Slide 1

Roger Ulrich, Ph.D., Fellow ATSCalistoga Pharmaceuticals, 2006-2011

Acerta Pharma, 2013-

The Development of a Novel Lipid Kinase Inhibitor, Idelalisib (CAL-101, GS-1101), for the

Treatment of Patients with Hematological Malignancies

Slide 2

Cancer Basics

Cancer: A group of more than 100 diseases

Lifetime cancer risk

‒ Developing any cancer, 1 in 2 (44.3%)

‒ Dying from cancer, 1 in 4 (23.2%)

The number of people in the US living with cancer

‒ All cancers: 13,000,000

‒ Leukemias and Non-Hodgkin lymphomas: 850,000

‒ About 150,000 people were diagnosed with leukemia or lymphoma in 2013 alone

Slide 3

Indolent Non-Hodgkin Lymphoma (iNHL)Chronic Lymphocytic Leukemia (CLL) Mantle Cell Lymphoma (MCL)

Incurable B-Cell Malignancies Often Affecting Older Patients

Patients suffer from recurrent:

Lymph node swelling

Sweats

Chills

Fatigue

Life-threatening infections

Slide 4

Regimens For Lymphoid Cancers Have Substantial Toxicity and Become Less Effective with Recurrent Treatment

CHOP/R, CVP/R, BR,

R, FCR

CHOP/R, CVP/R, BR,

R, FCR

REMISSIONDURATION

Unmet MedicalNeed Increases

2nd line1st line

Quality and Durability of Response Decline over Time

3rd line 4th line 5th line 6th 7th

Reference: Hallek, Hematology 2009

Slide 5

Current Standard of Care for iNHL and CLL Includes Chemotherapeutics and -CD20 Antibodies

• Chemotherapeutics are typically DNA alkylating agents or antimetabolites

• Single-agent chemotherapeutics (Chlorambucil, Fludarabine)

• Combinations• CHOP: Cyclophosphamide, Hydroxydaunorubicin (doxorubicin),

Oncovin (vincristine), Prednisone or prednisolone

• R-CHOP: Above plus Rituxan or Arzerra (anti CD20 antibodies)

• R-Bendamustine

• PMitCEBO is a combination of 5 drugs and a steroid, including mitoxantrone (mitozantrone), cyclophosphamide, etoposide, bleomycin, vincristine and prednisolone. May also include methotrexate.

Slide 6

DNA Alkylating Agents (Cyclophosphamide, Bendamustine)

• Nitrogen mustards (i.e. mustard gas), originally developed as chemical weapons during WWI

• Cyclophosphamide has been in use since the 1940s, bendamustine since the 1960s

Cyclophosphamide

Bendamustine

Slide 7

Reduction or elimination of side effects defines the need and objective for targeted therapeutics

• CTx kills rapidly dividing cells• Nausea, fatigue, vomiting, diarrhea, fever, hair loss,

constipation, loss of appetite, cough, headache, unintentional weight loss, difficulty breathing, rashes, and stomatitis, immunosuppression (myelosuppression), anemia, and low platelet counts.

Traditional Chemotherapeutics have a Myriad of Side Effects

Slide 8

Calistoga Pharmaceuticals evolved as a small, privately-owned pharmaceutical company

Founded in April 2006 in Seattle, WA‒ Mike Gallatin, PhD (ICOS)

‒ Neill Giese, PhD (COR, Millenium)

‒ Roger Ulrich, PhD (Merck, Abbott, Pharmacia & Upjohn, Upjohn)

Acquired by Gilead Sciences in April 2011

Isoform-Selective Inhibitors of Phosphatidylinositol 3-Kinase (PI3K) as Targeted Therapies for Cancer

Slide 11

PI3K Activity

• Activated PI3K translocates to the plasma membrane and catalyzes the conversion of PIP2 to PIP3

• PIP3 binds PDK1 via PH domain• PDK1 activates AKT (PKB)

Gunn and Hailes, 2008

Slide 12

Through Activation of AKT (PKB), PI3K Regulates Many Cellular Activities

Slide 13

PI3K is a Family of Enzymes

• Class 1 PI3Ks have a catalytic subunit (p110) with four types (isoforms) - p110a, p110b, p110g and p110d

• 1997: PI3K delta (PI3K) isoform discovered simultaneously by ICOS and the Ludwig Institute

