SBIR-STTR Award

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi's) have emerged as important new therapeutic agentstargeting a broadening class of gene mutations present in breast, ovarian, prostate and a host of other cancers.These drugs have been targeted to patients and/or tumors with BRCA-related gene mutations, but not all patientswhose tumors have these mutations respond to PARPi. Equally important, this approach misses patients whomay benefit from PARPi since tumors without BRCA-related genes may respond. Trevarx Biomedical Inc.'s(Trevarx) first licensed product, [18F]fluorthanatrace ([18F]FTT), is a PET-labeled analog of the PARPi rucaparib,and provides quantitative images of regional PARP expression. Early clinical trial data in ovarian and breastcancer carried out at the University of Pennsylvania (Penn), Washington University in St. Louis (WU) and MDAnderson Cancer Center (MDACC) support the accuracy of [18F]FTT tumor uptake as an in-vivo measure ofregional PARP1 drug binding and indicate its potential as a more effective PARPi imaging predictive biomarker.[18F]FTT has an established body of published academic research and a 2-3 year lead over other competitivePET PARPi imaging agents that have only recently completed first-in-human studies.Trevarx has the goal of making [18F]FTT widely available for clinical use as a companion diagnostic for PARPitherapy. Partnering with MDACC, Penn, and WU, Trevarx is developing a Phase 2 multi-center clinical trial inbreast cancer that will lead to a subsequent Phase 3 trial to support an [18F]FTT NDA. To support this goal,Trevarx must develop the validated GMP synthesis and testing for [18F]FTT that is required to support eventualcommercial production for Phase 3 trials and NDA submission. This Phase 1 STTR proposal by Trevarx andPenn will determine the best method for synthesizing [18F]FTT for widespread distribution by maximizing productconsistency and production yield with the following aims: (1) Evaluate the synthesis yield and productionrobustness of [18F]FTT using two common GMP-compliant chemistry modules via two different synthesis routes;and (2) test the feasibility of simplifying [18F]FTT purification using solid-phase extraction methods. Completionof these aims will result in an optimized synthesis platform that will lead to a Phase 2 STTR effort to roll out atraining and compliance program to sites that will participate in Phase 2 clinical trials and develop [18F]FTT forproduction with a commercial PET radiopharmaceutical supply partner to assure broadly available tracer supplyfor Phase 3 multi-center trials and prompt clinical rollout after drug approval. RELEVANCE: To further the development and commercialization of [18F]fluorthanatrace ([18F]FTT), a PET tracer of PARP1 expression and drug binding, Trevarx Biomedical Inc. and University of Pennsylvania is proposing a Phase 1 STTR grant to determine the best method for synthesizing [18F]FTT for widespread distribution and maximizing product consistency and production yield. The proposed effort will result in an optimized synthesis that will support a broadly available tracer supply for Phase 3 multi-center trials and prompt clinical rollout after drug approval, enabling better guidance of PARPi treatment for many cancer patients. inhibitor/antagonist ; inhibitor ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Breast ; malignant breast neoplasm ; Breast Cancer ; malignant breast tumor ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Chemistry ; High Pressure Liquid Chromatography ; HPLC ; High Performance Liquid Chromatography ; High Speed Liquid Chromatography ; Clinical Trials ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Genes ; Goals ; Grant ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Methods ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Patients ; Pennsylvania ; Poly(ADP-ribose) Polymerases ; PARP Polymerase ; PARS ; Poly(ADPribose) Polymerase ; poly ADP polymerase ; poly ADP ribose synthetase ; Positron-Emission Tomography ; PET ; PET Scan ; PET imaging ; PETSCAN ; PETT ; Positron Emission Tomography Medical Imaging ; Positron Emission Tomography Scan ; Rad.-PET ; positron emission tomographic (PET) imaging ; positron emission tomographic imaging ; positron emitting tomography ; Production ; Prostate ; Prostate Gland ; Prostatic Gland ; Publishing ; Research ; Testing ; Time ; Translations ; Universities ; Washington ; Work ; Measures ; Drug Approval ; base ; Label ; Radiopharmaceuticals ; Radiopharmaceutical Compound ; radioactive drugs ; radiotherapeutic drugs ; Ovarian ; Site ; Solid ; Clinical ; repaired ; repair ; Phase ; Multicenter Trials ; Multi-center trial ; Training ; analog ; uptake ; Phase II Clinical Trials ; Phase 2 Clinical Trials ; phase II protocol ; programs ; Route ; System ; Gene Alteration ; Gene Mutation ; Tumor Cell ; neoplastic cell ; sterile ; Sterility ; Genomics ; Cancer Treatment ; Malignant Neoplasm Therapy ; Malignant Neoplasm Treatment ; anti-cancer therapy ; anticancer therapy ; cancer-directed therapy ; cancer therapy ; Malignant Ovarian Neoplasm ; Malignant Ovarian Tumor ; Malignant Tumor of the Ovary ; Ovary Cancer ; ovarian cancer ; Malignant neoplasm of ovary ; Molecular Interaction ; Binding ; Address ; Academia ; Data ; Grant Proposals ; Applications Grants ; Multi-center clinical trial ; Multi-site clinical trial ; Multicenter clinical trial ; Multisite clinical trial ; Multi-Institutional Clinical Trial ; in vivo ; Cancer Center ; Cancer Patient ; Small Business Technology Transfer Research ; STTR ; Tracer ; Radiolabeled ; Development ; developmental ; Image ; imaging ; anticancer research ; anti-cancer research ; cancer research ; Consumption ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; commercialization ; tumor ; predictive marker ; predictive biomarkers ; predictive molecular biomarker ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; quantitative imaging ; phase III trial ; phase 3 trial ; imaging agent ; companion diagnostics ; clinical translation ; first-in-human ; first in man ; early phase clinical trial ; early clinical trial ; feasibility testing ;

