Funded Projects

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 While LAAM was withdrawn from the market despite being approved for OUD treatment, this project seeks to develop novel, patentable, convenient dosage forms of LAAM, including novel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.

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.

Safe and effective options are urgently needed to prevent and treat opioid use disorder and polysubstance use disorders. Previous research in humans and animals suggests that activating the calcium-activated potassium channel KCa2.2 is a promising therapeutic approach for treating substance use disorders and associated health conditions. This project will perform a virtual high-throughput screen using novel machine learning approaches to discover new molecules that interact with the KCa2.2 channel. The newly discovered molecules help develop novel drugs for the treatment of opioid use disorder and associated health conditions.

An increasing number of Americans use multiple drugs at the same time, and overdose deaths from stimulants have increased. However, there are no available treatments for stimulant use disorder. This project aims to develop new treatment (SBS-518) for cocaine use disorder. Previous research using animal models showed that SBS-518 decreases stimulant self-administration without being rewarding itself. The research will continue the development of SBS-518 toward testing in human research participants.

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.

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.

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.

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.

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.

Naltrexone is the only medication approved by the U.S. Food and Drug Administration to prevent relapse from opioid use disorder. This medication remains underused because it must be injected into muscle by a nurse and is relatively expensive. This project will develop and test a novel naltrexone skin patch that is easier to use, more comfortable, and inexpensive.

Difficulty breathing is a hallmark symptom of an opioid-related overdose and can result in permanent brain injury or death within minutes. This project will develop a community-deployable Automated External Respiration System device that can restore and sustain breathing in people experiencing opioid-induced respiratory depression. The device stimulates the phrenic nerve in the chest that controls breathing until other medical interventions are available or the patient recovers. The research will develop and validate the automated external respiration system for testing in human research participants and ultimately aims to develop a system usable in a community setting.

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).