SBIR-STTR Award

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.

Public Health Relevance Statement:
PROJECT NARRATIVE Hundreds of thousands of patients depend on tacrolimus-based immunosuppression for the survival of their donated organs, which commonly develops after the transplantation procedure. Currently available oral tacrolimus formulations require daily dosing, and their variable drug release results in sub-therapeutic efficacy and toxicity-inducing peaks, which leads to poor healthcare outcomes. To address this important issue, we have developed a monthly injectable formulation of tacrolimus which will release in a linear manner and result in superior safety and effectiveness.

Project Terms:
therapy efficacy; Outcome; manufacturing process; cost effective; Population; innovation; innovate; innovative; FDA approved; product development; safety testing; manufacturing scale-up; good laboratory practice; phase I trial; phase 1 trial; Formulation; Treatment-related toxicity; therapeutic toxicity; therapy toxicity; treatment toxicity; interpatient variability; inter-patient variability; organ transplant rejection; organ rejection; safety and feasibility; preclinical development; pre-clinical development; care outcomes; health care outcomes; healthcare outcomes; patient variability; patient variation; variability between patients; variation between patients; first-in-human; first in man; Infrastructure; medication nonadherence; medication non-adherence; post-transplant; post-transplantation; posttransplant; posttransplantation; organ transplant recipient; Acquired Immunodeficiency Syndrome; AIDS; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunologic Deficiency Syndrome; Animals; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral compound; anti-viral drugs; anti-viral medication; anti-viral therapeutic; anti-virals; antiviral compound; antiviral medication; antiviral therapeutic; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Biometry; Biometrics; Biostatistics; Blood; Blood Reticuloendothelial System; Chemistry; Clinical Research; Clinical Study; Clinical Trials; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environment; Exhibits; Goals; Graft Rejection; Transplant Rejection; Transplantation Rejection; Graft Survival; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; Kinetics; Laws; Lead; Pb element; heavy metal Pb; heavy metal lead; Leukocyte Adherence Inhibition Test; LAI Test; Manufactured Materials; Metabolism; Intermediary Metabolism; Metabolic Processes; Patents; Legal patent; Patients; Pharmacokinetics; Drug Kinetics; Pharmacology; Research; Investigators; Researchers; Research Personnel; Risk; Safety; Ovine; Ovis; Sheep; Technology; Testing; Toxicology; Transplantation; transplant; Universities; Virginia; Work; Drug Delivery Systems; Drug Delivery; Tacrolimus; Drug Monitoring; Injectable; Medical Care Costs; medical costs; Schedule; analytical method; base; method development; Organ; improved; Procedures; Prophylactic treatment; Prophylaxis; Area; Chronic; Clinical; Phase; Adolescent; Adolescent Youth; juvenile; juvenile human; Cytomegalovirus Retinitis; CMV retinitis; Cytomegaloviral Retinitis; Ensure; Intellectual Property; Therapeutic; tool; transplant patient; Transplant Recipients; drug blood level; Blood drug level result; Oral; subdermal; subcutaneous; meetings; Transplant Surgeon; experience; Performance; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; Maintenance Therapy; Therapeutic Index; Devices; Reporting; drug development; Documentation; pill; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Effectiveness; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; Address; Dose; Adherence; Animal Testing; Data; Polymer Chemistry; Regulatory Affairs; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; Preparation; Development; developmental; Calcineurin inhibitor; Calcineurin antagonist; medication compliance; drug adherence; drug compliance; medication adherence; pre-clinical; preclinical; pharmacokinetic model; Treatment Efficacy; intervention efficacy; therapeutic efficacy

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.

Public Health Relevance Statement:
PROJECT NARRATIVE Hundreds of thousands of patients depend on tacrolimus-based immunosuppression for the survival of their donated organs, which commonly develops after the transplantation procedure. Currently available oral tacrolimus formulations require daily dosing, and their variable drug release results in sub-therapeutic efficacy and toxicity-inducing peaks, which leads to poor healthcare outcomes. To address this important issue, we have developed a monthly injectable formulation of tacrolimus which will release in a linear manner and result in superior safety and effectiveness.

Project Terms:
AIDS; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunologic Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Oral Drug Administration; intraoral drug delivery; Oral Administration; Animals; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral compound; anti-viral drugs; anti-viral medication; anti-viral therapeutic; anti-virals; antiviral compound; antiviral medication; antiviral therapeutic; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Biometry; Biometrics; Biostatistics; Blood; Blood Reticuloendothelial System; Chemistry; Clinical Research; Clinical Study; Clinical Trials; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environment; Exhibits; Goals; Graft Rejection; Transplant Rejection; Transplantation Rejection; Graft Survival; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; Kinetics; Laws; Leukocyte Adherence Inhibition Test; LAI Test; Manufactured Materials; Metabolism; Intermediary Metabolism; Metabolic Processes; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Research; Research Personnel; Investigators; Researchers; Risk; Safety; Sheep; Ovine; Ovis; Technology; Testing; Toxicology; Transplantation; transplant; Universities; Virginia; Work; Drug Delivery; Drug Delivery Systems; Tacrolimus; Drug Monitoring; Injectable; medical costs; Medical Care Costs; Schedule; analytical method; method development; Organ; improved; Procedures; Prophylaxis; Prophylactic treatment; Area; Chronic; Clinical; Phase; Adolescent Youth; juvenile; juvenile human; Adolescent; CMV retinitis; Cytomegaloviral Retinitis; Cytomegalovirus Retinitis; Ensure; Intellectual Property; Therapeutic; Shapes; tool; Transplant Recipients; transplant patient; Blood drug level result; drug blood level; Oral; subcutaneous; subdermal; meetings; meeting; Transplant Surgeon; experience; Performance; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; Maintenance Therapy; Therapeutic Index; Devices; Reporting; drug development; Documentation; pill; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Effectiveness; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; Address; Dose; Adherence; Animal Testing; Data; Polymer Chemistry; Regulatory Affairs; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; validations; Preparation; preparations; Development; developmental; Calcineurin inhibitor; Calcineurin antagonist; medication compliance; drug adherence; drug compliance; medication adherence; pre-clinical; preclinical; pharmacokinetic model; intervention efficacy; therapeutic efficacy; therapy efficacy; Treatment Efficacy; Outcome; manufacturing process; cost effective; Population; innovate; innovative; innovation; FDA approved; product development; safety testing; commercial scale manufacturing; manufacturing ramp-up; scale up batch; scale up production; upscale manufacturing; manufacturing scale-up; good laboratory practice; phase 1 trial; phase I trial; Formulation; therapeutic toxicity; therapy associated toxicity; therapy related toxicity; therapy toxicity; treatment toxicity; treatment-associated toxicity; Treatment-related toxicity; inter-patient variability; interpatient variability; organ rejection; organ transplant rejection; safety and feasibility; pre-clinical development; preclinical development; health care outcomes; healthcare outcomes; care outcomes; patient variation; variability between patients; variation between patients; patient variability; first in man; first-in-human; Infrastructure; medication non-adherence; medication nonadherence; post-transplantation; posttransplant; posttransplantation; post-transplant; organ transplant recipient; pharmacologic; pre-Investigational New Drug meeting; Pre IND FDA meeting; Pre-IND mtg; pre-IND consultation; pre-IND discussion; pre-IND meeting; Good Manufacturing Process; Good manufacturing practice; manufacture