US DoD SBIR grants to develop small molecules for MDR Pseudomonas aeruginosa

Dear All,

The US Department of Defense (DoD) is offering funds through the Small Business Innovation Research (SBIR) program for a “Novel Antibiotic for the Treatment of Multidrug-Resistant Pseudomonas Aeruginosa Infections.” Antibody, phage, and vaccine approaches are out of scope and the business must be located in the United States.

To find the funding offer, navigate to https://www.dodsbirsttr.mil/submissions/login, look for “TOPIC INFO” on the top header, click on “Topics And Topic Q&A (SITIS)”, and then filter for Topic # DHA211-008. There is a lot more detail below my signature, but here are the key points:

• The objective is “Development of a small molecule, antibacterial drug candidate for the treatment of service members in the Military Health System infected by multidrug-resistant (MDR) Pseudomonas aeruginosa to include in vitro and in vivo efficacy in models of wounds, burns, sepsis and/or ventilator-associated pneumonia (VAP).
• The funding opportunity is available through the Small Business Innovation Research (SBIR) program which encourages US domestic small businesses (no more than 500 employees and at least 51% owned and controlled by U.S. individuals) to engage in Federal Research/Research and Development (R/R&D) with the potential for commercialization.
• The intent is to fund pre-clinical development: up to $0.25m is offered for feasibility (Phase I in SBIR parlance) and up to $1.1m for animal model work (SBIR’s Phase II). The SBIR program does not fund beyond this point, but there are other potential funding pathways (see notes below).
• The deadline for applications is 18 Feb 2021.

Might this be you and your co-workers? I hope so!  All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.

Extended details taken pretty much verbatim from the funding announcement
OBJECTIVE: Development of a small molecule, antibacterial drug candidate for the treatment of service members in the Military Health System infected by multidrug-resistant (MDR) Pseudomonas aeruginosa to include in vitro and in vivo efficacy in models of wounds, burns, sepsis and/or ventilator-associated pneumonia (VAP).

DESCRIPTION: Successful treatment and recovery of service members/warfighters wounded in the line of duty is frequently complicated by multidrug-resistant (MDR) bacterial infections. In the best medical evacuation systems spanning the past 18 years of conflict in Iraq and Afghanistan, U.S. troops injured in combat and moved to higher echelons of care were still at a high risk of developing post-injury infections. Wound infections can develop days following injury and are largely attributed to Gram-negative organisms acquired in the hospital setting (1). Pseudomonas aeruginosa is one of the most frequent causes of wound infections and can result in significant morbidity and mortality. A 2017 surveillance summary of P. aeruginosa infections in military treatment facilities reported 47.9% of P. aeruginosa infections were healthcare-associated cases and that none of the strains tested displayed 100% susceptibility to any antibiotic tested (2). Moreover, in the present coronavirus disease 2019 (COVID-19) era, patients on mechanical ventilation due to the disease can become coinfected with hospital-acquired P. aeruginosa strains leading to ventilator-associated pneumonia (VAP). VAP is estimated to occur in 9-27% of all mechanically-ventilated patients (3), and colonization by hospital-acquired MDR strains carries a mortality rate up to 60% (4).

Given the morbidity and mortality rates associated with drug-resistant infections of P. aeruginosa, the desired output of this project will be a novel chemical matter prototype for further preclinical development, with utility to treat antimicrobial-resistant P. aeruginosa in wounds, traumatic injury, sepsis and/or VAP. The development of an oral, injectable, and/or topical, small molecule therapeutic agent for the treatment of MDR P. aeruginosa infections in service members will provide a valuable therapeutic addition to the current standard-of-care in the Military Health System.

The desired product will have efficacy against clinically-relevant, MDR strains of P. aeruginosa.

• The product will demonstrate effectiveness in in vivo bacterial infection models (e.g., thigh, wound, pneumonia, burn, trauma, sepsis).
• Activity against P. aeruginosa biofilms and/or antibacterial coverage of other priority pathogens such as Acinetobacter baumannii and Klebsiella pneumoniae is desirable, but not required.
• Corresponding in vitro and in vivo pharmacokinetics, pharmacodynamics, and toxicity profiles must be both developmentally and clinically acceptable for oral, injectable, and/or topical administration.
• Prototype compounds may include small molecules, peptidomimetics (both up to MW 1000), or peptides (up to MW 2000).
• We will not accept proposals for antibody, bacteriophage, nor vaccine solutions.

John says: Here is a discussion of Phase I, II, and III in SBIR parlance … they are not the same as P1-3 drug development:
PHASE I: Phase I will center on defining a set of small molecules that are effective at inhibiting in vitro growth of MDR P. aeruginosa strains at low toxicity. The awardee should be able to demonstrate that the selected molecules perform similarly or better in vitro to current standard of care antibiotics in the treatment of MDR P. aeruginosa infections. Required Phase I deliverables will include 1) a practical chemical synthesis of small molecule antibiotic candidate compounds amenable to scale-up; 2) demonstration of in vitro efficacy against military-relevant, MDR strains of Pseudomonas aeruginosa to include minimum inhibitory concentrations (MICs); and 3) assessment of in vitro toxicity in relevant cell lines.

