Chronic respiratory diseases are the third leading cause of death, behind cardiovascular diseases and cancer, affecting approximately 550 million of people all over the world. Most of the chronic respiratory diseases are attributable to asthma and chronic obstructive pulmonary disease (COPD) with this latter being the major cause of deaths. Despite differences in etiology and symptoms, a common feature of asthma and COPD is an underlying degree of airways inflammation. The nature and severity of this inflammation might differ between and within different respiratory conditions and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients. A precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success. Inhibitors of the phosphodiesterase 4 (PDE4) enzyme like the oral PDE4 inhibitor roflumilast have shown a potential to reduce inflammatory-mediated processes and the frequency of exacerbations in certain groups of COPD patients with a chronic bronchitis phenotype. However, roflumilast use is dampened by class related side effects as nausea, diarrhea, weight loss and abdominal pain, resulting in both substantial treatment discontinuation in clinical practice and withdrawal from clinical trials. This has prompted the search for PDE4 inhibitors to be given by inhalation to reduce the systemic exposure (and thus optimize the systemic safety) and maximize the therapeutic effect in the lung. Tanimilast (international non-proprietary name of CHF6001) is a novel highly potent and selective inhaled PDE4 inhibitor with proven anti-inflammatory properties in various inflammatory cells, including leukocytes derived from asthma and COPD patients, as well as in experimental rodent models of pulmonary inflammation. Inhaled tanimilast has reached phase III clinical development by showing promising pharmacodynamic results associated with a good tolerability and safety profile, with no evidence of PDE4 inhibitors class-related side effects. In this review we will discuss the main outcomes of preclinical and clinical studies conducted during tanimilast development, with particular emphasis on the characterization of the pharmacodynamic profile that led to the identification of target populations with increased therapeutic potential in inflammatory respiratory diseases.
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Univ Hong Kong, LKS Fac Med, Dept Med, Hong Kong, Peoples R ChinaUniv Hong Kong, LKS Fac Med, Dept Med, Hong Kong, Peoples R China
Liang, Yingmin
Mak, Judith C. W.
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Univ Hong Kong, LKS Fac Med, Dept Med, Hong Kong, Peoples R China
Univ Hong Kong, LKS Fac Med, Dept Pharmacol, Hong Kong, Peoples R China
Univ Hong Kong, LKS Fac Med, Dept Pharm, Hong Kong, Peoples R ChinaUniv Hong Kong, LKS Fac Med, Dept Med, Hong Kong, Peoples R China
机构:
Verona Pharma, London, England
Univ British Columbia, Dept Anesthesiol Pharmacol & Therapeut, Vancouver, BC V5Z 1M9, CanadaVerona Pharma, London, England
Franciosi, Lui G.
Diamant, Zuzana
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Ctr Human Drug Res, Leiden, Netherlands
Skane Univ, Dept Resp Dis & Allergol, Lund, Sweden
Univ Groningen, Univ Med Ctr Groningen, Dept Gen Practice, NL-9713 AV Groningen, NetherlandsVerona Pharma, London, England
Diamant, Zuzana
Banner, Katharine H.
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Verona Pharma, London, EnglandVerona Pharma, London, England
Banner, Katharine H.
Zuiker, Rob
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Ctr Human Drug Res, Leiden, NetherlandsVerona Pharma, London, England
Zuiker, Rob
Morelli, Nicoletta
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Ctr Human Drug Res, Leiden, NetherlandsVerona Pharma, London, England
Morelli, Nicoletta
Kamerling, Ingrid M. C.
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Ctr Human Drug Res, Leiden, NetherlandsVerona Pharma, London, England
Kamerling, Ingrid M. C.
de Kam, Marieke L.
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Ctr Human Drug Res, Leiden, NetherlandsVerona Pharma, London, England
de Kam, Marieke L.
Burggraaf, Jacobus
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Ctr Human Drug Res, Leiden, NetherlandsVerona Pharma, London, England
Burggraaf, Jacobus
Cohen, Adam F.
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Ctr Human Drug Res, Leiden, NetherlandsVerona Pharma, London, England
Cohen, Adam F.
Cazzola, Mario
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Univ Roma Tor Vergata, Unit Resp Clin Pharmacol, Dept Syst Med, Rome, ItalyVerona Pharma, London, England
Cazzola, Mario
Calzetta, Luigino
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IRCCS, Dept Resp Rehabil, San Raffaele Pisana Hosp, Rome, ItalyVerona Pharma, London, England
Calzetta, Luigino
Singh, Dave
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Univ Manchester, Univ Hosp South Manchester Fdn Trust, Med Evaluat Unit, Manchester, Lancs, EnglandVerona Pharma, London, England
Singh, Dave
Spina, Domenico
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Verona Pharma, London, EnglandVerona Pharma, London, England
Spina, Domenico
Walker, Michael J. A.
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Verona Pharma, London, England
Univ British Columbia, Dept Anesthesiol Pharmacol & Therapeut, Vancouver, BC V5Z 1M9, CanadaVerona Pharma, London, England
Walker, Michael J. A.
Page, Clive P.
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Verona Pharma, London, England
Kings Coll London, Sackler Inst Pulm Pharmacol, Inst Pharmaceut Sci, London SE1 9NH, EnglandVerona Pharma, London, England
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Univ Manchester, Manchester Univ NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, EnglandUniv Manchester, Manchester Univ NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England
Singh, Dave
Emirova, Aida
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Chiesi, Global Clin Dev, Parma, ItalyUniv Manchester, Manchester Univ NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England
Emirova, Aida
Francisco, Catherine
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Chiesi, Global Clin Dev, Parma, ItalyUniv Manchester, Manchester Univ NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England
Francisco, Catherine
Santoro, Debora
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Chiesi, Global Clin Dev, Parma, ItalyUniv Manchester, Manchester Univ NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England
Santoro, Debora
Govoni, Mirco
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Chiesi, Global Clin Dev, Parma, ItalyUniv Manchester, Manchester Univ NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England
Govoni, Mirco
Nandeuil, Marie Anna
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Chiesi, Global Clin Dev, Parma, ItalyUniv Manchester, Manchester Univ NHS Fdn Trust, Med Evaluat Unit, Manchester, Lancs, England