Long-Acting Peripherally-Restricted Peptidic Kappa Opioid Receptor Agonists for Pain

PROJECT SUMMARY Pain management poses significant clinical challenges due to very high prevalence diversity of underlying causes and often a lack of safe and effective treatment options Approximately million Americans undergo inpatient surgical procedures every year and experience acute post operative pain An estimated million US adults suffer from chronic pain conditions Opioids are the most effective class of analgesics for moderate to severe pain and act primarily at mu opioid receptors MOR Unfortunately MOR activation is also associated with significant side effects including constipation mental clouding and drowsiness respiratory depression nausea vomiting itching and risks of dependence and addiction For lack of better options the number of opioid prescriptions and dose per prescription has increased over the past two decades This has led to a pain medication epidemic characterized by unprecedented levels of addiction and deaths either from unintentional overdose of medically prescribed drugs or illicit use of medications Peripherally selective peptidic kappa opioid receptor KOR agonists are emerging as a new class of analgesics We previously pioneered the development of peptidic KOR agonists These efforts led to the discovery of FE a k a CR an all D amino acid tetrapeptide with unprecedented KOR selectivity and peripherally restricted activity Clinical trials with CR and a closely related analog CR have established that peptidic KOR agonists i produce analgesia ii lack CNS side effects iii do not produce constipation and iv reduce the need for mu opioid supplemental therapy in acute post operative pain This first generation peptidic KOR agonist is however short acting requiring multiple daily intravenous injections thereby limiting clinical utility and commercial interest We propose to combine the above clinically validated peptidic KOR agonist modality with our proprietary and clinically validated peptide half life extension technology This involves the conjugation of an active peptide to a non targeting antibody carrier to create long acting KOR LA KOR agonists suitable for once weekly QW subcutaneous SC administration The proposed SBIR Phase I program will assess the feasibility to design a LA KOR agonist chemical series with suitable KOR potency selectivity analgesic activity and duration of action to warrant further development IMPACT andamp PROJECT NARRATIVE This program seeks to develop a new analgesic that will benefit patients by improving quality of life through effective non addictive convenient and well tolerated pain control Such medications will also be useful in helping to curb the pain medication epidemic by reducing mu opioid prescriptions and consequent abuse