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 The mouse models of Sickle Cell Disease (SCD) in use today do not fully recapitulate the severity and extent of human disease due to their small size and limited lifespan. In response, a Yucatan mini-pig model has been developed and monitored through a natural history study (NHS). The planned 2-year study was extended, and the third year has concluded. This NHS monitors parameters such as changes in body weight and condition, complete blood counts (CBCs) with differential and red blood cell (RBC) histology, and serum and urine chemistry. Additionally, brain MRIs, echocardiograms, chest X-rays, and other relevant examinations are conducted at intervals. Animal behavior was also tracked through daily observation and monthly activity/play monitoring. Gait analysis and other pain-related neurobehavioral assays were conducted to further assess for pain. Additionally, experiments to identify electrophysiological and neurochemical correlates related to pain signaling were conducted. Data analyses are in process, and the results will be published online for the larger research community to access. Targeting Endosomal GPCR (eGPCR) Signaling Platforms for the Treatment of Chronic Pain GPCRs can modulate pain at the cell surface or within internalized compartments (endosomes). It is hypothesized that superior pain relief can be achieved via endosomal targets shown to be responsible for ongoing signaling in chronic pain and which, due to their compartmentalization, may not have been well engaged by other therapies. Selective delivery of small molecule antagonists can be achieved with encapsulation in 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 in polymeric nanoparticles and has been shown to target endosomal neurokinin-1 receptor (NK1R) in spinal cord dorsal horn neurons after intrathecal administration. The initial proof of concept efficacy studies of the nanoparticle formulation were inconclusive due to solubility and instability issues of the model drug. Currently an alternative drug, with well characterized solubility and stability, will be encapsulated in polymeric nanoparticles to re-test the proof of concept in mouse models. 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 directly to the brain with minimal peripheral exposure. To date, the TDB team has completed confirmatory studies to evaluate NES100 in an in vivo acute pain model, using a sensitive bioanalytical method developed to detect L-ENK in plasma and brain. An in vivo chronic efficacy study is in progress. Manufacturing of non-GMP MET is near completion, formulation of NES100 for intranasal delivery is ongoing, GLP in vitro genetic toxicity studies are expected to being shortly, and GLP in vivo toxicology and safety assessments are planned. Completion of these activities will support the filing of an Investigational New Drug application to the Food and Drug Administration. Development of D3 Antagonist for Substance Use Disorder 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. Importantly, the lead compound did not alter activity of human cardiac potassium channels (hERG) in vitro at pharmacologically relevant concentrations. This collaboration aims to conduct IND-enabling studies to advance the lead compound to clinical studies for the treatment of OUD. GLP toxicology studies were recently completed. The positive study results support moving forward to GMP manufacturing of final drug product. These studies will be incorporated into an IND filing with FDA to enable subsequent clinical trials. 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. Meanwhile, kratom supporters claim that MG has significant value as a potential therapeutic for the treatment of chronic pain and opioid addiction. Because no kratom-derived product exists that meets FDA standards for Investigational New Drugs, neither set of assertions has been rigorously tested in humans. This project will allow these claims to be empirically evaluated by generating a preclinical data package and sufficient clinical drug product to enable an IND application and subsequent clinical investigations. To date, a purification process was developed to isolate MG from kratom alkaloid extract as a bioactive salt. Pharmacokinetic and toxicokinetic parameters have been evaluated in multiple species, and further in vitro PK studies to evaluate drug interactions and metabolism are underway. A capsule formulation appropriate for clinical testing has been developed, and active pharmaceutical ingredient (API) has been manufactured to support preclinical GLP toxicology studies and eventual clinical trials. Regulatory meetings with the FDA are scheduled, which will inform further IND-directed development plans. Development of a Non-Paralyzing BoNT-based Biopharmaceutical for the Treatment of Neuropathic Pain Several reports have highlighted a modest potential for botulinum toxin type A (BoNT/A) drugs (e.g., Botox) to block pain in animals and humans. However, the paralyzing activity of BoNT/A remains an obstacle to 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 still inactivate pain circuits. These molecules are safely produced as two inactive subunits and then assembled into stable functional complexes for local administration to treat pain. Neuresta developed an attenuated BoNT/A, termed BiTox, which has been shown to effectively block neuropathic pain in rodents at low concentrations (ng/kg body weight) without causing any detectable paralysis. In vivo studies are ongoing to assess its efficacy and toxicity. Preliminary results indicate that covalent BiTox has about 100-fold reduction in toxicity compared to native BoNT/A. Currently, the Chemistry, Manufacturing and Controls team is focused on developing safe and cost-effective manufacturing processes for the subunit components.