Calithera Biosciences : February 2020 Investor Deck

Targeting cancer, differently.

Susan M. Molineaux, Ph.D. | Founder, President & Chief Executive Officer

NASDAQ: CALA

Copyright © 2020 Calithera. All Rights Reserved.

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 1995. 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 (telaglenastat) 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 quarter ended September 30, 2019, filed with the Securities and Exchange Commission on November 12, 2019. 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

OUR SMALL MOLECULE

ONCO-METABOLISM

APPROACH BRINGS A NEW

AND UNIQUE PERSPECTIVE

TO FIGHTING CANCER

Our Drugs Target Unique Metabolic Pathways

Telaglenastat	INCB-001158	CB-280
Glutaminase Inhibitor	Arginase Inhibitor	Arginase Inhibitor

Tumor	Immune	Tissue
Cell
Metabolism	Metabolism
Metabolism

CB-708	CB-668
CD73 Inhibitor	IL4I1 inhibitor

4

Investment Highlights

Late Stage		Strong		Established		Diversified		Experienced
Clinical		Partnerships		Drug Discovery		Portfolio		Founder and
Development		with Industry		Engine				Management
Program in RCC		Leaders						Team
Registration		Development		Additional small		Tumor metabolism,		Founder and
enabling trial		partnership with		molecule drugs		immuno-oncology		management
fully enrolled		Incyte. Clinical		in the clinic		and cystic fibrosis		team members
		collaborations with						led Kyprolis
		Pfizer and Exelixis						to approval

5

Pipeline

DISCOVERY

PRE-IND

PHASE 1

PHASE 2

REGISTRATIONAL

Glutaminase Inhibitor Telaglenastat (CB-839)mRCC + cabozantinib CANTATA mRCC + everolimus ENTRATA

Solid Tumors + talazoparib*

Solid Tumors + palbociclib*

Lung NRF2/Keap1 mutation (planned)

Multiple Investigator Sponsored Trials (ISTs)

Arginase Inhibitor INCB001158 (CB-1158)

Solid Tumors + pembrolizumab

Solid Tumors + chemotherapy

Multiple Myeloma + daratumumab

Arginase Inhibitor CB-280:Cystic Fibrosis

CD73 Inhibitor CB-708:Immuno-Oncology

IL4I1 Inhibitor: Immuno-Oncology

* In collaboration with Pfizer

6

TUMOR AND IMMUNE METABOLISM PROGRAM

Glutaminase Inhibitor Telaglenastat CB-839

Glucose and Glutamine Metabolism in Tumors

Growth factor

signal transduction

Lactate

Growth factor signaling drives abnormal glucose metabolism in cancer cells1

Abnormal glucose metabolism, known as the Warburg effect, deprives the TCA cycle of critical metabolites1-3

Cancer cells compensate for the Warburg effect by increasing glutamine metabolism to sustain the TCA cycle for growth and proliferation1,4

1. Cantor & Sabatini. Cancer Disc. 2012;2(10):881-898; 2. Warburg et al. Science. 1956;123:309-314; 3. Phan et al. Cancer Biol Med.	8
2014;11(1):1-19; 4. Altman et al. Nature Rev Cancer. 2016;16:619-634.

Impact of Telaglenastat When Combined with Other Drugs

TELAGLENASTAT

	BLOCKS	BLOCKS DNA	BLOCKS	SUPPLIES
GLUTAMINE	GLUTATHIONE	GLUTAMINE
SYNTHESIS
METABOLISM	SYNTHESIS	TO T CELLS
Cabozantinib,				PD-1
everolimus,
PIK3CA		Taxanes,		inhibitors
mutations
	CDK4/6,	Nrf2/Keap
BLOCKS		PARP	Mutations
	inhibitors		T CELL
GLUCOSE				ACTIVATION
Nutrient	BLOCKS	GLUTATHIONE
deprivation	CELL DIVISION	REDOX CONTROL

Cell	Oxidative
division	stress

1. cell
   activation

9

CANTATA Study in Second and Third Line RCC Patients

Renal Cell Carcinoma	Prior Anti-	Telaglenastat
+
• N= 445	PD(L)1
Cabozantinib

• Second and third line patients
• Prior TKI or nivolumab +

	ipilimumab	STRATIFICATION			RANDOMIZATION
•	No prior cabozantinib
• Double-blinded and placebo				Cabozantinib
	controlled		IMDC
		+
•	Enrollment complete		Risk Category
		Placebo

