1. Previous Clinical Experience
The RESPONSE Trial CINC424B2301
Previous Clinical Experience
Victor Sandor, MD
VP Global Oncology Drug Development
Incyte Corporation 1

2. Outline INC424 clinical experience in healthy volunteers
Key findings from:
Single and multiple ascending dose studies
Drug interaction studies
Pharmacokinetics in patients with renal or hepatic insufficiency
INC424 clinical experience in MPNs
Polycythemia vera
Essential thrombocythemia
Myelofibrosis 2

3. Clinical Evaluation of INC424 in Phase I3

4. INC424 Phase I Clinical Summary
Study #
Study Description
# of Subjects
131
Single ascending dose in HVs 30
132
10-day multiple ascending dose in HVs 71
133
One-way interaction with ketoconazole and erythromycin in HVs 31
134
Single Dose mass balance and metabolite profile in HVs 6
135
One-way interaction with rifampin in HVs 12
136
Two-way interaction with methotrexate in RA patients 18
137
PK evaluation of 25 mg in subjects with hepatic dysfunction 32
138
Definitive QT study in HVs 50
139
Relative bioavailability of INC424 SR formulation in HVs 9
142
PK evaluation of 25 mg in subjects with renal impairment 40 4

5. INC424 Phase I Key Findings
Safety and tolerability
Well tolerated: most common AEs were headache, dizziness and nausea occurred with similar frequency in PBO and INC424 groups
Moderate to severe neutropenia noted in 3/9 subjects at 50 mg BID (highest dose evaluated in HVs): defined MTD as 25 mg BID
Pharmacokinetics and pharmacodynamics
Rapid absorption, PK linear with respect to dose, T1/2 = 3 hr
No accumulation of drug or metabolites with repeat administration
No significant effect of food (can be taken without regard to meals)
Dose-dependent inhibition of STAT3 phosphorylation in blood
Effects of renal Impairment
Subjects requiring dialysis showed prolonged PD activity; no significant effects observed in mild, moderate or severe impairment
Subjects with severe kidney disease (eGFR < 30) or on dialysis will be excluded from Phase III 5

6. INC424 Phase I Key Findings (cont’d)
Effects of hepatic dysfunction
AUCs were 88%, 29% and 66% higher in subjects with mild, moderate or severe hepatic dysfunction (vs. normal), respectively
Subjects with known hepatocellular disease or evidence of encephalopathy will be excluded from Phase III
Drug-drug interactions
Ketoconazole (potent CYP inhibitor) increased AUC 2x
Decrease INC424 dose with concomitant potent CYP inhibitors
Erythromycin (moderate CYP inhibitor) no significant impact on PK
No INC424 dose adjustment necessary
Rifampin (potent CYP inducer) decreased Cmax and AUC by 52% and 71%, respectively
Potent inducers (rifampin, St. John’s Wort) excluded from Phase III
Moderate inducers (e.g. rifabutin, phenytoin) will not require dose modification, but additional PK sampling will be required during use 6

7. Clinical Evaluation of INC424 in Phase II: Advanced PV7

8. Phase II Study in Advanced PV and ET
Part 1
Evaluation of 10 mg BID, 25 mg BID and 50 mg QD regimens in patients with advanced PV and ET for 8 weeks (6-8/group)
Part 2
Expansion at 10 mg BID in PV and 25 mg BID in ET with allowance for individualized dose titration
Polycythemia Vera (N=34)
Open-label, single arm study
of INC424
N = 73 patients
34 patients with PV
39 patients with ET
Eligibility criteria
HU refractory or intolerant
PV: HCT>45% or q3mo
phlebotomy requirement
ET: Platelet count > 650K
10 mg BID*
(n=7)
25 mg BID*
(n=8)
50 mg QD
(n=7)
10 mg BID
(n=12)
Part 1
Part 2
Essential Thrombocythemia (N=39)
10 mg BID
(n=8)
25 mg BID
(n=8)
50 mg QD
(n=8)
25 mg BID
(n=15)
Part 1
Part 2
Individualized dose titration was allowed subsequent to Week 8 8

