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Oncoceutics leerink global healthcare 2015
- 1. INC. Leerink Global Healthcare Conference Wolfgang Oster, MD, PhD, Chief Executive Officer Lee Schalop, MD, Chief Business Officer February 12, 2015
- 2. • Novel class of compounds with orthogonal profile • Compelling efficacy in aggressive and refractory liquid and solid tumors • Agnostic to resistance to targeted therapy and chemotherapy • No dose-limiting toxicities at therapeutic or exaggerated doses in preclinical studies • Phase I/II trials activated in hematological malignancies and solid tumors • Landmark Alliance with MD Anderson for early clinical development in hematological malignancies • Solid tumor trials spearheaded by leading cancer centers under co- funding/non-dilutive structures (CINJ, MGH, FCCC) www.oncoceutics.com Synopsis 2
- 3. • Phenotypic screen selected to discover novel therapeutic mechanisms, unlike target screening • Goal of screen was to identify a small molecule that engages natural pathways that kill treatment-resistant tumor cells and leave normal cells unharmed www.oncoceutics.com Discovery of Novel Class 3 0 0.5 1 1.5 2 0.E+00 1.E+04 2.E+04 3.E+04 4.E+04 5.E+04 TRAILReporterInduction Reporter Signal CancerCellsNormalCells Dividing CellsDead Cells Cell Cycle Analysis Sub-G1
- 4. • Uses a differentiated mechanism to manipulate a collection of signaling pathways that cancer cells rely on and that the immune system has evolved to eradicate them www.oncoceutics.com Engaging Critical Cancer Pathways 4 JAK/STAT • Some of the most successful oncology pathways are engaged: • Growth factor/ Ras signaling • ER stress • Immunosurveillance
- 5. www.oncoceutics.com • Novel pharmacophore, distinct from approved/investigational drugs > NCI library > Pubchem • Proprietary salt • Highly stable and soluble • Orally active • Penetrates BBB • Unique PK/PD enables infrequent dosing Chemical Characteristics 5 0 250 500 750 1000 1250 1500 ONC201 Temozolomide Vorinostat Bortezomib Ibrutinib #RelatedCompounds Structure Similarity Search of >63 Million Known Compounds ONC201 Angular Structure
- 6. • Chemical and biological studies have revealed a structure- activity relationship (SAR) • The unique therapeutic potential of ONC201 is extended to a specific subset of analogs • A host of properties can be manipulated to open additional therapeutic opportunities: • Potency • Activity spectrum • PK • Metabolism • Biodistribution www.oncoceutics.com Analog Program 6
- 7. www.oncoceutics.com Compound Use Phase Status ONC201 po Solid Tumors Phase I Enrolling ONC201 po Liquid Tumors Phase I/II Initiating ONC201 po + chemo Solid & Liquid Tumors Phase Ib Protocol development ONC201 iv Alternative to po Pre-IND Active ONC201 (alternative formulation) Alternative clinical utility Pre-clinical Active ONC201 analog 1 Various Tumor Types Pre-clinical Active ONC201 analog 2 Various Tumor Types Pre-clinical Active Portfolio • Oncoceutics has several products in different stages of preclinical to clinical development • Clinical applications of ONC201 include diverse tumor types and other products provide alternative drug profiles and potential applications 7
- 8. www.oncoceutics.com Discovery of Unexpected Activity • ONC201 was previously deemed inactive by NCI in vitro, providing intellectual property opportunities • This observation increased the need for external validation 8
- 9. Patent Issued • Method of Use in Brain Cancer Patents Pending • Method of Use in Other Cancers • Novel Salts • Dosing • Schedule • Formulations • Combination with Other Drugs • Methods of Administration • Analogs (COM) www.oncoceutics.com Intellectual Property 9
- 10. Keith Flaherty, MD – Clinical development Hensin Tsao, MD, PhD – Mutant BRAF melanoma Andrew Chi, MD and Tracy Batchelor, MD, PhD – GBM Michael Andreeff, MD, PhD and Hagop Kantarjian, MD – Leukemia, SPORE Michael Wang, MD & Larry Kwak, MD – NHL Madeleine Duvic, MD – Sezary syndrome Andreas Hayes Jordan, MD - DSRCT Anthony Conley, MD – Sarcomas Joseph Bertino, MD – Prostate Cancer Bruce Haffty, MD – Radiation, SCC Fahd Al-Mulla, MB, ChB, PhD, FRCP – Breast cancer , KFAS Foundation funded Haiching Ma, PhD – Target identification Cyril Benes, PhD (Harvard) –1,000 cancer cell line panel External Validation Martine Piccart, MD – Breast CancerKensuke Kojima, MD, PhD – Proteomics Wafik El-Deiry, MD, PhD, FACP – Combinations, MOA Anthony Olsznaski, MD – Phase I dose intensification 10www.oncoceutics.com
