Funded Projects

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Project # Sort descending	Project Title	Research Focus Area	Research Program	Administering IC	Institution(s)	Investigator(s)	Location(s)	Year Awarded
1UG3DA048385-01	Development of novel therapeutics for opioid dependence	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	KENNY, PAUL J.; KAMENECKA, THEODORE M	New York, NY	2018
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: This project proposes to develop novel Gpr151 antagonists to facilitate long-term abstinence in opioid-dependent individuals. Gpr151 is an orphan G-protein coupled receptor that is expressed almost exclusively in the medial habenula and co-localizes with ?-opioid receptors to regulate the inhibitory effects of opioids on habenular neurons. Mice with a null mutation in Gpr151 (Gpr151-/- mice) are resistant to the stimulant and rewarding effects of opioids and self-administer lower quantities of oxycodone. Based on this preliminary work, the study will seek to identify Gpr151 antagonists through a variety of methods and optimize them for potency, selectivity, drug metabolism, pharmacokinetics, and brain penetration properties. The study will evaluate effects of those with the most favorable drug-like physiochemical properties on electrophysiological responses of medial habenula to opioid drugs and assess the in vivo efficacy of these novel antagonists in wild-type and Gpr151-/- mice.
1UG3DA048386-01	Vaccines for fentanyl and its derivatives: A strategy to reduce illicit use and overdose	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	UNIVERSITY OF MINNESOTA	PRAVETONI, MARCO	Minneapolis, MN	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: The United States has seen dramatic increases in fatal overdoses due to heroin, counterfeit prescription drugs, and cocaine adulterated with fentanyl or fentanyl-like analogs. Current medications may not be sufficient to address the opioid overdose epidemic. As a complementary strategy, the researchers plan to develop vaccines against fentanyl and fentanyl-like compounds to reduce their abuse liability and the growing incidence of fatal overdoses. This research team has already developed vaccines against heroin and oxycodone that stimulate the production of antibodies effective in reducing opioid distribution to the brain, opioid-induced behaviors, and opioid-induced respiratory depression and have identified a promising fentanyl vaccine candidate cued up for optimization. Successful completion of an anti-fentanyl vaccine development project could offer a long-lasting, safe, and cost-effective intervention complementary to medication-assisted treatment (MAT) and may reduce overdoses in opioid users as well as protect people in professions (e.g., law enforcement, airport security, postal workers) at risk of accidental exposure to fentanyl and fentanyl analogs.
1UG3DA048387-01A1	Methocinnamox (MCAM): A novel ?-opioid receptor antagonist for opioid use disorders	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	University of Texas Health Science Center San Antonio	Woods, James	San Antonio, TX	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: MCAM is a novel opioid antagonist that can be used for opioid overdose reversal and has advantages over naloxone, including a pseudo-irreversible interaction with the ?-opioid receptor and a longer duration of action. Studies in animal models demonstrate MCAM’s long duration of action against the reinforcing and respiratory-depressant effects of remifentanil and heroin, indicating that could be a better treatment option for opioid use disorder. This project studies the pharmacodynamics of MCAM through animal toxicity and safety studies to establish the necessary and sufficient conditions from which to establish MCAM’s safety and antagonist activity in animals and humans. MCAM may be able to prevent all actions of any ?-receptor opioid drug in humans for a longer period of time than any other antagonist given acutely.
1UG3DA048388-01	Cannabidiol Effects on Craving and Relapse Prevention in Opioid Use Disorder	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	INSYS DEVELOPMENT COMPANY	ELKASHEF, AHMED	Chandler, AZ	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: To tackle the national public health emergency posed by opioid misuse, addiction, and overdose deaths, the development of effective new medications and the FDA drug approval process must be accelerated. In response to this call, INSYS Development Company, Inc. (INSYS) has developed a cannabidiol (CBD) oral solution that shows promise as a novel medication for prevention of relapse that addresses one of the five opportunities specified in the HEAL Initiative to improve treatment options. The first phase of this project involves clinical trials of CBD on cue-induced cravings, modulation of withdrawal, alterations of negative affect states, relapse to opioid use, and treatment retention in patients with OUD receiving buprenorphine treatment in a residential drug treatment facility. The findings from this phase will inform further studies in an outpatient setting. If successful, this project could advance to the development of a new monotherapy for the treatment of OUD.
