Funded Projects

Opioid use disorder (OUD) is a significant public health problem in the United States. Particularly troubling is the rapid evolution of an opioid epidemic within the past decade, characterized by a surge in unintentional overdose deaths involving synthetic opioids, such as fentanyl. The current standard of care for opioid overdose is reversal with opioid antagonist naloxone. Naloxone is effective at reversing overdose from prescription opioids and heroin, but less effective when combating fentanyl, due to fentanyl?s high potency. Therapeutic monoclonal antibodies (mAbs) against fentanyl could overcome this problem by specifically preventing the drug from entering the central nervous system, averting overdose and attenuating opioid-induced respiratory depression. This study will develop and design of laboratory protocols needed to establish a Good Manufacturing Practice (GMP) process, quality assurance protocol, and stability profile for a new human mAb against fentanyl. Subsequent production of current GMP material will enable Good Laboratory Practice (GLP) toxicology studies in rats and dogs and eventually a Phase I/IIa clinical trial. This material will also be used in final opioid-induced respiratory depression studies in mice and non-human primates to confirm therapeutic efficacy of final drug product. If successful, these activities will enable filing for an investigational new drug application for this mAb candidate with the FDA.

Currently no medications are approved by the U.S. Food and Drug Administration to treat cocaine use disorder, which compromises cognitive function associated with achieving goals such as working memory, the ability to update information, and mental flexibility. This project will test whether  stimulating dopamine activity in the brain with the drug rotigotine (approved to treat Parkinson’s disease) is effective for treating cocaine use disorder. Past research has also shown that rotigotine can improve nerve cell and cognitive function in Alzheimer’s disease. This project will conduct a clinical trial to test whether treatment with rotigotine combined with cognitive behavioral therapy can reduce cocaine use in people with cocaine use disorder.

Currently there are no effective treatments approved by the U.S. Food and Drug Administration for cocaine use disorder. This project will explore the use of a novel class of small molecules that selectively block the molecule phosphodiesterase 7 (PDE7). Past research suggests that the PDE7 class of compounds helps restore normal functions of the dopamine reward system altered by chronic exposure to cocaine. This research will use both preclinical and clinical research studies to develop and test a PDE7 blocker, toward development of the first oral treatment for cocaine use disorder. 

Substance use disorder (SUD) is a serious public health and socioeconomic burden. In this project, researchers will develop novel drug compounds that dually target orexin receptors and kappa opioid receptors, which have both been implicated in SUD. The compounds will then be tested for effectiveness in preclinical models of SUD, including models of cocaine, methamphetamine, and fentanyl use. This research has the potential to provide highly impactful and innovative treatment options for SUD via simultaneous modulation of multiple signaling pathways.

Several abuse-deterrent opioid products (primarily formulations) are currently marketed or in clinical development, but they fall short of being resistant to abuse. Rather than abuse-deterrent formulations, this project, in partnership with Ensyce Biosciences, has created two complementary, novel technologies that control the release of known opioids. One technology delivers prodrugs — drugs that are not active until they have been exposed to the right conditions within the body, at which point they are gradually converted into active drugs, making them difficult to tamper with and reducing the potential for misuse. Another technology makes it so that taking increasing numbers of pills inhibits the process of converting prodrug into active drug, reducing the potential for overdose. This project aims to refine the development of these two technologies and work to combine them, and to translate promising animal results into human use.

The adverse effects of morphine and other mu-opioid receptor (MOR) agonists are linked to the ?-arrestin pathway, while analgesia is tied to the G-protein pathway. Pathway specific or “biased” drug development can target G-protein specific agonists that avoid the negative consequences of ?-arrestin signaling activation and produce analgesia. Highly “biased” MOR agonists have promise as effective analgesics but devoid of opioid-induced adverse effects. Preclinical studies compared two compounds, MEB-1166 and MEB-1170, against Oliceridine and morphine. Both compounds displayed no respiratory depression, even at high doses, while morphine and Oliceridine significantly reduced respiratory function. In contrast to morphine, neither MEB-1166 nor MEB-1170 produced conditioned place preference, suggesting an absence of abuse liability. This study will characterize the pharmaceutical and pharmacological profiles and perform liability studies for these compounds.

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.

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.

New medication treatment approaches are needed to help address the severe epidemic of opioid use disorder (OUD) and opioid overdose deaths in the U.S. Currently available medications, such as methadone, buprenorphine, and extended release injection naltrexone (XR-NTX; trade name: Vivitrol), are highly efficacious, but their effectiveness in practice is limited by poor adherence, with many patients stopping treatment prematurely and relapsing. The goal of this proposal is to develop an innovative long-acting subcutaneous implanted formulation of naltrexone, the O’Neil Long-Acting Naltrexone Implant (OLANI), toward FDA approval. Expected to produce naltrexone blood levels sufficient to block the effects of opioids for 6 months after implant, OLANI circumvents the need for adherence to monthly injections with XR-NTX and could represent an important new addition to the medical armamentarium for treatment of OUD.

The ongoing epidemic of opioid use disorder (OUD), overdose, and death is unprecedented. Available pharmacologic therapies for OUD have failed to stem the tide, plagued by poor adherence and retention, the principal factors associated with relapse and treatment failure. More than 80 percent of individuals with OUD are untreated. More treatment options are needed. This proposal seeks to develop a better antagonist-based OUD pharmacotherapy for populations highly motivated to achieve abstinence, such as military personnel, criminal justice clients, and the currently employed. A series of novel and proprietary small molecules will be designed and synthesized to address the adherence problem by inducing effective opioid antagonism with a single injection lasting at least 2 months, and up to 4 months or more. The goal of this project is to advance to Phase 3 clinical trials toward FDA approval of our lead compound. If successful, this project could lead to a novel therapeutic with superior adherence and retention, resulting in a significant public health impact by reducing rates of relapse, overdose, and death.

In order to address the opioid crisis, this group has developed a candidate heroin/opioid vaccine that induces antibodies that bind heroin/opioid upon injection and subsequently prevent the drug from crossing the blood-brain barrier and interacting with the brain's µ-opioid receptor. They completed pre-clinical testing of the vaccine candidate in mice and rats and demonstrated that the animals were protected from subcutaneous and intravenous heroin challenge. Ongoing durability studies have demonstrated that antibody titer and protective efficacy were maintained 6 months after the last vaccination. This project proposes to advance the development of the vaccine candidate by conducting a Phase I/IIa human clinical trial, by performing vaccine synthesis, nonclinical studies, and then a clinical trial. The supplemental award will allow for testing the efficacy of fentanyl haptens and of the combination heroin–fentanyl vaccine.

Although effective, current pharmacotherapies for opioid use disorder (OUD) present serious limitations. For example, methadone, a mu opioid receptor (MOP) full agonist, has significant abuse liability and causes withdrawal after chronic use, while buprenorphine (Bup), an MOP partial agonist and kappa opioid receptor (KOP) antagonist, produces limited respiratory depression and is less effective than methadone in reducing drug use, craving, and relapse. To address the limitation of currently available MATs, this project uses a phased plan that will fast-track the IND development of a next-generation medication for OUD based on small-molecule compounds targeting the nociception opioid receptor (NOP)—with no misuse or dependence liability—that have shown promising efficacy in reducing oxycodone intake in rhesus monkeys trained to self-administer, with efficacies similar to that of buprenorphine. The project’s ultimate goal is to file an IND application for an NOP agonist as a promising new approach to treat illicit and prescription OUD that may offer an alternative to buprenorphine.

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.