Calithera Biosciences. January 2019

Transcription

1 Calithera Biosciences January 2019

2 Forward-Looking Statements This presentation and the accompanying oral commentary contain forward looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of We may, in some cases, use terms such as believe, will, may, estimate, continue, anticipate, intend, should, plan, might, approximately, expect, predict, could, potentially or the negative of these terms or other words that convey uncertainty of future events or outcomes to identify these forward looking statements. All statements other than statements of historical facts contained in this presentation and the accompanying oral commentary are forward looking statements, and such forward looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: plans regarding our anticipated clinical trials for our product candidates, including CB- 839 and CB-1158, the potential safety, efficacy and other benefits of and market opportunity of product candidates, the timing of and our ability to make regulatory filings and obtain and maintain regulatory approvals for our product candidates, statements relating to the development, regulatory and sales milestone payments of CB-1158 in connection with our collaboration with Incyte Corporation, our intellectual property position and cash needs. Forward looking statements involve known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward looking statements. We discuss many of these risks in greater detail under the heading "Risk Factors" contained in our Quarterly Report on Form 10 Q for the for the quarter ended September 30, 2018, filed with the Securities and Exchange Commission on November 7, Forward looking statements are not guarantees of future performance and our actual results of operations, financial condition and liquidity, and the development of the industry in which we operate may differ materially from the forward looking statements contained in this presentation and the accompanying oral commentary. Any forward looking statements that we make in this presentation and the accompanying oral commentary speak only as of the date of this presentation. We assume no obligation to update our forward looking statements whether as a result of new information, future events or otherwise. 2

3 Our onco-metabolism approach brings a new and unique perspective to fighting cancer VISION: Our goal is to be a fully-integrated biotechnology company that develops and commercializes pioneering small molecule drugs

4 Our Drugs Target Unique Metabolic Pathways Tumor Metabolism Immune Cell Metabolism Tissue Metabolism Glutaminase Inhibitor CB-839 Arginase Inhibitor INCB CD73 Inhibitor CB-708 Arginase Inhibitor CB-280 4

5 Investment Highlights CB-839 in Registration Enabling RCC Trial Arginase Phase 1/2b Clinical Program Established Drug Discovery Engine Diversified Portfolio Experienced Founder and Management Team Two randomized placebo controlled trials in renal cell carcinoma Codevelopment and cocommercializati on with Incyte Two new small molecule drugs to enter the clinic Tumor metabolism, immunooncology and cystic fibrosis Founders led Kyprolis to approval 5

6 Near Term Goals Advance the glutaminase inhibitor CB-839 in renal cell carcinoma towards commercialization Data from randomized trials expected in 2019 and 2020 Establish the arginase inhibitor INCB as an active therapy in cancer Single agent and combo data anticipated in 2H2019 Develop the arginase inhibitor CB-280 as a new treatment modality for cystic fibrosis IND filing expected in 1H2019 Advance the oral small molecule CD73 inhibitor CB- 708 into the clinic in cancer IND filing expected in

7 Pipeline Glutaminase Inhibitor CB-839 mrcc + Cabozantinib mrcc + Everolimus Solid Tumors + Nivolumab PIK3CAm CRC + Capecitabine (IST) Solid Tumors + Talazoparib or palbociclib Arginase Inhibitor INCB Monotherapy + Pembrolizumab Combos + Chemotherapy Arginase Inhibitor CB-280 Cystic Fibrosis Small Molecule CD73 Inhibitor CB-708 Immuno-Oncology Discovery Pre-IND Phase 1 Phase 2 Phase 3 CANTATA Trial ENTRATA Trial Potential registration trial Studies planned 7

8 Glutaminase Inhibitor CB-839 Tumor and Immune Metabolism Program

9 Impact of CB-839 When Combined with Other Drugs Cabozantinib, everolimus, PIK3CA mutations Blocks glutamine metabolism Blocks DNA synthesis CB-839 Supplies glutamine to T cells Blocks glutathione synthesis PD-1 inhibitors Blocks glucose Nutrient deprivation Taxanes, cdk4/6, PARP inhibitors Blocks cell division Dual Effects Nrf/Keap-2 Mutations Increases redox stress Activate T cells T cell activation Cell division Oxidative stress

10 Market Potential of CB-839 plus Cabozantinib in Second Line as Immunotherapy Moves to First Line Drug Treated Advanced RCC Patients by Line of Therapy Overall RCC Market is Expected to Grow from $2.7B to $7B by % Second line 17% Third line 1L 2L 3L 4L Sources: Decision Resources 2017, Renal Cell Carcinoma Major Markets = US, UK, France, Germany, Spain, Italy, Japan 10

11 Phase 1b RCC Studies of CB-839 with Everolimus or Cabozantinib Metastatic Renal Cell Carcinoma (RCC) Patients Dose Escalation Dose Expansion Endpoints CB-839 ( mg BID) + Everolimus (10 mg QD) CB-839 ( mg BID) + Cabozantinib (60 mg QD) Clear Cell & Papillary Clear Cell & Papillary Safety, anti-tumor activity, and recommended dose Tumor Response Assessed by RECIST Every 8 Weeks 11