9. PV Patient Characteristics
Characteristic (median)
PV (n = 34)
Age, years 58
Female
50%
Months from Diagnosis
115
Refractory to HU
74%
Hct %
46.7
Phlebotomy in last 6 months
76%
Platelets x109/L
527
WBC x109/L
13.2
Splenomegaly
Size, cm (range)
9 (1-21)
No. Prior Therapies
1 (1-3)
JAK2V617F positive
100%
JAK2V617F allele burden
72%

10. PV Patient Disposition
28 of 34 (82%) continue on study with a median follow-up 15 months (range 8-21 mos)
6 patients (18%) have discontinued treatment
2 due to AEs, 1 lack of response, 2 withdrew consent, 1 for disease progression
Majority of patients on study are being treated at doses of 5 mg BID (25%) or 10 mg BID (39%)
Median duration on 5 mg BID is 11 months
Median duration on 10 mg BID is 6 months

11. Treatment-related AEs*
Overall Safety in PV
INC424 (N=34)
Treatment-related AEs*
All Grades
Grade 3
Anemia
25 (73.5%)
0 (0%)
Thrombocytopenia
10 (29.4)
2 (5.9)
Leukopenia
5 (14.7)
0 (0.0)
Weight increased
Diarrhea
3 ( 8.8)
Hyperuricemia
Insomnia
Palpitations
*Occurring in at least 3 subjects; at least ‘possibly’ related
No treatment-related Grade 4 AEs have occurred on study
Hematologic AEs are generally reversible and managed with dose reduction or temporary interruption 11

12. Serious Adverse Events in PV
Five subjects have reported 8 treatment-emergent serious adverse events (SAEs)
Pneumonia and, one year later, congestive heart failure (both unrelated): subject continued on study
Pneumonia (unrelated): subject continued on study
Renal tumor (possibly related): subject discontinued
Gastric bleeding (unlikely related): subject continued on study
Atrial flutter (possibly related); thrombocytopenia and anemia (unrelated) 6 weeks post-treatment: subject discontinued

13. Hematocrit Control Hematocrit Control Response Rate Through Week 32
94% of patients have achieved hematocrit normalization in the
absence of phlebotomy after 32 weeks of treatment
This is an ITT analysis.

14. Threshold for response
Reduction in Palpated Spleen Length
Reduction in Palpated Spleen Length Through Week 36
Threshold for response
by palpation
Mean ± SE
The mean reduction in palpated spleen length after 36 weeks of treatment for patients with ≥ 5 cm spleen length at baseline is 74%
69% of patients achieved ≥ 50% reduction in spleen length after 36 weeks

15. Response Durability and Hematologic Remission
Phlebotomy independence and spleen response have been maintained in 100% of responding patients at their last follow-up visit (median duration > 1 year)
Complete Hematologic Remission
32% of patients with leukocytosis and/or thrombocytosis at baseline achieved complete hematologic remission (normal hematocrit, white count and platelet count) after 32 weeks of treatment

16. Mean Symptom Severity Scores
Symptomatic Improvement
Mean Symptom Severity Scores
Through Week 36
Rapid improvements in patient reported symptom scores observed following INC424 treatment
Responses have been durable in the majority of responding patients through the last follow-up visit on study
Pruritus
Bone pain
Night sweats 4 8 12 24 36

17. Starting Dose Selection in PV
Three regimens, 10 mg BID, 25 mg BID, and 50 mg QD, were evaluated in Phase 2
10 mg BID has achieved an optimal balance of efficacy and safety
All regimens equally effective at reducing palpable spleen length, however 10 mg BID and 25 mg BID were most effective in achieving HCT control without phlebotomy and normalizing platelets and WBCs
10 mg BID exhibited an attractive hematologic safety profile, with 2 of 19 subjects exhibiting ≥ Grade 2 toxicity, and both managed with dose modification/interruption
10 mg BID
(n=19)
25 mg BID
(n=8)
50 mg QD
(n=7)
Anemia
2 (Gr. 2)
Leukopenia
1 (Gr. 2)
2* (Gr. 2)
Thrombocytopenia
1 (Gr. 3)
1* (Gr. 2)
*Same subject

