Calithera Biosciences

Transcription

1 Calithera Biosciences R&D/Analyst Meeting New York, October 5, 2018

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 ongoing and anticipated clinical trials for our product candidates, including CB-839, INCB , CB-280 and CB-708, 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 INCB 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 June 30, 2018, filed with the Securities and Exchange Commission on August 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 Today s Agenda Calithera Strategy and Vision Glutaminase Inhibitor CB-839 in RCC Renal Cell Carcinoma Landscape Therapeutic Potential of CB-839 Q&A Session Break INCB Arginase Inhibitor CB-280 Cystic Fibrosis Program CD-73 Immuno-oncology Program Wrap Up and Q&A Session Susan Molineaux, Ph.D. Founder, CEO Keith Orford, MD, Ph.D. Senior VP Clinical Development Nizar M. Tannir, MD MD Anderson Cancer Center Keith Orford, MD, Ph.D. Senior VP Clinical Development Keith Orford, MD, Ph.D Senior VP Clinical Development Christopher Molineaux, Ph.D Senior VP Development Frank Parlati, Ph.D Vice President Research Susan Molineaux, Ph.D. Founder, CEO 8:00-8:10 a.m. 8:10-8:20 a.m. 8:20-8:35 a.m. 8:35-8:50 a.m. 8:50-9:00 a.m. 9:00-9:15 a.m. 9:15-9:30 a.m. 9:30-9:40 a.m. 9:40-9:50 a.m. 9:50-10:15 a.m. 3

4 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

5 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 5

6 Investment Highlights CB-839 in Registration Enabling RCC Trial Arginase Phase 1/2 Clinical Program Established Drug Discovery Engine Diversified Portfolio Experienced Founders 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 6

7 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 Data expected at a medical meeting in 1H19 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

8 Calithera Competitive Advantages Best-in-Class Chemistry Novel molecules with excellent pharmacological profiles Superior Biology Cutting edge therapeutic approaches validated in animal models Integrated Science Translational science biomarkers to enhance patient selection 8

9 Pipeline Glutaminase Inhibitor CB-839 mrcc + Cabozantinib mrcc + Everolimus Solid Tumors + Nivolumab PIK3CAm CRC + Capecitabine (IST) Arginase Inhibitor INCB Immuno-oncology 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 9

10 Scientific Management Team Susan M. Molineaux, PhD Founder, President and CEO Keith Orford, MD, PhD Senior VP of Clinical Development Christopher J. Molineaux, PhD Senior VP of Development Frank Parlati, PhD VP of Research Eric B. Sjogren, PhD Senior VP of Drug Discovery Sam Whiting, MD VP of Clinical Development 10

11 Calithera Biosciences: NASDAQ: CALA Calithera is Focused on Fighting Cancer by Developing, and Commercializing Novel Small Molecule Drugs That Target Tumor and Immune Metabolism Founded in 2010 Based in South San Francisco, CA Employees: 80 Cash and marketable securities as of June 30, 2018: $152.2M 11

12 Glutaminase Inhibitor CB-839 Renal Cell Carcinoma Program Keith Orford, MD, Ph.D. Senior Vice President Clinical Development

13 Tumor Proliferation Necessitates Metabolic Adaptation Tumor Cells Neovasculature Tumor Growth Nutrients, O 2 Adapted from: Jones and Thompson. (2009) Genes and Dev. 23: Metabolic stress Angiogenesis Metabolic adaptation 13

14 Cancers Cells Are Metabolically Re-wired Normal Cell Tumor Cell Lactate GLUCOSE Lactate GLUCOSE Pyruvate Energy Pyruvate Energy TCA Cycle Building Blocks for Cell Growth TCA Cycle Building Blocks for Cell Growth a-kg a-kg Glutamate Glutamate Glutaminase Glutaminase GLUTAMINE GLUTAMINE Minor Pathway Major Pathway