1UG3DA048502-01A1	Non-Invasive Vagal Nerve Stimulation in Patients with Opioid Use Disorders	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	EMORY UNIVERSITY	Bremner, James Douglas	Atlanta, Georgia	2020
NOFO Title: NOFO Number: PAR18-494
1UG3DA048508-01	Combined tDCS and Cognitive Training for the Treatment of Opioid Addiction	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	University of Minnesota	Lim, Kelvin	Minneapolis, MN	2019
NOFO Title: Device-Based Treatments for Substance Use Disorders (UG3/UH3, Clinical Trial Optional) NOFO Number: PAR-18-494
1UG3DA048734-01	Evaluating Suvorexant for Sleep Disturbance in Opioid Use Disorder	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	JOHNS HOPKINS UNIVERSITY	HUHN, ANDREW S; DUNN, KELLY E.	Baltimore, MD	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: A recent FDA public meeting identified sleep disturbance as a primary contributor to opioid use disorder (OUD) treatment failure. Suvorexant (SUVO; Belsomra®) is a dual orexin receptor antagonist that is FDA-approved for insomnia, with low addiction liability, that improves sleep continuity with a single dose, has an extremely safe and mild side-effect profile, has clear interactions with the opioid system, and has not yet been evaluated in OUD patients. The hypothesis is that SUVO will improve total sleep time during withdrawal, have no addiction liability, and be more efficacious than trazodone, a common OUD-associated insomnia medication. Primary outcomes will be objective sleep measures and addiction liability. Secondary measures will include objective, biological, and self-report measures of opioid withdrawal severity, treatment retention, craving, and stress. Results will advance the treatment of OUD, the understanding of sleep and opioids, and the use of SUVO in clinical populations.
1UG3DA048743-01	Advancing KNX100 for the treatment of opioid withdrawal: preclinical efficacy and toxicology, and a phase 1 clinical program.	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Kinoxis Therapeutics, PTY LTD	MacGregor, Iain	Camberwell, Vic, Australia	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Kinoxis has developed a novel small-molecule lead, KNX100, that reduces the severity of opioid withdrawal symptoms in preclinical animal models of opioid use disorder (OUD). KNX100 was discovered from a phenotypic screen of compounds derived from a fragment-based drug discovery program targeting the brain oxytocin system. KNX100 has a favorable pharmacokinetic and safety profile and has undergone testing for efficacy signals in two rodents and two non-human primate species. The proposed activity is to progress the development of KNX100 to treat opioid withdrawal in OUD. The overall objective of the project is to establish the safety and tolerability of KNX100 to enable human efficacy testing to commence in patients requiring treatment for opioid withdrawal. The long-term objective for this development program is to generate human efficacy data to support KNX100 as a potential treatment for opioid withdrawal symptoms and ultimately enable a New Drug Application to the FDA.
1UG3DA048745-01A1	Nalmefene Long-Acting Injectable (AP007) for the Treatment of Opioid Use Disorder	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Emergent Product Development Gaithersburg Inc.	Barry, John	Gaithersburg, MD	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Although medications are available to treat opioid use disorder (OUD), adherence with treatment programs remains a problem. Nalmefene is an opioid receptor antagonist that was previously approved for treatment of opioid overdose–induced respiratory depression that has a longer duration of action than naloxone. AP007 is a unique formulation of nalmefene-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles that when injected intramuscularly continually releases an effective dose of nalmefene and thus reduces opioid cravings in OUD patients. This group is developing AP007 and will have a lead formulation selected based on in vitro release kinetics data and in vivo pharmacokinetics data in rats. The objectives of the project are to determine safety and efficacy of AP007 in a swine opioid use/withdrawal model, preliminary safety in a first-in-human Phase 1 study, and preliminary efficacy in a Phase 2a multidose study. These results will be used to develop Phase 2 human and Phase 3 clinical studies.
