Long-acting injectable tacrolimus for chronic immunosuppression

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 (lt5 ng/ml) results in organ rejection whereas supra-therapeutic levels (rt15 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.