15 Glutamine is Needed for Multiple Functions in Tumor Cells Glutamine Glutamine Activation Tumor Cell Glutamate T Cell Protein synthesis Energy DNA synthesis Glutathione 15

16 CB-839 Combinations in RCC Result in Dual Metabolic Inhibition Normal Cell Tumor Cell Lactate GLUCOSE Lactate GLUCOSE Cabozantinib Everolimus Pyruvate Energy Pyruvate Energy TCA Cycle Building Blocks for Cell Growth TCA Cycle Building Blocks for Cell Growth a-kg a-kg Glutamate Glutamate Glutaminase Glutaminase CB-839 GLUTAMINE GLUTAMINE Minor Pathway Major Pathway

17 T u m o r V o l u m e ( m m 3 ) T u m o r V o l u m e ( m m 3 ) CB-839 Combines with Cabozantinib or Everolimus to Suppress Tumor Growth in Animals C B C a b o z a n t i n i b C B E v e r o l i m u s V e h i c l e V e h i c l e C B C a b o z a n t i n i b C o m b o D o s in g S t a r t C B E v e r o l i m u s C o m b o D o s in g S t a r t D a y P o s t I m p l a n t D a y P o s t I m p l a n t 17

18 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 18

19 CB-839 is Well Tolerated in Combination with Everolimus or Cabozantinib in RCC Patients Treatment-related Adverse Events Occurring in >15% Patients a CB Everolimus b n = 27 Adverse Event, n (%) All Grades Grade 3 Any 27 (100) 15 (56) Decreased appetite 11 (41) 0 Anemia 9 (33) 2 (7.4) AST increased 7 (26) 0 Diarrhea 6 (22) 0 Fatigue 6 (22) 3 (11) Mucosal inflammation 6 (22) 0 Nausea 6 (22) 0 Thrombocytopenia 6 (22) 1 (3.7) Creatinine increased 5 (19) 0 Dysgeusia 5 (18) 0 Proteinuria 5 (19) 0 Rash 5 (19) 0 Stomatitis 5 (19) 1 (3.7) a Related to either CB-839 or combination agent; b 1 DLT of pruritic rash at 400 mg ; c 1 DLT at 600 mg Additional Grade 3 TRAE occurring in at least 2 pts: hyperglycemia, hypertension, and neutropenia *Additional Grade 3 TRAE occurred in one patient each: hallucination, photophobia CB Cabozantinib n = 13 Adverse Event, n (%) All Grades Grade 3* Any 13 (100) 5 (38) Diarrhea 8 (61) 1 (7.7) Decreased appetite 6 (46) 0 ALT increased 5 (38) 0 Fatigue 5 (38) 0 AST increased 4 (31) 0 Nausea 4 (31) 0 Rash 4 (31) 0 Mucosal inflammation 3 (23) 0 Proteinuria 3 (23) 0 Vomiting 3 (23) 0 Weight decreased 3 (23) 0 Dehydration 2 (15) 0 Dysgeusia 2 (15) 0 Hypertension 2 (15) 1 (7.7) Platelet count decreased 2 (15) 1 (7.7) c Pruritus 2 (15) 0 Stomatitis 2 (15) 0 Safety data cutoff: July 23,

20 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):

21 RANDOMIZATION 2:1 Phase 2 ENTRATA Study Design Renal Cell Carcinoma N=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 21

22 % 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):

23 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 ) 23

24 RANDOMIZATION 1:1 Phase 2 Global CANTATA Study Renal Cell Carcinoma N=300 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

25 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 25

26 Therapeutic Potential of CB-839 Keith Orford, MD, Ph.D. Senior Vice President Clinical Development

27 CB-839 Has Potential as Broad Anti-Cancer Agent Mutated oncogenes can make cancer cells dependent on glutamine for growth and survival Glutaminase inhibitors have synergistic effects when combined with many cancer drugs CB-839 is a well tolerated, orally bioavailable, potent and allosteric inhibitor of glutaminase CB-839 has broad potential across multiple tumor types 27

