This FOA invites applications for pre-clinical research to develop novel, mechanism-based pharmacotherapies to selectively reverse respiratory depression induced by opioids or opioid-sedative drug combinations (e.g., opioids plus alcohol, benzodiazepines, gabapentin). Two phases of pre-clinical drug development will be supported. Phase I (UG3): identification and validation of candidate lead ligands for established druggable targets in relevant animal models or human cells/tissues; or characterization of newly-discovered targets with plans for development of druggable ligands; Phase II (UH3): development of hit to lead therapeutic candidate pipelines based on Phase I validation studies, with clearly prioritized assays and quantified go/no go milestones. Anticipated pitfalls and alternative strategies in case of a no go event are expected to be clearly outlined. Applicants who already have lead candidates may propose “critical path” and de-risking studies for the lead and backup molecules during UG3 and Investigational New Drug (IND) enabling studies during UH3. It is expected that applications will include a research plan for both Phases I and II based on systematic and quantifiable metrics delineating key milestones and go/no go decision points pertinent to moving the project closer to FDA approval and / or de-risking potential liabilities. Phase I research will be based on candidate ligands or targets that have been identified and require additional validation and optimization (i.e. not discovery). Phase II extends up to addressing preclinical functional outcomes, toxicology, and pharmacokinetics needed to support an Investigational New Drug (IND) application, and should include a product development plan appropriate to supporting an IND filing. This FOA targets that portion of therapeutic development between ligand or target validation and IND filing. Specific Phase I and II milestones will be formalized pre- and post-award and will serve as a schedule of performance expectations to maximize the output from each phase of study. Milestone performance will be a major, but not the only consideration factor in determining which applications will be selected to transition from Phase I to Phase II. Multi-disciplinary, multiple PI teams combining expertise in respiratory neurobiology, opioid pharmacology and pre-clinical drug development are strongly encouraged. Collaborations between academia, pharma and small businesses may be considered. This FOA is intended for pharmacotherapeutic development. Projects proposing device and model development or validation, elucidation of biological mechanisms, population-based epidemiology, or human subjects research will not be considered responsive to this FOA and will not be reviewed (examples of non-responsive topics are listed below). Reversal of respiratory depression, without inducing generalized opioid withdrawal, or interfering with analgesic effects, addresses a critical medical need for better strategies to couteract the life-threatening respiratory effects of opioids and opioid-sedative combination overdoses.
The NIH HEAL Initiative:This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://heal.nih.gov/.
Novel pharmacotherapies that selectively counteract opioid overdose-induced respiratory depression (OIRD) are urgently needed to address a dramatic increase in opioid related US deaths in recent years. Existing opioid receptor antagonists trigger acute withdrawal, interfere with analgesic properties, and may lead to renarcotization. Opioid antagonists are also insufficient to fully reverse respiratory depression produced by high-affinity, long-acting synthetic opioids, requiring ventilation to be protected for extended periods and until the synthetic opioid is cleared. Opioids are frequently combined with other substances that suppress respiration, including alcohol, benzodiazepines and gabapentin. Pharmacotherapies for OIRD are needed that counteract the effects of opioids, as well as opioid-sedative combinations. Respiratory depression is an unpredictable risk for millions of individuals using prescribed and/or illicit opioids and who are susceptible to overdose from recreational or medical use. Opioid-induced respiratory depression poses significant challenges for the management of patients with both chronic pain and compromised breathing conditions such as COPD, asthma, and sleep apnea. The development of pharmacotherapies, particularly alternatives to opioid receptor antagonists, to counteract opioid overdose and safeguard respiration are urgently needed to prevent opioid overdose deaths, and to enhance opioid-based strategies for pain management. Pharmacotherapies to stimulate respiration, without inducing generalized opioid withdrawal, or interfering with analgesic properties address the ultimate goal of developing better medical countermeasures for management of deleterious consequences of synthetic illicit, as well as prescription opioids.
Investigators interested in submitting applications to this FOA are strongly encouraged to contact NIH scientific staff (see Section VI, Agency Contacts) to discuss proposed aims and FOA requirements well in advance of the application receipt date.
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