Stifel Healthcare Conference

Transcription

1 Stifel Healthcare Conference November 13-14, 2018 DEVELOPING PRECISION MEDICINES TO TREAT CANCER

2 Forward-Looking Statements This presentation contains forward-looking statements. Such statements include, but are not limited to, statements regarding our research, preclinical and clinical development activities, plans and projected timelines for tipifarnib, KO-947 and KO-539, plans regarding regulatory filings, our expectations regarding the relative benefits of our product candidates versus competitive therapies, and our expectations regarding the therapeutic and commercial potential of our product candidates. The words believe, may, will, estimate, promise, plan, continue, anticipate, intend, expect, potential and similar expressions (including the negative thereof), are intended to identify forward-looking statements. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: our future preclinical studies and clinical trials may not be successful; the U.S. Food and Drug Administration (FDA) may not agree with our interpretation of the data from clinical trials of our product candidates; we may decide, or the FDA may require us, to conduct additional clinical trials or to modify our ongoing clinical trials; we may experience delays in the commencement, enrollment, completion or analysis of clinical testing for our product candidates, or significant issues regarding the adequacy of our clinical trial designs or the execution of our clinical trials may arise, which could result in increased costs and delays, or limit our ability to obtain regulatory approval; our product candidates may not receive regulatory approval or be successfully commercialized; unexpected adverse side effects or inadequate therapeutic efficacy of our product candidates could delay or prevent regulatory approval or commercialization; and we may not be able to obtain additional financing. Additional risks and uncertainties may emerge from time to time, and it is not possible for Kura s management to predict all risk factors and uncertainties. All forward-looking statements contained in this presentation speak only as of the date on which they were made. Other risks and uncertainties affecting us are described more fully in our filings with the Securities and Exchange Commission. We undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. 2

3 Nasdaq: KURA Kura Oncology Investment Highlights Developing precision medicines for genetically defined cancers with significant commercial potential Positive Phase 2 trial in HRAS mutant head and neck squamous cell carcinomas (HNSCC) for lead program, tipifarnib Significant association observed between HRAS mutant allele frequency and clinical benefit Registration-directed trial in HRAS mutant HNSCC initiated in November 2018 AIM-HN to enroll at least 59 patients, take approximately two years to enroll CXCL12 pathway identified as potential biomarker for tipifarnib in blood cancers Preliminary data from AITL and CXCL12+ cohorts in Phase 2 trial of PTCL at ASH 2018 Additional pipeline opportunities KO-947: Potent and selective ERK inhibitor in Phase 1 dose-escalation study KO-539: IND submission for menin-mll inhibitor anticipated in first quarter of 2019 Strong cash position: $187.4 million in cash as of September 30, 2018* Expanded leadership team with proven oncology drug development experience * Cash, cash equivalents and short-term investments 3

4 Product Candidate Pipeline PROGRAM PRECLINICAL CLINICAL PROOF OF CONCEPT PIVOTAL Tipifarnib Farnesyl Transferase Inhibitor Solid Tumors with HRAS Mutations Hematologic Malignancies Head and Neck Squamous Cell Carcinomas (HNSCC) Squamous Cell Carcinomas (excluding HNSCC) Peripheral T-cell Lymphomas (PTCL) Myelodysplastic Syndromes (MDS) KO-947 ERK Inhibitor KO-539 Menin-MLL Inhibitor Myeloid Neoplasias* Solid Tumors Acute Leukemias Investigator-Sponsored Trials HRAS Mutant Urothelial Carcinomas, Samsung Medical Center HRAS Mutant Lung Squamous Cell Carcinomas (LSCC), Spanish Lung Cancer Group * Myelodysplastic/myeloproliferative neoplasms (MDS/MPN), including chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) 4

