Ibrutinib (PCI-32765)First-In-Class BTK Inhibitor

IM Los Angeles 18 Jan 2013

1

The Discovery of Agammaglobulinemia in 1952

Colonel Ogden C. Bruton (a†908, †2003),Chief of Pediatrics at Walter Reed Army Hospital

From: Bruton, OC: Agammaglobulinemia,Pediatrics 1952 1952;9;722-728

2

1993 – Btk gene was cloned and characterized

2005 – First synthesis of Ibrutinib (PCI-32765)

2009 – First human treated with Ibrutinib

2014/2015 – Anticipated first regulatory approval

The Scientific Journey of Ibrutinib

1952 – Colonel Bruton described a genetic disorder, agammaglobulinemia

1950 1960 1970 1980 1990 2000 2010 2020

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3

B cell receptor signaling pathway

Btk is essential for:• BCR activation of NF-kB (apoptosis)1

• BCR activation of integrins (adhesion)2

• Chemokine-controlled migration and homing3

1Davis et al, Nature 463, 88-942Spaargaren et al, J. Exp. Med 198, 1539-503de Gorter et al, Immunity 26, 93–104 4

ibrutinib

Ibrutinib: First-in Class Inhibitor of BTK

• Forms a specific and irreversible bond with cysteine-481 in BTK

• Highly potent BTK inhibition at IC50=0.5nM

• Orally administered with once daily dosing resulting in 24-hr target inhibition

• Induces growth inhibition and apoptosis in B-cell tumor cells

• No cytotoxic effect on T-cells or NK-cells

5

Honigberg LA et al: Proc Natl Acad Sci USA.107:13075, 2010Herman SEM et al: Blood 117:6287-6296, 2011

Ponader, et al., ASH Meeting Abstracts 116:45, 2010 5

Inhibition of Downstream Signaling for IbrutinibD0HH2 Cell Line

6

PMA/Ionomycin

BCR

BtkY-551P

PLCγY-783

Anti-I gM

PCI -32765

Lyn,Fyn

P

ERK

BCR

BtkY-551PP

PLCγY-783

Anti-I gM

PCI -32765

Lyn,Fyn

PP

ERKPPP 

Anti-IgG

Y-223

PPP

P

pPLCγ1 Y783

pERK T202/Y204

PLCγ1

αIgG:

0

0 0.0

006

4 µ

M

0.0

032 µ

M

0.0

16 µ

M

0.0

8 µ

M

0.4

µM

2 µ

M

PCI-32765

- + + + + + + +

pBtk Y223

pSyk Y352

Syk

Btk

ERK

(1 hour drug exposure followed by washout)

Ibrutinib Inhibits BCR-driven Cell Adhesion

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Fibronectin-coated plate

B-CLL cells +PCI-32765

M. Spaargaren et al, manuscript in preparation

0

10

20

30

40

50

60

70

80

90

100

BSA+αIgM

Fibronectin(unstimulated)

Fibronectin+αIgM

Fibronectin+PMA

0.33µM

1.0µM

0.33µM

1.0µM

% A

dher

ence

Mechanism of Action: Migration and Homing

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all

+ CXCL 13 (1 µg/ml)

**

% M

igra

ted

cells

Efficacy Established in Spontaneous Canine Lymphoma

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all

10 year old Airedale terrier

Aggressive, surface IgG+ B-cell lymphoma

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9/10

/200

8

9/17

/200

8

9/24

/200

8

10/1

/200

8

10/8

/200

8

10/1

5/20

08

10/2

2/20

08

Lym

ph N

ode

size

(cm

)

Subman L

Subman R

Prescap L

Prescap R

Axillary L

Axillary R

Inguinal L

Inguinal R

Popliteal L

Popliteal R

excised

PCI-32765 treatment

79% decrease

in total tumor burden

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9/10

/200

8

9/17

/200

8

9/24

/200

8

10/1

/200

8

10/8

/200

8

10/1

5/20

08

10/2

2/20

08

Lym

ph N

ode

size

(cm

)

Subman L

Subman R

Prescap L

Prescap R

Axillary L

Axillary R

Inguinal L

Inguinal R

Popliteal L

Popliteal R

Subman L

Subman R

Prescap L

Prescap R

Axillary L

Axillary R

Inguinal L

Inguinal R

Popliteal L

Popliteal R

excised

PCI-32765 treatment

79% decrease

in total tumor burden

Probe- Labeled BTK

Probe assay

Day

0,

pre

-do

se

4-h

ou

rs

24-h

ou

rs

Day

7,

pre

-do

se

Day

0,

pre

-do

se

Day

7,

pre

-do

se

PBMCLymph Node

Probe Assay for BTK OccupancyComplete occupancy in Patient – 1.25 mg/kg once daily