28 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 KEAP1/NRF2 Mutations Increases redox stress Activate T cells T cell activation Cell division Oxidative stress

29 CB-839 Development Strategy Beyond RCC Genetically Defined Sub-populations Clinical Collaborations Exploratory Studies PIK3CA KEAP1/NRF2 KRAS Bristol-Myers Squibb Exelixis Pfizer ISTs CTEP studies 29

30 CB Nivolumab Phase 1/2 Trial Design Dose Escalation Melanoma Non-small cell lung cancer Renal cell carcinoma Standard dose nivolumab CB mg BID Melanoma Rescue NSCLC Rescue RCC Rescue RCC Prior IO RCC IO Naïve Prior IO Requirement At study entry, progressing on α-pd-(l)1* At study entry, progressing on α-pd- (L)1* or SD 6 mo without response α-pd-(l)1 in any prior line with no response No prior checkpoint inhibitors *Radiographic or RECIST progression per investigator assessment within 2 months of study entry with no intervening therapy 30

31 CB Nivolumab Phase 1/2 Update CB-839 can reverse actively progressing disease in PD-1 refractory patients Three responses in refractory melanoma patients actively progressing on anti-pd1 therapy Prolonged stable disease in refractory non-small cell lung cancer patients actively progressing on anti-pd1 therapy Biomarker analyses ongoing Subsequent development dependent on determining sub-population with clinical development pathway 31

32 CB Capecitibine in PIK3CA Mutant Colorectal Cancer PIK3CA Mutant Tumors Are More Sensitive to CB-839 in Combination with 5-FU in vivo Ph 1b Dose Escalation CB-839 ( mg BID) + capecitabine* (1000 mg/m2) (n=16) Cancers for which capecitabine is SOC Ph2 Dose Expansion CB-839 (800 mg BID) + capecitabine (5-FU therapy) (n=29) PIK3CA-mutant CRC refractory to prior 5-FU Ph1/2 Investigator Sponsored Trial led by Case Western initiated 2016 *Capecitabine is an oral fluoropyrimidine; similar to 5-FU 32

33 P r o g r e s s i o n - f r e e s u r v i v a l CB Capecitibine Phase 1b Data Presented at ASCO CRC patients refractory to 5-FU therapy 7 PIK3CA mutant Progression Free Survival Subgroup Analysis of CRC Pts by PIK3CA Status 6 wild type Safety PIK3CA mutant CRC PIK3CA wild-type CRC Minimal toxicity p= Ph 2 dose 800 mg BID CB Median PFS 26 weeks for PIK3CA mutant CRC 16 weeks for wild type CRC W e e k 33

34 CB-839 in PIK3CA Colorectal Cancer Favorable PFS in Phase 1 PIK3CA patients relative to historical third line colorectal cancer standard therapies PIK3CA mutant = 6 months PFS (n=7) PIK3CA wild type = 4 months PFS (n=6) Significant opportunity in late-line colorectal cancer PIK3CA mutations occur in approximately 20% of colorectal cancer 1 High unmet need Regorafenib and Lonsurf were approved with a PFS of 2 months, overall survival of 6 7 months 1 Decision Resources, CRC Disease Landscape and Forecast (August 2018) 34

35 Rationale for Combining CB-839 with PARP Inhibitors PARP inhibitors block repair of single stranded DNA breaks-active in cells with DNA repair mutations CB-839 promotes single stranded breaks in cancer cells by blocking nucleotide synthesis Potential to develop CB-839 with PARP inhibitors in both in DNA repair deficient & wild type cancer cells Plan to evaluate talazoparib + CB-839 in patients with renal cell carcinoma and triple negative breast cancer Pfizer clinical collaboration Phase 1/2 expected to begin 1Q

