NOVEL BI-SPECIFIC IMMUNOPROPHYLACTICS AGAINST MULTI-DRUG RESISTANT GRAM-NEGATIVE BACTERIAL INFECTIONS

The Centers for Disease Control and Prevention (CDC) estimates that at least two million illnesses and 23,000deaths annually are caused by antimicrobial-resistant bacteria in the United States. The Gram-negative (G-)pathogens are of particular concern, as they account for roughly 99,000 deaths and $20B in health care costs ayear. More alarming, treatment options for G- infections have become increasingly limited due to rapidemergence of multi-drug resistance (MDR) to existing and newly approved antimicrobial agents, highlighting theneed for alternative strategies to prevent MDR G- infections. Thus, an agent that leverages immunologicalmechanisms to prevent infection in high risk populations from drug susceptible and MDR strains wouldpossess a unique advantage in addressing this need. The innovative Cloudbreak? Antibody DrugConjugates (ADCs) platform, developed at Cidara Therapeutics, uses a fundamentally new immune-basedapproach to prevent and treat G- infections. Similar to successful cancer bispecific agents, ADCs bind conservedtargets on pathogens via a Targeting Moiety (TM) while simultaneously engaging multiple arms of the immunesystem via an Effector Moiety (EM). The TM is comprised of a dimeric peptide that binds tightly tolipopolysaccharide (LPS) and confers broad spectrum G- coverage with potent intrinsic antimicrobial activity.The EM is a human IgG1 Fc, which collectively activates complement dependent cytotoxicity (CDC), antibody(Ab)-dependent cell-mediated cytotoxicity (ADCC), and Ab-dependent cell phagocytosis (ADCP) to clear MDRG- pathogens from the host, via recognition by Fc? receptors on host cells.!This innovative approach involvingefficient cell targeting with inherent cell killing catalyzes a robust immune response by more effectively presentingthe pathogen to immune components for clearance. CTC-026 is our lead ADC candidate and has demonstratedhighly promising properties as an immunoprophylactic agent: broad spectrum antibacterial activity that is bothintrinsic and immune-driven, acute safety in rodents, in vivo efficacy in mouse models of Escherichia coli sepsisand Acinetobacter baumannii pneumonia, and a 67 hour plasma half-life in mice. Further optimization of potencyand spectrum and in-depth evaluation of pharmacological and toxicological properties of this lead are proposedin this application. The overarching goal of this proposal is to identify a qualified lead development candidatein Year 3 and an Investigational new drug (IND) candidate by the end of Year 5, that meets these criteria: 1)acceptable stability and solubility for IV formulation, 2) MIC90s ?1 µM against clinical isolates (including MDR) ofKlebsiella, Acinetobacter, Pseudomonas and E. coli, 3) MIC90s ?1 µM against MCR-1, MCR-2 and other colistin-resistant G- clinical isolates, 4) robust in vivo prophylactic efficacy against MDR G- infections in a time window48-72h prior to infection, 5) PK/PD parameters to support once weekly or better dosing in humans, 6) a NOAELin GLP toxicology studies in rats and Cynomolgus monkeys at least fivefold higher than the targeted clinicaldose, and 7) a scalable synthesis to GMP product.