18. Starting Dose Selection in PV
Subsequent to Week 8 of treatment, when individualized dose titrations are allowed, the majority of subjects are being maintained on doses of 5, 10, or 15 mg BID
10 mg BID will be the initial starting dose of INC424 in the Phase 3 RESPONSE study
10 mg QD if receiving a concomitant CYP inhibitor
Treatment Duration
5 mg BID
10 mg BID
15 mg BID
>15 mg BID
3 months
35%
32% 3%
30%
9 months
18%
15%
15 months
14%
38%
17%

19. Clinical Evaluation of INC424 in Phase II: Advanced ET19

20. ET Patient Characteristics
Characteristic (median)
ET (n = 39)
Age, years 51
Female
64%
Months from Diagnosis 88
Refractory to HU
87%
Hct %
41.0
Platelets x109/L
849 (mean 1009)
WBC x109/L
8.2
Splenomegaly
Size, cm (range)
10%
5 (3-7)
No. Prior Therapies
1 (1-3)
JAK2V617F positive
65%
JAK2V617F allele burden
16%

21. ET Patient Disposition
29 of 39 (74%) continue on study with a median follow-up 15 months (range 4-21 mos)
10 patients (26%) have discontinued treatment
4 due to AEs, 4 lack of response, 2 withdrew consent
Majority of patients on study are being treated at 10 BID or 25 BID (each 23%) with 60% at < 15 mg BID
Median duration on 10 mg BID is 12 months
Median duration on 25 mg BID is 18 months

22. Treatment-related AEs*
Overall Safety in ET
INC424 (N=39)
Treatment-related AEs*
All Grades
Grade 3
Anemia
29 (74.4%)
0 (0%)
Weight increased
9 (23.1)
Herpes zoster
2 (5.1)
0 (0.0)
Hyperuricemia
Leukopenia
Pain in extremity
Palpitations
*Occurring in at least 2 subjects; at least ‘possibly’ related
No treatment-related Grade 4 AEs have occurred on study
Hematologic AEs are generally reversible and managed with dose reduction or temporary interruption 22

23. Serious Adverse Events in ET
Six subjects have reported 6 treatment-emergent SAEs
Gastric bleeding (unrelated): subject continued on study
Bronchitis (unrelated): subject continued on study
Diarrhea (unrelated): subject continued on study
Renal failure (possibly related): subject discontinued
Cholecystitis (unlikely related): subject continued on study
Headache (unlikely related): subject continued on study

24. Platelet Count Reduction in ET
46% achieved normal platelet counts; 82% achieved < 600,000 or a > 50% reduction
16 of 18 subjects with baseline platelet counts > 900,000 have achieved greater than a 50% reduction

25. Clinical Evaluation of INC424 in Phase II: Myelofibrosis25

26. Phase I / II Study Design in MF
Established 25 mg BID and 100 mg QD as maximum tolerated doses
Phase 2
Expansion of 25 mg cohort
Individualized dose optimization based on safety and efficacy
N=153 patients
Myeloproliferative neoplasm
Primary myelofibrosis (MF)
Post-essential thrombocythemia MF
Post-polycythemia vera MF
Eligibility criteria
Relapsed / refractory disease or severe side effects from therapy
Newly diagnosed patients with intermediate- or high-risk disease (Lille system) or symptomatic splenomegaly / hepatomegaly
ECOG 0-2
Neutrophils >1500 cells/μL
Platelets >100,000 cells/μL
INCB (twice daily dosing) (n=116)
10 mg BID*
(n=29)
15 mg BID*
(n=35)
25 mg BID
(n=47)
50 mg BID
(n=5)
*Dose increases allowed (monthly, 5-mg increments) up to 25 mg daily, if no response and no toxicity (individualized dose adjustment).
INCB (once daily dosing) (n=37)
25 mg QD
(n=6)
50 mg QD
(n=22)
100 mg QD
(n=6)
200 mg QD
(n=3)
Dose reductions/interruptions were allowed for patients who developed grade 3/4 toxicities. If toxicity did not resolve within 2 cycles, therapy was discontinued.
Verstovsek S, et al. N Engl J Med. 2010;363: 26

