SBIR-STTR Award

The Problem: The limited availability of convenient and acceptable birth control methods has produced a global epidemic - uncontrolled population growth. This is inextricably linked to another public health problem, an epidemic of HIV (human immunodeficiency virus) and other sexually transmitted infections (STI). For women, a safe and effective vaginal contraceptive/microbicide would allow women to protect themselves, and help suppress these epidemics. Vaginal microbicide development has suffered numerous setbacks. No microbicide has been shown to be effective in recent clinical trials, and some may even increase the risk of acquiring HIV. Contraceptive development has also been limited - and the only non prescription widely available vaginal contraceptive - Nonoxynol -9 has serious safety concerns. Clearly, microbicide development needs to incorporate better preclinical methods for evaluating safety, develop combinations of active microbicidal ingredients to improve efficacy, and place more focus on their contraceptive effectiveness. NIH NICHD, NIAID) supports contraceptive research (NICHD), and development of methods to prevent STIs. Previous NIH funded accomplishments: PPCM is a second generation vaginal contraceptive/microbicide with the potential for HIV, HSV, HPV, and gonorrhea protection. PPCM inhibits HSV-2 infection of epithelial cells in culture and protects mice from genital herpes infection. PPCM, unlike other polyanions, is active in semen. PPCM is also contraceptive in vitro and in the rabbit. PPCM inhibits infections by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture and blocks transfer of HIV to target T-cells via migratory cells. When combined with tenofovir, PPCM shows synergistic anti-HIV activity in vitro. PPCM has been formulated into an aesthetically pleasing gel using GRAS ingredients at two concentrations. The gel maintains preclinical microbicidal and contraceptive activity, is lubricious and appears safe. SBIR Phase I grant goal and proposed project plan: The goals of our Phase I SBIR are to: a) finalize analytical methods for PPCM API and formulated gel in order to complete CGMP scale up and production;b) ensure PPCM can be scaled up from 20 gm quantities to production scale quantities of 1 kg;c) determine if PPCM is systemically absorbed via vaginal application in a rabbit model and;d) complete development of our preclinical, Phase 0 and Phase I clinical trial safety protocols. Accomplishing these goals will allow us to be prepared to conduct all work required to submit an IND application. Our long term goals are to: 1) launch PPCM as a contraceptive vaginal gel;2) to evaluate PPCM for prevention of non-HIV STIs (specifically HSV and gonorrhea) and;3) develop a contraceptive combination microbicidal product including an RTI with PPCM, to enhance HIV prevention and 3) to explore alternative delivery forms such as a vaginal tablet or vaginal ring.

Public Health Relevance:
Safe and effective contraception for women and the prevention of sexually transmitted diseases are closely linked. The goal of this Phase I SBIR is to further develop PPCM as a vaginal contraceptive microbicide. PPCM, a novel drug polymer, has received extensive preclinical evaluation in several major laboratories and is considered a very promising candidate for both contraception and sexually transmitted disease (STI) protection (1-5). As a microbicide, it has significant advantages in safety and effectiveness compared to other microbicides in development, and in combination with a reverse transcriptase inhibitor (RTI) promises to offer significant STI protection. As a contraceptive, PPCM has a dual mechanism for sperm inactivation. Unlike currently available spermicides, PPCM is not a surfactant and is not cytotoxic. This grant will provide funding necessary to complete a portion of the studies required by the FDA needed for submission of an IND application, and subsequent human clinical testing.

