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:

The current studies are designed to examine a novel approach to treating OUD, namely use of a vaccine (OXY-KLH) targeted against oxycodone, one of the most commonly misused prescription opioids, and a vaccine (M-KLH) targeted against heroin/morphine. The researchers will evaluate the safety, immunogenicity, and preliminary efficacy of OXY-KLH and M-KLH. Overall, the proposed studies will provide a great deal of information about the safety and potential efficacy of the vaccines in reducing the addiction liability of opioids, which will be administered in a controlled laboratory setting. If the outcomes of the proposed studies with OXY-KLH and M-KLH are favorable, development of the bivalent vaccine (OXY-KLH plus M-KLH) that will target oxycodone and heroin will proceed. The long-term goal of this research is to develop a multivalent vaccine directed against oxycodone, heroin, and other relevant opioids.

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 expansion of opioid prescribing in recent years to better treat pain has markedly increased their usage and availability and fueled an epidemic of abuse. Up to 80 percent of addicts reported initiating their habit through prescriptions drugs. Decreasing opioid prescriptions would lower opioid exposure, with fewer people receiving the drugs and less drug available for diversion. Study investigators have identified a novel target in the brain, distinct from any of the traditional opioid receptors capable of mediating potent analgesia without the reward behavior and side effects seen with traditional opioids. They targeted this site with a series of arylepoxamides and have identified a clinical candidate (MP1000) and backup compound. MP1000 is a potent analgesic in a range of thermal, inflammatory, and neuropathic analgesic assays. It fails to show reward behavior and does not produce respiratory depression at doses 5-fold greater than its analgesic ED50. Chronic administration does not produce physical dependence or withdrawal when challenged with an antagonist. It shows no cross tolerance to morphine and can be co-administered to subjects already on opioids for pain to lower their opioid usage (i.e., opioid sparing), facilitating the eventual discontinuation of the opioid. If successful, this project could lead to the development of a viable alternative to current opioid-based analgesics with reduced side effects (such as reward and respiratory depression) compared to opioids.

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.

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.

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: Prescription Drug Abuse (R01 Clinical Trial Optional)
NOFO Number: PA-18-058
Summary:

The ongoing opioid crisis has led to renewed concerns about the clinical prescription of addictive opioid analgesics. However, there are currently no suitable alternatives for treating severe or malignant pain. Studies of opioid signaling mechanisms in mice deficient in ?-arrestin have suggested that biased agonists displaying preferential activation of G-protein signaling over ?-arrestin signaling could offer a promising avenue for the development of opioid analgesics with a reduced adverse effects profile. However, there is no concluding evidence showing that such biased signaling can indeed be associated with reduced opioid side effects and, consequently, an improved safety profile. This research will address the need for preclinical data to rigorously evaluate this hypothesis with a program of in vivo studies to compare the effects of “balanced” opioids (morphine, oxycodone, and fentanyl) with that of the “biased” agonists PZM21 and two novel ligands provided by colleagues at the NIDA IRP in nonhuman primates. The results of these studies will provide critical information regarding the dependence liability of “biased” agonists that, in clinical practice, might be given on a repeated, or chronic, basis, potentially adding a powerful new tool for the safer management of severe or malignant pain.

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.

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.

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

Deaths from opioid overdose continue to rise; from 2015 to 2016, there was a 28 percent increase in the number of fatal overdoses. Currently available pharmacotherapies include MOR agonists (e.g., buprenorphine) and antagonists (e.g., naloxone), all of which suffer from specific and clear limitations. To address the main deficits in these treatments, the researchers will develop and optimize medications with longer duration of action that prevent and reverse the effects of opioids in a manner that is not surmounted by increasing doses of agonist. Their pilot studies in monkeys show that the pseudo irreversible MOR selective antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for remifentanil in a food/drug choice procedure, and reverses—as well as protects against—respiratory depression by heroin, with a single injection being effective for a week or longer. Bringing a medication like this to marketable fruition could significantly improve the treatment of OUD and save lives by providing insurmountable extended protection after rescue from overdose, including from ultra-potent fentanyl analogs.

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: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

Chronic pain affects an estimated 100 million Americans, or one third of the U.S. population, and it is the primary reason Americans are on disability. Although many treatments are available for pain, the most potent class of analgesics relies on opioid analogs, whose limitations and well-known adverse effects have contributed to the present opioid crisis. New pharmacotherapies for pain management are sorely needed. MTX1604, a synthetic endomorphin analog, has emerged as a highly effective analgesic that exhibits reduced reward potential and respiratory suppression, and a robust duration of efficacy in a variety of validated animal models of acute, neuropathic, inflammatory, post-operative, and visceral pain. This project will generate additional preclinical characterization data of MTX1604 and advance clinical development toward FDA approval. If successful, this medication development project could offer patients a novel non-addictive, potent, and safe analgesic and thus have a direct impact on the opioid crisis.

NOFO Title: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
NOFO Number: PA-18-591
Summary:

Neurostimulation techniques, such as transcranial direct current stimulation (tDCS), have been used as interventions for substance use disorders. This is a supplement to the currently NIDA-funded UG3 DA047793, “tDCS to Decrease Opioid Relapse,” which will measure behavioral and brain responses following tDCS stimulation delivered during tasks that use a particular brain network involved in cognitive control, and utilizing FMRI to assess the effects. This supplement allows the researchers to add an EEG measurement to the study, to get a complete picture of how tDCS might affect the function of key brain networks in ways that could be helpful for SUDs.