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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