Helping to End Addiction Long-term (HEAL): Development of Clinical Candidate Drugs for Pain, Addiction and Overdose

National Center For Advancing Translational Sciences

Investigators

Abstract

Characterization of a large-animal preclinical model of sickle cell disease Sickle Cell Disease (SCD) patients require improved pain therapeutics that optimize analgesic benefits to manage chronic and acute pain. There is also a need for a large-animal model of SCD to address the aspects of SCD research and therapeutics development that traditional murine models have not been able to fully realize. The Yucatan mini-pig is nearly the same size as an average human allowing longitudinal blood sampling and is to be a better translational model for human anatomy and physiology, notably for vasculature and pain pathways. SCD pigs have been developed utilizing CRISPR / Cas9 technology for molecular and phenotypic characterization inclusive of a planned two-year natural history study (NHS) and for subsequent colony expansion. The NHS is assessing the pathological changes over time in hematologic parameters, urine and blood chemistry, electrophysiologic pain and related behavioral measurements, diagnostic imaging of the brain and lungs, as well as other cardiopulmonary assessments culminating in a complete pathological analysis of tissues and organs. The goal is to make SCD pigs and NHS data - including pain assessments - widely available to the research community for a more complete evaluation and validation of the model. Targeting endosomal GPCR (eGPCR) signaling platforms for the treatment of chronic pain Pain is transmitted through the nervous system via G-protein coupled receptors (GPCRs) on neurons in the central and peripheral nervous systems including the brain and spinal cord. GPCRs can function at the cell surface or within internalized compartments called endosomes. It is hypothesized that superior pain relief can be achieved via endosomal targets that have been demonstrated to be responsible for ongoing signaling in chronic pain and which, due to their compartmentalization, may not have been well targeted by other therapies. Selective delivery of small molecule antagonists can be achieved with encapsulation into a nanoparticle that breaks down in the acidic endosome to release the antagonist, specifically targeting the eGPCRs involved in nociceptive signaling. The FDA-approved small molecule aprepitant (AP) is encapsulated into DIPMA polymers and has been shown to target the endosomal NK1R signaling of the spinal cord dorsal horn neurons after intrathecal administration. The project team is providing proof of concept and testing efficacy and potential side effects of the nanoparticle formulation. Fast, Centrally-Acting, Non-Addicting Novel Analgesic for Chronic Non-Cancer Pain Enkephalins, endogenous opioid ligands, preferentially bind to delta-opioid receptors to produce analgesia without the negative effects typically seen with mu-opioid receptor binding. Enkephalins have been well studied but not fully developed as drugs due to their rapid enzymatic degradation and poor brain permeation, even with the use of various penetration enhancers. To overcome these obstacles, Virpax Pharmaceuticals has developed NES100, a formulation of leucine-enkephalin (L-ENK) in a novel Molecular Envelope Technology (MET) that enables the efficient intranasal delivery of L-ENK exclusively to the brain with essentially no peripheral exposure. This collaborative effort includes confirmatory in vivo preclinical efficacy studies, PK-ADME studies, GMP manufacturing of L-ENK and MET and formulation of NES100 for nasal delivery, evaluation of abuse liability and toxicological and safety assessment. Development of D3 Antagonist for Substance Use Disorder Drugs of abuse elevate dopamine in the nucleus accumbens shell, a key component of the reward system. The dopamine D3 receptor (D3R) expressed in the ventral forebrain mesolimbic dopamine system is thought to influence reward, emotion, and motivation and, by extension, drug seeking and relapse. D3R-selective antagonists decrease craving for drugs of abuse and drug-seeking behavior and have been investigated clinically with promising results. However, these efforts were discontinued due to elevated blood pressure in a preclinical model when used in combination with cocaine. NIDA has developed highly selective D3R antagonists that have demonstrated efficacy in multiple preclinical models of addiction including reduction in self-administration and reinstatement of oxycodone and, notably, that did not alter activity of human cardiac potassium channels (hERG) in vitro at pharmacologically relevant concentrations. This collaboration is using the combined resources and expertise of NCATS, NIDA and their partners at Braeburn to conduct IND-enabling studies with the lead compound for the treatment of OUD. The team is conducting additional studies to identify a back-up compound. Developing a Mitragynine Formulation to Conduct Rigorously Controlled Clinical Trials with a Kratom Alkaloid Extract Mitragynine (MG), the active component of kratom, is popularly used as a treatment for opioid withdrawal, although the Drug Enforcement Administration (DEA) has indicated MG has a high abuse potential. Because no kratom-derived product that meets the FDA standards for Investigational New Drugs currently exists, the DEA assertion has not been rigorously tested in humans. Further, counterclaims from kratom supporters that MG has significant value as a potential therapeutic for the treatment of chronic pain and opioid addiction have also not been tested in rigorous placebo controlled clinical trials. This collaborative project will allow these claims to be empirically evaluated by generating a preclinical data package and sufficient clinical drug product. MRGX2 Antagonist for the Treatment of Chronic Abdominal Pain in Irritable Bowel Syndrome Pain is the cardinal symptom of irritable bowel syndrome (IBS). Opioids have been used for analgesic therapy, despite opioids being largely ineffective in treating functional bowel pain. Paradoxically, opioids lead to a worsening of bowel function and increase abdominal pain severity, termed narcotic bowel syndrome. The etiology of the underlying disease is unknown, though recent studies have revealed that mast cell number and mast cell mediator release are both increased in the bowel wall of IBS patients. Moreover, the number of mast cells in proximity to colonic sensory nerves correlates with the severity and frequency of abdominal pain. Therefore, it is hypothesized that mast cells release mediators, including histamine, that activate nerves to cause altered GI physiology and pain sensation. This collaboration focuses on the development of a small molecule therapeutic targeting the MRGX2 receptor to inhibit mediator release from intestinal mast cells. Development of a Non-Paralyzing BoNT-based Biopharmaceutical for the Treatment of Neuropathic Pain Several reports have highlighted a modest potential of botulinum toxin type A (BoNT/A) drugs (e.g., Botox) for blocking pain in animals and humans. However, the paralyzing activity of BoNT/A remains a fundamental obstacle for these applications. Recent evidence demonstrates that these hurdles can be overcome by implementing genetically altered detoxified or attenuated BoNT/A molecules with diminished paralytic activity that can inactivate pain circuits. These molecules are safely produced as two inactive subunits and then assembled into stable functional complexes for local administration into painful areas. The result, termed Covalent BiTox, has been shown to effectively block neuropathic pain in rodents at low (ng/kg body weight) concentrations without causing any detectable paralysis. This collaboration focuses on the development of a non-paralyzing BoNT-based biopharmaceutical for the treatment of neuropathic pain.