Kura Oncology, Inc. · NASDAQ:KURA
Kura Oncology — 9th European Scientific Oncology Conference (ESOC-9) (November 2016)
31 slides from Kura Oncology's conference presentation, Nov 4, 2016
Slide 1: Targeting the RAS-ERK Pathway
9th European Scientific Oncology Conference (ESOC-9) Targeting the RAS-ERK Pathway Antonio Gualberto MD PhD November 4, 2016
Slide 2: Forward-Looking Statements
FORWARD-LOOKING STATEMENTS This presentation contains forward-looking statements. Such statements include, but are not limited to, statements regarding our research, pre-clinical and clinical development activities, plans and projected timelines for tipifarnib, and our other programs, plans regardin
Slide 3: Kura Oncology
KURA ONCOLOGY • Clinical stage biopharmaceutical company engaged in the discovery and development of anti-cancer targeted therapies • Sites in La Jolla, CA (Research and HQ) and Cambridge, MA (Development) • Focused on the development of small molecules that target key cell signaling pathways and of
Slide 4: Kura's Two Most Advanced Programs Target the MAPK Pathway
KURA’S TWO MOST ADVANCED PROGRAMS TARGET THE MAPK PATHWAY • The MAPK pathway includes the signaling molecules Ras, Raf, MEK, and ERK. • Abnormal MAPK signaling may lead to: – increased or uncontrolled cell proliferation – resistance to apoptosis and – resistance to chemotherapy and targeted therapie
Slide 5: Pipeline of Selective Drug Candidates for Genetically Defined Cancers
PIPELINE OF SELECTIVE DRUG CANDIDATES FOR GENETICALLY DEFINED CANCERS Stage of Development Lead Anticipated Worldwide Preclinical Phase 1 Phase 2 Program Optimization Milestones Rights Additional data from HRAS mutant Solid Tumors Phase 2 1H 2017 Topline data Tipifarnib PTCL 1H 2017 * Farnesyl trans
Slide 6: Pipeline of Selective Drug Candidates for Genetically Defined Cancers
PIPELINE OF SELECTIVE DRUG CANDIDATES FOR GENETICALLY DEFINED CANCERS Stage of Development Lead Anticipated Worldwide Preclinical Phase 1 Phase 2 Program Optimization Milestones Rights Additional data from HRAS mutant Solid Tumors Phase 2 1H 2017 Topline data Tipifarnib PTCL 1H 2017 * Farnesyl trans
Slide 7: Tipifarnib – Farnesyl Transferase Inhibitor
TIPIFARNIB – FARNESYL TRANSFERASE INHIBITOR • Competitive inhibitor of CAAX peptide binding site of farnesyltransferase; In-licensed from Janssen • Extremely potent and highly selective inhibitor of farnesylation; no inhibition of GGTI • Previously studied in > 5,000 patients (70+ studies) • Managea
Slide 8: Mechanism of Action of Tipifarnib
MECHANISM OF ACTION OF TIPIFARNIB • Farnesyltransferase (FT) attaches farnesyl group to proteins, facilitating their localization to the inner membrane of the cell • Targets of FT include members of the RAS superfamily (KRAS/NRAS/HRAS) and other molecules critical for cell signaling • Blocking farne
Slide 9: HRAS as a Downstream Target of FTI
HRAS AS A DOWNSTREAM TARGET OF FTI • HRAS mutant HRAS G12V tumors are more sensitive to FTIs • Tumors with KRAS and NRAS mutations are less sensitive to FTIs 25 mg/kg BID results in <10% TGI in KRASm, 50% inhibition in RAS wt, and >80% TGI in HRASm 9
Slide 10: HRAS Mutant Solid Tumors
HRAS MUTANT SOLID TUMORS • HRAS mutant solid tumors include urothelial cancer (~15%), salivary gland tumors (SGT) (~15%), head and neck squamous cell carcinoma (SCCHN) (~5%) and other cancers (Data from TCGA) • HRAS is the predominantly mutated RAS species in urothelial cancer, SGT and SCCHN – More