10

Probe

Total Btk

Actin

Day

1,

pre

-do

se

Day

1,

4HR

Day

2,

pre

-do

se

Day

8,

pre

-do

se

Day

8,

4HR

Day

15,

pre

-do

se

Day

29,

pre

-do

se

x

Btk

Btk

32765

probe

Absence of drug:

Presence of drug:

probe

0 4 8 12 16 20 24 280

10

20

30

40

50

60

70

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Plasma Conc

% Active-Site Occupancy

Time Postdose (h)

Pla

sm

a C

on

ce

ntr

ati

on

(ng

/mL

)

BT

K A

cti

ve

-Sit

e O

cc

up

an

cy

Plasma concentration profile reflects inhibition profile of reversibly inhibited off targets

Occupancy indicates irreversible inhibition of BTK

Durable BTK inhibition following an oral dose

Plasma Concentration of PCI-32765 vs. BTK OccupancyPatients dosed at 2.5 mg/kg/day

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Phase 1 Study in NHL and CLL

-100

-50

0

50

100

150

CLL/SLL

MCL

DLBCL

FL

Other Indolent NHL

% C

han

ge

of

Tum

or

Bu

rden

12

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Phase 2 study in Mantle Cell Lymphoma- Best Response (Efficacy Population n=110, Median Follow Up 9.2 mo)

Wang M et al, ASH 201213

Best response with longer follow up

14Wang M et al, ASH 2012

Kaplan-Meier Progression-Free Survival and Duration of response

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All Treated Population 111

Median PFS (CI 95%) months 13.9 (6.64, NR)All Responded Population 75

Median DOR (CI 95%) months NR (NR, NR)

Responder

All Treated

PFS DOR

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18 mo PFS at 420 mg dose is estimated at 88% for R/R patients and 96% at 15 mo for TN patients.

Phase 2 Study in CLL- PFS with Ibrutinib Monotherapy

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R/R no del 17p PFS = 81%95% CI = [64%, 91%]

R/R del 17pPFS = 53%95% CI = [28%, 72%]

Historical data: 3-7 ms

R/R CLL patients by 17p status treated with ibrutinib(PCYC-1102-CA): Median PFS not reached (median f/u 22 ms)

Rapid Nodal Response Accompanied by Egress of CD19/CD5+ B-cells

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Day 22

C1D1

C1D8

C1D15

C1D22

C2D1

C3D1

C4D1

C5D1

C6D1

C7D22

50%

100%

150%

200%

AL

C %

Ch

an

ge

fro

m B

as

elin

e

Lymphocyte Count

CD

5

CD

5

CD19 CD19

Day 1 Day 8

Day 15

C1D1

C1D8

C1D15

C1D22

C2D1

C3D1

C4D1

C5D1

C6D1

C7D22

50%

100%

150%

200%

AL

C %

Ch

an

ge

fro

m B

as

elin

e

Lymphocyte Count

CD

5

CD

5

CD19 CD19

Day 1 Day 8

Day 8

C1D1

C1D8

C1D15

C1D22

C2D1

C3D1

C4D1

C5D1

C6D1

C7D22

50%

100%

150%

200%

AL

C %

Ch

an

ge

fro

m B

as

elin

e

Lymphocyte Count

CD

5

CD

5

CD19 CD19

Day 1 Day 8

C1D1

C1D8

C1D15

C1D22

C2D1

C3D1

C4D1

C5D1

C6D1

C7D22

50%

100%

150%

200%

AL

C %

Ch

an

ge

fro

m B

as

elin

e

Day 2Lymphocyte Count

CD

5

CD

5

CD19 CD19

Day 1 Day 8

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Treatment Emergent AEs in >10% of Patients Regardless of Relationship to Study Therapy (1014 cycles administered to all pts)

Wang M et al, ASH 201219

Treatment Emergent Infectious AEs ≥ Grade 3 Regardless of Relationship to Study Therapy(1014 cycles administered to all pts)

Wang M et al, ASH 201220

Conclusions

• Ibrutinib is a first-in-class, selective, covalent, irreversible inhibitor of BTK

• Orally, daily administered

• Well tolerated

• Activity demonstrated in range of B-cell malignancies with high ORR

– Mantle Cell Lymphoma

– CLL

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