IND-enabling preclinical development of a sustained-release Pritelivir intravaginal ring for the treatment and prophylaxis of Genital Herpes in women

SUMMARY (changes are underlined) The broad, long-term goal of this project is to develop a pritelivir intravaginal ring (IVR) for the treatment and pre-exposure prophylaxis of genital herpes, a common problem that affects more than 50 million Americans. Recurrences are common and may be painful. Infection is life-long. Pritelivir is a promising α-helicase inhibitor that proved superior to existing therapies in Phase 2 clinical trials, but whose clinical development as a systemic therapy has been arrested because of toxicity. Local therapy is therefore of special interest. We have developed a platform technology for the sustained release of antivirals. This technology led to the development of a ganciclovir intraocular implant - Vitrasert®, for the treatment of AIDS-related cytomegalovirus retinitis. The Vitrasert® is the only sustained release antiviral drug delivery product to be ever approved by the FDA. We have adapted this platform to IVRs and have successfully delivered other antiviral agents at therapeutic levels in preclinical and clinical trials. We propose to utilize this platform to develop sustained release IVR formulation for pritelivir. We achieved the specific aims of Phase I of this proposal which were to formulate sustained release intravaginal rings delivering pritelivir, to test the in vitro release characteristics of these formulations, and to test the in vivo safety and pharmacokinetics (PK) of the formulations in the FDA- approved sheep model. The successful completion of Phase I has enabled us to identify an IVR dose for the further development of a drug product that is safe, demonstrates sustained release for 28 days at satisfactory cervicovaginal fluid and tissue drug levels that will provide high potential efficacy. We, therefore, propose in Phase II to accomplish the FDA-mandated scientific and regulatory activities required to enable an Investigational New Drug (IND) approval. We propose to develop GMP manufacturing capacity for clinical lots of the lead formulation; to conduct a 3-month GLP, IND-enabling safety study in a sheep model to examine local and systemic toxicity of extended IVR use; to perform manufacturing process development, including product testing assays and early validation; to transfer manufacturing and analytical methods to a contract manufacturing organization; to perform IND-enabling chemistry, manufacturing and controls (CMC) activities for an IND submission; to complete and submit all clinical documents; and to coordinate all activities to submit an IND application to the FDA. The milestone for the successful completion of the proposed Phase II work is the approval of an IND to perform a first-in-human exploratory clinical trial. In Phase IIB of this grant, we will test the lead formulation for safety, PK and efficacy in HSV+ve volunteers. The team of investigators is expert in drug development, synthetic chemistry, pharmacokinetics, and clinical infectious disease. We have experience in collaborating with large pharmaceutical companies to enable New Drug Approvals (NDAs) of novel drug delivery systems. This project could lead rapidly to the development of an improved treatment and prophylaxis for genital herpes.NARRATIVE The broad, long-term goal of this project is to develop a pritelivir intravaginal ring for the treatment and pre- exposure prophylaxis of genital herpes, a common problem that affects more than 50 million Americans. On average, recurrences occur 4 times a year, and infection is life-long. Pritelivir is a promising α-helicase inhibitor that proved superior to existing therapies in Phase 2 clinical testing, but whose clinical development as a systemic therapy has been arrested because of toxicity. Local therapy is therefore, of special interest. We have developed a ring technology platform and have successfully delivered other antiviral agents at therapeutic levels in animal models and in clinical trials. Based on this platform, in a Phase I SBIR grant, we formulated pritelivir rings, and demonstrated safety and clinically relevant pharmacokinetics in an FDA-approved sheep model. We, therefore, propose a Phase II SBIR proposal to perform FDA-mandated Chemistry, Manufacturing and Controls (CMC), pre-clinical in vivo studies and protocol development in order to enable an Investigational New Drug (IND) approval. Successful completion of this work will lead to first-in-human clinical trial in a follow- on Phase IIB SBIR proposal.