1UG3DA048767-01	Development of a Soluble Epoxide Hydrolase Inhibitor to Spare or Replace Opioid Analgesics	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Eicosis, LLC	Hammock, Bruce	Davis, CA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: EicOsis is developing a first-in-class analgesic with efficacy against neuropathic pain that will reduce or replace the need for opioids and thus potentially prevent opioid use disorder (OUD). The target of the small molecule inhibitor EC5026 is the soluble epoxide hydrolase, a master regulatory enzyme that modulates the activity of endogenous bioactive lipids. The study will reach the next steps in clinical human clinical trials with EC5026 through additional preclinical studies to expand the efficacy into models of chronic pain conditions. Additionally, detailed pharmacokinetic, metabolism, and distribution studies are proposed that will provide the required information to optimize drug formulation and for advanced clinical trials examining efficacy in humans. EicOsis is meeting current development goals, and EC5026 is well positioned to meet the urgent need of reducing opioid use.
1UG3DA048768-01A1	Novel LAAM formulations to treat Opioid Use Disorder	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Virginia Commonwealth University	Xu, Qingguo	Richmond, VA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Levo-alpha-acetylmethadol (LAAM) offers numerous behavioral and clinical advantages for select opioid use disorder (OUD) patients who do not respond to standard treatment. While LAAM was withdrawn from the market despite being approved for OUD treatment, this project seeks to develop novel, patentable, convenient dosage forms of LAAM, including novel LAAM oral dosage formulations and novel buccal film formulations of LAAM. Morphology, mechanical property, drug release kinetics, and stability of the oral dosage and buccal film formulations will be characterized to determine the instant release or steady release of LAAM, respectively. The two lead LAAM formulations with adequate release and stability profiles will be chosen through optimization studies both in vitro and in vivo. A human pharmacokinetic/pharmacodynamic study will then be carried out on the two selected formulations.
1UG3DA048774-01	Injectable naltrexone 2-month depot formulations	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	PURDUE UNIVERSITY	PARK, KINAM	West Lafayette, IN	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Naltrexone (NTX) has been proven as an important, safe, and effective therapy in helping patients overcome opioid addition and in preventing overdose. Unfortunately, the therapeutic potential of NTX has been blunted by poor adherence. To combat this issue, a system must be developed to deliver NTX for longer durations than are currently available with a more patient-friendly format. The goal of this research is to optimize and scale up our laboratory PLGA-based microparticle formulations of NTX delivery (either 2 months or 7–10 days) and bridge it to a Phase 1 clinical trial. This innovation will result in a more patient-friendly format consisting of less painful injections and improved release kinetics. PLGA-based drug delivery systems have been used successfully in a number of small-molecule products and are the most widely utilized and studied biocompatible polymer systems in controlled release. Thus, the regulatory and development hurdles with the FDA will be lower than with other novel excipients or technologies. The significance of this research and product development is that the final outcome of this project will ultimately provide a new, readily viable, essential tool to help patients overcome opioid dependence.
1UG3DA048775-01	Novel nanovaccines against opioid use disorders	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	VIRGINIA POLYTECHNIC INST AND ST UNIV	ZHANG, CHENMING M; PRAVETONI, MARCO	Blacksburg, VA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Opioid use disorders (OUD) are a national public health emergency with more than 115 fatal overdoses occurring each day in the U.S. and an economic burden of more than $78 billion a year. Several medications are available for treating OUD, but their access is limited and efficacy is often sub-optimal. It is thus urgent to develop new, affordable strategies for the effective treatment of OUD. Immunopharmacotherapy has emerged as a promising treatment approach against OUD that relies on the induction of drug-specific antibodies to neutralize circulating drug molecules and reduce or cancel their effects. Several groups have attempted to apply this strategy with mixed results, suggesting that novel immunization platforms must be tested to further improve vaccine efficacy against OUD. This project will fabricate novel nanoparticle-based vaccines against OUD that are likely to boost their immunogenicity and lead to a more robust and effective immune response against the target opioid. The broad impact of this project resides in the rational design of nanoparticle-based vaccines that are safe and effective against opioids. This novel nanoparticle-based immunization strategy can be applied to the development of next-generation vaccines against a range of OUD and other substance use disorders.
