SBIR-STTR Award

In October 2017, the U.S. Government declared the current opioid epidemic the worst drug crisis in American history. Synthetically derived opioids such as fentanyl and fentanyl-derivatives have been at the forefront of this public health emergency, exhibiting the highest year-to-year contribution to overdose deaths. While the mu opioid receptor (MOR) antagonist naloxone has proven invaluable as an opioid overdose antidote, naloxone suffers from a very short duration of action (half-life ~ 1hr.) and has been found to be less effective against newer, long acting opioids including fentanyl (half-life ~7-10 hrs.). This leads to a highly lethal and increasingly prevalent phenomenon known as “renarcotization”, wherein an overdose patient revived with naloxone can re-enter an overdose state from residual fentanyl in the body. To counter renarcotization, naloxone must be given repeatedly and at significantly higher doses than fentanyl. This approach may be achievable in a hospital; however, renarcotization is often not recognized outside a medical setting and can lead to death. Thus, there is a critical need to develop a long acting MOR antagonist formulation that can address renarcotization by providing the multi-hour protection. The goal of this Phase I STTR project is to reformulate naloxone using FDA approved microencapsulation technology into a long acting injectable (LAI) that can provide 12-24 hrs. of sustained antagonist activity in vivo. Other attempts to address this issue by chemically modifying naloxone are likely to suffer significant regulatory and technical risk. Consegna’s innovation is to employ its proprietary Computational Drug Delivery™ software, called ADSR™, to perform in silico formulation optimization as well as to predict its in vitro dissolution and in vivo pharmacokinetic behavior. Approval can be sought thru the 505(b)(2) accelerated regulatory pathway to gain near-term entry into the market since the naloxone molecule is not modified and efficacy is not at risk. This new long acting naloxone formulation, named CP216, will utilize an innovative design to address both primary and secondary overdose (renarcotization) situations thru a combination of free form naloxone for immediate effect and microencapsulated naloxone for sustained protection. Our hypothesis is that sustained release of naloxone from microparticles, coupled with an immediate release of free naloxone, can provide the therapeutics levels needed to reverse the overdose and prevent renarcotization. To test this hypothesis, 1) design an appropriate microparticle formulation and assess the formulation’s payload and release behavior in vitro, 2) evaluate the pharmacokinetics in an animal model, and 3) complete a Quality-by-Design assessment for a Chemistry, Manufacturing, and Controls package. Consegna believes this project has a significant potential to lead to the first safe and effective product to address renarcotization, and will lead to a positive impact on public health.

Public Health Relevance Statement:
PROJECT NARRATIVE There were more than 72,000 drug overdose deaths in 2017, most involving opioids. The goal of this STTR Phase I project is to create a better antidote for opioid overdose and address a critical unmet medical need. While naloxone is an effective opioid overdose antidote, it does not last long enough to be effective for synthetic opioids such as fentanyl that have a long half-life. We plan to create a formulation that continuously releases naloxone at therapeutic levels long enough to prevent renarcotization.

Project Terms:
Acute; Address; Adipose tissue; American; analog; animal facility; Animal Model; Antidotes; Area; Behavior; behavior in vitro; Blood Circulation; Canis familiaris; Cessation of life; Chemicals; Chemistry; Clinical; Clinical Trials; combat; commercialization; Computer Simulation; Computer software; Coupled; Data; design; Dose; Drug Delivery Systems; Drug Kinetics; Emergency treatment; Ensure; Evaluation; Exhibits; FDA approved; Fentanyl; first responder; Formulation; Future; Generations; Goals; Government; Half-Life; Health; Heroin; Hospitals; Hour; Human; hydrophilicity; Hydrophobicity; In Vitro; in vivo; Inhalation; Injectable; innovation; Institutes; Intellectual Property; Intravenous; Knowledge; Law Enforcement; Lead; Legal patent; Life; Manufacturer Name; Maps; Medical; medical specialties; Metabolic; Microencapsulations; Modeling; Monitor; Morphology; mu opioid receptors; Naloxone; Names; nanoparticle; nanopolymer; Neurosciences; novel; off-patent; Opioid; Opioid agonist; Opioid Antagonist; opioid epidemic; opioid mortality; opioid overdose; Outcome; Overdose; overdose death; particle; Patient Noncompliance; Patients; Performance; Pharmaceutical Preparations; Phase; Plasma; Positioning Attribute; pre-clinical; preclinical trial; prevent; Prevention; Production; Property; Public Health; public health emergency; Recording of previous events; Regulatory Pathway; Reproducibility; Research; Research Institute; Residual state; Risk; Route; Sales; Sampling; Schedule; Secure; simulation; Small Business Technology Transfer Research; synthetic opioid; Technology; Testing; Therapeutic; Time; Tissues; uptake; Work

More than 80,000 Americans died in 2021 from fentanyl and other high-potency opioids. The emergence ofillicit, highly potent synthetic opioids such as fentanyl is a key contributing factor to the recent spike in opioid-related mortality, increasing ten-fold since 2016. While the mu opioid receptor (MOR) antagonist naloxone hasproven invaluable as an opioid overdose antidote, naloxone suffers from a very short duration of action (half-life ~1 hour) and is less effective against newer, longer-acting opioids, including fentanyl (half-life ~7-10 hours).This leads to a highly lethal and increasingly prevalent phenomenon known as "renarcotization," whereby anoverdose patient revived with naloxone re-enters an overdose state from residual fentanyl in the body.To counter renarcotization, naloxone must be given repeatedly and at significantly higher doses. While usuallyachievable in a hospital, renarcotization is often not recognized or monitored for outside of a medical settingand may lead to unexpected death. A critical, unmet need exists to develop a long-acting MOR antagonistformulation that prevents renarcotization by providing 12-24 hours of protection to allow opioid levels to dropbelow dangerous levels.The objective of this project is to advance development of CP216, a novel, long-acting naloxone formulation thatutilizes an innovative design to address both primary and secondary overdose through a combination of freeform naloxone for immediate effect and microencapsulated naloxone for sustained protection. This newformulation will be especially useful in rural areas, where access to emergency medical services is often delayed,or for Warfighters poisoned by weaponized opioids that need sustained protection while transported todefinitive medical care.Other attempts to address renarcotization using high or frequent doses of naloxone or nalmefene have limitedprotection for high-potency opioids and can induce precipitated opioid withdrawal (POW) in those with opioiddependence. POW is a severe and potentially life-threatening condition and for this reason causes someoverdose victims to refuse continued naloxone treatment after rescue. Still other efforts to chemically modifynaloxone are subject to significant regulatory and technical risk. Consegna's drug (CP216) is approvable throughthe accelerated 505(b)(2) regulatory pathway and is, according to recent studies, unlikely to induce POW andwould therefore gain more acceptance among overdose patients.Consegna believes this project will have a positive impact on public health by leading to the first safe andeffective product to completely address renarcotization.

Public Health Relevance Statement:
PROJECT NARRATIVE While naloxone is an effective opioid overdose antidote, in many cases its short half-life is ineffective against synthetic opioids with longer half-lives, such as fentanyl, leading to a phenomenon called renarcotization (whereby an overdose patient revived with naloxone re-enters an overdose state from residual opioid in the body after the naloxone wears off). The objective of this project is to create a better pharmacokinetic profile for naloxone delivery that continuously maintains naloxone at therapeutic levels long enough to prevent renarcotization. This novel product will directly lead to saving lives of opioid overdose victims.

Project Terms:
<μ opioid receptors><μ-OR><μOR>