Funded Projects

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.

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.

Addiction to opioids is related to the physiology of the brain’s dopamine-based reward system. As a modulator of dopaminergic systems, the neurotensin 1 receptor (NTR1) should be a molecular target for treating addictive disorders; however, few non-peptide brain penetrant neurotensin modulators have been identified, and orthosteric NTR1 ligands display side effects that have limited their clinical development. This group discovered a series of brain-penetrant NTR1 modulators, including a lead compound SBI-553, with a unique mechanism of action at NTR1. SBI-553 is an orally available, brain penetrant ?-arrestin biased allosteric modulator of NTR1, which shows efficacy in a range of addiction models and circumvents the clinically limiting side effects. While potentially high risk, the activity of SBI-553 has been validated in vitro and in vivo, and the initial safety profiling indicates no issues that would preclude further development. This study will develop SBI-553 as a treatment for opioid use disorder.

The ongoing opioid crisis has led to renewed concerns about the clinical prescription of addictive opioid analgesics. However, there are currently no suitable alternatives for treating severe or malignant pain. Studies of opioid signaling mechanisms in mice deficient in ?-arrestin have suggested that biased agonists displaying preferential activation of G-protein signaling over ?-arrestin signaling could offer a promising avenue for the development of opioid analgesics with a reduced adverse effects profile. However, there is no concluding evidence showing that such biased signaling can indeed be associated with reduced opioid side effects and, consequently, an improved safety profile. This research will address the need for preclinical data to rigorously evaluate this hypothesis with a program of in vivo studies to compare the effects of “balanced” opioids (morphine, oxycodone, and fentanyl) with that of the “biased” agonists PZM21 and two novel ligands provided by colleagues at the NIDA IRP in nonhuman primates. The results of these studies will provide critical information regarding the dependence liability of “biased” agonists that, in clinical practice, might be given on a repeated, or chronic, basis, potentially adding a powerful new tool for the safer management of severe or malignant pain.

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.

Tens of thousands of people die each year from opioid overdose. Many of these people began taking opioids for pain. A critical treatment goal is to reduce the development of opioid dependence either by enhancing opioid analgesia so lower doses can be used or by blocking withdrawal symptoms. Current pharmacological treatments in these two categories, although effective, present serious limitations. The recent finding that reducing the signaling through mu-delta opioid heterodimers appears to enhance opioid antinociception and reduce dependence suggests that a blocker of mixed mu-delta receptors (MDOR antagonist) could be effective in reducing dependence by limiting opioid tolerance and preventing opioid withdrawal. This research group has developed a compound with that characteristic, called D24M, which preliminary studies have shown could reduce opioid dependence by enhancing opioid antinociception, reducing opioid tolerance, or directly inhibiting opioid withdrawal. They propose to extend this research by investigating whether it can reduce chronic pain in an animal model that mimics the clinical situation of pain patients who transition to dependence. If these studies are successful, they could lead to the development of an optimized drug ready for Investigational New Drug (IND) application and enable translational and clinical testing.

Opioids have been significantly over-prescribed and are associated with numerous deaths, resulting in the nation’s current opioid crisis. The FDA recently approved the ?2 adrenergic agonist lofexidine as a non-addictive, non-opioid treatment for opioid use disorder (OUD), but there is a continued, urgent need to develop additional pharmacological alternatives to address both pain and OUD. The psychoactive, natural product, Mitragyna speciosa (kratom), has triggered significant interest in this space because Mitragynine, its main alkaloid, can interact with both mu opioid and ?2 receptors, offering a totally new approach for treating OUD. This project involves the synthesis and research of a series of Mitragynine analogs to better understand the pharmacological mechanisms that underlie Mitragynine’s opioid and adrenergic activities. If successful, this project will result in templates for the design of novel opioid receptor ligands. This advance would greatly improve the knowledge of interactions of these structurally novel compounds with opioid receptors and facilitate the development of these ligands as treatments for OUD.

There is an urgent need to prevent and reduce opioid use disorder (OUD) by reducing the need for opioid analgesia and preventing the escalation of opioid dosing in patients at greater risk of using more opioids following surgery. Brivoligide is a non-opioid drug candidate that can alter the course of postoperative pain for patients most likely to suffer increased pain and utilize more opioids following surgery. A single administration of brivoligide at the time of surgery can reduce acute postoperative pain in these patients by 30 percent to 40 percent beyond what can be achieved with the current standard of care for at least 28 days and reduce opioid utilization by 40 percent over a 3-month period following surgery. This project will support the research necessary to achieve regulatory approval of brivoligide with a broad indication, which will initially focus on the reduction of postoperative pain following mastectomy, a soft-tissue surgery model suitable to detect long-term pain and opioid reduction benefits. Brivoligide appears to be a very promising pharmacotherapy with the potential to greatly contribute to stemming the tide in the opioid crisis.

Kinoxis has developed a novel small-molecule lead, KNX100, that reduces the severity of opioid withdrawal symptoms in preclinical animal models of opioid use disorder (OUD). KNX100 was discovered from a phenotypic screen of compounds derived from a fragment-based drug discovery program targeting the brain oxytocin system. KNX100 has a favorable pharmacokinetic and safety profile and has undergone testing for efficacy signals in two rodents and two non-human primate species. The proposed activity is to progress the development of KNX100 to treat opioid withdrawal in OUD. The overall objective of the project is to establish the safety and tolerability of KNX100 to enable human efficacy testing to commence in patients requiring treatment for opioid withdrawal. The long-term objective for this development program is to generate human efficacy data to support KNX100 as a potential treatment for opioid withdrawal symptoms and ultimately enable a New Drug Application to the FDA.

There is an urgent need for longer acting opioid overdose reversal medications to treat acute fentanyl intoxication and overdose. This project will develop a novel molecule (CS-1103) that sticks to fentanyl and removes it from the body. Previous research with animal models shows that CS-1103 has several features that make it attractive for a new medication. It can reverse fentanyl-induced respiratory depression, preventing another overdose; work in combination with naloxone; and appears to be safe and well-tolerated. The research will continue exploration of CS-1103 toward testing CS-1103 in human research participants.

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.