5 Pipeline with Large Market Opportunity PROGRAM TUMOR TYPE EST. POPULATION BASED ON ANNUAL U.S. INCIDENCE* Tipifarnib Farnesyl Transferase Inhibitor KO-947 ERK Inhibitor KO-539 Menin-MLL Inhibitor Solid Tumors with HRAS Mutations Hematologic Malignancies HNSCC 2,900-4,700 LSCC 1,200-1,800 PTCL 2,000 MDS 3,000 AML 5,850 CMML 350 HNSCC 10,000-20,000 KRAS mut NSCLC 24,500 BRAF mut NSCLC 5,000 MLL-rearranged leukemias 3,200 NPM1 mut /DNMT3A mut AML 8,800 * Estimates of the biomarker-positive subset for each indication Estimate is between 5-8% of total HNSCC population, depending on allele frequency of HRAS mutations (Source: The Cancer Genome Atlas and internal data) Biomarker still under evaluation for these indications 5

6 Tipifarnib (Farnesyl Transferase Inhibitor)

7 Tipifarnib: Selective Farnesyl Transferase Inhibitor with Substantial Prior Clinical Experience Extremely potent and selective inhibitor of farnesyl transferase 1 licensed from Janssen Well characterized >5,000 patients treated in >70 prior studies Anecdotal activity of durable responses but developed before advent of personalized medicine approaches, including genetic selection Manageable safety profile as single agent therapy (< 25% treatment discontinuation) Tipifarnib adverse events (reported from 472 solid tumor patients): Myelosuppression (neutropenia 25%, anemia 31%, thrombocytopenia 19%) Non-heme > 25%: fatigue (41%) and GI unspecific (nausea 47%, anorexia 33%, diarrhea 32%, vomiting 32%) Tipifarnib 1 End et al Cancer Res 61:

8 Farnesylation is Required for HRAS Activity Normal FTase Tipifarnib Inhibits FTase Cell membrane Cell membrane HRAS FTase Tipifarnib FTase HRAS (mutant) HRAS HRAS HRAS (wild-type) Farnesyl transferase (FTase) attaches farnesyl group to proteins, facilitating localization to the inner cell membrane Membrane localization is required for HRAS signal transduction activity Blocking farnesylation prevents wild-type and mutant HRAS membrane localization NRAS and KRAS are susceptible to redundant forms of prenylation, but HRAS can only be farnesylated 8

9 KO-TIP-001: Phase 2 Proof-of-Concept Trial Solid Tumors with HRAS Mutations Cohort 1: Thyroid Cancer Cohort 2: Other / HNSCC Cohort 3: SCC (excluding HNSCC) Enrollment ongoing HNSCC Extension Enrollment ongoing Key eligibility: No curative therapy available, HRAS mutation, measurable disease (RECIST v1.1); ECOG performance status 0 or 1 Primary endpoint: Objective response rate (ORR) 1 Primary endpoint achieved in HRAS mutant HNSCC Sep 2017 Update on HRAS mutant HNSCC and preliminary results in HRAS mutant SCC Oct Objective response includes 30% tumor shrinkage as defined in RECIST 1.1 guideline (See A. Eisenhauer et al., Eur. J. Cancer 45 (2009): ) 9

10 HNSCC Patients (n=17 on study + 1 patient treated off protocol) Ho et al. European Society for Medical Oncology 2018 Congress #1046O Preliminary results as of 9/7/18 * Response confirmed on 10/15/18 10

11 HNSCC Patients Response By Prior Therapy Ho et al. European Society for Medical Oncology 2018 Congress #1046O Preliminary results as of 9/7/18 11

12 Other SCC Patients (n=6) Ho et al. European Society for Medical Oncology 2018 Congress #1046O Preliminary results as of 9/7/18 12

13 Association of HRAS Mutant Allele Frequency with Clinical Benefit from Tipifarnib (HNSCC, SCC, n=20) Ho et al. European Society for Medical Oncology 2018 Congress #1046 Study KO-TIP-001 patients with HN and non-hn SCC tumors with available HRAS mutant allele data (10/17/18); one additional HNSCC patient was treated off protocol Allele frequency for additional HNSCC PR available post-esmo=27.5% not included Pending analysis: 1 HNSCC pending 1st scan, 1 SCC pending 1st scan, 1 SCC SD 13

14 Phase 2 Trial: Conclusions Clinical proof-of-concept of tipifarnib demonstrated in recurrent/metastatic HNSCC carrying HRAS mutations Preliminary clinical activity observed in other SCCs Significant association observed between allele frequency and clinical benefit Rapid and durable responses Activity in disease resistant to chemotherapy, cetuximab and immunotherapy Adverse events consistent with known safety profile of tipifarnib Ho et al. European Society for Medical Oncology 2018 Congress #1046O 14

