Results from a Phase 2 Randomized, Placebo-Controlled, Double Blind Study of the Hedgehog Pathway Antagonist IPI-926

in Patients with Advanced ChondrosarcomaAndrew J. Wagner1, Peter Hohenberger2, Scott Okuno3, Mikael

Eriksson4, Shreyaskumar Patel5, Stefano Ferrari6, Paolo G. Casali7, Sant P. Chawla8, Molly Woehr9, Robert Ross9, Jessica O’Keefe9, Amy Hillock9,

George Demetri1, Peter Reichardt10

1Dana-Farber Cancer Institute; 2Universitatsmedizin Mannheim; 3Mayo Clinic; 4Skanes Universitetssjukhus i Lund; 5MD Anderson Cancer Center; 6IRCCS Istituto Ortopedico Rizzoli; 7Fondazione IRCCS Istituto Nazionale dei Tumori; 8Sarcoma

Oncology Center; 9Infinity Pharmaceuticals; 10Helios Klinikum Bad Saarow

CTOS 2013New York

Hedgehog Signaling Pathway

Inactive

Activated

•Plays a critical role in development

•Inactive in most adult cells

•Regulates normal chondrocyte proliferation, terminal differentiation, and endochondral bone development

Nuclear Gli-1

Cases stained Positive Negative

N= 30Conventional 21 (70%) 9 (30%)

Courtesy of Infinity Pharmaceuticals

Hh Pathway in Chondrosarcoma

Maeda et al, 2007; Long et al., 2001; Farquharson et al., 2001; Kimura et al., 2008; Tiet et al., 2006

• Chondrosarcomas express high levels of Hedgehog pathway factors

• Hedgehog increases proliferation of chondrosarcoma cells

No change in Gli-1,Cyclin D1/D2, Myc, or Bcl2

HH Pathway Inhibitors Block SMO

*

Vehicle IPI-926 Vehicle IPI-926 0

0.2

0.4

0.6

0.8

1

1.2

2^ΔΔ

CT

Human Gli-1

Wunder, Alman, et al.

IPI-926 Suppresses Hh Signaling and Chondrosarcoma Growth

IPI-926Control

Courtesy of Infinity Pharmaceuticals

Xenograft Growth Inhibition by IPI-926

Mean 43% (range 37-52%) tumor growth inhibition

Vehicle IPI-926 0

20

40

60

80

100

120

%En

dpoi

nt t

umor

vol

ume

Vehicle IPI-926 0

20

40

60

80

100

120

140%

End

poin

t Tum

or V

olum

e

Vehicle IPI-9260

20

40

60

80

100

120

140

% E

ndpo

int t

umor

wei

ght

Day of implant Established tumors

Tumor from Subject A

p<0.03 p<0.03 p<0.03

Oral, daily treatment of IPI-926, M-F, for 6-10 weeks, n= 8-15/group

Tumor from Subject CTumor from Subject B

Campbell et al. AACR 2011

Mon

ths

On

Trea

tmen

t

PatientCourtesy of Infinity Pharmaceuticals

Phase I study of IPI-926: CS patients

IPI-926-04: Phase 2 Randomized, Double-Blind Study of IPI-926 vs Placebo

in Metastatic/Locally Advanced (Unresectable) Chondrosarcoma

Randomization 2:1

IPI-926160mg QD

N=94

PlaceboQD

N=46

Off study drug

Optionalopen-label

IPI-926

Radiology Review

Confirmed PD

Double-blind Open-Label

Screening

Radiology Review

Confirmed PD

Sponsor: Infinity Pharmaceuticals; NCT01310816 Primary Objectives: Compare PFS of IPI-926 versus placebo; safetySecondary Objectives: TTP, OS, ORR, response duration, PKPreplanned futility analysis after 40% of expected 100 events – DMC met June 15, 2012

Requires RECIST progression in prior 24 weeks

Key Eligibility Criteria• Pathologically-diagnosed conventional chondrosarcoma• Metastasis to at least 1 location or locally advanced disease that

is deemed unresectable by a surgeon• At least 1 measurable target lesion per RECIST 1.1 • Radiographic progression of disease within 24 weeks prior to the

start of screening (date ICF signed), through the screening period• Progression must be based on at least two sets of scans (CT or

MRI), and as defined by RECIST 1.1• At least 18 years of age• ECOG performance status 0 or 1• Life expectancy of at least 3 months

Study AccrualCountry Total N=95

n (%)United States 36 (38)Germany 16 (17)Italy 10 (11)Great Britain 6 (6)Sweden 5 (5)France 4 (4)Poland 4 (4)The Netherlands 4 (4)Australia 3 (3)Canada 3 (3)Norway 2 (2)Russia 2 (2)Jul-1

