SBIR-STTR Award

The long term goal of this research is to reduce toxicity and graft rejection due to dosing problems with the calcineurin inhibitors by developing sustained release subcutaneous injectable formulations for the drugs tacrolimus and cyclosporine. Substantial inter-and intra-patient variability means that even frequent drug monitoring cannot eradicate rejection due to sub-therapeutic troughs or toxicity due to higher than necessary peak levels. In addition, non-adherence with the daily oral dosing regimen is a major cause of graft failure especially in adolescent patients. Pharmacokinetic modeling suggests that periodic subcutaneous dosing can reduce or eliminate many of these problems. The potency and the long elimination half life of these drugs make them suitable for depot formulation. In previous work, supported in part through SBIR Phase 1 and 2 funding, the PI has developed sustained release formulations approved by the FDA for the treatment of CMV retinitis, and for uveitis. We have also developed an intraocular delivery formulation for cyclosporine that proved useful in clinical trials in posterior uveitis, a preliminary subcutaneous formulations of cyclosporine that demonstrated modest sustained release. We have now developed, in part with NIH SBIR funding, a platform delivery technology for subcutaneous injectable sustained release that has demonstrated promising results in vivo for other drugs, and that we believe is can achieve clinically useful sustained release for the calcineurin inhibitors. The specific aims of this proposal are: to formulate sustained release suspensions of tacrolimus (TAC) and cyclosporine (CsA); to test the in vitro release characteristics of these formulations; and to test the in vivo pharmacokinetics and the local safety of the formulations in animals. The demonstration of sustained release of tacrolimus (3 weeks) or cyclosporine (1 week) in the absence of clinically relevant toxicity in the rat model will constitute the milestones of this Phase 1 project. More than 50,000 transplants requiring immunosupression are performed annually and the market for immunosuppressive drugs is expected to reach $2.5 Billion annually by 2008. Thus there is a market opportunity, even for a drug formulation that helps only a minority of patients. Because the likelihood of success is high (we know the drugs work; we are only changing the delivery route), because the costs of clinical trials can be reclaimed under the tax provisions of the Orphan Drug Act, and because we have developed similar products before, we are confident that the successful completion of this work will culminate in a commercial product of significant medical utility

The long term goal of this research is to reduce toxicity and graft rejection due to dosing problems with the calcineurin inhibitors by developing a sustained release subcutaneous injectable formulation of a calcineurin inhibitor. Substantial inter-and intra-patient variability of the calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (Tac) means that even frequent drug monitoring cannot eradicate rejection due to sub- therapeutic troughs or toxicity due to higher than necessary peak levels. In addition, non-adherence with the daily oral dosing regimen is a major cause of graft failure especially in adolescent patients. Pharmacokinetic modeling suggests that periodic subcutaneous dosing can reduce or eliminate many of these problems. The potency and the long elimination half-lives of CsA or Tac make them suitable for depot formulation. In Phase 1 we developed sustained release formulations for cyclosporine and tacrolimus, measured there in vitro dissolution and demonstrated tolerability and sustained release in an in vivo model. We have decided to focus on the development of sustained release CsA in this Phase 2 proposal because it was easier to crystallize and demonstrated superior pharmacokinetics when tested in rats. In addition, because the patents for the parent drug have expired for CsA (and remain in effect for Tac until 2013), we believe that there will be more flexibility in partnering for further development. The specific aims of this Phase 2 proposal are to: 1, optimize the parameters of the sustained release CsA formulation; 2, manufacture clinical lots of the optimized formulation under GMP; and 3, perform animal toxicity and pharmacokinetic studies in rats. The team of investigators is expert in polymer chemistry, pharmacokinetics, and drug development and transplantation biology. We have experience in all aspects of the drug development process, from concept to approval and marketing. The PI led the team that developed two other FDA approved drug delivery systems. More than 50,000 transplants requiring immunosupression are performed annually in the largest 7 markets (US, Japan, Germany, Britain, Canada, France, Italy), and the market for immunosuppressive drugs is estimated at $2.9 Billion annually (2007). We recognize that a sustained release formulation of cyclosporine or tacrolimus will only ever be used in a small percentage of patients. However, each 1% of this market represents $29 million in market opportunity. Our business model is to license to 'big pharma' at the earliest opportunity. Because the likelihood of success is high (we know the drugs work, we are only changing the delivery route), because the costs of clinical trials can be reclaimed under the tax provisions of the Orphan Drug Act, and because we have done this kind of deal before, we are confident that the successful completion of this work will culminate in a commercial product of significant medical utility.