15 Resolution of Disfiguring Skin Lesions with Tipifarnib Post-Immunotherapy Failure Patient : 69-year-old male with recurrent oral cavity SCC Prior therapies: TPEx (docetaxel CDDP cetuximab), nivolumab + lirilumab Molecular status: HRAS G12S, TP53 R248Q 27.5% HRAS mutant allele frequency Initial PR (40% tumor reduction) on Cycle 1 Day 15 (7 days tipifarnib + 7 days rest; 56% reduction at Cycle 3 Cycle 1 Day 1 Cycle 1 Day 7 Cycle 1 Day 20 Cycle 2 Day 1 Ho et al Multidisciplinary Head and Neck Cancers Symposium #217 Results based on preliminary data as of February 8, 2018 Images provided by Dr. Caroline Even and Dr. Charles Ferte, IGR, Paris 15

16 HNSCC Represents Significant Unmet Need Response rates of 5-16% and limited duration of clinical benefit are observed with existing 2 nd line therapies KEYTRUDA (PEMBROLIZUMAB) OPDIVO (NIVOLUMAB) ERBITUX (CETUXIMAB) Efficacy Study Single Arm 1 N=174 Nivolumab vs BSC 2 N=240 vs 121 Single Arm 3 N=103 Nivolumab Control 4 ORR Median PFS/TTP 16% (95% CI 11-23) 13.3% (95% CI ) 5.8% (95% CI ) 13% (95% CI 7-21) 2.0 months 2.0 months 2.3 months 2.3 months Median OS 8 months 7.5 months 5.1 months 6 months Current targeted therapies have not yet capitalized on the progress in the understanding of the molecular landscape of HNSCC 1 Keytruda package insert 2 Opdivo package insert 3 J. Clin. Oncol Jun 1;25(16): Investigator s choice of cetuximab, methotrexate or docetaxel 16

17 Tipifarnib Development Program in HRAS Mutant HNSCC HRAS mutant patients who are not eligible for participation in AIM-HN may be referred to RUN-HN Ongoing Phase 2 Proof-of-Concept Study Non-Interventional Screening & Outcomes Cohort Companion Diagnostic Test Collaborating with third parties for development and validation of qpcr-based companion diagnostic test to identify patients with HRAS mutant tumors for inclusion in AIM-HN trial Registration-Directed Trial 17

18 Successful End of Phase 2 Meeting with FDA Registration-directed trial of tipifarnib in at least 59 patients with HRAS mutant HNSCC who have received prior platinum-based therapy (AIM-HN) AIM-HN, if positive, could support an NDA seeking accelerated approval No requirement of prior immune therapy in AIM-HN Proposed safety database may be adequate to support an NDA filing If AIM-HN is positive, the totality of the data, including results of AIM-HN, SEQ-HN and RUN-HN will be evaluated to determine the appropriateness and nature of an approval and post-approval commitments 18

19 AIM-HN: Trial Design Global, registration-directed trial Targeting ~ 100 clinical sites worldwide Anticipate ~ two years to enroll Primary endpoint: ORR by independent radiological review Statistical assumptions At least 59 subjects; 80% power; 15% ORR (null hypothesis) and 30% ORR (response rate of interest) As currently designed, the trial may be adequate to support an NDA seeking accelerated approval (FDA end of Phase 2 meeting) Minimum tumor HRAS mutant allele frequency of 20% 600 mg BID starting dose Trial initiated and open for enrollment in November

20 Hallmarks of Cancer Characterize Biological Capabilities Key to Cancer Cell Growth and Survival Comprise biological capabilities acquired during the multistep development of human tumors Include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis Creating and sustaining the tumor microenvironment In addition, tumors contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the tumor microenvironment Hallmarks of Cancer: The Next Generation, D. Hanahan and R. Weinberg, Cell 144 (5), (2011) 20