27. 75% of randomized patients remain on study after 2+ years of follow-up
Non-hematologic Toxicities in MF
75% of randomized patients remain on study after 2+ years of follow-up
Related Adverse Events*
All Grades, %
Grade 3 or 4, %
Diarrhea
5.9
Fatigue
4.3
1.3
Headache
3.3
Peripheral edema
2.6
Pain in extremities
Urinary tract infection
Dizziness
Dyspnea
*AEs thought to be at least possibly related to study medication occurring in >2% of the study population. 27

28. Hematologic Toxicities in MF
35% had dose escalation to 20 or 25 mg
60% had dose reduction / interruption
Twice Daily Dosing
10 mg BID
(n=29)
15 mg BID
(n=35)
25 mg BID
(n=47)
Thrombocytopenia, n (%)
Grade 3
Grade 4
3 (10%)
1 (3%)
11 (23%)
3 (6%)
New-onset anemia* n / N (%)
3 / 19 (16%)
2 / 24 (8%)
8 / 30 (27%)
*Among patients who were transfusion-independent at baseline. 28

29. At Least Possibly Related
Serious Adverse Events
Serious Adverse Events
All Causality
No. of Patients (%)
At Least Possibly Related
All SAEs
59 (39)
12 (7.8)
Common SAEs
Pneumonia
10 (6.5)
1 (0.7)
Fever
6 (3.9)
2 (1.3)
Anemia
4 (2.6)
3 (2.0)
Acute Myeloid Leukemia
Asthenia
Systemic Inflammatory Response Syndrome
Anxiety
Constitutional symptoms
Insomnia
Use of gradual dose tapering or short-term courses of corticosteroids have been used in MF patients requiring treatment discontinuation 29

30. Rapid reduction in spleen size, durable beyond 1 year of therapy
Reduction in Palpated Spleen Lengths and MRI-Based Volumetric Assessment
Rapid reduction in spleen size, durable beyond 1 year of therapy
Parallel reduction in spleen size as detected by physical exam (length) and MRI (volume) 30

31. Percent of Patients Exhibiting a ≥ 50% Improvement in Symptom Score
Symptomatic Improvement in MF
Percent of Patients Exhibiting a ≥ 50% Improvement in Symptom Score
Symptoms scores were assessed using a modified version of the
patient-reported Myelofibrosis Symptom Assessment Form (MFSAF) 31

32. Phase III Program in MF Progressing
US Registration Study: COMFORT-I
Agreement with FDA on SPA
Design:
Blinded, randomized 1:1
INCB vs. placebo
Endpoints
Primary: A statistically significant proportion of patients achieving at least 35% reduction in spleen volume at 24 weeks as compared to placebo
Secondary: Durability of maintenance of a ≥ 35% reduction in spleen volume & a statistically significant proportion of patients achieving a ≥ 50% reduction in symptom score as compared to placebo
EU Registration Study: COMFORT- II
Received scientific advice from EMA
Design:
Unblinded, randomized 2:1
INCB vs. best available
Endpoints
Primary: A statistically significant proportion of patients achieving at least 35% reduction in spleen volume at 48 weeks as compared to best available
Secondary: Durability of maintenance of a ≥ 35% reduction in spleen volume
Fully enrolled; 309 patients
NDA filing expected 1H/2011
Fully enrolled; 219 patients
MAA filing expected mid-2011

33. INC424 Clinical Summary
The primary clinical risks with treatment are sequelae of decreased hematopoietic proliferation secondary to the inhibition of growth factor pathways by JAK2 inhibition
Anemia, thrombocytopenia and less frequently neutropenia have been observed in MPN patients and are generally managed by dose modification and/or dose interruption
INC424 has achieved marked and durable benefits in patients with myeloproliferative neoplasms
Spleen size, symptomatic burden, weight and exercise capacity in MF
Platelet count and symptomatic burden in advanced ET
Splenomegaly, phlebotomy dependence, leukocytosis, thrombocytosis, and symptomatic burden in advanced PV