A Single Dose Long-Acting Non-Addictive Polymer Conjugate Formulation of Buprenorphine that Provides Immediate and Prolonged Analgesia for Post-Operative Pain

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PA-18-574 Project Summary/Abstract SER-227 is a long-acting polymer pro-drug of buprenorphine that is being developed to treat post- operative pain following major surgeries such as bunionectomy, abdominoplasty, thoracotomy and knee and hip surgery. SER-227 has no biological activity by itself, but when administered in vivo by subcutaneous injection it enters the vascular compartment where a plasma esterase (butyrylcholinesterase, BChE) enzymatically releases the active pharmaceutical ingredient, buprenorphine. The polymer confers prolonged circulatory half-life, allowing buprenorphine to be released continuously over ~ 3-4 days. Buprenorphine is a mixed mu-agonist/antagonist at the mu opioid receptor (MOR), and an antagonist at the kappa opioid receptor. A single administration of SER-227 has been shown to provide both immediate and prolonged analgesia in the Brennan model. Prompt analgesia, which subsequently lasts ~ 3-4 days, should obviate the need to initiate therapy by a potentially addictive opioid in the hospital and allow patients to be discharged on non-additive drugs such as acetaminophen or NSAIDs. SER-227 is to be administered as a subcutaneous injection in the immediate post-operative period (e.g. recovery room). This product is intended to be a one-time injection (by a surgeon/anesthesiologist) that will provide both immediate and > 3 days of analgesia. SER-227 is predicted to demonstrate very low abuse liability (indeed, long-acting implants of buprenorphine are used to treat opioid use disorder) and is likely to be used largely in surgical centers; it is not intended for self-administration. A Research Strategy is presented that will focus on the early development and preclinical objectives of this program, where the ultimate goal is to demonstrate that SER-227 can be manufactured and tested preclinically to show that it is safe for use in a Phase I clinical study. 1. SER-227 chemistry and process optimization to generate a technical package, and 2. SER-227 manufactured under current Good Manufacturing Practices, and 3. Evaluated in formal toxicology studies in rodent and non-rodent animals so that justifications can be made to support a ‘first-in-man’ study, 4. Submission of an Investigational New Drug application (IND) along with a Phase I clinical protocol in normal volunteers to measure the safety, tolerability and pharmacokinetics of buprenorphine that is released from SER-227. This ‘Direct to Phase II’ submission is made under the ‘HEAL Initiative, Notice of Interest in Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Applications Directed at Enhanced Pain Management and Improved Treatments for Opioid Misuse and Addiction’. Based upon prior experience in studies of similar design, we anticipate this Phase of the program would take 18 to 24 months to complete.