Funded Projects

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.

NOFO Title: Device-Based Treatments for Substance Use Disorders (UG3/UH3, Clinical Trial Optional)
NOFO Number: PAR-18-494

NOFO Title: NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)
NOFO Number: PA-18-344
Summary:

Chronic pain is a significant public health problem associated with tremendous personal and economic burden. First-line treatment consists of opioid medications, but despite only moderate efficacy and unpleasant side effects, rates of opioid prescriptions have quadrupled over the past 15 years, and this has contributed to high rates of misuse, overdose, and mortality. Clearly, alternative, or non-opioid strategies for treating pain are needed. In this context, “opioid-sparing” medications refer to compounds that can be combined with and enhance the analgesic effects of lower-dose opioids without increasing the rewarding properties of either drug. There is preclinical evidence suggesting that cannabidiol (CBD) may have the potential to function as “opioid-sparing” medications, but its ability to alter opioid-mediated analgesia in humans has yet to be determined. This proposal will fill this gap by conducting a double-blind, placebo-controlled, within-subject randomized crossover study of the effects of CBD and morphine co-administration on pain sensitivity and subjective reinforcement on 28 healthy males and females. This is the first known study to investigate the ability of CBD to alter morphine’s analgesic effects in humans. If successful, the model will have a lasting impact on our ability to develop and test medications that reduce our reliance on chronic use of opioid medications for pain relief.

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:

Tens of thousands of people die each year from opioid overdose. Many of these people began taking opioids for pain. A critical treatment goal is to reduce the development of opioid dependence either by enhancing opioid analgesia so lower doses can be used or by blocking withdrawal symptoms. Current pharmacological treatments in these two categories, although effective, present serious limitations. The recent finding that reducing the signaling through mu-delta opioid heterodimers appears to enhance opioid antinociception and reduce dependence suggests that a blocker of mixed mu-delta receptors (MDOR antagonist) could be effective in reducing dependence by limiting opioid tolerance and preventing opioid withdrawal. This research group has developed a compound with that characteristic, called D24M, which preliminary studies have shown could reduce opioid dependence by enhancing opioid antinociception, reducing opioid tolerance, or directly inhibiting opioid withdrawal. They propose to extend this research by investigating whether it can reduce chronic pain in an animal model that mimics the clinical situation of pain patients who transition to dependence. If these studies are successful, they could lead to the development of an optimized drug ready for Investigational New Drug (IND) application and enable translational and clinical testing.

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).

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: PAR-20-092
Summary:

Fentanyl and its analogs are synthetic opioids that are 100 to 10,000 times more potent than morphine. Overdose from these opioids is extremely dangerous due to their ultra-potency and longer half-life than naloxone, the front-line treatment for fentanyl overdose. This research study will develop novel mu opioid receptor antagonists that bind to the same receptor as the opioid drugs and specifically counteract fentanyl and its analogs, thereby reversing the drugs’ acute toxicity more effectively and with fewer side effects than current treatments. The researchers will characterize novel fentanyl derivatives, identify promising compounds, and pursue preclinical development of these compounds as novel reversal agents against the acute toxicity of fentanyl. The goal is to file an Investigational New Drug application with the U.S. Food and Drug Administration.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: PAR-20-092
Summary:

The nation’s opioid epidemic remains a public health emergency, marked by high rates of opioid use and misuse among adults and a correlated rising incidence of neonatal opioid withdrawal syndrome (NOWS) in infants exposed to opioids before they are born. There are currently no pharmacotherapies approved by the Food and Drug Administration (FDA) for the treatment of NOWS. This research will complete manufacturing and clinical trial activities to evaluate and support FDA approval of a pediatric-appropriate formulation of lofexidine, a non-opioid medication approved for mitigation of opioid withdrawal symptoms in adults, as a first line-therapy in NOWS patients through two clinical trials to (1) identify an optimal dosing regimen of lofexidine for treatment of NOWS, and (2) evaluate the risks and benefits of its use in improving withdrawal symptoms, limiting infant exposure to other off-label narcotic medications and shortening the infant’s overall stay in the hospital.

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:

Medication-based treatment for opioid use disorder OUD aids in reducing mortality, opioid withdrawal, intake and opioid-seeking behaviors, however there is a clear need to increase the armamentarium of therapeutics for OUD. The ?non-classical? NOcicePtin receptor (NOPr) binds the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) and is a promising target based on the evidence for its function in the regulation of the rewarding and motivational effects of opioids and alcohol. This study plans to assess the ability of the novel and selective NOPr antagonist BTRX-246040 to block oxycodone intake without abuse liability, and to suppress oxycodone withdrawal and relapse-like behaviors in rats. The study will also determine Drug Metabolism and Pharmacokinetics interactions (DMPK) between oxycodone and BTRX-246040 and brain penetrability in male and female rats. If successful, these preclinical studies will be followed by a Phase 1 clinical trial in non-treatment seeking OUD participants. These investigations will advance the prospects of validating a novel medication for OUD.

NOFO Title: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
NOFO Number: PA-18-484
Summary:

Opioids remain the gold standard for treating moderate to severe pain, but their use is limited by numerous adverse effects, including tolerance, dependence, abuse, and overdose. Adverse effects could be avoided by combining an opioid with another drug, such that smaller doses of the opioid (in combination with another drug) produce the desired therapeutic effect. Direct-acting serotonin type 2 (5-HT2) receptor agonists interact in a synergistic manner with the opioid morphine to produce antinociceptive effects, suggesting a 5-HT2 receptor agonist could be combined with small amounts of an opioid to treat pain, thereby lowering the risk associated with larger doses. Unfortunately, very little is known about interactions between 5-HT2 receptor agonists and other opioids. The proposed studies will evaluate the therapeutic potential of mixtures of opioids and 5-HT2 receptor agonists using highly translatable and well-established procedures to characterize the antinociceptive, respiratory-depressant (overdose), positive-reinforcing (leading to misuse), and discriminative-stimulus (subjective) effects of drug mixtures as well as the impact of chronic treatment on the development of tolerance to and physical dependence on opioids. If successful, these studies will provide proof-of-concept for this innovative approach to pain treatment and evaluate the utility of targeting 5-HT receptors for analgesic drug development.

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.

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.

NOFO Title: HEAL Initiative: Novel Targets for Opioid Use Disorders and Opioid Overdose (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-DA-22-031
Summary:

Novel treatments for opioid use disorder are urgently needed. Previous research has shown that angiotensin-converting enzyme (ACE) can control levels and activity of natural, “endogenous,” opioids in a way that might reduce the rewarding effects of opioids like fentanyl. ACE inhibitors have been used to treat hypertension for decades, with no evidence of addiction or dependence. This research will evaluate ACE effects on endogenous opioids toward generating new, domain-specific ACE inhibitors with optimized properties for treating opioid use disorder. The research will also test the behavioral impact of these compounds in preclinical models of opioid use disorder. 

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: PAR-20-092
Summary:

This project aims to develop a new way to stimulate the delta opioid receptor to treat withdrawal and abstinence from chronic opioid use. Withdrawal can cause pain, depression, and anxiety, which contribute to relapse. The research will test promising drug candidates in animal models with the intention of bringing at least one effective and safe compound to the final stage of drug development before human clinical trials can begin.