The National Cancer Institute’s NExT Program Michael J. Difilippantonio, Ph.D. Program Manager for Therapeutic and Diagnostic Initiatives, DCTD, NCI October 02, 2012 Objectives • Division of Cancer Treatment and Diagnosis (DCTD), NCI • The NCI Experimental Therapeutics (NExT) Program • The Application and Review Process Division of Cancer Treatment and Diagnosis (DCTD), NCI • • • • • • • • Biometrics Research Branch (BRB) Cancer Diagnosis Program (CDP) Cancer Imaging Program (CIP) Cancer Therapy Evaluation Program (CTEP) Developmental Therapeutics Program (DTP) Radiation Research Program (RRP) Translational Research Program (TRP) Office of Cancer Complimentary and Alternative Medicine (OCCAM) FDA Approved Therapeutics Developed with Assistance from the NCI in Last Decade Year Agents Role of NCI Mechanism of Support 2010 Sipuleucel (Provenge®) RAID project National Cooperative Drug Discovery Grant 2010 Eribulin (Halaven®) Natural product discovery; screening; formulation of clinical product; efficacy testing; clinical candidate selection; firstin-human trial DCTD/DTP Frederick labs; 2009 Pralatrexate (Folytin®) RAID project; NCI produced GMP bulk drug DCTD/DTP contract resources for production of GMP quality bulk drug 2009 Romidepsin / Depsipeptide (Istodax®) Developed safe human dosing schedule in large animals; PK and Tox; produced drug for clinical trials; conducted first-inhuman trials in NIH CC DCTD/DTP pharmacology and toxicology and drug production 2007 Topotecan (Hycamtin®) 2004 Cetuximab (Erbitux®) Produced first lots for imaging and chimeric clones DTP Contracts; Cooperative Drug Discovery Grant 2004 5-Azacytidine (Vidaza®) Pre-clinical molecular pharmacology; produced pre-clinical and clinical drug supply; conducted pivotal trial DTP Contracts; Frederick 2003 Bortezomib (Velcade®) Extensive analog screening; MOA and PD studies; PK & Tox; clinical formulation DCTD/DTP Frederick labs; formulation, PK, Tox 2000 Temozolomide (Temodar®) Scale up synthesis and clinical formulation DCTD/DTP bulk drug and formulation contracts Selected NCI/CTEP-sponsored Group Trials Contributing to FDAapproved Indications for New Oncology Agents in Last Decade Year Agents Group Company 2007 Lapatininb (Tykerb®) Deoxycoformycin (Pentostatin®) NCCTG, CALGB, Intergroup 2006 Dasatinib (Sprycel®) Sunitinib (Sutent®) Pegaspargase (Oncaspar®) SWOG, Intergroup ECOG, Intergroup BMS Pfizer Enzon 2005 Lenalidomide (Revlimid®) Nelarabine (Arranon®) Sorafenib (Nexavar®) ECOG, Intergroup COG, CALGB ECOG, Intergroup Celgene GSK Bayer / Onyx 2004 5-Azacytidine (Vidaza®) Bevacizumab (Avastin®) Erlotinib (Tarceva®) Taxotere (Doxetaxol®) CALGB ECOG. Intergroup NCCTG, Intergroup SWOG Celgene Genetech Genentech / OSI Sanofi-Aventis 2002 Oxaliplatin (Eloxitin®) NCCTG, Intergroup Sanofi-Aventis 2001 Imatinib mexylate (Gleevec®) Letrozole (Femara®) COG, SWOG NCIC, Intergroup 2000 Arsenic trioxide (Trisenox®) CALGB GSK Bedford Labs Novartis Novartis Cell Therapeutics What’s NExT? Transformation of the NCI Therapeutics Pipeline Cancer Centers NIH Roadmap Biotech & Pharma RO1/PO1 SPORE MLPCN Intramural Imaging / IDG DDG RAID The NCI Experimental Therapeutics (NExT) Pipeline: Target discovery through early stage clinical trials Exploratory Screen Development Screening/ Designed Synthesis Drug Discovery Lead Development Candidate Seeking Clinical Candidate Early Development Phase 0 / I Trials Phase II/III Trials Registration Full Development Harmonize Activities into Single Pipeline Post Launch NExT Governance NOT A GRANT PROGRAM • Clear path to clinic/patient benefit • Provides access to NCI resources and drug development expertise • Integrates a variety of prior decentralized and uncoordinated programs • Simple application • PI has project involvement A Unique Partnership with the NCI to Facilitate Oncology Drug Discovery and Development • • • • Complete development of an orphan drug Exploratory screen development and optimization Preclinical development for molecularly targeted agents Develop formulation and manufacture GMP grade drug to conduct IND-enabling pre-clinical and clinical studies • A