Re-Engineering Early Phase Cancer Drug Development: Decreasing the Time from Novel Target to Novel Therapeutic
Re-Engineering Early Phase Cancer DrugDevelopment: Decreasing the Time from Novel Target to Novel Therapeutic James H. Doroshow, M.D. Deputy Director for Clinical & Translational Research National Cancer Institute, NIH 16th Annual Drug Discovery Symposium Robert H. Lurie Comprehensive Cancer Center & Center for Molecular Innovation & Drug Discovery Northwestern University Chicago, IL October 12, 2011
Most Drugs Fail in Late Stages of Development: Particularly in OncologyRates of success for compounds entering firstin man that progress to subsequent phase All indications • 70% of oncology drugs that enter Phase 2 fail to enter Phase 3 • 59% of oncology drugs that enter Phase 3 fail • Late stage failure leads to enormous risk • Failure is primarily due to lack of efficacy>toxicity Kola & Landis; Nature Reviews Drug Discovery 2004
Standard Drug Development Pipeline: Re-envisioned Hypothesis Clinical Generation Candidate Development Commercialization Drugs Assays Trials $1200 MM Cumulative Investment Risk Target $500-600 MM Validation Target/ Molecule Assay Lead Preclinical Discovery Development Optimization Development Phase Phase Phase Regis- Global Global I II III tration Launch Optimization Lead Generation $200-300 MM $20-60 MM RiskGOAL: Time: 12-15 Years Time: 6-8 Years
Therapeutics Discovered / Developed by NCI from Preclinical Stage Approved by FDA Past DecadeYear Agents Role of NCI Mechanism of Support2011 18F-NaFluoride Produced agent; filed first-ever NDA from an DCTD Frederick personnel; (PET Bone Scans) NIH Institute: developed distribution system extramural contracts; DCTD after NDA approved; bone scans absent 99Tc regulatory support2010 Eribulin Natural product discovery; screening; clinical DCTD/DTP Frederick labs; formulation; efficacy testing; clinical candidate analytical, formulation, PK, selection; first-in-human trials by NCI toxicology contracts; RO1 grant; U01 grant2009 Pralatrexate RAID project; NCI produced GMP bulk drug DCTD contract resources for production of GMP quality bulk drug2009 Romidepsin (Depsipeptide) Developed safe human dosing schedule in large DCTD/DTP pharmacology and animals; PK and Tox; produced drug for clinical toxicology and drug trials; conducted first-in-human trials in NIH CC production contracts; Frederick animal facilities2004 Cetuximab Produced first lots for imaging; chimeric Frederick Biologics Contracts; clones; NCI Drug Development Group Grantee Coop. Drug Discovery Grant2004 5-Azacytidine Pre-clinical molecular pharmacology; produced DTP Contracts; Frederick Labs; pre-clinical and clinical drug supply; conducted U01 Grants pivotal trial2003 Bortezomib Extensive analog screening; MOA and PD DCTD/DTP Frederick labs; studies; PK & Tox; clinical formulation formulation, PK, Tox contracts2000 Temozolomide Scale up synthesis and clinical formulation DCTD/DTP bulk drug and formulation contracts
NCI’s Approach to Discovering & Developing More Anticancer Drugs• Provide better discovery and development tools ü Public availability of screening data from approved & investigational agents ü Targeted combinations—in vitro and in vivo• Facilitate academic discovery per se• Provide structured resources to transition from R01 target discovery to the clinic
US FDA Approved Anticancer Agents Activity in the NCI 60 panel: Potency in µMName NSC # Mean GI50 Mean TGI50 Mean LC50Signaling agentsBortezomib 681239 0.00051 0.0063 3.6Dasatinib 732517 0.33 8.9 51Erlotinib 718781 5.5 59 >90Everolimus 733504 0.095 14 56Gefitinib 715055 3.2 19 49Imatinib 743414 15 43 81Lapatinib 745750 2.9 20 61Nilotinib 747599 2.9 13 49Sorafenib 747971 1.9 6.0 30Sunitinib 750690 2.2 9.6 31Temsirolimus 683864 0.038 51 >100Romidepsin 630176 0.00025 0.0081 0.038Vorinostat 701852 0.94 17 70 Molec. Cancer Ther. 9: 1451-1460, 2010
Plated Drug Sets: Dilution Serieshttp://dtp.cancer.gov/branches/dscb/oncology_drugset_explanation.html