PRIMARY ENDPOINT: PFS | SECONDARY ENDPOINT: Survival

FDA Fast track status | Registrational Intent

10

Telaglenastat + Cabozantinib in RCC Phase 1B

Best Response for Target Lesions		Tumor Burden Over Time

Papillary

Clear Cell

1	1	0	4	3	2	3	1	1	7	3	6

Prior Lines of

Advanced/Metastatic Therapy

50% Clear Cell Response Rate Compares Favorably to 17% Response Rate with Cabozantinib Alone1

Data Cutoff: Dec 24, 2018
1. Choueiri TK, et al. Lancet Oncol. 2016;17(7):917-927	11

Phase 2 ENTRATA Proof of Concept Study Design

Renal Cell Carcinoma			Number of	Telaglenastat
•	N = 69
		Prior TKI	+
•	Third line+ patients			Therapies	Everolimus
• Prior TKI and either
	cabozantinib	STRATIFICATION			RANDOMIZATION
	or anti-PD(L)1 therapy
					2:1

• No prior mTOR inhibitors

• Double-blind, placebo	MSKCC	Everolimus
+
controlled	Risk Category
Placebo
• Enrolled in the US

PRIMARY ENDPOINT: PFS | SECONDARY ENDPOINT: Survival*

Designed to validate telaglenastat safety/efficacy and support a potential filing based on CANTATA

* The secondary endpoint of overall survival is not yet mature

12

ENTRATA Demographics and Patient Characteristics

		Telaglenastat +	Placebo +
		Everolimus	Everolimus
Baseline Characteristics		(n=46)	(n=23)
Age	Median, years (range)	64.5 (47-85)	65.0 (37-76)
Sex	Male, n (%)	37 (80)	20 (87)
MSKCC risk, n (%)	Favorable	14 (30)	8 (35)
Intermediate or poor	32 (70)	15 (65)
	No. prior lines, median (range)	3 (2-7)	3 (2-5)
Prior therapies in
1 TKI	13 (28)	8 (35)
advanced/metastatic setting, n
≥ 2 TKI	33 (72)	15 (65)
(%)
	PD-(L)1	42 (91)	19 (83)
	Adrenal	16 (35)	3 (13)
	Bone	15 (33)	8 (35)
Sites of metastasis, n (%)	Brain	1 (2)	0
Liver	17 (37)	8 (35)
	Lung	31 (67)	16 (70)
	Lymph nodes	34 (74)	14 (61)

13

ENTRATA Top-Line Results: Primary Endpoint Met in Heavily Pre- treated Patients

		Telaglenastat +	Placebo +
	Statistical	Everolimus	Everolimus
Endpoint	Parameter	(n=46)	(n=23)
	Median	3.8 months	1.9 months
Progression-free
Hazard ratio		0.64
survival (primary)
	P-value(one-sided)		0.079
	Partial response, n (%)	1 (2.2%)	0
Best tumor response
Stable disease, n (%)	26 (56.5%)	11 (47.8%)

Doubled median PFS represents clinical proof of concept for telaglenastat

14

ENTRATA Progression-Free Survival

Survival Probability

Number at Risk

1.0

0.8

0.6

0.4

0.2												Follow-up
												Minimum: 3 months
0.0												Median: 7.5 months
0	1	2	3	4	5	6	7	8	9	10	11	12

Time (Months)

Telaglenastat + Everolimus:	46	44	28	25	15	13	10	9	7	7	2	2	0
Placebo + Everolimus:	23	23	10	8	6	6	5	5	2	1	1	0	0

* Stratified analysis

15

ENTRATA Safety Summary

	Telaglenastat +	Placebo +
	Everolimus	Everolimus
	(n=46)	(n=23)
		n (%)
All Grade AEs, any cause	46 (100)	23 (100)
Grade 3-4 AEs	35 (76.1)	13 (56.5)
Grade 5 AEa	2 (4.3)	1 (4.3)
AE leading to treatment discontinuation of any drug	13 (28.3)	7 (30.4)
Everolimus discontinuation	11 (23.9)	7 (30.4)
Telaglenastat/placebo discontinuation	12 (26.1)	7 (30.4)

