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.
The current standard of treatment for post-operative pain, in particular in-hospital procedures (those that require a hospital stay), is the administration of opioid drugs. This is frequently accomplished by an intravenous administration of morphine (or similar opioid) that can be controlled by the patient (patient- controlled analgesia, or PCA pump). In general, patients are transitioned to an oral opioid on day 2-3 at which time they undergo progressive ambulation in preparation for discharge. Patients are frequently discharged with a prescription for a potentially addictive opioid. In the event patients fill a prescription for an opioid following discharge, independent of whether they have had minor or major surgery, they are 15 times more likely to transition to chronic use of an opioid within the next 90-180 days.1 For patients, families and the medical community, the emergence of dependence and addiction following the use of opioids has become a serious concern and has driven the development of new approaches to pain management. The prevention and treatment of opioid use disorder (OUD) is a pressing social, ethical and medical challenge. In 2017 it was estimated that approximately 115 people died every day from an opioid overdose ? making it the single highest cause of accidental death in the US.2 The amount of prescription opioids sold to pharmacies, hospitals and physician?s offices quadrupled from 1999-2010 ? yet there was not a coincident increase in the amount of pain reported in the US population. In one of the largest cohort studies reported approximately 1 in 15 individuals prescribed an opioid for control of post-operative pain transitioned to chronic use within one year.3 The current crisis posed by OUD has been decades in the making and combatting it will take time and a coherent plan involving a number of different strategies aimed at prevention, intervention and treatment. The reduction or elimination of the need to administer addictive opioid drugs in the immediate post-operative period would target the initial gateway where patients are first exposed to addictive drugs.4 SER-227 is a long acting formulation of buprenorphine that is being developed to treat patients with post- operative pain that may be administered as a subcutaneous injection in the immediate post-operative period. This product is intended to be a one-time injection (by a surgeon/anesthesiologist) that will provide > 3 days of analgesia, after which patients would transition to non-addictive medications (such as ibuprofen or acetaminophen). SER-227 will have limited abuse liability and is not intended for self- administration. While some consider buprenorphine a relatively weak mu-agonist, a very recent (2018) meta-analysis of randomized, controlled clinical trials comparing buprenorphine in its existing formulation (Buprenex) to IV morphine via a PCA pump 5, showed that buprenorphine ? (1) was equal to morphine in analgesic efficacy, (2) buprenorphine had a ceiling effect on respiratory depression but not analgesia whereas morphine risk increases with dose, (3) there was no difference for major side effects such as nausea and sedation, (4) no difference in need for rescue analgesia or time to rescue analgesia, and (5) buprenorphine was superior to morphine in some adverse events ? primarily pruritis (a troublesome side effect in the post-operative management of patients). SER-227 may be a very important advance in the treatment of post-operative pain, while simultaneously addressing the initial gateway in the hospital to a potentially addictive opioid.