12 Renal Cell Carcinoma Phase 1 Safety Data Treatment-related adverse events occurring in 15% patients a CB Everolimus n = 27 Adverse Event, n (%) All Grades Grade 3 Any 26 (96) 13 (48) Decreased appetite 9 (33) 0 Rash 8 (30) 2 (7) Anemia 7 (26) 2 (7) Thrombocytopenia 7 (26) 1 (4) b Diarrhea 6 (22) 0 Fatigue 6 (22) 3 (11) Mucosal inflammation 6 (22) 0 AST increased 5 (19) 0 Creatinine increased 5 (19) 0 Proteinuria 5 (19) 0 Stomatitis 5 (19) 1 (4) Dermatitis acneiform 4 (15) 0 Dysgeusia 4 (15) 0 Epistaxis 4 (15) 0 Hyperglycemia 4 (15) 2 (7) Myalgia 4 (15) 0 Nausea 4 (15) 0 CB Cabozantinib n = 12 Adverse Event, n (%) All Grades Grade 3 Any 12 (100) 4 (33) Diarrhea 7 (58) 1 (8) ALT increased 6 (50) 0 AST increased 5 (42) 0 Decreased appetite 4 (33) 0 Nausea 4 (33) 0 Rash 4 (33) 0 Fatigue 3 (25) 0 Abdominal pain 2 (17) 0 Dehydration 2 (17) 0 Dysgeusia 2 (17) 0 Mucosal inflammation 2 (17) 0 Proteinuria 2 (17) 0 Stomatitis 2 (17) 0 Thrombocytopenia 2 (17) 1 (8) c Vomiting 2 (17) 0 a Related to either CB-839 or combination agent; b 1 DLT at 400 mg ; c 1 DLT at 600 mg Safety data cutoff: Oct 23,

13 CB-839 and Everolimus Have a Favorable PFS and Disease Control Rate in Renal Cell Carcinoma Patients Median PFS of 5.8 Months vs Historic PFS of 3.7 Months for Everolimus in 3 rd Line Patients 1 Clear Cell RCC: 92% DCR with 1 PR and 21 SD 1 Wells JC, et al. Eur Urol. 2017;71(2):

14 RANDOMIZATION 2:1 Phase 2 ENTRATA Study Design Renal Cell Carcinoma N= Approximately 66 Third line+ patients Prior TKI and either cabozantinib or anti-pd(l)1 therapy STRATIFICATION Number of Prior TKI Therapies CB-839 (800 mg BID) + Everolimus (10 mg QD) No prior mtor inhibitors Double-blind, placebo controlled Enrolling in the US MSKCC Risk Category Everolimus (10 mg QD) + Placebo PRIMARY ENDPOINT: PFS SECONDARY ENDPOINT: Survival Designed to validate CB-839 safety/efficacy and support a CANTATA filing 14

15 % c h a n g e i n t a r g e t l e s i o n s CB Cabozantinib in Clear Cell RCC B e s t R e s p o n s e f o r T a r g e t L e s i o n s b y P a t i e n t T u m o r B u r d e n O v e r T i m e b y P a t i e n t % c h a n g e i n t a r g e t l e s i o n s f i l l e d s y m b o l s = o n s t u d y Prior Lines of Advanced/Metastatic Therapy T i m e ( m o n t h s ) 50% Response Rate Compares Favorably to 17% Response Rate with Cabozantinib Alone 1 Data Cutoff: August 23, Choueiri TK, et al. Lancet Oncol. 2016;17(7):

16 CB Cabozantinib in Clear Cell RCC 5 Out of 10 Patients on Study for Over a Year, with 4 Patients Ongoing P R ( % ) Prior Lines of Advanced/ Metastatic Therapy P R ( % ) P R ( % ) P R ( % ) o n s t u d y 31 P R ( % ) Data Cutoff: August 23, 2018 T i m e o n s t u d y ( m o n t h s ) 16

17 RANDOMIZATION 1:1 Phase 2 Global CANTATA Study Renal Cell Carcinoma N= Approximately 400 Second and third line patients Prior TKI or nivolumab + ipilimumab STRATIFICATION Prior Anti- PD(L)1 CB-839 (800 mg BID) + Cabozantinib (60 mg QD) No prior cabozantinib Double-blinded and placebo controlled Enrolling in US, EU, AU and NZ IMDC Risk Category Cabozantinib (60 mg QD) + Placebo PRIMARY ENDPOINT: PFS SECONDARY ENDPOINT: Survival FDA Fast track status Positioned for an NDA filing in

18 Arginase Inhibitor INCB Collaboration With Incyte

19 T-Cells Deprived of Arginine are Dormant Yet Expand When Arginine is Replenished 19

20 Immunosuppression in the Tumor Microenvironment Limited number of patients derive significant benefit from checkpoint inhibitors Tumor-infiltrating myeloid cells suppress T cell and NK cell function and limit the activity of checkpoint inhibitors Arginase is secreted by Myeloid Derived Suppressor Cells (MDSCs), which infiltrate tumors and suppress the immune response Arginase secretion by MDSCs depletes local arginine, which has been shown to suppress immune activation Inhibiting arginase offers a novel strategy to relieve immunosuppression and to enhance checkpoint inhibitors 20