1UG3DA049598-01	Novel Therapeutics for Opioid Use Disorder in the Acute Overdose and Maintenance Settings	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Epiodyne, Inc.	Schmidt, William	San Francisco, CA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Opioid use disorder (OUD) and opioid overdose (OD) are major health issues. Breathing can be restored after OD by naloxone, but its short half-life can require multiple administrations to reverse OD, and OD symptoms may return after initial reversal if illicit opioids are still present after the effects of naloxone have worn off. Additionally, while the standard treatment of OUD with buprenorphine and methadone reduces relapse and mortality, access and adoption are limited by dosage forms, metabolic liabilities, and potential for misuse and diversion. This study seeks to develop chemically novel, potent mu-opioid receptor (MOR) antagonists and low- and mid-efficacy partial agonists. Current lead counts can outcompete opioid overdoses in preclinical models with a longer half-life, a key naloxone liability for treating OD. The potent, low-efficacy partial agonists add a low opioid tone, diminishing the aversive effects of pure antagonists. These, and the mid-efficacy partial agonists, are leads to maintenance therapeutics for OUD.
1UG3DA049599-01	Development of a Potent and Highly Selective NaV1.7 Inhibitor for the Treatment of Acute Pain with the Goal of Reducing Opioid Use and Preventing Opioid Use Disorders	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	University of British Columbia	Hunter, John; Phillips, Anthony	Vancouver, BC, Canada	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002
1UG3DA049694-01	Combining Pregabalin with Lofexidine: Can it Increase the Success of Transition to Naltrexone?	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	University of Pennsylvania	Kampman, Kyle	Philadelphia, PA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Extended-release naltrexone (XR-NTX) reduces overdose risk; however, transitioning to XR-NTX requires detoxification, which is a major hurdle. Non-opioid detoxification with an alpha-2 adrenergic receptor agonist, such as lofexidine, may shorten detoxification time, but it does not reduce the subjective effects of withdrawal. Pregabalin potentiates the activity of glutamic acid decarboxylase, inhibits calcium influx and release of excitatory neurotransmitters, raises GABA levels, and is approved for neuropathic pain, for fibromyalgia, and as an adjunctive therapy for adults with partial onset seizures. The study will test whether pregabalin can be combined with lofexidine to better reduce the subjective effects of opioid withdrawal than lofexidine alone and increase the proportion of patients that transition to XR-NTX. Such a dosing combination could lower the detoxification hurdle for patients who are interested in antagonist treatment or who are in settings where it is unavailable or difficult to access.
1UG3DA050271-01	R-methadone-TAAP/MPAR: an abuse deterrent methadone prodrug with overdose protection: Pre-Clinical Development and Phase 1 Clinical Trial	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Ensysce Biosciences, Inc.	Kirkpatrick, Lynn	San Diego, CA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Methadone is useful in the treatment of opioid dependence; however, methadone misuse and methadone-related fatalities have increased. Ensysce has created two complementary, novel technologies that can be applied to methadone. Their Trypsin Activated Abuse Protection (TAAP™) prodrugs are “enzyme-activated” to release clinically effective opioid drugs only when taken orally and exposed to the correct physiologic conditions, such as exposure to trypsin in the small bowel. Their multi-pill abuse resistance (MPAR™) feature involves in situ bioregulation of opioid delivery from the TAAP™ systems, enabling control over oral multi-dose pharmacokinetic profiles. It is envisaged that an R-methadone-TAAP™ prodrug would demonstrate similar reduced addiction liability as with other opioid-TAAP products. The objective of this proposal is to develop an R-methadone-TAAP™/MPAR™ drug through Phase 1 clinical studies and to translate R-methadone-TAAP™/MPAR™ results into humans, to ultimately reduce the misuse and oral overdose potential of methadone.