1

Aug-11

Sep-11

Oct-11

Nov-11

Dec-11

Jan-12

Feb-12

Mar-12

Apr-12

May-12

0

10

20

30

40

50

60

70

80

90

100

Cumulative AccrualMonthly Accrual

IPI-926 N=64

Placebo N=31

Total N=95 IPI-926

N=64Placebo N=31

Total N=95

Age (years) Years since diagnosis

n 64 31 95 <4 41/64 (64) 18/30 (60) 59/94 (63)Mean (SD) 53.7 (12.8) 50.6 (11.5)52.7 (12.4) 4-7 17 (27) 6 (20) 23 (24)Range (min, max) 24, 82 25, 70 24, 82 >8 6 (9) 6 (20) 12 (13)<65 (%) 48/64 (75) 27/31 (87) 75/95 (79)>65 (%) 16 (25) 4 (13) 20 (21) ECOG status

0 24/63 (38) 12/31 (39) 36/94 (38)Female, n (%) 19/64 (30) 11/31 (35) 30/95 (32) 1 39 (62) 19 (61) 58 (62)

Disease Type Baseline disease grade

Metastatic 56 (88) 28 (90) 84 (88) 1 12/43 (28) 4/23 (17) 16/66 (24)Locally Advanced 8 (13) 3 (10) 11 (12) 2 27 (63) 14 (61) 41 (62)

3 4 (9) 5 (22) 9 (14)Systemic TherapyNo prior lines 38 (59) 18 (58) 56 (59)One or more lines 26 (41) 13 (42) 39 (41)

Patient Characteristics

Treatment Emergent Adverse Events in >10% of Patients

IPI-926 N=62 Placebo N=30

Any Grade n (%)

3-4 n (%)

5 n (%) Any Grade

n (%)3-4

n (%)5

n (%)

At least one AE 53 (85) 20 (32) 3 (5) 22 (73) 9 (30) 0

ALT increased 21 (34) 8 (13) 0 0 0 0AST increased 16 (26) 1 (2) 0 0 0 0Constipation 10 (16) 0 0 2 (7) 1 (3) 0Decreased Appetite 10 (16) 1 (2) 0 3 (10) 0 0Muscle Spasms 10 (16) 0 0 2 (7) 0 0Diarrhea 9 (15) 0 0 1 (3) 0 0Vomiting 8 (13) 0 0 0 0 0Alk Phos increased 7 (11) 0 0 1 (3) 0 0Alopecia 6 (10) 0 0 0 0 0Dysguesia 6 (10) 0 0 0 0 0Cough 5 (8) 0 0 3 (10) 0 0

Best Percent Change in Target Lesions (RECIST)

Partial Response

Progressive Disease

PFSIPI-926 Placebo

mPFS (95% CI) 3.7 mos

(1.8, 3.7)2.9 mos

(1.8, 5.6)HR

(95% CI) 1.09 (0.59, 1.99)

OS

IPI-926 PlacebomOS

(95% CI) >8.5 mos (6.2, NE)

>7.5 mos(5.0, NE)

HR (95% CI) 1.01

(0.30, 3.47)

Summary

• Rapid accrual to randomized studies of rare diseases is feasible with world-wide collaboration

• IPI-926 was generally well-tolerated when administered to patients with chondrosarcoma

• There was no apparent improvement in PFS in patients with advanced, progressing chondrosarcoma

• A small subset of patients treated with IPI-926 had minor reductions in tumor size

Additional Investigations

• Gli1 staining of tumor specimens

• Hh pathway mutational analysis

• IDH1/IDH2 mutational analysis, 2HG plasma concentration, and correlation with rate of progression

Tarpey et al. Nature Genetics 2013

Thank YouPatients and their Families

Study Teams

Team at Infinity

Markman AustraliaTattersall AustraliaBrodowicz AustriaSamonigg AustriaBlackstein CanadaBlay FranceDuffaud FranceLe Cesne FranceBompas FranceHohenberger GermanyReichardt GermanyBauer GermanyFerrari ItalyCasali ItalyGelderblom NetherlandsSundby-Hall NorwayMazurkiewicz PolandRutkowski PolandTeplyakov RussiaLichinitser RussiaKudryavtseva RussiaValverde Morales SpainEriksson SwedenBiswas United KingdomWhelan United KingdomGrimer United KingdomCowie United Kingdom

Wagner USAChugh USAOkuno USAPatel USARiedel USARyan USAvon Mehren USAChmielowski USAJones USAMatushansky USAMeyer USASeetharam USABenedetto USAPriebat USAElias USAKraft USAChawla USAStaddon USAVan Tine USAGouw USAAttia USA