PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) has a profound negative impact on quality of life of nearly 70% of cancer patients receiving chemotherapy. While systemic administration of opiates, NSAIDs, and anticonvulsants can relieve pain for short intervals, they are not suitable for chronic therapy. Aside from efficacy, many of the potent agents are beset with limiting side effects and issues related to dependence and addiction. RAFT Pharmaceuticals (RAFT) proposes a Direct-to-Phase 2 SBIR proposal presenting a novel approach to reversal of preexisting neuropathic pain via regulation of lipid rafts in spinal and dorsal root ganglia (DRG) cells. Our lead candidate, RFT1081, which is a modified apoA-I binding protein (AIBP), promotes removal of cholesterol selectively from the plasma membrane of activated and inflammatory cells. This targeting is due to AIBP binding to Toll-like receptor 4 (TLR4), which is highly expressed on the surface of inflammatory microglia, macrophages and activated DRG nociceptors. RFT1081-mediated disruption of lipid rafts harboring activated TLR4 abrogates the facilitatory cycle of neuroinflammation and nociceptors’ spontaneous activity and alleviates chronic pain phenotypes. In a prior project, we developed a non-GMP scaled-up upstream and downstream manufacturing process for RFT1081 and conducted its detailed characterization; conducted pharmacokinetics studies of spinally delivered RFT1081 in mice and designed pharmacodynamics assays to evaluate RFT1081 target engagement; established dose-dependent efficacy profile for AIBP treatment in CIPN mice; and conducted a non-GLP dose-range tolerability study of RFT1081 in rats. These data provide support and justify further development of RFT1081 in the proposed Direct-to-Phase 2 SBIR studies. In this milestones-driven project, we plan to manufacture a RFT1081 drug product lot for toxicology studies using a cGMP-compatible process and analytical assays. The RFT1081 drug product lot, conforming to RAFT’s specifications and in optimized formulation will be thoroughly characterized for storage and in-use stability. The initial single-dose toxicology studies will be performed in rats. We will then also evaluate the pharmacology, local and systemic toxicity, and immune response to repeated i.t. administration of RAFT1081 in rats, dogs and non-human primates to further study the safety of the drug and to select a pharmacologically relevant non-rodent species for further IND- enabling preclinical evaluation. RFT1081 will also be evaluated in a model of cisplatin cancer therapy to ensure it does not interfere with chemotherapy action. The project will conclude with developing a detailed synopsis of an integrated first-in-human study and an overall indication-supporting clinical strategy, followed by preparation for and conducting a pre-IND meeting with the FDA. We expect that this Phase 2 SBIR project outcomes will include: 1) successful scale-up of RFT1081 suitable for future cGMP manufacturing, 2) completion of dose- ranging toxicology studies and selection of a relevant non-rodent species, and 3) a viable IND-enabling and clinical development strategy vetted with the FDA to de-risk future steps of RFT1081 development.

NARRATIVE Chronic pain is a major healthcare problem. Because no effective therapy is available, the misuse of opioids contributes to the growing epidemic of addiction. Capitalizing on the discovery of a novel mechanism involved in the development of chemotherapy-induced peripheral neuropathy (CIPN), this project is to advance a non-opioid, first-in-class therapeutic, which effectively reverses CIPN associated pain, toward IND and clinical testing.