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Long-acting injectable tacrolimus for chronic immunosuppression

长效注射用他克莫司治疗慢性免疫抑制

基本信息

批准号：
10662560
负责人：
Sarjan Shah
金额：
$ 102.36万
依托单位：
AURITEC PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662560
关键词：
Acquired Immunodeficiency Syndrome Address Adherence Adolescent Animal Model Animal Testing Animals Antiviral Agents Area Biological Assay Biological Availability Biometry Blood Blood drug level result Calcineurin inhibitor Chemistry Chronic Clinical Clinical Research Clinical Trials Cytomegalovirus Retinitis Data Development Devices Documentation Dose Drug Delivery Systems Drug Kinetics Drug Monitoring Effectiveness Ensure Environment Exhibits FDA approved Formulation Goals Good Manufacturing Process Graft Rejection Graft Survival Immunosuppression Infrastructure Injectable Intellectual Property Kinetics Laws Legal patent Leukocyte Adherence Inhibition Test Maintenance Therapy Manufactured Materials Medical Care Costs Metabolism Oral Oral Administration Organ Outcome Patients Performance Pharmaceutical Preparations Pharmacologic Substance Phase Polymer Chemistry Population Preparation Procedures Prophylactic treatment Regulatory Affairs Reporting Research Research Personnel Risk Safety Schedule Shapes Sheep Small Business Innovation Research Grant Tacrolimus Technology Testing Therapeutic Therapeutic Index Toxic effect Toxicology Transplant Recipients Transplant Surgeon Transplantation Treatment Efficacy Treatment-related toxicity Universities Validation Virginia Work analytical method care outcomes compliance behavior cost effective drug development experience first-in-human good laboratory practice improved innovation interpatient variability manufacture manufacturing process manufacturing scale-up medication compliance medication nonadherence meetings method development organ transplant recipient organ transplant rejection patient variability pharmacokinetic model pharmacologic phase I trial pill post-transplant pre-Investigational New Drug meeting pre-clinical preclinical development product development research clinical testing safety and feasibility safety testing subcutaneous tool

项目摘要

PROJECT SUMMARY The broad, long-term goal of this Direct to Phase II SBIR is to improve immunosuppression outcomes in organ transplant recipients by developing a long-acting injectable calcineurin inhibitor (CNI). For more than two decades, tacrolimus is a valuable pharmacological tool in the prophylaxis of organ transplant rejection. It is commercially available as twice and once-daily oral pills. Oral formulations undergo first-pass metabolism and suffer from low and variable bioavailability which in turn leads to high intra- and inter- patient pharmacokinetic (PK) variability. Tacrolimus has a narrow therapeutic index, hence sub-therapeutic blood levels (<5 ng/ml) results in organ rejection whereas supra-therapeutic levels (>15 ng/ml) are toxic. Daily dosing has been associated with medication non-adherence. The medical costs transplant recipients with poor adherence are ~$30,000 higher than patients with high adherence at 3 years post-transplant. Thus, the three reported unmet needs are higher medication adherence, better outcomes of graft survival, and linear PK profile. Auritec Pharmaceuticals has developed a subcutaneous injectable formulation of tacrolimus that provides consistent therapeutic blood levels of the drug for 30 days after a single administration. The product is based on Auritec’s innovative Plexis technology that has shown clinical proof of concept in two Phase 1 trials. The Plexis technology is differentiated from other long-acting injectable technologies in terms of its high drug loading, scalable manufacturing process, and more linear release kinetics. The product has demonstrated safe and sustained release of tacrolimus in a first-in-human safety/PK study using the “exploratory IND” approach. PK modeling shows that a monthly dosing schedule can be readily achieved in transplant recipients to maintain tacrolimus blood levels in the safe and efficacious range (5-15 ng/ml). The benefits of our product include 1) complete medication adherence for 1 month after one administration; 2) fewer episodes of graft rejections; 3) simpler dosing schedule, and; 4) a smooth PK profile without sub- or supra-therapeutic levels. The populations anticipated to benefit from the product are: Patients who have demonstrated tolerability to tacrolimus but find it challenging to adhere to a daily fixed schedule (such as younger patients) and/or rapid metabolizers of tacrolimus. The end result will be a cost-effective maintenance therapy for maintenance therapy. The specific aims of this Direct to Phase II SBIR are to perform activities in pursuit of a “traditional Phase 1 IND” allowance. The proposed work includes - manufacturing in accordance with current Good Manufacturing Practices (cGMP); animal testing in compliance with Good Laboratory Practices (GLP); analytical method development; Chemistry, Manufacturing and Controls (CMC) testing; and finally, IND submission to the FDA. These efforts will result in an IND approval and allow for the first-in-human testing of safety, PK, and preliminary efficacy in transplant recipients. Successful completion of this work will further de-risk the product by bringing it closer to clinical testing and making it attractive to investors.

项目总结