Public Health Relevance:
The leading cause of failure in heart, liver, and kidney transplants in children is that kids just stop taking their medicines. The beatific 8 year old who promises never to miss a day, is soon the spiky haired 14 year old who knows better about everything. Missing just a few days can be fatal. We have developed an injectable formulation for the immunosuppressive cyclosporine which has the potential to be delivered weekly, or even less frequently. Because of the long half life of cyclosporine, missing our injection by a day or two is not likely to be a serious problem. Parents can monitor a weekly or semi-monthly schedule much more carefully than daily dosing. An additional benefit of this delivery system is that peak levels that lead to toxicity are blunted, and trough levels, which can lead to failure, are less likely to occur. In Phase 1 we demonstrated proof of concept in an animal model. In Phase 2 we propose to optimize the parameters of the delivery system, manufacture it according to FDA standards, and confirm its delivery profile and safety in further animal studies.

Public Health Relevance Statement:
The leading cause of failure in heart, liver, and kidney transplants in children is that kids just stop taking their medicines. The beatific 8 year old who promises never to miss a day, is soon the spiky haired 14 year old who knows better about everything. Missing just a few days can be fatal. We have developed an injectable formulation for the immunosuppressive cyclosporine which has the potential to be delivered weekly, or even less frequently. Because of the long half life of cyclosporine, missing our injection by a day or two is not likely to be a serious problem. Parents can monitor a weekly or semi-monthly schedule much more carefully than daily dosing. An additional benefit of this delivery system is that peak levels that lead to toxicity are blunted, and trough levels, which can lead to failure, are less likely to occur. In Phase 1 we demonstrated proof of concept in an animal model. In Phase 2 we propose to optimize the parameters of the delivery system, manufacture it according to FDA standards, and confirm its delivery profile and safety in further animal studies.

Project Terms:
0-11 years old; 14 year old; 8 year old; Adherence; Adherence (attribute); Adolescent; Adolescent Youth; Animal Model; Animal Models and Related Studies; Animals; Biology; Businesses; Calcineurin antagonist; Calcineurin inhibitor; Canada; Canine Species; Canis familiaris; Child; Child Youth; Children (0-21); Ciclosporin; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; CsA; Cyclosporin A; Cyclosporine; Cyclosporine A; Cyclosporines; Cyclosporins; Development; Dogs; Dose; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Monitoring; Drug Targeting; Drug Targetings; Drugs; Drugs, Investigational; FDA approved; FLR; Failure (biologic function); Flexibility; Formulation; Formulations, Drug; France; Germany; Goals; Graft Rejection; Grafting, Kidney; Grant; Half-Life; Half-Lifes; Heart; Human, Child; Immunosuppressants; Immunosuppressive Agents; In Vitro; Individual; Injectable; Injection of therapeutic agent; Injections; Investigational Drugs; Investigational New Drugs; Investigators; Italy; Japan; Kidney Transplantation; Kidney Transplants; Knowledge; Lead; Legal patent; Licensing; Liver; Mammals, Dogs; Mammals, Rats; Mammals, Rodents; Marketing; Measures; Medical; Medication; Medicine; Method LOINC Axis 6; Methodology; Modeling; Monitor; Oral; Orphan Drugs; Parents; Patents; Patients; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Pliability; Polymer Chemistry; Process; Production; Protocols, Treatment; RGM; Rat; Rattus; Regimen; Renal Transplantation; Renal Transplants; Research; Research Personnel; Researchers; Rodent; Rodentia; Rodentias; Route; SCHED; Safety; Sandimmun; SangCya; Schedule; Science of Medicine; System; System, LOINC Axis 4; Tacrolimus; Taxes; Testing; Therapeutic; Time; Toxic effect; Toxicities; Transplant Rejection; Transplantation; Transplantation Rejection; Treatment Protocols; Treatment Regimen; Treatment Schedule; Work; body system, hepatic; canine; children; clinical investigation; clinical lot; commercialization; cost; domestic dog; drug development; drug/agent; eight year old; experience; failure; fourteen year old; graft failure; heavy metal Pb; heavy metal lead; immunosuppressive; in vivo Model; innovate; innovation; innovative; juvenile; juvenile human; model organism; neoral; novel; organ system, hepatic; particle; pharmacokinetic model; pre-clinical; preclinical; prevent; preventing; public health relevance; sandimmune; subcutaneous; success; transplant; youngster