1. Roger Ulrich, Ph.D., Fellow ATS Calistoga Pharmaceuticals, 2006-2011
The Development of a Novel Lipid Kinase Inhibitor, Idelalisib (CAL-101, GS-1101), for the Treatment of Patients with Hematological Malignancies
Roger Ulrich, Ph.D., Fellow ATS
Calistoga Pharmaceuticals,
Acerta Pharma, 2013- 1

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
Cancer prevalence is defined as the total number of people living with cancer at any point in time. 2

3. CORPORATE OVERVIEW
April 17
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

4. Unmet Medical Need Increases
Regimens For Lymphoid Cancers Have Substantial Toxicity and Become Less Effective with Recurrent Treatment
RESPONSE
Unmet Medical
Need Increases
CHOP/R, CVP/R, BR, R, FCR
Regimens for lymphoid cancers have substantial toxicity,
and multiple administrations of regimens that often incorporate the same agents (like rituximab) over and over again make treatment options less effective over time.
BTW 7 prior treatments are seen very often in the patient population we enroll in our trials. In fact, up to 14 or 15 therapies have been observed.
REMISSION
DURATION
1st line
2nd line
3rd line
4th line
5th line
6th
7th
Quality and Durability of Response Decline over Time
Reference: Hallek, Hematology 2009

5. Current Standard of Care for iNHL and CLL Includes Chemotherapeutics and a-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.

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

7. Traditional Chemotherapeutics have a Myriad of Side Effects
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.
Reduction or elimination of side effects defines the need and objective for targeted therapeutics

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

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

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

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

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 (PI3Kd) isoform discovered simultaneously by ICOS and the Ludwig Institute
2006 Calistoga licensed assets from ICOS
Alpha
Beta
Gamma
Delta
Class I PI3 Kinases
Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A Apr 29;94(9):
ICOS Corporation: Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, Cooper JA, Hoekstra MF. p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem Aug 1;272(31):
B-cell signaling, development and survival

14. Malignant B-cell membrane
PI3K Inhibition Can Target Multiple Survival Signals in B-Cell Malignancies
Stromal cell
T-cell
Signaling
stimulus
IL-6
PI3K Inhibitor
BAFF
CXCL13
BCR
IL-6R
CXCR5
CD40
BAFFR
Malignant B-cell membrane
LYN
gp130
gp130
JAK
TRAF6
SYK
JAK
LYN/SYK a b g
PI3K
STAT
T308
S473
AKT
NF-kB
pathway
mTOR
BTK
PLCg2
PKC
GSK-3
p70s6k
elf4E
T308
S473
AKT
NF-kB
pathway
mTOR
BTK
PLCg2
PKC
GSK-3
p70s6k
elf4E
STAT
BTK
Targeted inhibition of
PI3K delta in turn causes a
block in proliferation,
a decrease in cell viability and
disrupts the stromal support for the malignant cells for example in the lymph node. Inhibition of PI3K delta can be measured by
the reduction in AKT phophorylation.
PLCg2
PI3K Inhibition Causes
Proliferation
Viability
Stromal support
Reference: Lannutti, Blood 2011

15. Idelalisib Potently and Selectively Inhibits PI3K
Class I PI3K Isoform
Cell Type
Mouse embryonic fibroblasts
Human basophils
Cell-Based Activity
PDGF-induced pAKT
LPA-induced pAKT
fMLP-induced CD63+
FceR1-induced CD63+
EC50 (nM)
>20,000
1,900
3,000 8 a b g d
CAL-101 (CAL-101) is an
oral drug, it is
small and it
specifically inhibits the PI3K delta isoform.
Listed here are the EC 50s for CAL-101 in PI3-K Class I isoform-specific assays demonstrating the high selectivity for the delta isoform
Reference: Lannutti, Blood 2011