Slide 11: Encouraging Phase 2 Data Supports HRAS Hypothesis in Head and Neck Cancer
ENCOURAGING PHASE 2 DATA SUPPORTS HRAS HYPOTHESIS IN HEAD AND NECK CANCER • Trial Design – 36 patient study in two 18-patient cohorts, each with a Simon two-stage design • Cohort 1: Thyroid cancer • Cohort 2: Other HRAS mutant solid tumors – Primary Objective: ORR. 10% (H0) vs 30% (H1) ORR hypothese
Slide 12: KO-TIP-001 (Stage 1): Evaluable SCCHN and SGT Patients
KO-TIP-001 (STAGE 1): EVALUABLE SCCHN AND SGT PATIENTS* *Preliminary data as of 20 Oct 2016 12
Slide 13: Questions
QUESTIONS • Why would HRAS mutant inhibition affect the progression of head and neck tumors ? • Why would FTI translate to tumor regression in SCCHN ? • Could tipifarnib address an unmet medical need in SCCHN ? 13
Slide 14: Role of HRAS in SCCHN
ROLE OF HRAS IN SCCHN • “A subgroup of oral cavity tumors…displays infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA...The three-gene constellation of wild-type TP53 with mutant HRAS and CASP8 suggested an alternative tumorigenesis pathway involving RAS an
Slide 15: Role of HRAS in Squamous Lung Cancer
ROLE OF HRAS IN SQUAMOUS LUNG CANCER • “Lung SqCCs share many alterations in common with head and neck squamous cell carcinomas without evidence of human papilloma virus (HPV) infection, including mutation in PIK3CA, PTEN, TP53, CDKN2A, NOTCH1 and HRAS, suggesting that the biology of these two disea
Slide 16: HRAS Mediates Resistance to Anti-EGFR Therapy in SCCHN
HRAS MEDIATES RESISTANCE TO ANTI-EGFR THERAPY IN SCCHN • HRAS mutations drive resistance to erlotinib and cetuximab in SCCHN cell lines 1,2 • RAS-mediated acquired resistance to cetuximab in SCCHN patients3 – 46% of patients with on-treatment disease progression showed acquired RAS mutations, while
Slide 17: HRAS Mutant Squamous Cell Carcinomas Are Resistant to Cetuximab but Sensitive to Tipifarnib
HRAS MUTANT SQUAMOUS CELL CARCINOMAS ARE RESISTANT TO CETUXIMAB BUT SENSITIVE TO TIPIFARNIB HRAS A146P Head & Neck SCC HRAS Q61K Lung SCC 1600 2000 1200 1600 1200 Tumor volume (mm3) 800 800 400 400 0 0 0 20 40 0 10 20 30 Vehicle 2000 1500 Cetuximab Tipifarnib 1500 1000 1000 500 500 0 0 0 10 20 30 0
Slide 18: Patient 005-005
PATIENT 005-005 • Elderly white male with a metastatic squamous head and neck cancer (primary tracheal tumor) • Non hotspot HRAS Q22K (and an INK4 gene deletion) – HRAS Q22K is likely a driver mutation • Observed in Costello syndrome (tumor predisposition due to germline HRAS mutations) • Equivalent
Slide 19: 005-005 CT Scans
005-005 CT SCANS 08/17/2015 (Baseline) 12/22/2015 (Cycle 4 Day 22) Provided by Alan Ho, MD, MSKCC 19
Slide 20: Patients 005-007 and 005-009
PATIENTS 005-007 AND 005-009 • Patients 005-007 and 005-009 are two male subjects with advanced oral cavity squamous head and neck tumors that carry the HRAS hotspot mutation Q61K – Both patients have wild type TP53, CASP8 and PIK3CA status 1 – Patient 005-007 presented 12 additional cancer-related
Slide 21: Patients 005-007 and 005-009
PATIENTS 005-007 AND 005-009 • Patient 005-007 – Experienced a disease stabilization with tipifarnib that lasted 7 months. – At that time, the patient left the tipifarnib study due to symptomatic deterioration (progression by imaging was not confirmed) • Patient 005-009 – Experienced a PR at C2D22 –
