Peptide-antibody conjugate kappa-opioid receptor (PAC-KOR) agonists for treatment of chronic itch

用于治疗慢性瘙痒的肽抗体缀合物 kappa-阿片受体 (PAC-KOR) 激动剂

• 批准号: 10481985
• 负责人: Pierre Riviere
• 金额: $ 49.94万
• 依托单位: PEPTIDE LOGIC, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-08 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481985
• 关键词: Address; Adherence; Adverse effects; Affect; American; Animals; Biological Assay; Bioreactors; Cell Line; Cells; Chronic Kidney Failure; Clinical; Constipation; Data; Dependence; Development; Dose; Drug Exposure; Drug Kinetics; End stage renal failure; Ensure; Enzyme-Linked Immunosorbent Assay; Euphoria; Exhibits; FDA approved; Feeds; Female; Filtration; Frequencies; Future; G-Protein-Coupled Receptors; Half-Life; Hemodialysis; Human; Impairment; Kidney; Logic; Mediating; Mental Depression; Monoclonal Antibodies; Mus; Opioid; Opioid agonist; Patients; Peptide antibodies; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Preparation; Production; Proteins; Pruritus; Quality of life; Renal function; Reproducibility; Research; Route; Safety; Sedation procedure; Sensory; Site; Spinal; Structure of trigeminal ganglion; System; Technology; Testing; Transgenic Mice; Ventilatory Depression; Wild Type Mouse; addiction; antibody conjugate; base; chronic itch; chronic pain; clinical candidate; comorbidity; cost; design; dysphoria; efficacy study; experience; improved; infection risk; kappa opioid receptors; male; mortality risk; mu opioid receptors; neonatal Fc receptor; neuronal circuitry; next generation; novel; opioid epidemic; patient population; pharmacodynamic model; pharmacokinetics and pharmacodynamics; poor sleep; prescription opioid; programs; response; side effect; sleep quality; spinal nerve posterior root; stable cell line; standard of care; subcutaneous

ABSTRACT: There are >37 million Americans suffering from CKD, including >495,000 patients with end stage renal disease (ESRD) requiring hemodialysis (CKD-HD) and >17 million affected by advanced CKD (stages 3-5) who are not dialysis dependent (CKD-nonHD). About one third of both CKD-HD and CKD-nonHD patients experience moderate-to-severe chronic itch a.k.a. uremic pruritus. Intense and generalized systemic itching is associated with poor sleep quality, depression, reduced quality of life (QoL), increased risk of infection, and increased risk of death. It is important to note that, in addition to pruritus, >50% of both CKD-HD and CKD-nonHD patients also experience chronic pain, and that 30-50% of these patients are prescribed opioids resulting in additional comorbidities and reduced QoL. Until recently, there was no approved drug for uremic pruritus in the US and there is still no approved non-addictive analgesic to replace opioids for CKD-associated chronic pain. Difelikefalin is a peripherally restricted and short-acting tetrapeptide KOR agonist that was recently approved by the FDA for moderate-to-severe uremic pruritus in CKD-HD patients. It is the first and only approved drug for this indication in the US. Difelikefalin has significant shortcomings, including kidney-mediated clearance and short half-life in patients with functioning kidneys limiting its development outside the CKD-HD patient population. Using a proprietary peptide-antibody conjugate (PAC) technology, we have created PAC-KOR agonists with a unique target product profile (TPP) characterized by the following key features: (i) potent and selective KOR agonist to ensure efficacy while minimizing dose and cost of goods (COGS), (ii) peripherally-restricted to avoid CNS side-effects and ensure safety, and (iii) long half-life enabling once-weekly to once-monthly subcutaneous (SC) dosing by autoinjector to maximize convenience, adherence, exposure, and efficacy. This application seeks to confirm the pharmacodynamic (PD) and pharmacokinetic (PK) profile of our clinical candidate and create stable cell lines to support future development. Impact and

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