pharmacodynamic assay or imaging technique to determine if an agent is modulating its target • Proof-of-concept or first-in-human studies • Other resources to support drug discovery and development NExT Resources Currently Support • • • • Investigational drugs, biologics and NP’s Investigational imaging agents Academic, biotech and pharma projects HTS, Hit-to-Lead, Lead Optimization, Clinical Candidate, Phase 0, 1 and 2 clinical trials NOT basic research August 2009 Chemical Biological Consortium (CBC) Mission Dramatically increase the flow of early-stage drug candidates into the DCTD therapeutics pipeline by leveraging knowledge from innovative research and discoveries made at leading academic institutions and biotechnology companies And Provide the extramural community the opportunity to participate in a highly collaborative drug discovery partnership with the NCI Chemical Biological Consortium (CBC) • Comprehensive Chemical Biology Screening Centers (4)  Identify targets, develop assays and adapt these assays to HTS platforms, screen numerous compounds against a variety of different assays each year, and provide Structure- Activity Relationship (SAR) analysis • Specialized Application Centers (3)  Provide expertise and experience in specific technologies needed to successfully develop and implement complex and technically difficult assays that may not be amenable to HTS • Chemical Diversity Centers (4)  Capable of applying medicinal and synthetic chemistry to advance hits to lead status Chemical Biological Consortium (CBC) University of Minnesota Chemical Diversity Center The Fragment Discovery Center (FDC at UCSF) The University of Pittsburgh Chemical Diversity Center (UP-CDC) The University of Pittsburgh Specialized Application Center VT NH MA RI CT NJ DE SRI International The NIH Chemical Genomics Center (NCGC) DC Georgetown University Medical Center Sanford Burnham Institute Vanderbilt Institute of Chemical Biology Southern Research Emory Chemical Biology Discovery Center North Carolina Comprehensive Chemical Biology Center Gain early access to enabling, leading-edge translational technologies and tools • • • • • PK/PD Modeling Tox/Safety Pharmacology GMP Scale-Up Imaging supported by Cancer Imaging Program Development and validation of PD assays during preclinical stages is supported by the Pharmacodynamics Assay Development & Implementation Section (PADIS) and during clinical stages by the National Clinical Target Validation Laboratory (NCTVL). • Clinical Assay Development Program (CADP) development and validation of clinical assays (including diagnostic). • Currently sponsors over 100 INDs • Approx. 11,000 registered investigators at over 3,300 institutions • Over 750 active protocols • 150-250 new protocols/year • Approx. 30,000 patients accrued/year • Over 80 collaborative agreements (CRADAs, CTAs, and CSAs) with pharmaceutical companies (Collaborators) • Concept application – 5 pages – – – – – – Background Hypothesis Research strategy Specific request to NCI Justification Uniqueness • Appendices – – – – IP Information Current and pending support PI biosketch Other Documentation as appropriate • This selection is based on the following criteria. – Scientific Merit – Feasibility – NCI Mission – Novelty – Clinical Need Scoring: 1 = Exceptional 3 = Excellent 6 = Satisfactory 9 = Poor • Special consideration to unmet needs in therapeutic oncology, including "undruggable" targets, orphan malignancies, and pediatric cancer External Input Internal Scientific Decisions Resource Allocation Senior Advisory Committee (SAC) http://next.cancer.gov/ Cycle Open for Submission Submission Deadline January 15, 2013 February 15, 2013 May 15, 2013 September 15, 2013 June 15, 2013 October 15, 2013 NCI next or next at NCI Applications from Academic, Non-Profit, Biotech, Pharma or Government sector through 9/2011 Total Applications (Total 235) Top Tier (Total 40) • Applications – SEP members and Federal employees are subject to Confidentiality in relation to NExT Applications. COI conditions do apply. • CDA’s (Confidential Disclosure Agreements) – Necessary when brining