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.
Public Health Relevance Statement: 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.
Project Terms: Pain management; Pain Control; Pain Therapy; pain treatment; Non-Steroidal Anti-Inflammatory Agents; NSAIDs; Non Steroidal Antiinflammatory Agents; Nonsteroidal Anti-Inflammatory Agents; Nonsteroidal Antiinflammatory Agents; Nonsteroidal Antiinflammatory Drug; non-steroidal anti-inflammatory drugs; non-steroidal antiinflammatory drugs; nonsteroidal anti-inflammatory drugs; Anticonvulsants; Anticonvulsant Agent; Anticonvulsant Drugs; Anticonvulsive Agents; Anticonvulsive Drugs; Biological Assay; Assay; Bioassay; Biologic Assays; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Cells; Cell Body; Cholesterol; Cisplatin; CDDP; Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatina; Cisplatinum; Cysplatyna; Dichlorodiammineplatinum; Peyrone's Chloride; Peyrone's Salt; Platinum Diamminodichloride; cis dichlorodiammineplatinum; cis platinum compound; cis-Diaminedichloroplatinum; cis-Diamminedichloroplatinum; cis-Diamminedichloroplatinum(II); cis-Dichlorodiammineplatinum(II); cis-Platinum; Clinical Research; Clinical Study; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Endotoxins; Epidemic; Future; Spinal Ganglia; Dorsal Root Ganglia; dorsal root ganglion; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Inflammation; macrophage; MÏ; Methods; Mus; Mice; Mice Mammals; Murine; NIH; National Institutes of Health; United States National Institutes of Health; nociceptive neurons; pain-sensing neurons; pain-sensing sensory neurons; pain-sensing somatosensory neurons; Nociceptors; Painful; Pain; Patients; Peripheral Nerves; Pharmacokinetics; Drug Kinetics; Pharmacology; Phenotype; Proteins; QOL; Quality of life; Common Rat Strains; Rat; Rats Mammals; Rattus; Research; Risk; Rodentia; Rodents Mammals; Rodent; Safety; Spinal Nerve Roots; Spinal Roots; Spinal nerve root structure; Toxicology; Translating; Apolipoprotein A-I; Apo A-1; Apo A-I; Apo A1; Apo AI; ApoA-1; ApoA-I; Apolipoprotein A-1; Apolipoprotein A1; Apolipoprotein AI; Healthcare; health care; Mediating; chronic pain; Injury; injuries; Organ; Surface; Chronic; Clinical; Phase; Biological; biologic; Microglia; Hortega cell; gitter cell; mesoglia; microglial cell; microgliocyte; perivascular glial cell; Ensure; gangliocyte; ganglion cell; non-human primate; nonhuman primate; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Opiates; Opioid; Development Plans; non-narcotic analgesic; non-opiate analgesic; non-opioid; non-opioid therapeutics; nonnarcotic analgesics; nonopiate analgesic; nonopioid; nonopioid analgesics; non-opioid analgesic; No-Observed-Effect Levels; NOEL; NOAEL; No-Observed-Adverse-Effect Level; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; Inflammatory; programs; Dependence; Spinal; meetings; particle; success; Toxicities; Toxic effect; sterile; Sterility; novel; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Regulation; Pharmacodynamics; Modeling; response; Cell Membrane Lipid Rafts; Sphingolipid Microdomains; Sphingolipid-Cholesterol Rafts; lipid raft; Membrane Microdomains; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; drug standard; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Homolog of Drosophila TOLL; TLR4; Toll Homologue; toll-like receptor 4; TLR4 gene; Dose; Data; Cancer Patient; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; Preparation; Process; Development; developmental; safety study; preclinical study; pre-clinical study; painful neuropathy; neuropathic pain; National Institute of Neurological Disorders and Stroke; NINDS; National Institute of Neurological Diseases and Stroke; neuroinflammation; neuroinflammatory; design; designing; novel strategies; new approaches; novel approaches; novel strategy; Outcome; manufacturing process; scale up; human study; chemotherapy; addiction; addictive disorder; effective therapy; effective treatment; preclinical evaluation; pre-clinical evaluation; cGMP production; process optimization; manufacturing scale-up; biobank; biorepository; Chemotherapy-induced peripheral neuropathy; Formulation; systemic toxicity; experimental study; experiment; experimental research; clinical development; pain relief; relieve pain; lead candidate; first-in-human; first in man; opioid misuse; non-medical opioid use; nonmedical opioid use; opiate misuse; side effect; medication safety; drug safety; pharmaceutical safety; Helping to End Addiction Long-term; HEAL Initiative; Helping End Addiction Long-term; Helping End Addiction Longterm; Helping to End Addiction Longterm