21 Tipifarnib Inhibits Multiple Biological Capabilities Which May Explain Broad Observed Clinical Activity Sustaining proliferative signaling HRAS HRAS mutant solid tumors Tipifarnib Activating invasion and metastasis CXCL12 Pathway Other solid tumors and hematologic malignancies Creating the tumor microenvironment CXCL12 Pathway Hematologic malignancies Potential clinical benefit Objective responses Disease stabilization Enhanced survival 21

22 CXCL12 Pathway: A Central Actor in Human Cancer 22

23 Clinical Benefit from Tipifarnib in PTCL is Associated with CXCL12 Expression and Genotype 1 Tipifarnib almost doubled the PFS of prior standard of care in CXCL12-positive patients Median PFS of CXCL12 high patients on their last prior therapy was 105 days Median PFS of patients with reference CXCL12 gene on their last prior therapy was 85 days 1 Witzig et al. ASH 2017 #

24 Myeloid Cell Life Cycle Marrow blood Vessel CXCR4 re-expression at neutrophil aging CXCR4 Bone Marrow Mesenchymal cell CXCL12 Mature segmented Neutrophil CXCL12 CXCR4 CXCR2 Maturating Neutrophils CXCR4 Senescent Apoptotic Neutrophil CXCR4 and CXCR2 are myeloid receptors that regulate, respectively, bone marrow homing and mobilization of myeloid cells 1 As part of normal homeostasis, senescent neutrophils re-express CXCR4, return to the bone marrow and may undergo apoptosis at low levels of CXCL12 expression 2 AML blasts express CXCR4 and CXCR2 3 Leukemia cells that expresses high CXCR4 and low CXCR2 grow at the bone marrow (BM) vascular niche and are highly dependent on the CXCL12 pathway 3 1 Coffelt et al. Nat Rev Cancer Jul;16(7): Martin et al. Immunity Oct;19(4): Ahn et al. Appl Immunohistochem Mol Morphol Jan;21(1):

25 PFS probability (%) Survival probability (%) PFS probability (%) PFS probability (%) CXCR4/CXCR2 Expression Ratio Identified as a Potential Biomarker for Tipifarnib in Bone Marrow Tumors Quintiles 1 st -4 th days INT17 Tipi in AML Relapsed/Refractory 5 th quintile 182 days p=0.06 Quintiles of CXCR4/CXCR2 Ratio 1 st 2 nd 3 rd 4 th 5 th (highest quintile) Time (days) th 5 th (highest quintile) Time (Days) 29 vs 57 days N=58, p= CXCR4/CXCR2 Quartiles 1 st - 3 rd 4 th (highest quartile) CTEP20 AML Tipi in 1 st line frail, elderly 67 vs 406 days N=34, p=0.09 TIP-004 CMML Tipi in Relapsed/Refractory CXCR4/CXCR2 Tertiles 1 st 2 nd 3 rd (highest tertile) 84 vs 280 days N=15, p= AML/CMML - Retrospective analyses of three tipifarnib Phase 2 studies (INT17 2, CTEP20 3 and TIP ) revealed an association between the ratio of CXCR4 to CXCR2 and the clinical activity of tipifarnib that was consistent across endpoints, clinical settings and indications 1 Gualberto et al. ASH 2017 # Harousseau et al Blood 109: Lancet et al Blood 109: Patnaik et al, ASH 2017 #

26 Survival probability (%) Survival probability (%) Survival probability (%) High CXCR4/CXCR2 Does Not Predict Better Outcome for AML Patients Treated with SoC Age Matched Controls Quartiles of CXCR4/CXCR2 Ratio 1 st - 3 rd (lower quartiles) 4 th 728 vs 179 days CTEP20 TIPIFARNIB P= AMLCG CONTROL 176 vs 236 days (ns) Time (days) Time (days) TCGA AML - CONTROL 210 vs 231 days (ns) Study Subset Treatment N Age Median OS Deceased CTEP20 All samples Tipifarnib days 83% AMLCG1999 >60 years AraC based TCGA AML 1 >60 years SoC Time (days) Outcome of unselected 1L elderly, unfit AML patients with tipifarnib similar to that of other therapies Significantly better outcome with tipifarnib observed in a subset of AML patients with high CXCR4/CXCR2 Patients treated with other therapies do not benefit from high CXCR4/CXCR2 selection 1 TCGA. N Engl J Med. 2013;368:

