Duration by Design: Discovery of Revefenacin, the First-in-Class Nebulized Once-Daily Bronchodilator for the Treatment of Patients With COPD

SESSION TITLE: Pharmacotherapuetics SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM PURPOSE: Translation of inhalation-by-design drug discovery to late-stage development remains a challenge. Herein, we report a preclinical “duration-by-design” program with the goal to identify a long-acting muscarinic antagonist with structural/pharmacological features ideally suited for once-daily (QD) nebulized delivery. METHODS: A rational preclinical screening and selection effort incorporated predefined structural and pharmacologic criteria requisite for a QD bronchodilator. A nonester, nonquarternary ammonium orthosteric group was predicted to assist with tissue residency and maximize chemical stability for aqueous formulation and aerosol delivery. To enable binding to distal muscarinic receptor sites, this group was linked with secondary binding elements to construct antagonists of unique molecular size and properties distinct from previously reported inhaled antagonists. Candidates were screened in vitro for extended receptor half-life and in vivo for lung tissue retention. An in vivo lung selectivity index (LSI) was employed to confirm high-functional lung vs peripheral tissue activity. Finally, metabolic “softness” was assessed to predict ex-lung enzymatic deactivation of potency in the periphery. RESULTS: A 4-piperidyl-2-biphenyl head group served as a starting point to replace the ester-based functionality common in inhaled antagonists (eg, ipratropium, tiotropium, aclidinium, glycopyrrolate). Subnanomolar M1-M3 receptor potencies were observed by extending this head group with an N-ethyl-(4-aminomethyl) benzamide linker. Analogs were prepared to explore receptor interactions unlikely to be accessible to precedent agents. The final development candidate, TD-4208 (pINN revefenacin), with a 4-aminocarbonyl-1-piperidinyl methyl terminus, was selected after demonstrating an optimal 24-hour lung tissue half-life post inhalation and a favorable LSI vs tiotropium. The terminal amide in revefenacin’s structure was found to provide a metabolically labile functionality, appearing stable in lung but readily hydrolyzed to the less-potent carboxylate metabolite in systemic circulation. CONCLUSIONS: Application of a duration-by-design discovery platform resulted in the selection of revefenacin, a novel nebulized QD long-acting muscarinic antagonist currently under evaluation in phase 3. CLINICAL IMPLICATIONS: Duration by design has the potential to optimize properties of an inhaled agent to deliver a lung-selective QD therapy. DISCLOSURE: Yuhua Ji: Employee: Former employee of Theravance Biopharma US, Inc. Craig Husfeld: Employee: Former employee of Theravance, Inc M. Teresa Pulido-Rios: Employee: Employee of Theravance Biopharma US, Inc. Alexander McNamara: Employee: Employee of Theravance Biopharma US, Inc. Glenmar P. Obedencio: Employee: Employee of Theravance Biopharma US, Inc. Mike Baldwin: Employee: Employee of Theravance Biopharma US, Inc. David Bourdet: Employee: Employee of Theravance Biopharma US, Inc. Sharath Hegde: Employee: Employee of Theravance Biopharma US, Inc. Mathai Mammen: Employee: Former employee of Theravance Biopharma US, Inc. Edmund Moran: Employee: Employee of Theravance Biopharma US, Inc. The presentation will discuss revefenacin, a new drug entity currently under investigation for the treatment of patients with chronic obstructive pulmonary disease (COPD).