AE leading to dose interruption or reduction of any drug

Everolimus interruption or reduction

Telaglenastat/placebo interruption or reduction

35 (76.1)	14 (60.9)
35 (76.1)	14 (60.9)
32 (69.6)	13 (56.5)

1. None were considered treatment-related per investigator

16

ENTRATA Safety: Treatment-Emergent Adverse Events

	Telaglenastat + Everolimus	Placebo + Everolimus
AE in >20 % of patients n (%)	(n=46)				(n=23)
	Any Grade	Grade ≥3	Any Grade	Grade ≥3
Any event	46 (100)	37	(80)	23	(100)	14	(61)
Fatigue	20 (44)	2	(4)	10 (44)	2	(9)
Anemia	18 (39)	8 (17)	8	(35)	4 (17)
Serum creatinine increased	15 (33)		0	6	(26)	1	(4)
Cough	15 (33)		0	9	(39)		0
Nausea	15 (33)	1	(2)	4	(17)		0
Decreased appetite	14 (30)		0	4	(17)		0
Dyspnea	14 (30)	1	(2)	6	(26)	1	(4)
Peripheral edema	12 (26)	1	(2)	4	(17)		0
Pruritus	11 (24)	1	(2)	7	(30)	1	(4)
Constipation	10 (22)	1	(2)	2 (9)		0
Photophobia	10 (22)		0	2 (9)		0
Stomatitis	10 (22)	1	(2)	6	(26)	1	(4)
Diarrhea	9 (20)	1	(2)	11 (48)		0
Hyperglycemia	6 (13)	2	(4)	6	(26)	1	(4)

17

Market Potential of Telaglenastat plus Cabozantinib in Second Line as Immunotherapy Moves to First Line

Overall RCC Market is Expected to Grow from over $2B to approximately $7B by 2026

Advanced RCC Drug Treated Patients by Line of Therapy

FIRST LINE	SECOND LINE
IO/IO or IO/Kinase combinations	Kinase inhibitors
Kinase inhibitors	IO therapy

	THIRD LINE +
51%	Kinase inhibitors
mTOR inhibitors

31% 49%

18%

Sources: Decision Resources 2018, Renal Cell Carcinoma
Major Markets = US, UK, France, Germany, Spain, Italy, Japan	18

Telaglenastat Potential New Therapy in RCC and Solid Tumors

• ENTRATA trial has met primary endpoint
• • Telaglenastat + everolimus versus placebo + everolimus
  • Doubled median PFS
  • Proof of concept for telaglenastat in RCC
• CANTATA pivotal trial enrolled
• • Telaglenastat + cabozantinib versus placebo + cabozantinib
  • Fast Track designation
  • Top-lineresults expected in 2H2020
• Broad potential in multiple oncology indications
• • Trial planned in NRF2/Keap1 lung cancer patients

19

Telaglenastat development in NSCLC with KEAP1/ NRF2 Mutations

• Randomized Phase 2 to initiate 1H2020
• • PD-1/chemo+ placebo vs. PD-1/chemo + telaglenastat
  • First line NSCLC patients will be pre-selected for KEAP1/NRF2 mutations
  • Incidence of target mutations is estimated to be 20-25% of first line NSCLC
• Rationale for unique development opportunity in selected NSCLC population
• • KEAP1/ NRF2 mutations are significant genetic prognostic factor of poor outcomes in NSCLC - regardless of treatment.
  • • Overall survival 7.8 (mutant) vs. 20.4 (wild type) months in first line patients (Skoulidis, ASCO 2019)
  • KEAP1/ NRF2 pathway drives the production of glutathione
  • The mutations result in hyper-activation of glutathione synthesis - creating a dependence on glutamine
  • Preclinically, KEAP1/NRF2 mutations cause NSCLC models to be highly aggressive and uniquely sensitive to telaglenastat

20

KEAP1mut

Telaglenastat

et al. 2017

•

•

•

mut

21

KEAP1mut/NRF2mut NSCLC cells are Sensitive to Telaglenastat

Relative Cell Growth/Death (% control)

Sensitive

t-testChi-Square

100 p=0.00 p=0.047

2

50

0

-50

Resistant

Death Growth

A549 H2023 DFCI024 H1568 H1648 H920 H358 H1993 H2030 H2122 H322 Calu3 H2347 HCC2302 H23 CALU6 H1703 HCC827 H596 H441 H661 H1869 H1437 HCC515 H647	H1650 H1975 H1355 H226 H650 H2087 H2073 HCC15 H1563 H1299 H1781 H2085 H810 H838 H1693 ChaGoK1 H727
KEAP1mut	NRF2mut

