1. ASH 2012: New JAK Inhibitors for Myelofibrosis
Srdan (Serge) Verstovsek
M.D., Ph.D.
Professor of Medicine
Department of Leukemia
University of Texas
MD Anderson Cancer Center
Houston, Texas, USA 1

2. Long-Term Outcome of Ruxolitinib Treatment in Patients With Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V,
DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT,
Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO,
Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S,
Sun W, Sandor V, Kantarjian HM
Abstract 800

3. COMFORT-I
Background
Placebo-controlled, randomized, double-blind, phase III study
Ruxolitinib starting doses:
Baseline platelet count ×109/L: 15 mg BID
Baseline platelet count >200×109/L: 20 mg BID
Doses individually titrated based on safety and efficacy
Ruxolitinib treatment significantly reduced spleen size and improved myelofibrosis (MF_-related symptoms and QoL and was also associated with a survival advantage relative to placebo1
Objective
To describe long-term efficacy and safety of ruxolitinib with 1 year of additional follow-up beyond previously published data (median follow-up ~24 months)
Data cutoff for current analysis: March 1, 2012.
1. Verstovsek S, et al. N Engl J Med. 2012;366(9):

4. Patient Disposition at Current Analysis
Patients, n (%)
Ruxolitinib (n = 155)
Placebo
(n = 151)
Placebo Ruxolitinib (n=111)
Still on treatment
100 (64.5)
73 (65.8)
Discontinued
55 (35.5)
40 (26.5)
38 (34.2)
Crossed over
111 (73.5)
Primary reasons for discontinuation
Death
13 (8.4)
10 (6.6)
11 (9.9)
Adverse event
11 (7.1)
9 (6.0)
7 (6.3)
Consent withdrawn
9 (5.8)
6 (4.0)
9 (8.1)
Disease progression
12 (7.7)
12 (7.9)
5 (4.5)
Other
10 (6.5)
3 (2.0)
Noncompliance with study medication ̶
1 (0.9)
12/7/12: T_14_1_99_1_1_351DISP01 and T_14_1_99_1_2_351DISP02
Median time to crossover from ASH 2011 COMFORT-I subgroups presentation
All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis
Median time to crossover: 41.1 weeks

5. Spleen Volume Reduction
Primary Analysis (Week 24)1 (Median follow-up ~7 months)* 80 60 40
-80
Change From Baseline, %
Individual Patients
-20 20
-40
-60
35% Decrease
Ruxolitinib (n = 154)
Placebo (n = 153)
-100
Last Available Measurement† (Median follow-up ~24 months)* 80
Ruxolitinib (n = 154)
Crossover (n = 111) 60 40 20
Change From Baseline, %
-20
35% Decrease
-40
-60
-80
Individual Patients
-100
Second figure: F_14_4_99_42_3_351SPV_WATERF03
Mean reduction in spleen volume: Week 24 = 31.6%; Week 96 = 34.9%
Majority of ruxolitinib-treated patients maintained a spleen volume reduction
Majority of crossover patients experienced spleen volume reduction relative to original baseline (median follow-up on ruxolitinib: ~14 months)
Lesser degree of reduction likely because these patients experienced a period of spleen growth on placebo before starting ruxolitinib
Note 1: The SV from an unscheduled visit, which was closest to Week 24 (Days 168) and was within the window of 168±28 days, was used if the patient missed the scheduled SV measurement; particularly, this method was implemented for all crossover patients.
Note 2: Placebo = data collected during placebo treatment; for crossover patients, post-crossover data were excluded.
Note 3: Ruxolitinib After Crossover = post-crossover data using the last value prior to the first ruxolitinib dose as the baseline.
Note 4: The n-value is the number of intent-to-treat patients used as the denominator.
*Median follow-up for patients originally randomized to ruxolitinib †Change from baseline to last available spleen volume measurement
1. Verstovsek S, et al. N Engl J Med. 2012;366(9):

6. Spleen Volume Reduction Total Abdominal Symptom Score
Reduction in MF-Related Symptoms by Spleen Volume Reduction at Week 241
Total Symptom Score
Mean % Change From
Baseline ± SEM 70 30
-10
-50
-70 50 10
-30
n = 99
n = 20 P = .0004
n = 46 P<.0001
n = 60 P<.0001
All Placebo
Ruxolitinib
Spleen Volume Reduction
<10%
10 to <35%
≥35%
Improvement
Worsening
Total Abdominal Symptom Score
n = 96
n = 20 P = .0304
n = 44 P = .001
n = 59 P<.0001
P value vs all placebo. Total Abdominal Symptom Score: abdominal pain, pain under left ribs, and early satiety.
1. Mesa R, et al. Blood. 2011;118: Abstract 3842.

