SBIR-STTR Award

Ind-Enabling Studies of the Potent Lpxc Inhibitor Lpc-233 as a Novel Antibiotic Against Gram-Negative Pathogens
Award last edited on: 9/13/2021

Sponsored Program
SBIR
Awarding Agency
NIH : NIAID
Total Award Amount
$1,591,745
Award Phase
2
Solicitation Topic Code
-----

Principal Investigator
Clayton Duncan

Company Information

Valanbio Therapeutics Inc

4101 Lake Boone Trail Suite 300
Raleigh, NC 27607
   N/A
   valanbioinfo@gmail.com
   N/A
Location: Single
Congr. District: 02
County: Wake

Phase I

Contract Number: 1R44AI152896-01
Start Date: 4/16/2020    Completed: 3/31/2022
Phase I year
2020
Phase I Amount
$797,403
The rapidly increasing incidences of infections caused by multidrug-resistant Gram-negative bacteria represent an emerging global health care crisis. The fact that no new class of medication against Gram- negative bacteria has been introduced into practice over half of a century, combined with the lengthy development and approval process, add to the urgency to accelerate and streamline research and development processes for new treatment approaches to Gram-negative bacterial infections. LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is an essential enzyme in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide and the major lipid component of the outer monolayer of the Gram-negative bacterial outer membrane. Constitutive lipid A biosynthesis is required for bacterial viability and fitness in the human host. As such, LpxC is an attractive target to create a novel class of small molecule inhibitors as antibacterial agents specific to Gram-negative bacterial pathogens. Extensive research over the last two decades shows that (1) potent LpxC inhibitors display outstanding bactericidal effect; (2) with few exceptions in vitro, virtually all Gram-negative bacteria are sensitive to LpxC inhibition in vivo; and (3) LpxC inhibitors are not inactivated by common resistance mechanisms such as extended- spectrum ?-lactamases (ESBL) or carbapenemases. Although dose-limiting adverse effects have limited the development of the most advanced LpxC inhibitors, ACHN-975 (Achaogen) and RC-0 1 (Recida Therapeutics), these compounds do not show the same liabilities, suggesting that the observed adverse effects do not represent a class limitation. Valanbio Therapeutics was founded to translate basic research activities from Duke University into a potential new class of antibacterial agents against Gram-negative pathogens. Duke University and Valanbio Therapeutics have identified a lead LpxC inhibitor, LPC-233, which we seek to advance to the clinical stage testing. LPC-233 is potently and broadly bactericidal against Gram-negative bacteria in vitro and significantly reduces bacterial counts in the murine thigh infection model at doses as low as 2 mg/kg BID. It also displays an outstanding safety profile in rats. In this proposal, Valanbio Therapeutics plans to (1) develop GMP- compatible large-scale synthesis of LPC-233; (2) continue to evaluate and optimize the efficacy and dosing regimen of LPC-233 against susceptible and multidrug-resistant Gram-negative bacterial pathogens in mice; (3) investigate the potential dose-limiting safety liabilities in vitro and in vivo. The successful execution of the proposed studies will clear the path for IND filing and advance LPC-233 to Phase I human clinical trials.

Public Health Relevance Statement:
Project Narrative The wide dissemination of multidrug-resistant Gram-negative pathogens, particularly those in hospitals with large numbers of vulnerable patients, poses a major public health threat. Valanbio Therapeutics seeks to address this urgent unmet public need by developing novel antibiotics targeting the essential enzyme LpxC in Gram-negative bacteria. Successful completion of the proposed research will address (1) the critical barriers of cGMP synthesis, (2) dosing regimen optimization and efficacy evaluation against multiple Gram-negative pathogens and (3) in vitro and in vivo safety concerns to advance Valanbio’s lead compound LPC-233 to Phase I human clinical trials.