36 CB PARP Inhibitor Synergize to Inhibit Tumor Growth D U DU 145 x e n oxenograft g r a f t T u m o r V o l u m e ( m m 3 ) v e h i c le C B t a l a z o p a r i b c o m b o D a y s P o s t I m p l a n t CB-839 Synergizes with PARP Inhibitors to Impair DNA Synthesis, Enhance DNA Damage, and Block Cell Proliferation 36

37 Rationale for Combining CB-839 with CDK 4/6 CB-839 decreases nucleotides in tumor cells, impairing DNA synthesis, and cell cycle progression CB-839 synergizes with a CDK4/6 inhibitor to block cell cycle progression and cell proliferation CDK4/6 inhibitors have modest single agent activity; combined with hormone therapy, they are effective therapy Plan to evaluate IBRANCE + CB-839 in patients with KRAS mutated colorectal cancer and patients with KRAS mutated non-small cell lung cancer Pfizer clinical collaboration Phase 1/2 expected to begin 1Q

38 T u m o r V o l u m e ( m m 3 ) CB CDK4/6 Inhibitor Combine to Inhibit Tumor Growth H C T x e n o g r a f t HCT 116 Xenograft v e h i c l e C B p a l b o c i c l i b c o m b o * * * * D a y s P o s t I m p l a n t 38

39 KEAP1/NRF2 Loss Renders Cancer Cells Dependent on Glutaminase Synthetic Lethality with Glutaminase Inhibitor 39

40 KEAP1/NRF2 Future Directions KEAP1/NRF2 mutation are present in approximately 20% of lung adenocarcinomas CB-839 has increased activity in mutant cells relative to wild type NCI/CTEP study will evaluate CB-839 as a monotherapy in a basket study Evaluating future development plans and rationale combinations for development 40

41 CB-839 Planned NCI CTEP Studies NF1, KEAP Mutation Basket Trial CB-839 monotherapy in NF1, KEAP1 or LKB1/STK11 mutations Lung Cancer CB osimertinib in EGFR mutant, non-t790 NSCLC after failure of other EGFR targeted therapy Glioma CB radiation + temozolomide in IDH mutant Gr II/III Multiple Myeloma CB carfilzomib/dexamethasone in refractory patients 41

42 CB-839 Additional Investigator-Sponsored Trials Colorectal Cancer: Vanderbilt-Ingram Cancer Center CB panitumumab + irinotecan Metastatic and Refractory RAS Wildtype Colorectal Safety, response, imaging with novel PET/CT biomarkers Myelodysplastic Syndrome: MD Anderson Cancer Center CB azacitadine First Line, High Risk MDS Safety, response by modified IWG response criteria MDS 42

43 INCB Arginase Inhibitor Keith Orford, MD, Ph.D. Senior Vice President Clinical Development

44 T-Cells Deprived of Arginine are Dormant Yet Expand When Arginine is Replenished 44

45 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 45

46 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 46

47 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 47

48 A r g i n a s e 1 ( n g / m L ) A r g i n i n e ( m M ) Elevated Arginase and Depleted Arginine Levels are Observed in Cancer Patient Plasma Plasma Arginase 1 Plasma Arginine N = N = * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * H e a l t h y D o n o r H e a d & N e c k B l a d d e r M e s o t h e l i o m a S m a l l C e l l L u n g C R C N S C L C A M L R C C B r e a s t H e a l t h y D o n o r H e a d & N e c k M e s o t h e l i o m a S m a l l C e l l L u n g C R C N S C L C A M L R C C B r e a s t 48

49 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 49

50 INCB001158: Preliminary Evidence of Peripheral Immune Modulation INCB Increased the Number of Peripheral Circulating PD-1 + T-cells, and the Level of CD3z Cell Surface Expression on Cytokine-producing NK Cells CD4 + /FoxP3 - CD8 + NK Cells 50