27 High CXCR4/CXCR2 Expression is Associated with Bone Marrow Homing of AML Blasts st Quartiles of CXCR4/CXCR2 Ratio 2 nd 3 rd 4 th (highest) CXCR4 and CXCR2 regulate, respectively, bone marrow homing and mobilization of myeloid cells AML patients with a high CXCR4/CXCR2 ratio have AML that is preferentially located at bone marrow Bone Marrow Blasts (%) Data from studies CTEP20 and INT17 Peripheral Blood Blasts (%) 27 These data suggest that bone marrow homing could be utilized as a surrogate of high CXCR4/CXCR2 ratio and a potential biomarker of tipifarnib activity

28 Bone Marrow Homing of AML Blasts Predicts Clinical Benefit from Tipifarnib 1 1 Gualberto et al. ASH 2017 # Harousseau et al Blood 114: TCGA. N Engl J Med. 2013;368: SoC: Subjects treated with standard of care treatment 28

29 Ongoing Phase 2 Trials in Hematologic Malignancies KO-TIP-002 KO-TIP-003 KO-TIP-004 Indications PTCL MDS Myeloid Neoplasias Cohorts Patients with angioimmunoblastic T-cell lymphoma (AITL) Patients with PTCL who have the absence of a single nucleotide variation in the 3 untranslated region of the CXCL12 gene Patients with neutropenia at study entry, evaluating CXCL12 pathway biomarkers Patients with MDS/MPN overlap syndrome (includes CMML) with CXCL12 pathway biomarkers Relapsed/refractory AML patients with CXCL12 pathway biomarkers Preliminary data from AITL and CXCL12+ cohorts in PTCL at ASH

30 Significant Unmet Need Remains in PTCL Approved therapies in relapsed/refractory PTCL approved based on singlearm clinical trials of 130 patients or less with response rates in the range of 25-27% and limited duration of clinical benefit in unselected populations BELEODAQ (BELINOSTAT) ISTODAX (ROMIDEPSIN) FOLOTYN (PRALATREXATE) Efficacy Study Single Arm 1 N=120 Single Arm 2 N=130 Single Arm 3 N=109 Prior Therapies (range) 2 (1-8) 2 (1-8) 3 (1-12) Overall Response Rate 25.8% 26.2% 27% Median PFS/TTP 1.6 months 4.0 months 3.5 months Median Overall Survival 7.9 months 11.3 months 14.5 months Dosing IV infusion 4 IV infusion 5 IV push 6 1 Beleodaq package insert 2 Istodax package insert 3 Folotyn package insert 4 1,000 mg/m 2 administered over 30 mins by IV infusion once daily on days 1-5 of a 21-day cycle 5 14 mg/m 2 administered over a 4-hour period by IV on days 1, 8 and 15 of a 28-day cycle 6 30 mg/m 2 administered over 3-5 mins as an IV push once weekly for 6 weeks in 7-week cycles 30

31 Patent Protection for Tipifarnib Based on Genetically Defined Patient Populations U.S. patent 9,707,221 issued in July 2017 provides exclusivity for tipifarnib in HRAS mutant HNSCC indication to 2036 Corresponding patents beginning to issue in foreign countries U.S. patent 9,956,215 issued in May 2018 provides exclusivity for tipifarnib in certain CXCL12-expressing cancers to 2037 Additional patent applications pending in the U.S. and foreign countries for tipifarnib in other biomarkers and disease indications Patents illustrates potential of broader strategy to generate intellectual property related to use of drug candidates in biomarker-defined populations 31

32 Development Strategy for Tipifarnib Clinical Proof-of- Concept Positive Phase 2 Study in HRAS Mutant HNSCC Initial Registration AIM-HN Trial in HRAS Mutant HNSCC Label Expansion Potential Indications for Future Pivotal Trials Include: LSCC, PTCL, MDS, AML Success Criteria: Biomarker validation Evidence of durable, clinical benefit Sufficient ORR Potential for rapid clinical development Opportunity to move into earlier lines of therapy Attractive U.S. oncology commercial market Potential for regulatory exclusivity and/or patent protection Life Cycle Management Extend Tipifarnib / FTase Franchise Rational combination strategies with standard of care and novel therapeutics Advance toward earlier lines of therapy Next-generation farnesyl transferase inhibitors 32