:Poly (ADP-ribose) polymerase inhibitors (PARPi's) have emerged as important therapeutic agents targeting abroadening class of gene mutations approved for treatment of breast, ovarian, prostate, and other cancers.Genomic assays of BRCA-related genes and tumor homologous repair deficiency are used as companiondiagnostics for PARPi therapy but have imperfect predictive efficacy for PARPi response. Trevarx BiomedicalInc.'s (Trevarx) product, [18F]Fluorthanatrace ([18F]FTT), a PET-radiolabeled analog of the PARPi, rucaparib,provides quantitative images of regional PARP expression and drug engagement for all approved PARPi's. Itcan thus serve as a PARPi companion diagnostic to identify those most likely to respond to PARPi therapy, andimportantly, those unlikely to respond. Over 175 patients imaged in single center clinical trials support theaccuracy of [18F]FTT tumor uptake as an in-vivo measure of regional PARPi drug binding, and as an effectiveimaging-based biomarker of PARP-1 protein levels. A pre-IND meeting with FDA suggested that approval wouldrequire: (1) a Phase 3 tissue correlating [18F]FTT uptake and PARP-1 protein expression in tumor samples and(2) multi-center Phase 2 studies of [18F]FTT's accuracy in predicting PARPi response. A 3-center Phase 2 trialPET-tissue comparison study has been initiated as a pilot for the larger Phase 3 trial, and striking new single-center Phase 2 results on [18F]FTT predictive accuracy strongly support Phase 2 multi-center trials underdevelopment. The focus of this proposal is to establish wide-spread radiopharmaceutical supply to support theexpanded multi-center trials needed for approval and subsequent clinical translation.With a 3 year competitive lead, [18F]FTT is projected to enter a Phase 3 tracer-tissue trial and multi-center Phase2 predictive efficacy trials to support an NDA in 2025. The steps described in this project will reduce the extendedtimeline for FDA approval that has been observed with previous PET radiotracers. Building on the success ofour Phase I STTR project (1R41CA2612590-01), this STTR Phase II proposal by Trevarx and Penn will minimizethis timeline by establishing methods for unifying radiosynthesis, maximizing product consistency and productionyield, and generating a database to manage a larger supply chain for [18F]FTT. We aim to establish a newparadigm for rapid commercialization of PET radiopharmaceuticals by providing a "best practice" template bycombining efforts in academic centers and commercial radiopharmaceutical supplier prior to Phase 3 toefficiently bring a novel PET radiotracer to market. Our STTR Phase II proposal establishes a roadmap to movefrom a single center academic trial to Phase 3 multi-center trials to efficient cGMP commercial production uponNDA approval. In this revised application, we provide more details on [18F]FTT production ( i.e., synthesis kitdevelopment and product formulation) and our strategy for the combined academic/commercial rollout of ourradiotracer to prepare for the Phase 3 multi-center clinical trial recommended by the FDA in our Pre-IND meeting.

Public Health Relevance Statement:
NARRATIVE: To develop and commercialize [18F]fluorthanatrace ([18F]FTT), a PET tracer that measures PARP-1 expression and PARP inhibitor target engagement, Trevarx Biomedical Inc. and the University of Pennsylvania are proposing a Phase II STTR project to develop an efficient method for synthesizing [18F]FTT for widespread distribution, one that maximizes product consistency and production yield. The proposed project will result in a standardized procedure that will support larger multi-center trials that can be easily adapted by commercial radiopharmacies to provide a widescale supply of [18F]FTT following FDA approval, thereby providing a valuable imaging biomarker that will enable better guidance of PARPi treatment for many cancer patients. This project is innovative since it will establish a new roadmap for the rapid commercialization of PET radiopharmaceuticals to efficiently bring novel PET tracers to market.

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