51 INCB Broad Development Strategy INCB is a potent oral inhibitor of arginase Focus on disease indications where arginase expression is high Explore development as a monotherapy Develop in combination with PD-1 inhibitors Enroll PD-1 experienced patients (actively progressing or prolonged stable disease on immediate prior PD-1 therapy) and PD-1 naïve patients Develop in combination with chemotherapy Use biomarkers in clinical development Gated development plan 51

52 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 52

53 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 53

54 CB-280 Cystic Fibrosis Program Christopher J. Molineaux, Ph.D Senior VP Development

55 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. 55

56 Cystic Fibrosis Program CB-280 Despite Recent Advances in New Therapies, There is Still Unmet Need Currently approved therapies and those in development leave room for clinical improvement Multiple novel mechanisms (anti-infectives, anti-inflammatory agents) are in development Arginine-nitric oxide modulation has shown preclinical & clinical efficacy CB-280 is an Analog of INCB CB-280 is a potent and selective oral inhibitor of arginase CB-280 will be the first arginase inhibitor to enter the clinic in CF IND and initiation of Phase 1 in healthy volunteers expected 1H19 56

57 Arginase Plays a Critical Role in CF Airway Disease Genetic Defect in CFTR Impaired Ion Transport and Mucociliary Clearance Microbial Infection Mucus Plugging Airway Obstruction Impaired Antimicrobial Activity Neutrophil Predominant Inflammation Increased Arginase Secretion Broncho-constriction Airway Remodeling Decreased Airway Arginine and NO + Increased Airway Polyamines and Proline 57

58 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 58

59 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 59

60 Arginase Inhibition Improves Airway Function and Decreases Infection in CF Mouse Models Arginase inhibitors have been tested in CFTR deficient mice 1 Arginase inhibitors following Pseudomonas aeruginosa exposure in this model Improved airway function Decrease Pseudomonas aeruginosa infection Pharmacologically active in mice Inhibit arginase in the airway Increase arginine levels in the airway Improvements in airway function and increased resistance to infection support clinical testing 1 In collaboration with Lou Ann Brown, Emory University 60

61 NO and Arginine Supplementation Have Considerable Limitations That Can Be Overcome by CB-280 Oral or Inhaled Arginine High arginine doses required Short-lived effect due to rapid arginine consumption Frequent dosing needed Inhaled Nitric Oxide High inhalation doses required Prolonged dosing of minutes Frequent dosing of 3 4x/day needed due to short half life Oral Arginine Inhibitor Potent and continuous inhibition of arginase Sustained increases in arginine Convenient oral bid dosing Drug-drug interactions not expected No other approach directly addresses the mechanistic contribution of proline and spermine 61

62 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 62

63 CD73 Immuno-Oncology Program Frank Parlati, PhD. Vice President of Research

64 Adenosine is a Key Immunosuppressive Molecule in Tumors Blockade of adenosine production is expected to reverse immunosuppression in the tumor microenvironment and enhance the activity of other IO therapies 64

65 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 65

66 CD73 Competitive Landscape Adenosine receptor antagonists and CD73 antibodies have recently entered the clinic Early results show that A2AR antagonists have monotherapy activity, and both A2AR antagonists and CD73 inhibitors have combination activity with PD-1 antibodies Small molecules have potential advantages Antibodies that indirectly inhibit the catalytic enzyme site may not completely block CD73 activity Our potent and selective oral CD73 inhibitor completely inhibits the enzyme, and penetrates tumors Potential to be first oral CD73 tested in the clinic 66

67 Adenosine Blocks T Cell Proliferation H u m a n T C e l l s P r o l i f e r a t i o n ( % o f C o n t r o l ) C D 8 + C D 4 + Adenosine concentrations above >1 µm suppress T cell proliferation Complete T cell suppression at 10 µm adenosine A d e n o s i n e ( m M ) Human CD3+ T cells stimulated with anti-cd3/cd28 + IL-2 plus ADAi for 72h 67

