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

帮助长期戒除成瘾 (HEAL)：开发治疗疼痛、成瘾和药物过量的临床候选药物

基本信息

批准号：
10686744
负责人：
Donald Lo
金额：
$ 1031.68万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686744
关键词：
3-Dimensional Absence of pain sensation Acute Acute Pain Address Alkaloids Analgesics Animal Behavior Animal Model Animals Area Attenuated Back Binding Biodistribution Biological Assay Biological Availability Biological Products Blood Body Weight Botox Botulinum Toxin Type A Brain Breeding Cardiac Cell model Cell surface Chemistry Chronic Clinical Clinical Trials Cocaine Collaborations Communities Complement Complex Controlled Clinical Trials Data Development Diagnostic Disease Dose Drug Kinetics Drug Modelings Due Process Echocardiography Emotions Encapsulated Endosomes Enhancers Enkephalins Evaluation Formulation G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genes Hand Health Helping to End Addiction Long-term Human Human Activities Human Biology In Vitro Infrastructure Intervention Investigational Drugs Investigational New Drug Application Lead Leucine Enkephalin Life Ligands Longevity Magnetic Resonance Imaging Methods Miniature Swine Mitragyna Modality Modeling Molecular Monitor Motivation National Center for Advancing Translational Sciences National Institute of Drug Abuse Natural History Nociception Opiate Addiction Opioid Receptor Binding Overdose Oxycodone Pain Pain Measurement Paralysed Patients Penetration Peripheral Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Placebo Control Plasma Play Polymers Posterior Horn Cells Potassium Channel Pre-Clinical Model Process Production Productivity Prosencephalon Public Health Publishing Recombinants Records Relapse Reporting Research Research Contracts Research Personnel Resources Rewards Risk Rodent Safety Schedule Science Scientist Self Administration Severities Sickle Cell Sickle Cell Anemia Signal Transduction Sodium Chloride Spinal cord posterior horn Substance Use Disorder TACR1 gene Technology Testing Therapeutic Thoracic Radiography Tissue Microarray Tissues Toxicology Translational Research United States Food and Drug Administration United States National Institutes of Health Urine Validation Work abuse liability addiction antagonist aprepitant base bioprinting blood pressure elevation capsule chronic pain chronic pain management clinical development clinical investigation delta opioid receptor dopamine D3 receptor drug candidate drug craving drug of abuse drug seeking behavior efficacy study efficacy testing endogenous opioids experience first-in-human gait examination gene therapy high throughput screening human model improved in vivo induced pluripotent stem cell innovation meetings mesolimbic system mouse model mu opioid receptors nanoparticle neurobehavioral non-cancer chronic pain novel novel therapeutics opioid epidemic opioid misuse opioid use opioid use disorder opioid withdrawal pain relief painful neuropathy pharmacokinetics and pharmacodynamics porcine model pre-clinical preclinical development preclinical efficacy programs receptor research clinical testing response safety assessment safety study side effect small molecule therapeutic development

项目摘要

Characterization of a large-animal preclinical model of sickle cell disease The available Sickle Cell Disease (SCD) murine models in use today are not able to fully demonstrate severity and extent of disease processes 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 has been completed and was extended into a third year. This NHS is monitoring parameters such as CBCs, blood and urine chemistry, and blood smears which visualize sickled erythrocytes. Additionally, brain MRIs, echocardiograms, chest X-rays, and other relevant diagnostic examinations are conducted periodically on a set interval. The animals behavior was also tracked through pain observation, activity/play monitoring, changes in body weight and condition, and gait analysis as well as other pain-related neurobehavioral assessments. The NHS data will be published online for the larger research community to access. In addition, should the model be realized, a breeding program is being considered for mini pigs to be acquired by the broader research community for a more complete evaluation and validation of the model. Targeting endosomal GPCR (eGPCR) signaling platforms for the treatment of chronic pain GPCRs can modulate pain 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. In FY22, the Endosome team troubleshooted the instability of model drug aprepitant (AP) to re-test the proof of concept. 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 minimal peripheral exposure. Preclinical development efforts are underway to advance NES100 to clinical evaluation. To date, the Therapeutic Development Branch (TDB) team has completed confirmatory in vivo acute efficacy studies to evaluate NES100 in an acute pain assay, a sensitive bioanalytical method to detect L-ENK in plasma and brain for pharmacokinetic (PK) biodistribution studies, dose range finding studies, and GMP manufacturing of L-ENK for toxicology and clinical evaluation. An in vivo chronic efficacy study is in progress. GMP MET is currently in the manufacturing phase and formulation of NES100 for intranasal delivery is ongoing. GLP toxicological and safety assessments are expected to begin shortly. Completion of all 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 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 and NIDA to conduct IND-enabling studies with the lead compound for the treatment of OUD. Currently, GMP production of lead compound is near completion. A pre-IND meeting is scheduled with FDA in November 2022, prior to initiating GLP toxicology studies. 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 to enable an IND application. To date, purification process was developed to extract MG from kratom alkaloid extract and stabilized as a bioactive salt. Studies in three species to assess pharmacokinetic parameters are complete. GMP manufacture of API is complete and a capsule formulation appropriate for clinical testing has been developed and PK parameters will be evaluated in DRF studies in two species, expected to begin shortly followed by the definitive GLP toxicology studies and safety evaluations. 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. In FY22, pilot batches of BiTox were produced. Highly sensitive assays were successfully developed to assess the assembly and quality of recombinant Bi-Tox in support of advancing CMC development.