Transformation of the NCI Therapeutics Pipeline Cancer SPORE RO1/PO1 Biotech & Small Pharma CentersRoadmap Intramural Imaging/IDG RAID DDG CBC Created The NCI Experimental Therapeutics (NExT) Pipeline: Target discovery through early stage clinical trials Exploratory Screening/ Phase 0 / Early Phase Screen Designed Lead Candidate Clinical II Trials I Trials Development Synthesis Development Seeking Candidate Drug Discovery Early Development 8
Where Did We Need to Go?Rapid translation of discoveries into public health benefits Created NCI Experimental Therapeutics Program (NExT): Unified Discovery & Development utilizing NCI Frederick as a Critical Resource A single pipeline for all therapeutic development resources: One Pipeline, Many Points of Entry NExT Program Coop Grps INCLUDES Targets • Investigational drugs and biologics Therapeutics • Investigational imaging agents and theranostics • Academic & Biotech & Pharma projects • Includes Phase 0, I and II Programs
Goals of the NExT Program• Develop treatments for unmet medical needs (e.g, rare cancers and pediatric tumors) • Provide resources for natural product development and the development of high risk targets • Move discoveries from TCGA into drug discovery • Support development of biological agents • Develop qualiﬁed PD and predicEve molecular markers for the clinic • Focus on discovery and development projects from academic invesEgators and small biotechs
NCI Chemical Biology Consortium (CBC)• Mission: Dramatically increase flow of early stage drug candidates into NCI therapeutics pipeline• Vision:• Develop integrated network of chemists, biologists, and molecular oncologists, with synthetic chemistry support ü Active management by NCI and external advisory boards ü Unify discovery with NCI pre-clinical and clinical development ü Linked to other NCI initiatives; NCI Intramural chemistry integral partner• Focus on unmet needs in therapeutics: “undruggable” targets, under-represented malignancies• Enable a clear, robust pipeline all the way from target discovery through clinical trials for academic, small biotech, and pharma investigators FRONT END: NCI’s Experimental Therapeutics Platform 11
Chemical Biology Consortium Vision Why is CBC different?• Builds on >50 yrs of NCI experience in cancer drug development• Not intended to replicate Pharma NCI• CBC members will submit own projects and take on those of other investigators• Focus on bringing academic targets Discovery Risk and molecules to patients• Will not shy away from difficult Biotech targets• Longer time horizon• NCI committed to supporting CBC Big projects from inception through proof-of-concept, PD-driven clinical Pharma trials if milestones achieved: Only NCI could do this• Inclusive involvement of CBC members in shared projects Market Risk developed in parallel across consortium
Multiple Entry Points into the NExT Exploratory Screen Screening/ Development Designed Lead Development Candidate Clinical Synthesis Seeking Candidate Parallel Optimal Efficacy in Target Primary HTS medicinal potency/ pivotal in vivoidentification chemistry selectivity models Model Development and Small Animal Early Stage Later Stage Assay Target Validation Imaging Center Pharmacodynamics Validation
Therapeutics Discovery & Development Support Provided by NCI (NExT)• Medicinal chemistry, HTS, lead op7miza7on • Enhanced synthesis of small molecules and pep7des • Scale-‐up produc7on of small molecules, biologicals, & imaging agents • Isola7on and puriﬁca7on of naturally occurring substances • Development of early stage, clinical pharmacodynamic assays • Exploratory toxicology studies and pharmacokine7c evalua7on • PK/PD/eﬃcacy/ADME studies (bioanaly7cal method development) • Development of suitable formula7ons • Range-‐ﬁnding ini7al toxicology and IND-‐directed toxicology • Product development planning and advice in IND prepara7on • Later-‐stage preclinical development of monoclonal an7bodies, recombinant proteins, and gene therapy agents • Manufacture of drug supplies • Analy7cal methods development for bulk material; formula7on • CLIA-‐grade clinical assay development for later trials • Produc7on of clinical dosage forms • Stability tes7ng of clinical dosage forms • Regulatory support and early phase trials
NCI Experimental TherapeuticsHow Does An Extramural Investigator Access NCI’s Drug Discovery and Development Resources?