Project Terms:
Address; Adverse effects; Anabolism; Anti-Bacterial Agents; Antibiotics; antimicrobial drug; Bacterial Counts; bactericide; Basic Science; Binding; Biochemical; Biological; Biological Availability; Canis familiaris; carbapenem resistance; carbapenemase; Cardiovascular system; Centers for Disease Control and Prevention (U.S.); Chemicals; Chromatography; Clinic; Clinical; clinical candidate; Clinical Trials; Collaborations; Complex; Continuous Infusion; Cyclic GMP; cytotoxicity; Data; design; Development; Diastolic blood pressure; Dose; Dose-Limiting; Drops; Drug resistance; Effectiveness; efficacy evaluation; Enterobacteriaceae; Enzyme Inhibitor Drugs; Enzymes; Escherichia coli; exhaust; Family; fitness; Focal Infection; Formulation; global health; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Half-Life; Head; Healthcare; Hospitals; Hour; Human; Hydrophobicity; In Vitro; in vivo; Incidence; Infection; Infusion procedures; inhibitor/antagonist; Intention; intravenous administration; Investigation; Kilogram; Kinetics; Klebsiella pneumoniae; Lactamase; Lead; Legal patent; Lipid A; lipid biosynthesis; Lipids; Lipopolysaccharides; Medical; Membrane; Modeling; monolayer; Multi-Drug Resistance; Mus; mutant; N-acetylglucosamine deacetylase; novel; novel therapeutics; Oral; Organism; pathogen; pathogenic bacteria; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plague; posters; Procedures; Process; Production; professor; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Public Health; Publications; Rattus; Regimen; Research; Research Activity; research and development; Resistance; resistance mechanism; Route; Safety; safety study; Secure; Sepsis; Series; small molecule inhibitor; Structure; Superbug; Systemic infection; Testing; Therapeutic; Thigh structure; Toxic effect; Toxicology; Translating; Treatment Protocols; Universities; virtual; Work; Yersinia pestis

Phase II

Contract Number: 5R44AI152896-02
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
2021
Phase II Amount
$794,342
The rapidly increasing incidences of infections caused by multidrug-resistant Gram-negative bacteria represent an emerging global health care crisis. The fact that no new class of medication against Gram- negative bacteria has been introduced into practice over half of a century, combined with the lengthy development and approval process, add to the urgency to accelerate and streamline research and development processes for new treatment approaches to Gram-negative bacterial infections.LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is an essential enzyme in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide and the major lipid component of the outer monolayer of the Gram-negative bacterial outer membrane. Constitutive lipid A biosynthesis is required for bacterial viability and fitness in the human host. As such, LpxC is an attractive target to create a novel class of small molecule inhibitors as antibacterial agents specific to Gram-negative bacterial pathogens. Extensive research over the last two decades shows that (1) potent LpxC inhibitors display outstanding bactericidal effect; (2) with few exceptions in vitro, virtually all Gram-negative bacteria are sensitive to LpxC inhibition in vivo; and (3) LpxC inhibitors are not inactivated by common resistance mechanisms such as extended- spectrum ?-lactamases (ESBL) or carbapenemases. Although dose-limiting adverse effects have limited the development of the most advanced LpxC inhibitors, ACHN-975 (Achaogen) and RC-0 1 (Recida Therapeutics), these compounds do not show the same liabilities, suggesting that the observed adverse effects do not represent a class limitation.Valanbio Therapeutics was founded to translate basic research activities from Duke University into a potential new class of antibacterial agents against Gram-negative pathogens. Duke University and Valanbio Therapeutics have identified a lead LpxC inhibitor, LPC-233, which we seek to advance to the clinical stage testing. LPC-233 is potently and broadly bactericidal against Gram-negative bacteria in vitro and significantly reduces bacterial counts in the murine thigh infection model at doses as low as 2 mg/kg BID. It also displays an outstanding safety profile in rats. In this proposal, Valanbio Therapeutics plans to (1) develop GMP- compatible large-scale synthesis of LPC-233; (2) continue to evaluate and optimize the efficacy and dosing regimen of LPC-233 against susceptible and multidrug-resistant Gram-negative bacterial pathogens in mice; (3) investigate the potential dose-limiting safety liabilities in vitro and in vivo. The successful execution of the proposed studies will clear the path for IND filing and advance LPC-233 to Phase I human clinical trials. Public Health Relevance Statement Project NarrativeThe wide dissemination of multidrug-resistant Gram-negative pathogens, particularly those in hospitals with large numbers of vulnerable patients, poses a major public health threat. Valanbio Therapeutics seeks to address this urgent unmet public need by developing novel antibiotics targeting the essential enzyme LpxC in Gram-negative bacteria. Successful completion of the proposed research will address (1) the critical barriers of cGMP synthesis, (2) dosing regimen optimization and efficacy evaluation against multiple Gram-negative pathogens and (3) in vitro and in vivo safety concerns to advance Valanbio’s lead compound LPC-233 to Phase I human clinical trials.