PHASE II: Required Phase II deliverables will include 1) demonstration of in vivo efficacy equivalent or superior to current standard-of-care against military-relevant, MDR strains of P. aeruginosa in validated, clinically-relevant models of wounds, burns, sepsis and/or VAP. In vivo models must include at least one clinically-relevant, higher order animal species model of wounds, pneumonia, burns and/or sepsis for one of the small molecule solutions which successfully completed Phase I of this SBIR. Porcine models of wound infection, sepsis (peritonitis or intravascular infusion of live bacteria), and/or VAP is preferable, but any clinically-relevant models of these indications would be acceptable; 2) demonstration of safe and clinically-acceptable in vivo pharmacokinetics and pharmacodynamics profiles; 3) demonstration of an acceptable resistance profile following standard protocols; 4) demonstration of safety in acute toxicity and safety pharmacology assessments in a rodent species (non-Good Laboratory Practices [GLP]); 5) a plan for declaration as a preclinical candidate in order to proceed toward the assembly of an investigational new drug (IND) submission package in Phase III; 6) development of a safe, scalable, reproducible synthesis of the small molecule antibiotic candidate compound; and 7) development of a safe and clinically-acceptable formulation for the intended route of administration of said small molecule solution. An initial FDA regulatory plan should be submitted during Phase II.

PHASE III DUAL USE APPLICATIONS: The vision or end state for this product is FDA approval as a small molecule therapeutic agent for the treatment of patients with wounds and/or burns infected with MDR P. aeruginosa. Additionally, the product may also or alternatively be approved for the treatment of VAP and/or sepsis. Phase III will require the completion of a preclinical data package, to include preclinical toxicity assessment in a higher order species following Good Laboratory Practices (GLP) and Good manufacturing Practices (GMP), for inclusion in an investigational new drug (IND) submission to the United States Food and Drug Administration (FDA) in order to commence clinical trials. A possible funding source for these studies and early clinical trials is the Joint Warfighter Medical Research Program (JWMRP) through the Joint Program Committee-2 (JPC-2) under the Congressionally Directed Medical Research Program (CDMRP), which offers focused support for early clinical testing of medical solutions. The Biomedical Advanced Research and Development Authority (BARDA) is an additional potential funding source as its focus is mainly on countermeasures for public health threats. A viable commercial technology transfer partner would be required to complete the full FDA-approval process. Potential commercial applications for this product include analogous applications, as mentioned above, in public, medical treatment facilities, as well as potential Gram-negative biothreat indications.

More details on SBIR grants in general
This funding opportunity is aimed at supporting development of a novel therapeutic agent(s) targeting multidrug-resistant Pseudomonas aeruginosa and is through the Small Business Innovation Research (SBIR) program which encourages domestic small businesses (no more than 500 employees and at least 51% owned and controlled by U.S. individuals) to engage in Federal Research/Research and Development (R/R&D) with the potential for commercialization. The SBIR program is structured in three phases (JR says: watch out — these 3 phases are NOT the usual 3 phases of clinical development!):

• Phase I. The objective of Phase I is to establish the technical merit, feasibility, and commercial potential of the proposed R&D efforts and to determine the quality of performance of the small business awardee organization prior to providing further Federal support in Phase II. SBIR/STTR Phase I awards are up to $250,000 for 6 months (SBIR).
• Phase II. The objective of Phase II is to continue the R/R&D efforts initiated in Phase I. Funding is based on the results achieved in Phase I and the scientific and technical merit and commercial potential of the project proposed in Phase II. Typically, only Phase I awardees are eligible for a Phase II award. SBIR Phase II awards are up to 1.1M for 2 years.
• Phase III. The objective of Phase III, where appropriate, is for the small business to pursue commercialization objectives resulting from the Phase I/II R/R&D activities. The SBIR program do not fund Phase III. At some Federal agencies, Phase III may involve follow-on non-SBIR funded R&D or production contracts for products, processes or services intended for use by the U.S. Government or private industry.

To learn more about this funding opportunity and to view the SBIR Topic: “Development of a small molecule, antibacterial drug candidate for the treatment of service members in the Military Health System infected by multidrug-resistant (MDR) Pseudomonas aeruginosa to include in vitro and in vivo efficacy in models of wounds, burns, sepsis and/or ventilator-associated pneumonia (VAP)” please go to the link below, click on “TOPIC INFO” on the top header -> Topics And Topic Q&A (SITIS) -> and scroll to Topic # DHA211-008.

https://www.dodsbirsttr.mil/submissions/login

Deadline for proposal submission is February 18th, 2021