One target-multiple indications: a call for an integrated common mechanisms strategy.

Ever-increasing research and development costs are putting constant pressure on the pharmaceutical industry to improve their efficiency. Efforts to increase the output of the research pipeline have yielded limited success. Traditionally, maximization of the value of a drug is attempted through life-cycle management, which is initiated late in development, or when the drug is already on the market. Validated targets can be exploited further through development of a follow-up drug, which may offer advantages regarding safety or convenience. In this article, we propose to systematically evaluate the full therapeutic potential of a drug target, proprietary chemical lead structure, or drug candidate as broad and as early as possible and we call this the 'common mechanism' approach.

[1]  S. Nasraway,et al.  Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock , 1998, The Lancet.

[2]  J. Saklatvala.  Tumour necrosis factor α stimulates resorption and inhibits synthesis of proteoglycan in cartilage , 1986, Nature.

[3]  David W Carley,et al.  Drug repurposing: identify, develop and commercialize new uses for existing or abandoned drugs. Part I. , 2005, IDrugs : the investigational drugs journal.

[4]  J. Folkman.  Opinion: Angiogenesis: an organizing principle for drug discovery? , 2007, Nature Reviews Drug Discovery.

[5]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[6]  H. Neumayer,et al.  Expression and activity of soluble guanylate cyclase in injury and repair of anti-thy1 glomerulonephritis. , 2004, Kidney International.

[7]  G. Morris,et al.  Tumour necrosis factor alpha in severe congestive cardiac failure. , 1993, British heart journal.

[8]  R. Busse,et al.  Increased nitrovasodilator sensitivity in endothelial nitric oxide synthase knockout mice: role of soluble guanylyl cyclase. , 2000, Hypertension.

[9]  G. Rook,et al.  An inhibitor of the toxicity of tumour necrosis factor in the serum of patients with sarcoidosis, tuberculosis and Crohn's disease , 1990, Clinical and Experimental Immunology.

[10]  J. Stasch,et al.  Cardiorenal and Humoral Properties of a Novel Direct Soluble Guanylate Cyclase Stimulator BAY 41-2272 in Experimental Congestive Heart Failure , 2003, Circulation.

[11]  R. Hargreaves,et al.  Clinical biomarkers in drug discovery and development , 2003, Nature Reviews Drug Discovery.

[12]  O. V. Evgenov,et al.  NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential , 2006, Nature Reviews Drug Discovery.

[13]  J. Stasch,et al.  NO‐ and haem‐independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle , 2002, British journal of pharmacology.

[14]  Kevin J. Tracey,et al.  Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia , 1987, Nature.

[15]  I Royston,et al.  IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. , 1997, Blood.

[16]  D. Wallach,et al.  Elevated tumour necrosis factor‐alpha (TNF‐α) biological activity in psoriatic skin lesions , 1994, Clinical and experimental immunology.

[17]  B. Beutler,et al.  Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. , 1985, Science.

[18]  S. Moncada,et al.  BAY41-2272, a novel nitric oxide independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro. , 2003, The Journal of urology.

[19]  W. Seeger,et al.  Activation of Soluble Guanylate Cyclase Reverses Experimental Pulmonary Hypertension and Vascular Remodeling , 2006, Circulation.

[20]  M. Feldmann,et al.  Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Stasch,et al.  NO‐independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy , 2006, British journal of pharmacology.

[22]  T. Ashburn,et al.  Drug repositioning: identifying and developing new uses for existing drugs , 2004, Nature Reviews Drug Discovery.

[23]  R. W. Hansen,et al.  The price of innovation: new estimates of drug development costs. , 2003, Journal of health economics.

[24]  R. Fanin,et al.  Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. , 2002, Arthritis and rheumatism.

[25]  E. Chung,et al.  Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-&agr;, in Patients With Moderate-to-Severe Heart Failure: Results of the Anti-TNF Therapy Against Congestive Heart failure (ATTACH) Trial , 2003, Circulation.

[26]  C. Maury,et al.  Raised serum levels of cachectin/tumor necrosis factor alpha in renal allograft rejection , 1987, The Journal of experimental medicine.

[27]  E. Antunes,et al.  Protective Effects of BAY 41-2272 (sGC Stimulator) on Hypertension, Heart, and Cardiomyocyte Hypertrophy Induced by Chronic L-NAME Treatment in Rats , 2006, Journal of cardiovascular pharmacology.

[28]  S. Steinberg,et al.  Compressing drug development timelines in oncology using phase '0' trials , 2007, Nature Reviews Cancer.

[29]  O. V. Evgenov,et al.  Soluble Guanylate Cyclase Activator Reverses Acute Pulmonary Hypertension and Augments the Pulmonary Vasodilator Response to Inhaled Nitric Oxide in Awake Lambs , 2004, Circulation.

[30]  Louis A Tartaglia.  Complementary new approaches enable repositioning of failed drug candidates , 2006, Expert opinion on investigational drugs.

[31]  S. Moncada,et al.  Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor , 1987, Nature.