Thesaurus Terms:
9-(2-Phosphonomethoxypropyl)Adenine;9-(2-Phosphonylmethoxypropyl)Adenine;9-Pmpa;Aids Virus;Absorption;Acquired Immune Deficiency Syndrome Virus;Acquired Immunodeficiency Syndrome Virus;Animals;Blood Circulation;Bloodstream;Cell Culture Techniques;Cells;Circulation;Clinical;Clinical Evaluation;Clinical Testing;Clinical Trial Protocol;Clinical Trials;Clinical Trials, Phase I;Clinical Trials, Unspecified;Clinical Trial Protocol Document;Consultations;Contraception;Contraceptive Agents;Contraceptive Agents, Spermatocidal;Contraceptive Methods;Contraceptives;Contracting Opportunities;Contracts;Development;Drug Formulations;Drugs;Drugs, Investigational;Early-Stage Clinical Trials;Ensure;Epidemic;Epithelial Cells;Excretory Function;Fertility Control;Formulation;Formulations, Drug;Funding;Gel;Generations;Genital System, Female, Vagina;Goals;Gonococcal Infection;Gonorrhea;Grant;Hhv-2;Hiv;Hpv;Hsv;Hsv-2;Hsv2;Htlv-Iii;Herpes Genitalis;Herpes Simplex Virus;Herpes Simplex Virus 2;Herpes Simplex Virus Type 2;Herpes Simplex, Genital;Herpes Labialis Virus;Herpesvirus 2 (Alpha), Human;Herpesvirus 2, Human;Herpesvirus Hominis;Herpesvirus Progenitalis;Human;Human (Alpha) Herpes Virus 2;Human Herpesvirus 2;Human Immunodeficiency Viruses;Human Papillomavirus;Human T-Cell Leukemia Virus Type Iii;Human T-Cell Lymphotropic Virus Type Iii;Human T-Lymphotropic Virus Type Iii;Human Herpes Simplex Virus Type 2;Human, General;In Vitro;Infection;Infectious Human Wart Virus;Inhibition Of Fertilization;Intermediary Metabolism;Investigational Drugs;Investigational New Drug Application;Investigational New Drugs;Knowledge;Lav-Htlv-Iii;Label;Laboratories;Laboratory Infection;Link;Lymphadenopathy-Associated Virus;Metbl;Mammals, Mice;Mammals, Rabbits;Man (Taxonomy);Man, Modern;Manufacturer;Manufacturer Name;Measures;Medication;Metabolic Processes;Metabolism;Methods;Mice;Modeling;Molecular Weight;Murine;Mus;Niaid;Nichd;Nih;National Institute Of Allergy And Infectious Disease;National Institute Of Child Health And Human Development;National Institutes Of Health;National Institutes Of Health (U.S.);Nonoxynol 9;Oryctolagus Cuniculus;Papilloma Virus, Human;Papillomavirus, Human;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Phase 1 Clinical Trials;Phase I Clinical Trials;Phase I Study;Polymers;Population Growth;Prevention;Process;Process Of Absorption;Production;Protocol;Protocols Documentation;Public Health;Rabbit, Domestic;Rabbits;Radio;Research;Reverse Transcriptase Inhibitors;Risk;Samma;Sbir;Sbirs (R43/44);Std;Sttr;Safety;Semen;Seminal Fluid;Sexually Transmitted Diseases;Sexually Transmitted Disorder;Sexually Transmitted Infection;Simplexvirus;Small Business Innovation Research;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Sperm;Spermatocidal Agents;Spermatocidal Drugs;Spermatocides;Spermatozoa;Spermicidal Agents;Spermicidal Contraceptive Agents;T Lymphocyte;T-Cells;T-Lymphocyte;Tablets;Tenofovir;Testing;Thymus-Dependent Lymphocytes;Toxic Effect;Toxicities;United States National Institutes Of Health;Vagina;Vaginal;Vaginal Gel;Vaginal Jellies;Vaginal Ring;Venereal Diseases;Venereal Disorders;Venereal Infections;Virus-Genital Herpes;Virus-Hiv;Woman;Work;Absorption;Analytical Method;Base;Birth Control;Clinical Investigation;Clinical Test;Clinical Trial Phase I;Compare Effectiveness;Contraceptive Effectiveness;Contraceptive Microbicide;Cytotoxic;Design;Designing;Drug /Agent;Drug/Agent;Excretion;Genital Herpes;Good Laboratory Practice;Herpes Genitalia;Herpes Simplex Ii;Herpesvirus;Human Alphaherpesvirus 2;Human Herpesvirus 1 Group;Human Immunodeficiency Virus;Human Papillomavirus;Improved;In Vitro Activity;Method Development;Microbicidal;Microbicide;Model;Novel;Phase 1 Study;Phase 1 Trial;Phase I Trial;Polyanion;Pre-Clinical;Preclinical;Preclinical Evaluation;Prevent;Preventing;Protocol, Phase I;Public Health Medicine (Field);Research Clinical Testing;Safety Study;Scale Up;Sperm Cell;Spermaticide;Spermicide;Stability Testing;Surfactant;Tablet (Pharmacologic);Thymus Derived Lymphocyte;Vaginal Microbicide;Venereal Herpes;Wart Virus;Zoosperm