• 2006 Calistoga licensed assets from ICOS

Alpha Beta Gamma Delta

Class I PI3 Kinases

B-cell signaling, developmentand survival

Slide 14

PI3K Inhibition Can Target Multiple Survival Signals in B-Cell Malignancies

T308 S473AKTNF-B

pathway

mTOR

BTK

PLC2

PKC GSK-3

p70s6k elf4E

BCR

PI3K

CD40

STAT

JAKTRAF6 JAK

LYN

SYK LYN/SYK

T-cell Signalingstimulus

gp130 gp130

STAT BTK

PLC2

Malignant B-cell membrane

T308 S473AKTNF-B

pathway

mTOR

BTK

PLC2

PKC GSK-3

p70s6k elf4E

PI3K InhibitorPI3K

InhibitorCXCR5BAFFR

Stromal cell

IL-6R

CXCL13BAFFIL-6

Reference: Lannutti, Blood 2011

PI3K Inhibition CausesProliferationViabilityStromal support

Slide 15

Class IPI3K Isoform

Cell TypeMouse

embryonic fibroblasts

Mouse embryonic fibroblasts

Human basophils

Human basophils

Cell-Based Activity

PDGF-induced pAKT

LPA-induced pAKT

fMLP-induced CD63+

FcR1-induced CD63+

EC50 (nM) >20,000 1,900 3,000 8

Idelalisib Potently and Selectively Inhibits PI3K

Reference: Lannutti, Blood 2011

Slide 16

In a Kinome Scan, CAL-101 Shows No Activity Against Protein Kinases

Slide 17

Idelalisib was Developed as an Oral Twice-Daily Tablet

Drug substance‒Chirality: Single enantiomer. 100% EE‒Purity: >99.8%‒14C radioisotope and 2H standard for DMPK

Drug product‒Compressed, coated tablet

•75- , 100-mg, and 150-mg strengths

Slide 18

Preclinical Development Supported Initial Clinical Development in Healthy Subjects

Safety pharmacology‒ No hERG inhibition (implying low risk of QT interval prolongation)

‒ No effects in cardiovascular, respiratory, and CNS safety studies

Repeat-dose toxicology (4 weeks and 13 weeks) in rats and dogs

‒ Reversible lymphoid depletion, consistent with mechanism of action

‒ Transient liver enzyme elevations at high dose levels in dogs that reverse despite continued dosing

Non-Genotoxic‒ Negative in Ames assay, human peripheral blood lymphocyte assay, and rat

micronucleus study

Slide 19

0 2 4 6 8 10 120.1

1

10

100

1,000

24 36 48

Idelalisib in Fed State [12]

Condition [N]

Time from Idelalisib Administration, hours

Idel

alis

ib P

lasm

a C

once

ntr

atio

nG

eom

etri

c M

ean, n

g/m

L

Idelalisib in Fasting State [12]

A

0 2 4 6 8 10 120.1

1

10

100

1,000

24 36 48

Idelalisib in Fasting State + Ketoconazole [11]

Condition [N]

Time from Idelalisib Administration, hours

Idel

alis

ib P

lasm

a C

once

ntr

atio

nG

eom

etri

c M

ean, n

g/m

L

Idelalisib in Fasting State [12]

B

Clinical Studies with Idelalisib in Healthy Subjects

0 2 4 6 8 10 120.1

1

10

100

1,000

24 36 48

Idelalisib in Fed State [12]

Condition [N]

Time from Idelalisib Administration, hours

Idel

alis

ib P

lasm

a C

once

ntr

atio

nG

eom

etri

c M

ean, n

g/m

L

Idelalisib in Fasting State [12]

A

0 2 4 6 8 10 120.1

1

10

100

1,000

24 36 48

Idelalisib in Fasting State + Ketoconazole [11]

Condition [N]

Time from Idelalisib Administration, hours

Idel

alis

ib P

lasm

a C

once

ntr

atio

nG

eom

etri

c M

ean, n

g/m

L

Idelalisib in Fasting State [12]

B

Slide 20

Major Metabolic and Elimination Pathways have Been Elucidated from Phase 1 NHV Studies

Slide 20

N

N

NHN

N

HN

N

F O

N

N

NHN

N

HNNH

F O

O

N

N

NHN

N

HNNH

F O

O

Oxidized CAL-101 (CAL-244)

CAL-244 glucuronide

Glucuronidation

Glucuronidation

Urinary excretion

CYP3A

CAL-101

Biliary excretion

F

NH

NH

O

H N

N

N

N

N H

O

Hydrolyzed CAL-101 (CAL-272)

Hydrolysis

F

N

N

O

N

N

N

NNH

O

OHOH

HO

HO

O

F

N

N

O

H N

N

N

N

NO

HO

HOOH

O H

O

Major glucuronide (CAL-277)

Minor glucuronide (CAL-273)

Enzymatic, non-enzymatic?