1UG3DA050303-01	Development of an implantable closed-loop system for delivery of naloxone for the prevention of opioid-related overdose deaths	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Washington University	Rogers, John	St. Louis, MO	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Current opioid overdose treatment requires administration of naloxone by first responders, which requires timely identification of the overdose, the need for a rescue injection, and immediate availability of the medication. The development of a fail-safe treatment that would provide a life-saving dose of naloxone without the need for intervention by another party could significantly reduce mortality. The researchers aim to develop a new medical device comprising an implantable, closed-loop system that senses the presence of an opioid overdose, automatically administers a life-saving bolus injection of naloxone, and simultaneously alerts first responders.
1UG3DA050306-01	1-Year Sustained Release Naltrexone Implant for the prevention of relapse to opioid dependence	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Delpor, Inc.	Martin, Francis	South San Francisco, CA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: There is a need for longer-acting prophylactic pharmacologic options for opioid use disorder (OUD) patients during maintenance therapy. This study tests a titanium implant loaded with a formulation of naltrexone and a naturally occurring carboxylic acid. The device is implanted subcutaneously with local anesthetic during an in-office procedure. The technology is based on a unique formulation that keeps the pH within the reservoir low and promotes passive diffusion of naltrexone. The benefits of the product include complete medication adherence for one year after administration, fewer relapses, smooth profile ensuring complete prophylaxis without sub-therapeutic plasma troughs, full reversibility, and similar efficacy with less drug exposure. This technology has been validated clinically with another drug and tested preclinically with naltrexone. This project will finalize the chemistry manufacturing and controls, produce IND supplies, conduct an IND-enabling safety study, and submit the IND.
1UG3DA050308-01	Clinical Evaluation of C4X3256, a Non-Opioid, Highly-Selective Orexin-1 Receptor Antagonist for the Treatment of Opioid Use Disorder	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Indivior	Heidbreder, Christian	North Chesterfield, VA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: There is a need for pharmacologic treatment options for opioid use disorder (OUD) that do not pose addiction liability and do not require complete withdrawal from opioids prior to treatment. Nonclinical studies support a role for the orexin system in drug seeking; compounds that selectively block signaling at the orexin-1 receptor (OX1R) reduce drug use. C4X3256, a non-opioid, highly selective OX1R antagonist, has a long residence time at the OX1R along with reduced intravenous self-administration and cue-induced reinstatement in animal models of nicotine addiction, suggesting it could be an addiction treatment. Proposed studies will move C4X3256 from preclinical development through Phase I testing in subjects with OUD. The clinical, preclinical, and supporting pharmaceutical development studies proposed will allow C4X3256 to move to Phase II studies.
1UG3DA050310-01	A once-weekly oral methadone for maintenance therapy for opioid use disorder	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Lyndra Therapeutics, Inc.	Bellinger, Andrew; Zale, Steve	Boston, MA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Methadone maintenance therapy has been shown to facilitate recovery and prevent deaths from opioid use disorder (OUD). This proposal is for development of a once-weekly oral methadone for maintenance therapy for OUD. Lyndra has developed an oral gastric residence dosage form that has been demonstrated to provide at least seven days of continuous delivery. A once-weekly oral methadone product could lower a major barrier to treatment for many patients, reduce the stigma and socioeconomic impact of medication-assisted therapy, and increase the capacity of methadone treatment centers by reducing the number of patient visits. This study will perform pharmaceutical development and pharmacological characterization of a once-weekly oral methadone dosage form, leading to the selection of a clinical candidate for a first-in-human trial and submission of an IND. Clinical trials will then be performed to evaluate the safety and pharmacokinetics of the once-weekly oral methadone dosage form in subjects with OUD.