7. Durability of Spleen Volume Reduction
1.0
≥10% reduction (n = 90)
0.8
0.6
Probability
≥35% reduction
0.4
0.2
12/7/12: F_14_4_99_38_5_351DOR_UPDATE5 8 16 24 32 40 48 56 64 72 80 88 96
104
112
No. at risk
Weeks From Onset
Note 1: The duration was defined only for those patients who had at least one measurement of ≥35% reduction prior to spleen progression.
Note 2: Ruxolitinib After Crossover = post-crossover data using the last value prior to the first ruxolitinib dose as the baseline. 90 84 75 72 63 57 52 47 43 41 35 4 4 4
90/155 (58%) had a 35% reduction at any time point during the study
64% maintained a ≥35% reduction for at least 2 years
≥35% reduction: Time from first 35% reduction to <35% reduction and 25% increase from nadir.
≥10% reduction: Time from first 35% reduction to <10% reduction from baseline.

8. Global Health Status/QoL Mean Change From Baseline
EORTC QLQ-C30 Over Time
Global Health Status/QoL
Mean Change From Baseline BL 12 24 36 48 60 72 84 96
Weeks 20 10 -5
-10
-15 15 5
Fatigue BL 12 24 36 48 60 72 84 96 10
-10
-15
-20
-25 5 -5
Weeks
Ruxolitinib
Placebo
Role Functioning
Physical Functioning 15 15 10
12/7/12:
F_14_4_99_4_1_EORTC_MPLOT1
F_14_4_99_4_2_EORTC_MPLOT2
F_14_4_99_4_3_EORTC_MPLOT3
F_14_4_99_4_7_EORTC_MPLOT7 10 5 5
Mean Change From Baseline -5
-10 -5
-15
-20 BL 12 24 36 48 60 72 96 84
Weeks
-10 BL 12 24 36 48 60 72 96 84
Weeks
Arrows indicate improvement.

9. Overall Survival: ITT Population
1.0
0.8
Ruxolitinib
Placebo
0.6
HR = 0.58 (95% CI: 0.36, 0.95); P = .028
Survival Probability
No. of deaths: Ruxolitinib = 27; Placebo = 41
0.4
Median follow-up: 102 weeks
0.2
Age-adjusted HR* = 0.61 (95% CI: 0.37, 0.99); P = .040
12/7/12: F_14_4_99_1_25_351OS_UPDATE01F 12 24 36 48 60 72 84 96
108
120
132
Weeks
148
142
133
117
111
102 95 74 32 7
Placebo
154
145
136
125
121
113 96 44 6
Ruxolitinib
No. at risk
155
Note: For this unplanned analysis, P-values are descriptive and nominally significant.
*Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J Med. 2012;366(9): (median age: ruxolitinib, 66 years; placebo, 70 years; P<.05).

10. Incidence of New Onset Nonhematologic Adverse Events Regardless of Causality
Percent of Patients
0–<6 Months
6–<12 Months
12–<18 Months
18–<24 Months
≥24 Months
RUX
PBO
Fatigue
25.7
31.9
5.8
7.9
8.4
5.4
Diarrhea
23.2
22.9
5.7
3.4
10.3
Ecchymosis
18.1
9.2
5.5
4.3
1.6
Dyspnea
16.8
16.1
4.5
6.4
4.8
4.9
Peripheral edema
16.7
5.3
6.3
5.1
Headache
15.5
5.0
0.9
2.1
1.5
Dizziness
14.2
6.5
3.2
Nausea
12.8
17.0
5.2
3.0
8.0
Constipation
12.0
12.1
4.2
5.9
8.7
Vomiting
10.8
2.5
1.0
4.0
Pain in extremity
11.4
10.7
8.5
Pyrexia
11.3
2.4
3.7
6.7
8.2
Insomnia
2.0
2.8
4.1
Abdominal pain
10.1
40.7
Arthralgia
4.4
Cutoff is >10% at any time point in RUX-treated patients, but this tends to apply to just the 0-6 month interval.
12/7/12: T_14_3_98_8_1_1_AELT01A and T_14_3_98_8_1_2_AELT01B
No reports of a specific withdrawal syndrome after discontinuation of ruxolitinib

11. Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time
Ruxolitinib Grade 4
Ruxolitinib Grade 3
Placebo Grade 3
Placebo Grade 4
Anemia
Thrombocytopenia
12/7/12:
T_14_3_98_9_2_LBCTC02
T_14_3_98_9_3_LBCTC03
T_14_3_98_9_5_LBCTC05
T_14_3_98_9_6_LBCTC06
9.9
2.9
0.7
All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for 0–<6 months only

12. Mean Hemoglobin Levels Over Time
Mean hemoglobin nadirs after 8–12 weeks of therapy and recovers to a new steady state which remains stable with longer-term therapy 5
Ruxolitinib
Placebo -5
Mean Percentage Change From Baseline
-10
12/7/12: F_14_4_97_1_6_HGB_MPLOT2
-15
-20 BL 12 24 36 48 60 72 84 96
Weeks
Median hemoglobin at baseline: Ruxolitinib, 105 g/L; Placebo, 105 g/L
Mean hemoglobin levels dropped to a nadir 8-12 weeks after initiation of therapy, then recovered to a new steady state slightly below baseline values by week 24, and remained stable throughout the remaining 2 years of follow-up

13. Hemoglobin Levels Over Time by Ruxolitinib Titrated Dose
10 mg BID
<10 mg BID
≥20 mg BID
15 mg BID
12/7/12: F_14_4_99_37_2_4_351HGBRETB04 and T_351HGBRETB01
<10 mg BID= <20 mg average total daily dose
10 mg BID= 20-<30 mg average total daily dose
15 mg BID= 30-<40 mg average total daily dose
≥20 mg BID= ≥40 average total daily dose BL
Patients titrated to 10 mg BID after nadir hemoglobin showed faster and more complete return of hemoglobin to pretreatment levels
Titrated dose is defined as the average dose patients received between Weeks 8 and 56. Hemoglobin levels within 60 days of transfusion are not included.

14. Efficacy by Titrated Dose
n=101
n=24
n=26
n=23
n=39
n=21
Spleen Volume
n=103
n=22
n=38
n=20
Total Symptom Score
n=35
n=28
n=31
n=17
Week 24
Week 48
12/7/12: F_14_4_99_34_1B_EFFBYADOSE10BID1B, F_14_4_99_34_2B_EFFBYADOSE10BID2B, and F_14_4_99_35_1B_EFFBYADOSE10BID48WK1B
DOSE GROUPINGS AVAILABLE WHEN VIEWED IN NOTES PAGE VIEW
Week 24
Total daily dose
Mean
Median N
< 10 BID
< 20
9.8286 10 25
= 10 BID
= 20 20 26
15 BID
> 20-30 30 24
20 BID
> 30-40 40
>20 BID
> 40 50
Week 48 28 31 17
Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment.
Verstovsek S, et al. Blood. 2012;120: Abstract 800.

15. Long-Term Efficacy, Safety, and Survival Findings From COMFORT-II, a Phase 3 Study Comparing Ruxolitinib With Best Available Therapy for the Treatment of Myelofibrosis
Abstract 801
Cervantes F, Kiladjian J-J, Niederwieser D, Sirulnik A, Stalbovskaya V, McQuitty M, Hunter DS, Levy RS, Passamonti F, Barbui T, Barosi G, Gisslinger H, Vannucchi AM, Knoops L, Harrison CN