The goal of this project is to continue development of a novel, dual indication vaginal contraceptive anti-herpes microbicide product containing PPCM. We will conduct all tasks required to generate the Pharmacology/Toxicology and Chemistry Manufacturing and Controls (CMC) information required for IND submission, and outline the early clinical study designs with FDA. Development will be Go/No Go Decision and milestone driven to efficiently (resource, cost and time) evaluate the drug product in biologically relevant models for activity and safety, meet FDA and ICH requirements and manufacture drug and product suitable for early clinical trial material. We will address compliance issues experienced in recent HIV microbicide trials by developing three prototypes and evaluating their consumer acceptability, safety and efficacy; then selecting the superior product form for final preclinical studies. Within ten months of grant approval, prototype formulations of three different vaginal formulations (aqueous gel, ovule and thin film) will be quickly prepared using modified recipes from industry, analytically tested and evaluated in four non GLP models: 10-day Rabbit Vaginal Irritation (RVI), cutting edge in vitro models for safety, HSV-prevention in the mouse model and contraception in the rabbit (funded by NICHD) providing us with data to select one product form for further development. Utilizing the 1kg of PPCM manufactured by Regis Chemical in the Phase I SBIR, one dosage form will be selected, incorporating consumer feedback using vehicle control products, to be taken forward by a commercial contract manufacturer through thorough development of the product formula, process and package. The CMO will produce product for use in IND enabling GLP toxicology and product stability studies. Reasonably priced quotes were obtained from the most reputable CMOs in the field. From the initiation of Phase II SBIR grant approval, a pre-IND meeting briefing document will be compiled and issued. The document will be accompanied with IND development questions addressed to FDA for response. These will include questions to finalize the Pharmacology/Toxicology study protocols and Phase I-II clinical study designs. In parallel to that, preparations will be made for manufacturing and quality control testing of a 1kg GMP batch of drug substance (PPCM) for clinical use. The first item will be to implement the Quality Agreement (commitments by both parties to satisfy quality and regulatory requirements); manufacturing controls; and qualified/validated analytical test methods required to release and monitor the stability of the GMP lot of drug substance suitable for early clinical trials.

Public Health Relevance Statement:


Public Health Relevance:
The goal of this Phase II SBIR is to further develop Polyphenylenecarboxymethylene (PPCM) as a dual indication vaginal contraceptive microbicide. PPCM, a novel drug polymer, has received extensive preclinical evaluation by several major laboratories and is considered a very promising candidate for both contraception and sexually transmitted infections (STI) protection. Statistics from CDC inform us that there are 19 million new STI in the USA each year and 16.2% of adults have genital herpes (HSV). Moreover, 49% of all pregnancies are unplanned. As a microbicide, PPCM has significant advantages in safety and effectiveness compared to polyanion microbicides and in combination with a reverse transcriptase inhibitor (RTI) promises to offer significant STI protection. As a contraceptive, PPCM has a dual mechanism for sperm inactivation. During this grant we will also address the problem of consumer acceptance of vaginal products by seeking early consumer input on product aesthetics. This grant will provide funding necessary to select an aesthetically acceptable, safe and effective product form and complete all preclinical studies required by the FDA for submission of an Investigational New Drug (IND) application subsequent to human clinical testing.

Project Terms:
Address; Adult; Agreement; analytical method; Animals; aqueous; capsule (pharmacologic); Centers for Disease Control and Prevention (U.S.); Chemicals; Chemistry; Clinical; Clinical Research; clinical toxicology; Clinical Trials; compare effectiveness; Contraceptive Agents; Contraceptive methods; contraceptive microbicide; Contractor; Contracts; cost; Cyclic GMP; Data; Development; Dosage Forms; drug development; Drug Formulations; Esthetics; Evaluation; experience; Feedback; Film; Funding; Gel; Gelatin; genital herpes; GMP lots; Goals; Grant; HIV; Human; In Vitro; in vitro Model; in vivo; Industry; Investigational Drugs; Investigational New Drug Application; irritation; Laboratories; Liquid substance; Manufacturer Name; Marketing; meetings; Methods; microbicide; Modeling; Monitor; mouse model; Mus; National Institute of Child Health and Human Development; non-drug; novel; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; polyanion; Polymers; preclinical evaluation; preclinical study; Preparation; Prevention; Price; Process; product development; Production; Protocols documentation; prototype; public health relevance; Qualifying; Quality Control; Recipe; reproductive; research clinical testing; Research Design; Resources; response; Reverse Transcriptase Inhibitors; Safety; safety study; Sampling; Schedule; screening; Sexually Transmitted Diseases; Simplexvirus; Small Business Innovation Research Grant; sperm cell; statistics; Teleconferences; Testing; Time; Toxicology; Unplanned pregnancy; Vagina; vaginal microbicide; Water; Writing