Funded Projects

The sodium channel NaV1.8 is a promising target for the development of effective, non-addictive pain medications. Recent evidence from clinical studies indicates that medications that target NaV1.8 are effective at managing postoperative, neuropathic, and inflammatory pain, but with side effects and prohibitively high cost. This project will test the safety and compatibility in the body of an NaV1.8-targeted molecule, toward developing an effective, non-addictive, once daily oral medication for the treatment of acute postsurgical pain and chronic neuropathic. 

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.

The widespread availability of fentanyl and other potent synthetic opioids has dramatically increased opioid-related fatal overdoses. This project will develop and manufacture immune molecules (monoclonal antibodies) to reverse and treat overdose from fentanyl by keeping it out of the brain. This research will advance promising results in animal studies (preventing and reversing fentanyl- and carfentanil-induced breathing problems and irregular heartbeat) to clinical testing in people with opioid use disorder and others at high risk of opioid overdose from accidental or deliberate exposure to fentanyl and fentanyl-like drugs.

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.

There is a need for pharmacologic treatment options for opioid use disorder (OUD) that do not pose addiction liability and do not require complete withdrawal from opioids prior to treatment. Nonclinical studies support a role for the orexin system in drug seeking; compounds that selectively block signaling at the orexin-1 receptor (OX1R) reduce drug use. C4X3256, a non-opioid, highly selective OX1R antagonist, has a long residence time at the OX1R along with reduced intravenous self-administration and cue-induced reinstatement in animal models of nicotine addiction, suggesting it could be an addiction treatment. Proposed studies will move C4X3256 from preclinical development through Phase I testing in subjects with OUD. The clinical, preclinical, and supporting pharmaceutical development studies proposed will allow C4X3256 to move to Phase II studies.

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.

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.

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.

There is an urgent need for a new generation of non-addictive, pain-relieving medications that do not cause problematic side effects like breathing problems or constipation. The overarching project is testing a new potential medication that interacts in a new way with the opioid system in human research participants. This supplement will help cover costs associated with the Safety Review Committee meeting required by the U.S. Food and Drug Administration.

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.

Buprenorphine (BUP) is an FDA-approved medication-assisted therapy (MAT) that improves outcomes and saves lives in patients with opioid use disorder (OUD). It is available in multiple dosage forms and routes of administration, including daily sublingual (SL) and buccal tablets and films, a monthly subcutaneous (SC) injectable, and a 6-month SC implant; however, these forms leave many patients untreated or undertreated. This product, in a partnership with Lyndra Therapeutics, aims to develop a once-weekly oral BUP dosage form for maintenance therapy for OUD, using a new oral dosage formulation developed by Lyndra. A long-acting oral BUP may address important limitations of current MATs by providing improved PK with less euphoria than SL, a patient- and provider-preferred route of administration, and an optimal dosing interval for improved patient adherence with the potential for cost-effective direct observed therapy.

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.