- 11. • Efficacy: Preclinical profile has been validated by multiple leading investigators in state-of-the-art refractory models: • Cell lines (>500) • Primary patient samples (>25) • In vivo models (xenografts, orthotopic, transgenic) • Safety: No effects on normal cells or normal tissues in GLP toxicology at >10 therapeutic dose Reproducible Efficacy and Safety Profile www.oncoceutics.com 11 NOAEL >10-fold therapeutic dose Species dose (mg / kg) Human equivalent dose (mg)* Ratio to Expected Therapeutic Dose Cohort 1 0 0 N/A Cohort 2 12.5 125 1 Cohort 3 125 1250 10 Cohort 4 225 2250 18 Cohort 1 0 0 Cohort 2 4.2 125 1 Cohort 3 42 1250 10 Cohort 4 120 3571 28.6 * Allometrically scalled to a human fixed dose Rats Dogs
- 12. • Effective in tumor cells with complex resistance to powerful approved anti-cancer therapies: • Interim analysis of MGH/Sanger/Wellcome Trust 1000 cell line panel screen confirmed mutation-agnostic efficacy across 428 genes curated for cancer relevance Efficacy in Therapy-Resistant Cancers www.oncoceutics.com 12 • 5-FU (Efudex) • Doxorubicin (Adriamycin) • Temozolomide (Temodar) • Cetuximab (Erbitux) • Gefitinib (Iressa) • Erlotinib (Tarceva) • Trastuzumab (Herceptin) • Lapatinib (Tykerb) • Vemurafenib (Zelboraf) • Ibrutinib (Imbruvica) • Bortezomib (Velcade)
- 13. SpecificApoptosis • ONC201 is active in blastic (mt p53) MCL patient samples • Robust ONC201 activity is observed in ibrutinib- refractory MCL Ishizawa and Andreeff et al. ONC201 Kills Highly Resistant Lymphomas Apoptosis: www.oncoceutics.com 13
- 14. • Single dose oral ONC201 doubled the survival of mice with intracranial brain tumors • In combination with Avastin, ONC201 tripled the survival of mice with intracranial brain tumors and was well tolerated 0% 50% 100% 0 50 100 Survival Days Control TIC10 bev TIC10 + bev BeforeRx1week Vehicle ONC201 ONC201 + bevONC201 bevVehicle ONC201 Kills Brain Tumors www.oncoceutics.com Allen and El-Deiry et al 14
- 15. New GBM IC50 GBM8: 300 nM GBM18: 4-5 uM Recurrent GBM IC50 GBM67R: 4 uM GBM152: 700-800 nM • ONC201 kills primary GBM cells in 3D culture (neurospheres) enriched for cancer stem cells • Effective in both newly-diagnosed and recurrent GBM samples ONC201 Kills Brain Tumors Andrew Chi and Tracy Batchelor www.oncoceutics.com 15
- 16. SpecificApoptosis ONC201 Kills Tumor But Not Normal Cells • ONC201 does not induce apoptosis in normal bone marrow at highly efficacious doses www.oncoceutics.com Ishizawa and Andreeff et al. 16
- 17. www.oncoceutics.com SpecificApoptosis • Depletion of cancer stem cell efficacy has been documented in several aggressive cancers in vitro : AML, GBM, CRC ONC201 Kills Cancer Stem Cells Ishizawa and Andreeff et al. 17 • ONC201-induced anti-cancer stem cell effects have also been demonstrated in several CRC models in vivo
- 18. NHL, MM, leukemias, and GBM selected based on: • Robust induction of apoptosis • Consistent efficacy in primary patient samples • Sensitivity pattern • GI50/potency • Confirmed by MGH/Sanger/Wellcome Trust screen • Engages relevant mechanisms for these tumors • Medical need indications with expedited approval options • Indications with attractive addressable market opportunity • Broad and diverse clinical program: multiple shots on goal www.oncoceutics.com Tumor Type Selection Criteria for Clinical Trials 18
- 19. Active Clinical Trials • Cancer Institute of New Jersey: Phase I Solid Tumors • MD Anderson Cancer Center: Phase I/II Leukemia Clinical Trials in Initiation • MD Anderson Cancer Center: Phase I/II Lymphoma Planned Clinical Trials • MGH / Dana Farber: Phase II GBM Additional Opportunities www.oncoceutics.com Clinical Trials 19
- 20. • Oncoceutics and collaborative groups have been awarded the following highly competitive grants for research and development • Represents significant endorsement of the novelty, therapeutic potential, and commercial viability of the company’s technology by NCI and others Competitive Grant Awards Title Amount Institution/ Mechanism Development and Commercialization of Novel Cancer Therapeutic TIC10 $1.3mm PA DOH Commercialization Grant Target Identification of ONC201, a First-in-Class Drug to Treat Glioblastoma $25,000 Musella Foundation Clinical Efficacy of the Antitumor Agent ONC201 in GBM $1.15mm NIH SBIR (Impact Score 20; pending official notice) TRAIL Upregulation by TIC10 Analogs $225,000 NIH SBIR TIC10 anti-tumor effect through regulation of Foxo3a and TRAIL $1.9mm NIH RO1 www.oncoceutics.com 20
- 21. • Significant validation through partnerships with leading cancer centers • Creating awareness and interest with key opinion leaders • Non-dilutive funding >$10mm ONC201 Academic-Corporate Partnerships 21www.oncoceutics.com
- 22. • Funding in place to complete phase I/II programs with >150 patients at >4 clinical sites • Expected to arrive at clinical results to devise NDA- directed strategy • Interested in development/commercial partnerships for lead compound ONC201 and analogs www.oncoceutics.com Looking Forward Through 2016 22