Where Are the New Cough Treatments: A Debriefing of Recent Clinical Proof-of-Concept Trials with the NOP Agonist SCH 486757

Abstract

Cough continues to be one of the top reasons why patients seek medical attention from health care providers. The prescription antitussive market is dominated by opioids, such as codeine that produces inconsistent efficacy and is often accompanied by significant side effect liabilities. Consequently, cough represents an unmet medical need and an underserved market. Yet, against the backdrop of increasing cough research, the development of novel treatments has been exceptionally challenging with dextromethorphan being the last US drug approved for cough almost a half century ago. We support the position that an unambiguous and actionable ‘road map’ that clearly delineates the pathway forward for new cough suppressants from basic research to and beyond clinical proof-of-concept studies will be an important aspect for future success of this pharmacological class of drug. Pivotal to the establishment of such a road map will be the review of lessons learned from antitussive agents that have been recently progressed to proof-of-concept trials. In the present commentary, we briefly discuss observations and challenges pertaining to SCH 486757, a selective orally active NOP agonist that has recently advanced to human antitussive testing.

Nociceptin/orphanin FQ receptor expression in clinical pain disorders and functional effects in cultured neurons

“…Intracisternal N/OFQ and morphine also produced antinociceptive effects [17]. Peripherally mediated effects show promise, including a recent study describing efficacy of NOP receptor agonist SCH 486757 in suppressing capsaicin induced cough in a guinea pig model [34], currently being evaluated in a clinical trial [35].…”

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…Based upon a large number of studies demonstrating the involvement of the NOP receptor in cough and airway microvasculature, Merck Sharp & Dohme conducted clinical trials on the full NOP receptor agonist SCH 486757. Phase II trials indicated no improvement over the comparator, codeine (McLeod et al, 2011), although the authors made the point that these are difficult clinical trials since the patients often improve spontaneously during the course of the trial.…”

Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

“…250 Due to lack of efficacy, the somnolence of patients and sedation, the continued clinical development of SCH 486757 was abandoned. [250][251] Nevertheless, years later the biased character of SCH 486757 was determined by calculating the factor, compared to N/OFQ, of 0.81, calculated with the operational model (Equation 2), resulting in a G protein-biased ligand. 248…”