Panel of NSCLC Tumor Cell Lines Treated with CB-839 (1 μM) for 72 Hours

Effects of CB-839 on the growth/death of a panel of cancer cell lines

-	% cell growth compared to untreated cells
-	% cell death compared to starting cell number	22

COLLABORATION WITH INCYTE

Arginase Inhibitor INCB001158

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

Normal T-Cells

MDSC/neutrophil

Arginine

Arginine

Expressions of TCRς

Production of IFNγ

Proliferation

Arginase

Dormant T-Cells

24

Executing a Broad Development Program for INCB001158

Monotherapy

Cohorts

NSCLC

Colorectal

Other

PD-1 Combo

(Naïve)

MSS

colorectal

Gastric

Squamous

H&N

Mesothel.

PD-1 Combo (Experienced)

NSCLC

Melanoma

Urothelial

MSI

Colorectal

Chemo		Daratumumab
combos		SC Combo

FOLFOXMultiple Myeloma

Gem/Cis

Paclitaxel

25

INCB001158 Monotherapy and Combination with Pembrolizumab

Treatment-related AEs occurring in ≥5% of patients receiving INCB001158 at 100 mg BID

Monotherapy

	INCB001158 Monotherapy
			(n=85)
AE, n (%)	Any Grade	Grade 3-4
Any AE	28	(33)	3 (4)
Fatigue	8	(9)	1 (1)
Constipation	6	(7)	0
Decreased appetite	6	(7)	1 (1)
Nausea	5	(6)	0

No treatment-related Grade 5 AEs

Immune-related AEs

• Monotherapy: Gr 3 colitis (n=1), Gr 2 malaise (n=1)
• Combination: Consistent w/ pembrolizumab safety profile

Data cut: July 22, 2019

Combination with Pembrolizumab

INCB001158 + Pembrolizumab

(n=114)

AE, n (%)	Any Grade	Grade 3-4
Any AE	70	(61)	15	(13)
Diarrhea	18	(16)	1 (1)
AST increased	13 (11)	2	(2)
Fatigue	13 (11)	1	(1)
Rash	10 (9)		0
Nausea	9 (8)		0
ALT increased	8	(7)	2	(2)
Constipation	8	(7)		0
Anemia	6	(5)	2	(2)
Hyponatremia	6	(5)	1	(1)
Hypothyroidism	6	(5)		0

INCB001158 MSS CRC Objective Responses Treatment Duration

INCB001158 Monotherapy (N=33a): 3% ORR, 27% DCR

INCB001158 + Pembrolizumab (N=43a): 7% ORR, 30% DCR

Combination with Pembrolizumab

PR

Prior lines adv/	2	7	1	5	4	2	2	1	2	2	2	3	1	3	2	3	5	3	3	4	7	3	2	6	4	1	4	2	4	2	5	3	5	4	11	1	3	2
met therapy:

Historic ORR with CPI therapies in 2L/3L MSS CRC: 0-1%1-4	6-month PFS rate: 20%
Historic CPI 6-month PFS rate: ~10%1-4
Data cut: July 22, 2019. a. Response evaluable patients include those who discontinued treatment without a postbaseline scan for reasons other
than unrelated toxicity, death, or withdrawal of consent; b. 37 of 43 response-evaluable patients per protocol had postbaseline scans. 1. Le et al,
NEJM 2015;372:2509-2520; 2. Eng et al, Lancet Oncol 2019; 20:849-861; 3. Brahmer et al. NEJM 2012;366(26):2455-65; 4. Chen et al JCO	27
2019;37(suppl):abstr 3512

Disease Characteristics of MSS CRC Patients with Response or Prolonged Stable Disease

Disease Features			Change in Target Lesions Over Time
	PR or SD ≥ 6 months
Disease Feature	Monotherapy	Combination
(n=2/33)	(n=7/43)
≥2 prior lines of	2/2	7/7
therapy
Progressed within 6	2/2	5/7
on prior therapy
				All responders
≥4 RECIST-evaluable
2/2	4/7		had decrease
lesions
			in visceral mets
Data cut: July 22, 2019
				Closed circle: off study
			28

Biomarker Analysis: INCB001158 + Pembrolizumab in MSS CRC

Increase in CD8+ cells post-treatment		Trend towards greater CD8+ increase in patients' PR or
	SD2

a. SD ≥56 days
NOTE: Mean pre- and post-treatment (Day 29) values include non-paired samples; non-evaluable patients excluded from the analysis. P-values are provided	29
for descriptive purposes only.