16. Ruxolitinib After Crossover From BAT
Patient Disposition
n (%)
Ruxolitinib
(n = 146)
BAT
(n = 73)
Ruxolitinib After Crossover From BAT
(n = 45)
Still on treatment
81 (55.5)
26 (57.8)
Discontinued
65 (44.5)
73 (100.0)
19 (42.2)
Crossed over --
45 (61.6)
Primary reasons for discontinuation
Adverse event
20 (13.7)
5 (6.8)
5 (11.1)
Consent withdrawn
8 (5.5)
9 (12.3)
Protocol deviation
2 (1.4)
Disease progression
16 (11.0)
4 (5.5)
Noncompliance with study medication
3 (2.1)
1 (2.2)
Noncompliance with study procedures
1 (1.4)
Unsatisfactory therapeutic effect
Other
14 (9.6)
2 (4.4)
The majority of patients randomized to ruxolitinib remained on treatment after more than 2 years on study

17. Mean % Change From Baseline in Spleen Volume Over Time
136
125
111 98 78 64 53
Ruxolitinib, 42 31
n =
146 10
BAT
Excluding patients who crossed over to ruxolitinib 60 44 39 34 24 16 6 2 73
n =
BAT
n = 60 45 40 34 24 20 15 8 11 73 3
Including patients who crossed over to ruxolitinib
BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover

18. Overall Survival
1.0
No. of Patients
Events
Censored
146
20 (13.7%)
126 (86.3%) 73
16 (21.9%)
57 (78.1%)
Ruxolitinib
BAT
BAT
Ruxolitinib
n =
146
138
127
117
109 30 73 61 51 49 45 12
Lost to follow-up (cumulative)
3.4%
9.6%
11.0%
14.4%
14.4%
13.7%
24.7%
26.0%
27.4%
27.4%
Suggests a relative reduction in the risk of death with ruxolitinib compared with BAT (HR = 0.51; 95% CI, ; log-rank test P = .041)a
a P values are provided for descriptive purposes and were not adjusted for multiple comparisons.

19. Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts (50–100×109/L)
Abstract 176
Talpaz M, Paquette R, Afrin L, Hamburg S, Jamieson K, Terebelo H, Ortega G, Lyons RM, Tiu R, Winton E, Natrajan K, Odenike O, Peng W, O’Neill P, Erickson-Viitanen S, Leopold L, Sandor V, Levy R, Kantarjian H, Verstovsek S

20. Distribution of Ruxolitinib Dose Over Time
In patients who completed 24 weeks of treatment, most have optimized their dose of ruxolitinib to 10 mg BID or higher
10 BID
10 / 15
15 BID
15 BID
10 / 15
10 BID
10 / 15
10 BID
5 / 10
10 BID
5 BID
10 BID
5 / 10
5 / 10
5 / 10
5 BID
5 BID
5 BID
5 BID
5 BID
n values represent patients with available dose information at the time of data analysis.
Data shown for each time point represent the dose that patients were on during the previous 4 weeks.

21. Reductions in Total Symptom Score and Spleen Length
Weeks 4 8 12 16 20 24
TDD, mg
Mean
10.0
13.2
15.1
16.8
18.3
19.1
Median 10 15
Weeks 4 8 12 16 20 24
TDD, mg
Mean
10.0
13.2
15.1
16.8
18.3
19.1
Median 10 15
Percent change from baseline is not calculated for patients with a “0” TSS or palpable spleen size of “0 cm” at baseline. Mean and median dose shown for patients with available dosing information.
TDD, total daily dose.

22. Change From Qualifying Platelet Count to Nadir and to Week 24 of Individual Patients
Qualifying to Nadir
Qualifying to Week 24
Individual Patients
160
140
120
100 80 60 40 20
Platelet Count (×109/L)
160
140
120
100
Platelet Count. ×109/L 80 60 40 20
Individual Patients

23. Phase III Study SAR302503 vs. placebo
Multinational, multicenter, randomized, double-blind, placebo-controlled
RANDOMI Z A T I ON
Q4 weeks
SAR mg
Daily oral doses
n=75
- Intermediate-2 or high-risk Primary MF
Post-Polycythemia Vera MF
Post-Essential Thrombocythemia MF
End
of C6
Q 4 weeks
SAR mg
Daily oral doses
n=75
Cross over 1/1
EOT
No Stratification factors
Randomization 1/1/1
1 cycle = 28 days
Q 4 weeks
Placebo
Daily oral doses
n=75
End of C6 or progressive disease
225 patients at ~128 sites
Recruitment: 8 months, 25 countries
Safety data monitored by DMC (~Q6 months)
Cross over possible
Enrollment Completed (Sept 2012)