in non-NExT staff and outside experts for additional review. • Collaborative Agreements – A variety of mechanisms necessary to memorialize interactions between the applicant and the NExT program, will vary based on stage/type of project. (CBC Participant’s agreement, MTA, CTA, Collaborative Agreement, CRADA). NExT Pipeline – Phase and Agreement Types Chemical Biology Consortium target discovery through lead compound CBC Consortium Agreement Formerly RAID and DDG – “Mid-phase projects CTEP – Sponsored Clinical Trials “NExT MTA”, CDA’s, MTA’s CTA’s, CRADA’s and CSA’s subject to CTEP IP Option Associated Agreement Slide Graphic courtesy of Barbara Mroczkowski Early Stage - CBC • Utilizes the CBC Agreement mechanism – The advantage of this system is that all work can be done under a single agreement that includes provisions for confidentiality – The disadvantage is that no tangible Intellectual Property rights or options can be conferred under this agreement, making it unsuitable for late stage development Mid Stage Projects – Lead Compound through Phase 0/1 • NExT MTA • “Not-to-file” language in these agreements for NCI internal studies • Non-SAIC Contractors have language in their contracts wherein they are required to offer the first option to negotiate an exclusive or non-exclusive license • SAIC contractors subject to third party language described in the DEC Late Stage Projects – CTEP Sponsored Clinical Trials • Utilizes CRADA’s, CTA’s and CSA’s to bring in agents for clinical studies • IP terms for both NCI use and for cooperative group trials (CTEP IP Option), new language may have some reach through on downstream inventions. • CTA’s – quicker but many collaborators dislike them due to the lack of IP terms on NCI inventions (IP Option still applies), we may not bring in money under a CDA either (other than direct payments to contractors • CRADA’s – time consuming but allows the NCI to bring in funding support from Collaborators and offer licensing rights to the Collaborator Question Can the applicant get his/her HTS results back and then submit, for example, an R01 application based on these hits? Can he/she establish commercialsponsored research agreements supporting the project further in his/her laboratory, or does the NExT program have “rights” to the project indefinitely? Answer A PI may leave with his/her project and forego any further use of NExT resources; however, the NCI retains the right to continue with the project independently if it so chooses: “Materials generated by the CBC will also be defined deliverables and be available to the government for use and future development.” “Yes” to both submitting R01 applications and establishing commercial agreements. Question To what extent is the project’s originating PI involved? Who decides the scope of work to be performed within NExT and the “exit point” for the project from the NExT program? Can the PI influence these decisions? Answer The PI is an integral member of the Project Team. As a PI you are privy to all information related to your project as it moves through the various Stage Gates into the clinic. As part of the project team, you oversee the scientific direction of the project to ensure that it stays on course to meet key milestones. External SEPs in conjunction with NCI Committees will monitor project progress through Stage Gates and will prioritize projects in the NCI pipeline. Receptor targeted optical agent for tumor margin detection – request to NCI • Optimize the protein-dye reaction: time, temperature, ratios • Verify targeting in vitro and in vivo • Establish purity - >95% mass and optical purity • Evaluate stability, formulation • Transfer to biologics GMP contractor • IND directed toxicology • Assistance with IND filing Therapeutic with imaging • Protein drug totally species specific • No meaningful toxicology possible • NCI project team determined that imaging first would best protect human subjects – Much lower dose – Biodistribution to determine off-target • NCI prepared chelates for PET and SPECT – Stability, dosimetry, in vitro bioactivity • FDA negotiation on - going