Arginase Inhibition and Increase in Plasma Arginine

Post-Dosing with INCB001158 Monotherapy

Potent Target Inhibition at All Doses Evaluateda		Dose-Related Increases in Plasma Argininea

Steady-state INCB001158 pharmacokinetics at trough exceeded the arginase IC90 at all doses INCB001158 inhibited plasma arginase activity and induced dose-related increases in mean plasma arginine

a. Effects on arginase inhibition and plasma arginine levels were similar in patients receiving INCB001158 in combination with pembrolizumab
(data not shown)	30

MSS CRC Monotherapy and Combination Demographics

				INCB001158 +
		INCB001158 Monotherapy	Pembrolizumab
Baseline Characteristics	n=33	n=43
Median age, years (range)	56 (42-87)	57 (35-80)
0	7 (21)	12	(28)
ECOG PS, n (%)
1	26 (79)	31 (72)
Median prior lines of therapy in	3 (0-5)	3 (1-11)
advanced/metastatic setting, n (range)
Median time since diagnosis, years (range)	3.2 (0.6-13)	3.0 (0.4-15)
Liver metastases, n (%)	24 (73)	28 (65)
Prior anti-PD-(L)1, n (%)	7 (21)		0
KRAS status, n (%)	Mutant	21	(64)	29	(67)
Wild-type	10	(30)	12	(28)
BRAF status, n (%)	Mutant	2	(6)	4	(9)
Wild-type	23	(70)	26	(60)

Data cut: July 22, 2019

31

Conclusions

• INCB001158 is the first arginase inhibitor in clinical trials
• INCB001158 was well tolerated alone and in combination with pembrolizumab
• Responses were observed in MSS CRC, a tumor type refractory to PD-(L)1 therapy
• • 1 monotherapy response (n=33) in a patient who had progressed on immediate prior PD-(L)1 exposure
  • 3 responses in combination with pembrolizumab (n=43); 6-month PFS rate of 20%
• Pharmacodynamic increases in total intratumoral CD8+ cells were seen post-treatment with INCB001158 + pembrolizumab in MSS CRC patients
• Clinical studies with INCB001158 in solid tumors and hematologic malignancies are ongoing

32

CYSTIC FIBROSIS PROGRAM

Arginase Inhibitor CB-280

Cystic Fibrosis: Rationale for Use of Arginase Inhibitors

Despite recent advances using CFTR modulator therapies, there is still a need for new

therapies with different mechanisms of action

• FEV1 improvements are significant with CFTR modulator therapy, yet many CF patients still have significantly impaired lung function
• An arginase inhibitor is expected to confer additional benefit when combined with standard of care therapies
• Arginase inhibition may benefit all CF patients, regardless of mutational status
• Inhibition of arginase should increase NO, increase anti-microbial effects and improve airway function.
• Market size for CF is expected to grow from approximately $4B to $8B in 2024

Source: Evaluate Pharma Research 2019	34

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-280is an investigational 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
Complete		on Background Therapy

35

Well Positioned for Success

Financials

• Estimated cash and investments of $157.4 M at December 31, 2019
• 63.5M shares outstanding
• No debt
• Significant funding from potential future milestones

37

2020 Milestones

TELAGLENASTAT NSCLC Initiate	INCB001158 Advance	CANTATA Announce topline
trial with genetic biomarker
NRF2/KEAP1	enrollment	results of pivotal trial

1

3

5

2

4

6

CB-280 Initiate trial in	TELAGLENASTAT Enroll	PRECLINICAL PIPELINE
Cystic Fibrosis patients	combination trials with Pfizer	Advance pipeline

38

Investment Highlights

Late Stage		Strong		Established		Diversified		Experienced
Clinical		Partnerships		Drug Discovery		Portfolio		Founder and
Development		with Industry		Engine				Management
Program in RCC		Leaders						Team

Targeting cancer, differently.

THANK YOU

NASDAQ: CALA

Copyright © 2020 Calithera. All Rights Reserved.