Disease Modifying Analgesia with CA8 Gene Therapy

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Chronic pain costs about $650 billion annually,1,2 and most chronic noncancer pain remains inadequately treated.3 In the absence of suitable analgesic alternatives, an epidemic of opioid overuse, abuse, and life- threatening complications has occurred.4 To address this unmet need, we set out to identify novel nonopioid analgesics and discovered that dorsal root ganglion (DRG) carbonic anhydrase-8 (CA8) expression regulates analgesic responses.5 CA8 delivered using gene therapy via clinically relevant routes of administration acts as a ‘local anesthetic’ transducing DRG to produce profound long lasting analgesia (equivalent >200mg of oral morphine in 60kg adult), without motor blockade or clinical pathology in chronic animal pain models.6-9 Prior NIH funding supported the creation, characterization and validation of replication defective HSV (rdHSV) CA8 expressing biotherapeutics (vHCA8) using gene therapy candidates. This HEAL UG3/UH3 Proposal (NS-21- 010) includes 6 Projects designed to optimize and develop through an IND-in effect for a novel non-opioid analgesic lead candidate with the goal of treating chronic knee osteoarthritis (OA) pain. UG3 Program: PROJECT 1: Conduct dose-ranging, safety (NOAEL), efficacy (analgesia) and neuronal specificity for each promoter construct (e.g., pCMV, pAdvillin, pTrkA) using clinically relevant routes of administration. MILESTONE 1: Define the safety and efficacy (including PD, biodistribution, histopathology, etc.) of each vHCA8 construct and select the least invasive route of administration and the safest most effective vHCA8 promoter construct for further development. PROJECT 2: Determine the safety and efficacy (analgesia) of the lead vHCA8 promoter construct as a treatment for chronic OA pain. MILESTONE 2: Demonstrate the lead vHCA8 biotherapeutic candidate treats chronic OA pain that produces persistent analgesia and anti-hyperalgesia without toxicity. UH3 Program: In collaboration with LDT: PROJECT 3: Engage NIH Contract Development and Manufacturing Organization (CDMO); establish process and analytical methods development supporting characterization of vHCA8 drug substance (DS) and drug product (DP); manufacture DS for GLP Toxicology studies (Tox); develop DP formulation; run stability; and complete CM&C IND sections. MILESTONE 3: Complete manufacturing process and analytical development to support IND; manufacture DS for GLP Tox and write IND CM&C sections. PROJECT 4: Engage NIH contracted clinical CRO, develop initial clinical protocol, conduct Pre-IND Meeting. MILESTONE 4: Define regulatory path. PROJECT 5: Engage NIH contracted CRO with required Tox capabilities; conduct GLP Tox; integrate all preclinical data into IND, submit IND. MILESTONE 5. IND in-effect. PROJECT 6: Establish NewCo; in-license IP. MILESTONE 6: NewCo controls IP protecting commercial opportunities; establish freedom-to- operate (FTO). Timeline: Years 1 - 5. SUMMARY: At the end of these UG3/UH3 Programs, one vHCA8 biotherapeutic candidate will be ready for Phase 1 clinical studies as a novel non-opioid long-acting analgesic delivered as a first-in-class local anesthetic with disease-modifying potential.