NExT Application Process Extramural scientists may propose targets, screens, ormolecules for entry into the NExT pipeline; 3 receipt dates per year https://dctd.cancer.gov/nextapp or https://dctd.cancer.gov/nextregistration
NExT Pipeline: Oversight and Decision Support Anticipate ~20-30 projects in the pipeline per year
Prioritization Process Used To Ascertain Which Compounds To Move Forward?• This selection is based on the following criteria. – Scientific Merit Scoring: 1 = Exceptional – Feasibility 3 = Excellent – NCI Mission 6 = Satisfactory – Novelty 9 = Poor – Clinical Need• A Stage Gate evaluation process to benchmark the progress and priority of projects within the portfolio• This evaluation process is also to provide guidance about the priority utilization of the capacity – based resources provided by NCI
265 NExT Applications Received in Cycles 1-8 Source of NExT Applications
LDHA: Therapeutic Target in Cancer• The proto-oncogene c-myc can drive glutamine as well as glucose metabolism. In cancer, c-myc deregulation can result in the added uptake of glucose and its conversion to lactate, thereby contributing to the “Warburg Effect”.• ChIP sequencing confirmed that Lactate Dehydrogenase A (LDHA), an enzyme that converts lactate to pyruvate, is a direct downstream target of Myc.• Knockdown of LDHA decreased colony formation and reduced the growth of tumors in breast and lung cancer xenografts.• Japanese families that completely lack LDHA are otherwise normal except for exertional myopathy.• FX11 is a selective, small molecule, active site LDHA inhibitor identified from a malarial LDH screen that provides proof-of-concept for targeting cancer metabolism in human lymphoma and pancreatic cancer models.
FX11 Treatment Leads to Regression of Tumorsin Lymphoma and Pancreatic Xenograft Models Lymphoma Pancreas FX11
LDHA : Next Steps Screen development and Hit to Lead Lead Optimization Candidate Seeking high-throughput screening Primary uHTS NCGC: hit validation/med Co-crystallization with HTS “hits” chemistry NIH Chemical Genomics Center Secondary biochemical and cell-based screens Dang Lab FX11 Lead Compound Ki 4 uMü HTS screen to identify new scaffoldsü Co-crystallization with FX11ü Optimize SAR for lead compound FX11, increase potency and improve solubility
Portfolio Stratified by Agent Class Natural Product Imaging 5% 3% Biologic 35% Small Molecule 57% Projects that are closed or awaiting resourcing are not included
Interim Project Evaluation Projects Closed by NExT Bayer Healthcare (Including Legacy Projects from RAID) In-House Target Validation Nat. Rev. Drug Discov. 10: 643-‐644, 2011 3% 33% 33% 64% 67% § Results Not Replicated § Results Not Replicated § Reproducible § Did Not Meet Milestones § Not applicable
ASSAYS: Proof of Mechanism in Early Trials• Demonstrate drug action on intended tumor target (proof of mechanism) in a human malignancy early in development – evaluate hypotheses surrounding mechanism of action per se – evidence of target modulation in the clinic assists decision to move agent forward, or not . . . – evaluate relationship of drug schedule and systemic exposure to target effects; examine relevance of marker chosen to represent target modulation – prior to expectation of efficacy• Potential to investigate molecular effects of the agent in non- malignant tissues – relevance of ‘surrogate’ tissues – genetic toxicology• NOT: predictive of clinical benefit – only later stage (larger) trials can define relevance of target modulation to tumor growth inhibition Clin. Cancer Res. 14: 3658-3663, 2008
Developing the ‘Right’ Assay Toolsfor Early Stage Proof of Mechanism Studies
Clinical Qualification of PD Assay: “Humanizing” Preclinical Models “Clinical Readiness” of PD Assay:Therapeutically relevant in preclinical model: Replicate the clinical setting inwhich the assay will be practiced: • Clinical procedures for sample acquisition and handling • Storage requirements and transferability • Time frames achievable in clinical setting • Inter- and intratumoral variability • Stability of baseline • Minimum doses required for target effect; does target inhibition correlate with altered tumor growth or toxicity in vivo • Suitability of surrogate tissues • Actually works when you do a “DRY RUN” Now You Can Start!