1UG3DA050311-01	Mu Opioid Receptor Modulator Development to Treat Opioid Use Disorder	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Virginia Commonwealth University	Zhang, Yan	Richmond, VA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: There is a need to develop a mu-opioid receptor (MOR) treatment with enhanced therapeutic effects and reduced undesirable effects. Recently, several highly selective and potent MOR modulators have been identified as novel leads for opioid use disorder treatment. They all showed more promising pharmacological profiles compared to other known drugs in this category. The current proposal will focus on further development of these leads for preclinical IND-enabling studies and dynamic drug discovery and development pipeline construction. This project plans to further validate therapeutic profiles of the current leads with self-administration and pharmacokinetic studies and expand the small-molecule library to build a dynamic drug discovery and development pipeline. Preclinical IND-enabling studies on the identified lead(s) will be conducted, and in vivo pharmacokinetics and pharmacodynamics profiles of the new hits will be compared with current leads to define the next generation of lead compound(s).
1UG3DA050316-01	Development of SBI-553, an allosteric modulator of NTR1, for the treatment of substance use disorders	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Sanford Burnham Prebys Medical Discovery Institute	Pinkerton, Anthony	La Jolla, CA	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: Addiction to opioids is related to the physiology of the brain’s dopamine-based reward system. As a modulator of dopaminergic systems, the neurotensin 1 receptor (NTR1) should be a molecular target for treating addictive disorders; however, few non-peptide brain penetrant neurotensin modulators have been identified, and orthosteric NTR1 ligands display side effects that have limited their clinical development. This group discovered a series of brain-penetrant NTR1 modulators, including a lead compound SBI-553, with a unique mechanism of action at NTR1. SBI-553 is an orally available, brain penetrant ?-arrestin biased allosteric modulator of NTR1, which shows efficacy in a range of addiction models and circumvents the clinically limiting side effects. While potentially high risk, the activity of SBI-553 has been validated in vitro and in vivo, and the initial safety profiling indicates no issues that would preclude further development. This study will develop SBI-553 as a treatment for opioid use disorder.
1UG3DA050317-01	Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	The University of Texas Medical Branch at Galveston	Cunningham, Kathryn	Galveston, TX	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: To address the need for novel therapeutics for opioid use disorder (OUD), this research group identified ghrelin as an endogenous regulator of the mesocorticostriatal circuit, which contributes to the enhanced motivational attributes of addictive drugs and drug-associated cues. Ghrelin binds to the growth hormone secretagogue receptor 1? (GHS1?R) to transduce several physiological and behavioral processes, including the reward-related effects of opioid agonists. Systemic administration of a GHS1?R antagonist/inverse agonist dose-dependently attenuated self-administration of the addictive opioid analgesic oxycodone as well as oxycodone-seeking. This project proposes to employ a suite of validated rodent OUD models to define the preclinical profile for PF5190457, a selective GHS1?R antagonist/inverse agonist. PF5190457’s abuse liability, ability to suppress withdrawal and relapse-like behaviors, drug metabolism and pharmacokinetics, and brain penetrability in rats will be assessed. Phase 1 clinical studies in non–treatment seeking OUD participants will follow to assess the safety and tolerability of PF5190457.
1UG3DA050322-01	Preclinical and clinical evaluation of the NMDA modulator NYX-783 for OUD	Novel Therapeutic Options for Opioid Use Disorder and Overdose	Focusing Medication Development to Prevent and Treat Opioid Use Disorder and Overdose	NIDA	Yale University	DiLeone, Ralph	New Haven, CT	2019
NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional) NOFO Number: RFA-DA-19-002 Summary: This study will conduct preclinical and clinical assessments of the NMDA modulator NYX-783 for treatment of opioid drug-seeking and relapse to opioid use disorder (OUD). NYX-783, a novel small molecule being developed by Aptinyx, has shown evidence of safety/tolerability in Phase 1 studies and is currently in Phase 2 trials for post-traumatic stress disorder. This project will test the safety, tolerability, and pharmacokinetics (PK) of NYX-718 in morphine-maintained patients in residential settings and then conduct a combined inpatient (safety/tolerability/PK) / outpatient (preliminary efficacy) study testing NYX-783’s effects on opioid use and relapse, stress/cue reactivity, craving, and quality of life in OUD subjects maintained on standard extended release naltrexone over a 10-week period. Successful completion of these studies will set the stage for larger scale Phase 2/3 studies of efficacy in OUD that will ultimately be required for FDA approval of NYX-783 for the treatment of drug-seeking and relapse in OUD.