IND-enabling Preclinical Development of a Sustained-release Pritelivir Intravaginal ring for the Treatment and Prophylaxis of Genital Herpes

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SUMMARY 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 30 million Americans. Recurrences are common and may be painful, and infection is life-long, yet few treatment options exist. Pritelivir is a promising α-helicase inhibitor that has been proven superior to existing therapies in Phase 2 clinical trials, but whose clinical development as a systemic therapy has been slowed due to observed unexplained systemic toxicity in primates. Therefore, pritelivir-based local therapy is of special interest. We have developed a platform technology for the sustained release of antivirals. This technology has successfully led to the development and commercialization of a ganciclovir intraocular implant – Vitrasert®, for the treatment of AIDS-related cytomegalovirus retinitis. This platform has been adapted to IVRs and through its use we have successfully delivered other antiviral agents at therapeutic levels in preclinical and clinical trials. We seek to utilize this platform to develop a sustained release IVR formulation for pritelivir. We achieved the specific aims of our Phase I and II SBIR, which were to: formulate pritelivir-releasing IVRs; test their in vitro release and in vivo safety and pharmacokinetics (PK) in animals; perform chemistry, manufacturing, and controls (CMC) activities; develop clinical documents; and submit an Investigational New Drug (IND) application to the FDA. The successful completion of this Phase I/II SBIR work has enabled us to identify an IVR dose for the further development of a drug product that is safe and demonstrates sustained release for 28 days and at clinically relevant levels. The IND has been placed on Clinical Hold, pending completion of additional nonclinical pharmacology and toxicology studies, CMC testing, and device evaluation. We, therefore, propose in Phase IIB to accomplish the FDA-guided nonclinical activities required to enable an IND allowance. The proposed Specific Aims of this Phase IIB SBIR are to: develop GMP-grade manufacturing capacity for the drug substance; conduct pharmacology and toxicology studies in rodents and nonrodents; manufacture GMP- grade drug product; perform device testing in accordance with CRDH’s comments; and re-submit an IND application to the FDA. The milestone for the successful completion of the proposed Phase IIB work is the approval of an IND to perform a first-in-human exploratory clinical trial for a pritelivir IVR. In future work, we will test the lead formulation for safety and PK in female volunteers in accordance with our FDA-approved clinical protocol. The team of investigators are experts in drug development, synthetic chemistry, pharmacokinetics, and clinical infectious disease, and have experience 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.