Slide 22: Conclusions / Discussion Points
CONCLUSIONS / DISCUSSION POINTS • A subset of SCCHN appears sensitive to FTI with tipifarnib – Additional SCCHN patients will be enrolled in KO-TIP-001 to verify the initial findings – Due to the commonalities between SCCHN and SCC-NSCLC, sensitivity of SCC- NSCLC to tipifarnib might be expected • H
Slide 23: KO-947 – Strong Activity in MAPK Pathway Models with Flexible Dosing
KO-947 – STRONG ACTIVITY IN MAPK PATHWAY MODELS WITH FLEXIBLE DOSING Rationale: • Aberrant signaling caused by mutations or tipifarnib dysregulation of the MAPK pathway Ras associated with numerous tumor types. • Inhibitors of Raf and MEK have validated ERK the MAPK pathway in cancer. Raf • Acquired
Slide 24: KO-947 Compares Favorably with Clinical Stage Competitor Compounds
KO-947 COMPARES FAVORABLY WITH CLINICAL STAGE COMPETITOR COMPOUNDS Compound KO-947 GDC-0994 BVD-523 Erk Enzymatic IC50 9.7 nM 14 nM 14 nM Kinase Selectivity >50X vs 415 kinases >50 fold* >1000X vs 75 kinases** Cellular p90RSK IC50 14 nM 179 nM 365 nM Cellular p90RSK Wash-out (24 hrs) 54 nM >10 uM -
Slide 25: KO-947 Is Broadly Active Against MAPK Pathway Mutant Cell Lines
KO-947 IS BROADLY ACTIVE AGAINST MAPK PATHWAY MUTANT CELL LINES 1200 KO-947 1000 GDC-0994 Proliferation IC50 (nM) 800 600 400 200 0 BRAF NRAS KRAS other • KO-947 is more potent than GDC-0994 in cell lines with MAPK activating mutations Kura Oncology data 25
Slide 26: KO-947 Demonstrates Prolonged Suppression of ERK Signaling
KO-947 DEMONSTRATES PROLONGED SUPPRESSION OF ERK SIGNALING Pharmacodynamic Modulation After a Single Oral Dose KRAS H2122 Model 0h 6h 24h 32h 48h 72h pRSK 50 mg/kg GAPDH pRSK 100 mg/kg GAPDH KO-947 pRSK 200 mg/kg GAPDH pRSK 300 mg/kg GAPDH pRSK GDC-0994 200 mg/kg GAPDH • Extended pharmacology of KO-
Slide 27: KO-947: Translational Research Identified Potential Lead Clinical Indications
KO-947: TRANSLATIONAL RESEARCH IDENTIFIED POTENTIAL LEAD CLINICAL INDICATIONS 2,500 Pancreatic 1000 Lung Colorectal 1000 MAPK Pathway Tumor volume (mm3) 2,000 KRASmut PDAC 800 KRASmut NSCLC KRASmut CRC KO-947 Q2d KO-947 Q2d 800 KO-947 Q2d Mutations 1,500 GEM KO-947 2Qw 5-FU 600 600 1,000 400 400 500
Slide 28: KO-947: Advancement to Clinical Testing
KO-947: ADVANCEMENT TO CLINICAL TESTING IND-enabling studies and preparation completed/ongoing Development IV route of administration selected for clinical studies Plans Potential biomarkers being characterized Anticipated IND submission 2H 2016 Milestones Initiate Phase 1 study 1H 2017 28
Slide 29: Overall Conclusions
OVERALL CONCLUSIONS • Although knowledge on the RAS-ERK pathway has accumulated in last 40 years, therapeutic development in this area has been limited • Tipifarnib and KO-947 might be able to provide clinical benefit in settings of unmet medical need by linking pharmacological intervention to RAS-
Slide 30: Acknowledgements
ACKNOWLEDGEMENTS • KO-TIP-001 investigators (Alan Ho, MD) and site study teams • Catherine Scholz and the Tipifarnib and KO-947 (ERK) Development Teams • Carrie Melvin, David Wages and the KO-TIP-001 Study Team • Francis Burrows, Dana Hu-Lowe, Yi Liu and the KO-947 Project Team • Our patients and th
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