Postoperative pain is a prevalent source of pain requiring appropriate management to reduce its impact upon quality of life. Even with the availability of several analgesics, postoperative pain is often under medicated because of concern related to the adverse consequence of the available therapeutics (e.g., NSAIDs and opiates), including addiction and decreased survival of cancer patients. To this end we have undertaken development ofRFT1124, a modified apolipoprotein A-I binding protein (AIBP), which exerts its action through specific targetingof membrane lipid rafts by altering local membrane cholesterol dynamics in dorsal root ganglion (DRG) neuronsand macrophages and in spinal microglia that express TLR4 (TLR4-rafts) and are known to be engaged inprocessing acute and chronic pain secondary to nerve and tissue injury. We have discovered that TLR4-raftsare heavily expressed on macrophages and exclusively on nociceptive DRG neurons. We have shown that it ispossible to specifically target these TLR4-rafts through the actions of RFT1124 (AIBP), which binds to TLR4 andspecifically disrupts the associated lipid rafts. In vitro, AIBP blocks the ectopic activity of human DRG nociceptorsisolated from painful dermatomes. In vivo, intravenous injection of AIBP prior to paw incision prevented thedevelopment of tactile allodynia in rats. These exciting new data, together with our published studies showingAIBP efficacy and mechanism of action in chemotherapy-induced peripheral neuropathy, suggest the potentialof AIBP (RFT1124) in treatment of postoperative pain. In Phase I of this Fast-Track STTR proposal, we willdefine the efficacy of intravenous RFT1124 delivery on postoperative pain in rats, including: (i) dose response;(ii) dependence on the time of pre or post incision administration; (iii) sex differences. In Phase II, we plan tomanufacture and release RFT1124 drug product for expanded efficacy and toxicology studies using cGMP-compatible processes and analytical assays. Further, a pharmacokinetics of RFT1124 in blood and DRG and anon-GLP safety assessment of intravenous delivery of RFT1124 will be conducted to establish an estimate ofsafety margin and target organs. As an independent biomarker of activity, we will characterize the effects ofRFT1124 on hyperactivity in rat DRG neurons otherwise produced by surgical incision in male and female rats.The efficacy studies will be extended to human DRG nociceptive neurons in culture, with the DRG obtained fromdonors of both sexes. Target engagement will be tested with an AIBP variant, which like RFT1124 alters lipidrafts but does not bind TLR4. We anticipate significant suppression of allodynic behavior and ectopic activityinduced by surgical injury after incision by RFT1124 but not the AIBP variant lacking the TLR4-binding domain.These studies will provide the enabling data set to initiate a pre-IND meeting with the FDA in anticipation ofmoving RFT1124 into first-in-human clinical trials.CONFIDENTIAL
Public Health Relevance Statement: PROJECT NARRATIVE The management of pain following surgery remains an area of clear unmet medical need. The goal of this project is to validate an approach to advance a novel, non-opioid drug candidate for the treatment of postoperative pain.
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