systems therapeutic category classification (2), it would appear the majority of the modern therapeutics for rheumatoid arthritis are in Category II, i.e., the pivotal interaction between pharmacologic processes and pathophysiologic processes involves a fundamental biochemical mechanism, related to the disease evolution, although not necessarily an etiologic pathway.
  • In spite of significant developments over the past two decades, there clearly is room for considerable improvements in the efficacy characteristics of therapeutics for rheumatoid arthritis.

References

  1. Drugs@FDA: Medical Review of Xeljanz, Tables 2 and 3 in Clinical Review, accessed October 2015. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf
  2. TRI-institute: Systems Therapeutics: A Diagram and Four Categories. April 2015. http://tri-institute.org, April 2015 post.

Refer to page 26 of Progression of Modern Therapeutics (2014 Report) available under Reports on this website; this report also includes the methodology used. Note the present graph and text have been modified based on information presented in reference 1.