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

Project: Research project

Grant Details


PROJECT SUMMARYPain management poses significant clinical challenges due to very high prevalence, diversity of underlyingcauses, and often a lack of safe and effective treatment options. Approximately 50 million Americans undergoinpatient surgical procedures every year and experience acute post-operative pain. An estimated 100 millionUS adults suffer from chronic pain conditions. Opioids are the most effective class of analgesics for moderate tosevere pain and act primarily at mu opioid receptors (MOR). Unfortunately MOR activation is also associatedwith 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 opioidprescriptions and dose per prescription has increased over the past two decades. This has led to a ?painmedication epidemic? characterized by unprecedented levels of addiction and deaths either from unintentionaloverdose of medically prescribed drugs or illicit use of medications.Peripherally-selective peptidic kappa opioid receptor (KOR) agonists are emerging as a new class ofanalgesics. We previously pioneered the development of peptidic KOR agonists. These efforts led to thediscovery of FE 200665 (a.k.a. CR665), an all D-amino acid tetrapeptide with unprecedented KOR selectivityand peripherally restricted activity. Clinical trials with CR665, and a closely related analog CR845, haveestablished that peptidic KOR agonists (i) produce analgesia, (ii) lack CNS side-effects, (iii) do not produceconstipation, and (iv) reduce the need for mu opioid supplemental therapy in acute post-operative pain. This firstgeneration peptidic KOR agonist is however short-acting, requiring multiple daily intravenous injections, therebylimiting clinical utility and commercial interest.We propose to combine the above clinically-validated peptidic KOR agonist modality with our proprietary andclinically-validated peptide half-life extension technology. This involves the conjugation of an active peptide to anon-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 aLA-KOR agonist chemical series with suitable KOR potency, selectivity, analgesic activity and duration of actionto warrant further development. IMPACT &
Effective start/end date8/1/167/31/17


  • National Institutes of Health: $206,927.00


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