Funded Projects

Opioids account for nearly 70 percent of overdose deaths in the United States, with fentanyl and heroin use the most common causes. The goal of this project is to create a vaccine to elicit serum antibodies that bind and sequester the drug in the blood, preventing it from crossing the blood-brain barrier where it acts on the central nervous system. Current opioid vaccine strategies require multiple boosts and months to reach peak titers, the level of antibodies in a blood sample, and have yet to show protection against lethal overdose. In this project, researchers will use a bacteriophage virus-like particle vaccine platform to engineer and test the effectiveness of a combined vaccine to elicit high titer antibodies quickly to protect against lethal overdose from fentanyl or heroin.

Opioid use and addiction affects more than 2 million Americans and contribute to a large proportion of all drug overdose deaths. Current treatments for opioid use disorder (e.g., methadone and buprenorphine) are not always effective, may be misused, and can have side effects that discourage treatment continuation. Therefore, Cerevel Therapeutics is evaluating a novel compound, CVL-936, which targets brain molecules called dopamine D3 receptors. These receptors are involved in the brain’s reward and relapse pathways and are present in higher levels in people with addictions. In animal studies, the molecule reduced self-administration of nicotine and fentanyl, including in relapse situations. The project will test the safety and tolerability of CVL-936 in animals and healthy humans and will examine its effectiveness in reducing craving in people with opioid use disorder.

Naloxone is a safe and effective opioid antagonist, but currently available products are burdened with high cost and limited accessibility due to a need for a prescription or being kept behind-the-counter. In response to the FDA putting out an unprecedented call for an over the counter naloxone product, Pocket Naloxone Corp. is developing a novel intranasal delivery method for naloxone intended to be low-priced and widely accessible. This project will culminate in a New Drug Application to the FDA for over-the-counter approval to meet the urgent need for widespread access to a reliable, easy-to-use naloxone product for use in an emergency by non-medical individuals.

Kappa opioid receptors (KOR) are expressed in brain areas that control reward, motivation, and anxiety. Upon opioid drug withdrawal and abstinence, dysregulated KOR signaling can result in aversive physical and affective states that are a major driver of relapse. Preclinical data have demonstrated that antagonism of KOR can reduce the physical symptoms of opioid withdrawal. Currently, the alpha 2-adrenergic agonist lofexidine is the only approved therapy for the mitigation of the physical symptoms of opioid withdrawal but it is only modestly effective and can have significant unwanted side effects. Cerevel Therapeutics has identified a novel selective KOR antagonist, CVL-354, with unique properties and good preclinical safety margins. This project will assess this drug in early human safety/pharmacokinetics and occupancy studies. Future studies will then be able to assess efficacy of this drug in acute opioid withdrawal.

Over 2 million Americans have an Opioid Use Disorder (OUD) and the risks associated with misuse of opioids have prompted a public health crisis. There are three effective FDA-approved drugs for medication assisted treatment (MAT) of OUD. However, while MAT can reduce overall OUD related mortality by as much as fifty percent, relapse and treatment discontinuation are common within the first 5 to 12 weeks of MAT. As longer treatment retention is correlated with better long-term outcomes, the development of an adjunctive medication to alleviate key psychiatric symptoms associated with treatment failure would address an important unmet need. This study seeks to evaluate the safety and efficacy of brexpiprazole as adjunctive treatment to buprenorphine/naloxone in OUD. If successful, this study could enhance the effectiveness of OUD treatments by extending the duration of treatment, thereby reducing the likelihood for relapse and overdose.

The excruciating multiday experience of opioid withdrawal syndrome (OWS), is exacerbated by the opioid antagonist drugs naloxone and naltrexone. This industry-academia collaboration will explore the potential of the glutamate AMPA receptor antagonist Tezampanel (TZP). Animal studies have shown reduced hyperactivity in brain circuits involved in OWS, without relying on direct stimulation or antagonism of the opioid system ,and has already been delivered to over 500 human subjects and found to be safe for a potential migraine indication. This proposal will build up the evidence needed to apply for and conduct open label and blinded placebo-controlled human trials of TZP safety and efficacy for OWS. If successful, this project will allow planning for a pivotal registration trial for TZP for OWS, and as a transitional treatment to long-term recovery on naltrexone and help us stem the tide of the opioid crisis.

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.

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.

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.

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.

More than 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10 percent of the world’s population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids, and the use of opioids for pain treatment has resulted in what has been called an “epidemic” of opioid abuse, addiction, and lethal overdoses. Through a process of rational drug design, the research team has generated a new chemical entity (NCE) and have given it the name Kindolor, a non-opiate, non-addicting molecule that was shown to reduce or eliminate chronic pain in five animal models at doses compatible with use of Kindolor in humans. This project intends to complete the pre-clinical studies required for an IND application, which, if approved, would allow for proceeding onto the Phase 1 and 2 studies to assess safety and efficacy of the compound against osteoarthritic pain.