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

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 17

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 18

19. Clinical Studies with Idelalisib in Healthy Subjects

20. Major Metabolic and Elimination Pathways have Been Elucidated from Phase 1 NHV Studies
Biliary excretion F N H O N H F O
Hydrolysis
Enzymatic, non-enzymatic?
Hydrolyzed CAL-101 (CAL-272)
CYP3A
Glucuronidation
CAL-101 F N O H N H F O F N O H
Urinary excretion
Oxidized CAL-101 (CAL-244)
Major glucuronide (CAL-277)
Minor glucuronide (CAL-273) N H F O
Glucuronidation
CAL-244 glucuronide

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

22. CORPORATE OVERVIEW
April 17
Patients in a Single-Agent CAL-101 Study Had Unfavorable Prognostic Characteristics and Multiple Prior Therapies
NHL (N=103)
Characteristic
MCL (N=40)
iNHL (N=63)
CLL (N=54)
Age, median
[range], years 69
[52-83] 63
[32-91]
[37-82]
Bulky disease, % 60 44 82
Adverse genetics (del 17p), % -- 31
Prior therapies, median
[range], n 4
[1-14]
[1-10] 5
[2-15]
Prior therapy type, %
Rituximab
100 98
Alkylating agent 89 87
Anthracycline/anthracenedione 85 51
Purine analog 22 43
Bortezomib (MCL)/
Alemtuzumab (CLL) 33

23. CORPORATE OVERVIEW
April 17
Single-Agent Idelalisib Resulted in Tumor Shrinkage in Most Patients with MCL and iNHL

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

25. ITT Responsea Rate 95% CI
Idelalisib Combination Therapies Substantially Increased Overall Response Rate in Patients with CLL
ITT Responsea Rate 95% CI
Mono
(N=55) +R
(N=19) +F
(N=7) +B
(N=14)
+R+B
(N=14)
Although lymph node response were comparable in different treatment groups,
combining GS-1101 with
rituximab
Or bendamustine significantly improved the overall response
LNR OR
LNR OR
LNR OR
LNR OR
Overall Response
(OR)b
Lymph Node
Response
(LNR)a
a Decrease by 50% in the nodal SPD
b Response by IWCLL criteria [Hallek 2008] 25

26. CLL Patients Realize Clinical Benefit
Pretreatment
With CAL-101 Treatment
And here is what this means for the individual patient:
This is a 38 y/o pt experiencing a dramatic decrease in lymph node sizes clearly benefitting from CAL-101 single-agent therapy
Shortly after CAL-101 treatment initiation, her ALC increased almost 3 fold above 5000/ul, and she met the criterial for CLL disease progression. If not ignored, the pt would have been taken off study.
Instead, by not considering the transient and asymptomatic lymphocytosis, the pt remained on study with persistent control of the lymphadenopathy.
38 year old CLL patient

27. September 11, 2013
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, 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.

28. October 9, 2013
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, 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.
PRESS RELEASE
Gilead to Stop Phase 3 Study 116 of Idelalisib in Chronic Lymphocytic Leukemia Early Because of Positive Risk-Benefit
FOSTER CITY, Calif.--(BUSINESS WIRE)--October 09,
Following a recommendation by an independent Data Monitoring Committee (DMC), Gilead Sciences, Inc. (Nasdaq:GILD) today announced that its Phase 3 study (Study 116) evaluating idelalisib in previously-treated chronic lymphocytic leukemia (CLL) patients who are not fit for chemotherapy will be stopped early. This DMC recommendation is based on a predefined interim analysis showing highly statistically significant efficacy for the primary endpoint of progression-free survival in patients receiving idelalisib plus rituximab compared to those receiving rituximab alone. The safety profile of idelalisib was acceptable and consistent with prior experience in combination with rituximab in previously treated CLL. Gilead has informed the U.S. Food and Drug Administration (FDA) of the plan to end the study and will engage in a dialogue with the FDA regarding a regulatory filing in CLL. Data from Study 116 will be submitted for presentation at an upcoming scientific conference.
Idelalisib combined with rituximab produces responses in 97% of patients with CLL, granted Breakthrough Therapy Designation by FDA

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 ( )
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