21 A Small Arginine Decrease is Immunosuppressive to Activated T-Cells Normal plasma arginine levels are mm Arginine levels below 40 mm suppress T-cell proliferation 21

22 Cancer Patients Have Arginase + Myeloid Cell Infiltrate in Tissue, High Arginase/ Low Arginine Head and Neck Tumor H&E Arginase 1 Plasma Arginase Healthy Donors Cancer Patients Plasma Arginine Healthy Donors Cancer Patients 22

23 INCB001158: Phase 1 Pharmacokinetics and Pharmacodynamics Inhibited 90-95% of plasma arginase, plasma arginine levels increased several fold Generally well tolerated: One case each: anemia, fatigue, increased AST, myalgia. No serious adverse events Reversible, asymptomatic elevations of urinary orotic acid > 5X ULN threshold in 2 patients Post Dose Plasma Arginase Activity Post Dose Plasma Arginine 23

24 INCB Broad Development Program Monotherapy Cohorts PD-1 Combo (Naïve) PD-1 Combo (Experienced) Chemotherapy combos NSCLC MSS colorectal NSCLC FOLFOX Colorectal Gastric Squamous H&N Melanoma Urothelial Gem/Cis Other Mesothelioma MSI Colorectal Paclitaxel 24

25 INCB Broad Development Strategy Focus on disease indications where arginase expression is high Develop as a monotherapy, and in combination with PD-1 inhibitors Enroll PD-1 experienced patients (progression or stable disease as best response to PD-1 in most recent therapy) and PD-1 naïve patients Develop in combination with chemotherapy Use biomarkers in clinical development Gated development plan 25

26 Incyte Partnership Broad clinical development program for INCB $45M upfront + $8M equity investment $12M milestone received Co-development co-commercialization deal 40% U.S. profit share Low to mid-double digit royalties ex-us Up to $430M potential milestones Calithera has rights to develop arginase inhibitors including CB-280 in select indications outside oncology 26

27 Arginase Inhibitor CB-280 Cystic Fibrosis Program

28 Airway Disease in CF Has Complex Pathophysiology and Remains an Unmet Need CFTR dysfunction is primary underlying cause of disease and is a direct target Vicious cycle of airway obstruction, infection, and inflammation leads to significant morbidity and mortality Currently available CF therapies do not fully address all mechanisms involved in CF airway disease: bronchoconstriction, airway remodeling, and infection Early proof of concept clinical studies with nitric oxide (NO) and arginine treatments suggest this pathway is important in cystic fibrosis. 28

29 High Arginase in CF Airways Impairs Airway Function and Promotes Infection Decreased NO NOS Arginine Arginase Increased Ornithine Increased Spermine + Proline Impaired Bronchodilation Decreased Antimicrobial Activity Decreased FEV1 Increased Infection Bronchoconstriction Airway Remodeling 29

30 CB-280 Directly Targets Arginase Mediated Pathology in CF CB-280 Increased NO NOS Arginine Arginase Decreased Ornithine Decreased Spermine + Proline Bronchodilation Increased Antimicrobial Activity Improved FEV1 Decreased Infection Bronchodilation Decreased Airway Remodeling 30

31 CB-280 Cystic Fibrosis Summary and Conclusions Lung disease in CF has multiple contributory mechanisms Arginase plays a critical role in CF airway disease Decreases NO production and increases production of polyamines and proline Therapeutic manipulation of the arginine-no pathway has shown efficacy, but current approaches have considerable limitations CB-280 is a first-in-class orally dosed arginase inhibitor that can uniquely address arginase mediated airway disease in CF Phase 1 Healthy Volunteers Phase 1B CF Patients Stable on Background Therapy 31

32 CD73 Inhibitor CB-708 Immune Metabolism Program

33 Adenosine is a Key Immunosuppressive Agent in Tumors Blockade of adenosine is expected to reverse immunosuppression in the tumor microenvironment and enhance the activity of other IO agents 33

34 CD73 Small Molecule Inhibitor of the Adenosine Pathway CD73 enzyme converts AMP to adenosine CD73 is both a cell surface enzyme and a secreted enzyme Expressed on tumors, stromal, endothelial and immune cells AMP Phosphate CD73 Adenosine CB-708 binds to the active site of CD73 Inhibits both forms of CD73 Highly selective, potent oral small molecule Continuous inhibition of CD73 activity in vivo IND and Phase 1 trial initiation in 2019 Extracellular Intracellular Knapp 2012 Structure 34

35 Financials Financial strength and supportive partnerships Cash and securities of $136.6 at December 31, M shares outstanding as of November 2, 2018 No debt Significant funding from collaboration and potential future milestones 35

36 2019 Milestones Initiate Additional CB-839 Combination Trials with Pfizer Expand Preclinical Pipeline INCB Data Presentation Complete Enrollment of Global CANTATA Trial Advance CB-280 Program into Clinical Trials in Cystic Fibrosis Report Results of Phase 2 ENTRATA Trial Advance CD73 Program into Clinical Trials 36