24. A Phase II Randomized Dose-Ranging Study of the JAK2-Selective Inhibitor SAR in Patients With Intermediate-2 or High-Risk Primary Myelofibrosis (MF), Post-Polycythemia Vera MF, or Post-Essential Thrombocythemia MF
Abstract 2837
Talpaz M, Jamieson C, Gabrail NY, Lebedinsky C, Neumann F, Gao G, Liu F, Tefferi A, Pardanani A

25. ARD11936 Study Design
Intermediate-2 or high-risk primary MF (IWG-MRT criteria)
Post-polycythemia vera myelofibrosis according to the 2008 World Health Organization (WHO) criteria
RANDOMIZATION
SAR mg orally once daily
SAR mg orally once daily
Patients who continued to benefit clinically could remain on study until the occurrence of disease progression or unacceptable toxicity
1 cycle = 28 days
SAR mg orally once daily
Primary endpoint:
Secondary endpoints:
% change in spleen volume at EOC 3 by central review assessed by MRI
% of patients who achieve ≥35% reduction in spleen volume from baseline
To measure improvement in baseline MPN-associated symptoms
Safety (NCI CTCAE v4.03), PK/PD
EOC, end of cycle; MF, myelofibrosis; MPN-SAF, myeloproliferative neoplasm symptom assessment form; MRI, magnetic resonance imaging; PK/PD, pharmacokinetics/pharmacodynamics

26. Change in Spleen Volume, %
Percent Change in Spleen Volume From Baseline in Individual Patients at the End of Cycle 3
30 –
20 –
10 –
0 –
-10 –
-20 –
-30 –
-40 –
-50 –
-60 –
-70 –
-80 –
Change in Spleen Volume, %
35%
SAR302503
300 mg (n = 8)
SAR302503
400 mg (n = 10)
SAR302503
500 mg (n = 10)
There was a dose-dependent increase in spleen response with increasing doses of SAR

27. Symptom Reduction at the End of Cycle 3 by the MPN-SAF in Patients With Symptoms Present at Baselinea
SAR302503
300 mg
n = 10
400 mg
500 mg
n = 11
Proportion of patients with ≥50% reduction in total MPN-SAF score from baseline n (%) [95% CI]
5 (50)
[ ]
4 (36)
[ ]
Symptom Response,a n/N
Night sweats
5/5 (100%)
5/6 (83%)
4/4 (100%)
Itching
6/7 (86%)
1/3 (33%)
3/4 (75%)
Abdominal discomfort
4/7 (57%)
3/7 (43%)
3/6 (50%)
Abdominal pain
3/5 (60%)
Bone pain
2/3 (67%)
1/4 (25%)
Early satiety
Inactivity
2/6 (33%)
aA response was defined as a 2-point improvement in or resolution of the symptom.
MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form

28. Most Common Nonhematologic Adverse Eventsa
SAR302503
300 mg
n = 10
400 mg
500 mg
n = 11
n (%)
All grades
Grade 3/4
All Grades
Fatigue
3 (30)
1 (10)
4 (36)
Diarrhea
7 (70)
9 (90)
2 (20)
6 (55)
Nausea
6 (60)
5 (50)
8 (73)
Vomiting
4 (40)
7 (64)
Constipation
1 (9)
Pruritis
Edema, peripheral
Infections
3 (27)
Hyperkalemia
Paresthesia
2 (18)
Dyspnea
Cough
aReported in ≥10% of patients across all dose groups. Safety was assessed in patients who received at least one dose of study drug.

29. Laboratory Abnormalities
SAR302503
300 mg
n = 10
400 mg
500 mg
n = 11
n (%)
All grades
Grade 3/4
All Grades
Anemia
9 (100)a
3 (33)a
10 (100)
3 (30)
10 (91)
6 (55)
Neutropenia
1 (10)
Thrombocytopenia
5 (50)
2 (20)
1 (9)
aData available for 9 patients in the 300 mg group
Anemia was the most common hematologic toxicity.
Grade 3/4 thrombocytopenia was minimal.

30. THANK YOU