Slide 21

In Cancer Patients, CAL-101 Shows Little Increase in Exposure at Doses >150 mg

Plasma Exposure by Dose Level

0

5000

10000

15000

0

1000

2000

3000

4000

CmaxAUC Ctrough

0

50 (N

=10)

100 (

N=12)

150 (

N=24)

200 (

N=26)

350 (

N=14)

Dose (mg/dose BID)

AUC 0-

6h

SEM

(ng

hour

/mL)

Cm

ax & C

trough SEM

(ng/mL)

Slide 22

NHL (N=103)

CharacteristicMCL

(N=40)iNHL

(N=63)CLL

(N=54)

Age, median[range], years

69 [52-83]

63[32-91]

63 [37-82]

Bulky disease, % 60 44 82

Adverse genetics (del 17p), % -- -- 31

Prior therapies, median [range], n

4 [1-14]

4[1-10]

5[2-15]

Prior therapy type, %

Rituximab 100 100 98

Alkylating agent 100 89 87

Anthracycline/anthracenedione 85 51 --

Purine analog 22 43 100

Bortezomib (MCL)/Alemtuzumab (CLL)

60 -- 33

Patients in a Single-Agent CAL-101 Study Had Unfavorable Prognostic Characteristics and Multiple Prior Therapies

Slide 23

Best On-Treatment Change in Tumor Size(ITT Analysis)

-100

0

-50*

+25

+50

+75

+100

MCL(N=38a)

iNHL(N=50b)

Inevaluable (patients without a follow-up tumor assessment)

* Criterion for response [Cheson 2007]a Tumor assessments for 2 patients have not been recordedb Tumor assessments for 4 patients have not been recorded

Inevaluable (patients without a follow-up tumor assessment; includes 6 patients with LPL with no adenopathy)

% C

han

ge

in L

ymp

h N

od

e A

rea

Single-Agent Idelalisib Resulted in Tumor Shrinkage in Most Patients with MCL and iNHL

Slide 24

Best On-Treatment Change in Tumor Size(ITT Analysis, N=55)

-100

-75

-25

0

-50*

+25

+50

+75

+100

Inevaluable (patients without a follow-up tumor assessment)Patients with del (17p)

* Criterion for response [Hallek 2008]

% C

hang

e in

Lym

ph N

ode

Area

Single-Agent Idelalisib Resulted in Tumor Shrinkage in All Evaluable Patients with CLL, Including Those with del (17p)

Slide 25

0

20

40

60

80

100

84%n=46

24%n=13

84%n=16

84%n=16

71%n=5

71%n=5

79%n=11

79%n=11

86%n=12

86%n=12

a Decrease by 50% in the nodal SPDb Response by IWCLL criteria [Hallek 2008]

Idelalisib Combination Therapies Substantially Increased Overall Response Rate in Patients with CLL

Mono(N=55)

Overa

ll

Response

(OR)b

Lymph N

ode

Response

(LNR)a

LNR OR LNR OR LNR OR LNR OR

+R (N=19)

+F (N=7)

+B (N=14)

+R+B (N=14)

Slide 26

CLL Patients Realize Clinical Benefit

Pretreatment With CAL-101 Treatment

38 year old CLL patient

Slide 27

Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma

-- Idelalisib Would Be First PI3K Delta Targeted Therapy Approved for a Hematological Cancer and First New Class of Therapy Approved for iNHL in More Than a Decade –

FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 11, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of idelalisib, an investigational, targeted, oral inhibitor of PI3K delta, for the treatment of indolent non-Hodgkin’s lymphoma (iNHL). The data submitted in this NDA support the use of idelalisib for patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy.

Idelalisib achieved an overall response rate of 54 percent, with a median duration of response of 12 months.

September 11, 2013

Slide 28

Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma

-- Idelalisib Would Be First PI3K Delta Targeted Therapy Approved for a Hematological Cancer and First New Class of Therapy Approved for iNHL in More Than a Decade –

FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 11, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of idelalisib, an investigational, targeted, oral inhibitor of PI3K delta, for the treatment of indolent non-Hodgkin’s lymphoma (iNHL). The data submitted in this NDA support the use of idelalisib for patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy.

Idelalisib combined with rituximab produces responses in 97% of patients with CLL, granted Breakthrough

Therapy Designation by FDA

October 9, 2013

Slide 29

Idelalisib is On Track for Approval in the US and Europe

• NDAs for both iNHL and CLL submitted, approval expected this year

• There are many to thank for this success:• Calistoga Pharmaceuticals Inc. and our investors (2006-2011)

• Gilead Sciences

• Our many nonclinical and clinical investigators

• Especially, to our cancer patients for their willingness to take a chance on an untried new drug