33 KO-947 (ERK Inhibitor)

34 KO-947: Potent ERK1/2 Inhibitor Aberrant signaling caused by mutations or dysregulation of MAPK pathway associated with numerous tumor types Inhibitors of RAF and MEK have validated MAPK pathway in cancer Competitors have demonstrated limited clinical activity in selected patients, but it has been challenging to drive durable PD and clinical activity A Differentiated ERK Inhibitor Potent and selective KO-947 RAS Prolonged pathway modulation enables intermittent dosing IV route selected for initial clinical study to drive higher dose intensity Currently in Phase 1 dose-escalation trial ERK Nucleus MEK RAF ERK1/2: Extracellular Signal-Regulated Kinases 1/2 34

35 KO-947: Translational Research Identified Potential Lead Clinical Indications EXTENSIVE PRECLINICAL EVALUATION OF KO-947 ANTI- TUMOR ACTIVITY IN MAPK DYSREGULATED TUMORS KO-947 evaluated in ~200 PDX models across 20 potential indications Identified broad tumor classes sensitive to ERK inhibition (> 50% response rates in preclinical models) KRAS- and BRAF-mutant adenocarcinomas Squamous cell carcinomas 11q13 amplification identified as a potential biomarker of activity in squamous cell carcinomas POTENTIAL INDICATIONS REPRESENT HIGH UNMET NEED POTENTIAL INDICATION U.S. INCIDENCE Head and Neck Squamous Cell Carcinomas (HNSCC) 10,000-20,000 * KRAS mut Non-Small Cell Lung Cancer (NSCLC) 24,500 BRAF mut Non-Small Cell Lung Cancer (NSCLC) 5,000 * Estimate of the biomarker-positive subset; biomarker still under evaluation 35

36 KO-539 (Menin-MLL Inhibitor)

37 KO-539: Potent Inhibitor of Menin-MLL Interaction KO-539 is a potent, selective small molecule inhibitor of the menin-mll interaction, designed for treatment of acute leukemias Robust antitumor activity of KO-539 observed in mixed lineage leukemias rearranged (MLL-r) as well as disseminated NPM1 mut and DNMT3A mut AML PDX models Preliminary data suggests KO-539 exerts anti-leukemic activity by induction of myeloid differentiation in AML blasts The menin-mll complex appears to be a central node in epigenetic dysregulation driven by several distinct oncogenic driver mutations important in diverse leukemias and myeloproliferative disorders Menin-MLL inhibitors have the potential to treat approximately 50% of acute leukemias KO

38 Percent Circulating WBC Body Weight (g) Percent survival KO-539 Produces Lasting Complete Remissions in a NPM1/DNMT3A/IDH2/FLT3-Mutant AML Model Vehicle KO mg/kg QD Overall survival AM7577 Model KO mg/kg QD Quizartinib 3mg/kg QD CD45+ human AML blasts Days of therapy 0 Last dose Days of therapy Last dose Tolerability Days of therapy Presented at AACR-NCI-EORTC (October 28, 2017) 38

39 Anticipated Milestones & Financial Highlights Tipifarnib Farnesyl Transferase Inhibitor KO-947 ERK Inhibitor KO-539 Menin-MLL Inhibitor PROGRAM MILESTONES STATUS HRAS mutant Solid Tumors Hematologic Malignancies End-of-Phase 2 meeting with FDA Initiation of cooperative group study in LSCC Initiation of registration-directed trial in HNSCC Additional data from Phase 2 trial (KO-TIP-001) 2019 Patent for tipifarnib in certain CXCL12-expressing cancers Preliminary data from AITL and CXCL12+ cohorts in PTCL ASH 2018 Potential biomarker of activity in squamous cell carcinomas Data from Phase 1 dose-escalation trial 2019 Anti-tumor activity in preclinical models of AML Submission of IND application Q Financial Highlights Nasdaq: KURA Shares outstanding: 38.0M basic, 3.3M options* Cash, cash equivalents and short-term investments: $187.4M* * As of 3Q Q 39

40 DEVELOPING PRECISION MEDICINES TO TREAT CANCER