68 % A c t i v i t y % D i v i d e d CB-708 is a Highly Potent Inhibitor of CD73 Human Recombinant CD73 H u m a n r C D 7 3 Human H u m a n CD8+ C D 8 + T Cell C e l l ProliferationP r o l i f e r a t i o n N o A M P C t r l 8 0 IC 50 = 170 pm IC 50 =6.5 nm C B ( n M ) C B ( n M ) 68

69 P l a s m a C B ( n M ) P l a s m a C D 7 3 A c t i v i t y CB-708 is Orally Bioavailable CB-708 Exposure Remains Above IC 90 for 24 h 92% Inhibition of Plasma CD73 in Mice C B P h a r m a c o k i n e t i c s i n R a t s ( 5 0 m g / k g o r a l d o s e ) C B I n h i b i t s M o u s e P l a s m a C D I C 9 0 = 3 n M % I n h i b i t i o n T i m e ( h r ) 0 V e h i c l e C B ( 1 0 m g / k g ) C B ( 2 5 m g / k g ) C B ( 5 0 m g / k g ) 69

70 T u m o r V o l u m e ( m m 3 ) T u m o r V o l u m e ( m m 3 ) T u m o r V o l u m e ( m m 3 ) T u m o r V o l u m e ( m m 3 ) CB-708 Has Single Agent Activity in the EG7 Syngeneic Model E G 7 M o d e l ( T - c e l l l y m p h o m a ) V e h i c l e C B ( 1 0 m g / k g ) C B ( 2 5 m g / k g ) V e h i c l e T u m o r V o l u m e ( m m 3 ) C B , 1 0 m g / k g C B ( 5 0 m g / k g ) D a y s P o s t I m p l a n t D a y s P o s t I m p l a n t C B , 2 5 m g / k g C B , 5 0 m g / k g CR D a y s P o s t I m p l a n t D a y s P o s t I m p l a n t D a y s P o s t I m p l a n t Efficacy of orally administered CB-708 at all doses 70

71 T u m o r V o l u m e ( m m 3 ) T u m o r V o l u m e ( m m 3 ) T u m o r V o l u m e ( m m 3 ) CB-708 Analog Enhances the Activity of a-pd-l1 In Vivo V e h i c l e C B A, m g / k g E G 7 M o d e l ( T - c e l l l y m p h o m a ) V e h i c l e C B A, m g / k g a - P D - L 1, 5 m g / k g T u m o r V o l u m e ( m m 3 ) T u m o r V o l u m e ( m m 3 ) C B A + a - P D - L 1 D a y s P o s t I m p l a n t D a y s P o s t I m p l a n t a - P D - L 1, 5 m g / k g C B A + a - P D - L CRs D a y s P o s t I m p l a n t D a y s P o s t I m p l a n t D a y s P o s t I m p l a n t CB-708A is an analog of CB

72 CD73 Summary and Conclusion CD73 is expressed on tumor cells, immune cells and stroma, and generates high levels of adenosine, an immunosuppressive metabolite Inhibition of CD 73 increases tumor inflammation, is active in several syngeneic tumor models, and enhances activity of checkpoint inhibitors, A2AR inhibition, and chemotherapy CD73 is expressed across a wide range of tumors, often correlates with poor prognosis Calithera has a small molecule CD73 inhibitor with potential to be first oral molecule in the clinic 72

73 Calithera Biosciences Susan Molineaux Ph.D, Founder & CEO

74 Financials Financial strength and supportive partnerships Cash and securities of $152.2 at June 30, M shares outstanding at June 30, 2018 No debt Significant funding from collaboration and potential future milestones 74

75 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 Data expected at a medical meeting in 1H19 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

76 2019 Milestones Initiate Additional CB-839 Combination Trials INCB Data Presentation Advance CD73 Program into Clinical Trials Report Results of Phase 2 ENTRATA Trial Advance CB-280 Program into Clinical Trials in Cystic Fibrosis Expand Preclinical Pipeline Complete Enrollment of Global CANTATA Trial 76