Funded Projects

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.

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.

EicOsis is developing a first-in-class analgesic with efficacy against neuropathic pain that will reduce or replace the need for opioids and thus potentially prevent opioid use disorder (OUD). The target of the small molecule inhibitor EC5026 is the soluble epoxide hydrolase, a master regulatory enzyme that modulates the activity of endogenous bioactive lipids. The study will reach the next steps in clinical human clinical trials with EC5026 through additional preclinical studies to expand the efficacy into models of chronic pain conditions. Additionally, detailed pharmacokinetic, metabolism, and distribution studies are proposed that will provide the required information to optimize drug formulation and for advanced clinical trials examining efficacy in humans. EicOsis is meeting current development goals, and EC5026 is well positioned to meet the urgent need of reducing opioid use.

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.

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.

Although medications are available to treat opioid use disorder (OUD), adherence with treatment programs remains a problem. Nalmefene is an opioid receptor antagonist that was previously approved for treatment of opioid overdose–induced respiratory depression that has a longer duration of action than naloxone. AP007 is a unique formulation of nalmefene-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles that when injected intramuscularly continually releases an effective dose of nalmefene and thus reduces opioid cravings in OUD patients. This group is developing AP007 and will have a lead formulation selected based on in vitro release kinetics data and in vivo pharmacokinetics data in rats. The objectives of the project are to determine safety and efficacy of AP007 in a swine opioid use/withdrawal model, preliminary safety in a first-in-human Phase 1 study, and preliminary efficacy in a Phase 2a multidose study. These results will be used to develop Phase 2 human and Phase 3 clinical studies.

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.

High relapse rates among people with opioid use disorder (OUD) indicate that addiction involves appetitive pathways. Peripheral stimulation of the glucagon-like peptide-1 receptor (GLP-1R) “satiety” pathway could reduce heroin seeking and taking. Pretreatment with a GLP-1R agonist reduces heroin taking, seeking, and drug-induced reinstatement in rats. This project tests whether GLP-1R agonists can reduce relapse in humans with OUD. A pilot study will be conducted to determine whether once-daily treatment with the shorter acting GLP-1R agonist, liraglutide, can safely and effectively reduce cravings among OUD patients. Animal models will be used to test the efficacy and safety of a longer-acting GLP-1R agonist, semaglutide, and then a clinical trial will be conducted to test whether semaglutide will reduce relapse and use in animal models. If successful, the study will show that treatment with GLP-1R agonists can safely and effectively reduce opioid craving, seeking, and relapse.

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 dependence is a leading cause of premature illness and death. Previous research suggests that a protein called G-protein coupled receptor (GPR88) controls many addiction-relevant behavioral and physiological actions of opioids. This research study will validate GPR88 as a drug target for opioid use disorder as well as develop novel, brain-penetrant GPR88-binding molecules with properties optimized for treating opioid dependence. This research is an initial step toward the goal of developing GPR88-binding molecules as novel therapeutics to facilitate abstinence in people dependent on opioids.

Given recent increases in co-use of opioids and methamphetamine, there is a dire need for novel treatment strategies that prevent relapse to drug use in both opioid use disorder (OUD) and methamphetamine use disorder (MUD). The localization of certain receptors for the neurotransmitter glutamate—metabotropic glutamate receptor subtypes 2 and 3 (mGlu2/3)—and the mechanism through which they transmit signals, strongly suggest that activation of both of these receptors will effectively treat multiple symptoms that contribute to relapse, such as responsiveness to drug cues, physical withdrawal symptoms, neuroinflammation, and sleep disturbances. This project seeks to evaluate molecules that can activate mGlu2/3 receptors without binding to the same site as glutamate (i.e., positive allosteric modulators) as a novel pharmacological treatment for preventing relapse to OUD. The research also will examine the potential of such modulators for treating MUD.

There are currently no medications approved by the U.S. Food and Drug Administration to treat methamphetamine use disorder, even though risky patterns of methamphetamine use and overdose deaths have increased in recent years. Research using animal models shows that immune molecules that latch onto methamphetamine (anti-methamphetamine antibodies) show promise in blocking the effects of the drug. This project aims to identify a long-acting monoclonal antibody targeted to methamphetamine and conduct development and safety studies to prepare for future testing of the antibody treatment in humans.

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.