Comparing Effect of Four Tumor Harvest Methods on phosphoAKT Levels phospho-AKT +C C011 Untreated Jurkats Resection After CO2 SAC Resection After CO2 SAC (Cell Signaling #9271) Cryobiopsy + Anesthesia Cryobiopsy + Anesthesia Resection + Anesthesia Resection + Anesthesia FNA + Anesthesia FNA + Anesthesia200140 pAKT Settings100 Min 20.0 80 Max 75.0 60 60 kDa 1 min exp. 50 40 30 368 β-Actin Actin Settings Min 20.0 Max 3000.0 30 sec exp. Separated on an 8% Tris-Gly Gel
Indenoisoquinolines • Unique, non-camptothecin Topo I inhibitors; chemically stable • Prolonged Topo I-Drug-DNA complex formation • Unique patterns of DNA cleavage • Not substrates for ABCG2 efflux pump • Produce dose- and time-dependent DNA double strand cleavage demonstrable as phosphorylation of the H2AX histone • Low cross-resistance with camptothecin analogs (irinotecan; topotecan) • Discovered by Yves Pommier (NCI intra- mural program); developed by DCTD • FIH Randomized NCI Phase I trial of NSC 724998 vs 725776 Develop comprehensive PD package for proof of mechanism evaluation PRIOR to first-in-human studies
Development of a Validated ELISA for Topo I Quantitation: Indenoisoquinoline First-in-Human Trial Topo I ELISA Correlation of Topo I mRNA (Array) to Protein (ELISA) in NCI 60 Cell Panel 12 R2 = 0.6915 HRP Y Y Y Topo I (ng/mL/µ g protein) Y Y 10 Y 8 Top1 6 Y 4 2 Y = MAH IgM MAb C21 (BD) capture Ab Y = RAH pAb Ab28432 (AbCam) primary Ab 0 Y-HRP= GAR-HRP-XSA secondary Ab 50 100 150 200 250 300 350 400 (XSA =extra serum absorbed) Topo I mRNA (average microarray intensity)Comparison of Topo I Protein by Western Blot Effect of Topotecan on to Protein (ELISA) Topo I Activity in vitro (ELISA) 100 ELISA WB 75 Relative Topo I level 50 25 A375 Melanoma 0 HCT-116 HT-29 H322M SR SKMEL28 A498 HL-60* Molec. Cancer Ther. 8: 1878-1884, 2009
Topoisomerase I Inhibition and Correlation with Efficacy In Vivo Using Topo I ELISATopoisomerase I Levels in Xenograft Extracts AAXR2-18, YKR2-39, YPR2-2, AAYR2-17 Treated with Topotecan or Vehicle Control Effect of NSC 724998 on Topo I Levels in A375 Xenografts Topo 1 (ng/ml/µg ptn) Vehicle Control 4h Topotecan (15 MG/KG) treated + NSC 724998 (mg/kg) Vehicle Controls Solid red line = Avg vehicle control Dashed red line = Avg ± 1 and 2 SD Black line = Dose Response
Pharmacodynamic Assay Development for Proof of Mechanism Early Phase Trials: A Resource Intensive Enterprise REQUIRES • Develop “FDA-quality” assays for target status, downstream effects, and toxicity markers • Relate drug effect markers to tumor effect and drug exposure in preclinical models of Phase 0/1 target lesions • Develop procedures for biopsies of tumor and normal tissues using clinical instruments that provide samples available for biomarker assay development that mimic what is available in the clinic • Formalize biopsy, specimen handling, and analytical assays as SOPs • Implement PD assay SOPs in clinical arena of operations • Conduct laboratory analysis of clinical specimens • Laboratory QA/QC; qualify outside labs for testing, and prepare qualifying sample sets and analytes to disseminate technology
Current Stages of Therapeutics Development: Trials N=30 N=300 N=3000 FDA Phase I Phase II Phase III
Improving the Impact of Early Clinical Trials Target Assessment Preliminary estimate accuracy of measurement of drug effect on target Downstream molecular interactions Early read on efficacy Understanding toxicitySupporting assays N=10-60 N=200-300 N=600-800 FDAin model systems Target Development Qualify Assays Target Validation Initial Proof of Mechanism Comparative benefit of target inhibitionOptimize Association of MOA with efficacy “Phase 0” Assay Minimum data to define safety
Target Inhibition as the Endpoint of a Phase II Trial: Proof of Concept Study of Oral Topotecan in Advanced Solid Neoplasms Expressing HIF-1αNCI-05-C-0186: Giovanni Melillo, MD PI • Eligibility: HIF-1α +ve solid tumors of any histology (>10% of tumor cells by IHC) • Treatment: Oral chronic topotecan (1.2 mg/m2 PO daily x 5 days x 2 wks q28 days) • Primary endpoint: Inhibition of HIF-1α expression in tumor • Schema: Biopsy PET Biopsy DCE-MRI PET PET CT CT DCE-MRI DCE-MRI D1 D8 D29 D36 Cycle 1 Cycle 2 PD endpoints: • IHC (MVD, Glut-1) • mRNA expression (HIF-1 target genes, VEGF, PGK-1, CAIX) • serum/plasma markers (VEGF, osteopontin) • CEP (circulating endothelial precursor cells)
Pilot Study of Oral Topotecan in Advanced Solid Neoplasms Expressing HIF-1αü Accrual: 16 patients • 12 evaluable: 1 melanoma, 1 bladder, 1 breast, 2 ovarian ca., 1 SCLC, 1 bladder, 1 H/N, 4 CRC [PRs in SCLC, Ovarian cancer] • 4 not evaluable: 1 ASPS, 1 adrenal, 1 colon, 1 pancreasü Toxicities: myelosuppression, diarrhea (first 2 pts., at 1.6 mg/m2), well tolerated at 1.2 mg/m2 HIF-1α staining in patient #4 (breast cancer) Baseline Biopsy After 2 Cycles of Topotecan Clin. Cancer Res. 17: 5123-5131, 2011
Evolution of the Oncologic Drug Development Paradigm 1991 2011• Develop estimates of response • Perform flexible evaluations of rates and characterize side effects therapeutic activity and toxicity over a in a non-randomized fashion broad range of continuous endpoints• For minimally pretreated patients • For a wide variety of: acceptable subjects, prior treatments, extent and with measurable disease after evaluability of disease and “standard” therapy performance status• In a specific tumor type • In a wide range of genotypically,• With a drug (that has a non- rather than histologically, specific specific mechanism of action) diseases, under conditions that allow assessment of the biochemical effect of an intervention in tumor and normal tissue • With one or more molecules that produce specific effects on defined targets (as well as possible off-target interactions) • Using the minimum necessary data set to assure the safety and efficacy of a novel therapy
DCTD Division of Cancer Treatment and Diagnosis Accelerating Cancer Diagnosis and Drug Development v Developmental v DCTD Therapeutics Jason Cristofaro Jerry Collins Joe Tomaszewski Barbara Mrochowski Melinda Hollingshead Ralph Parchment v CTEP Robert Kinders Jamie Zweibel Tom Pfister Jeff Abrams Myrtle Davis Bev Teicher Shivaani Kummar v Cancer Imaging Paula Jacobs v Center for Cancer Research Yves Pommier v Cancer Diagnosis Lee Helman Barbara Conley Bob Wiltrout Mickey Williams William Bonner
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