JAK2 Inhibitors are Safe and Effective for Patients with

JAK2 InhibitorsforMyelofibrosisSrdan (Serge) VerstovsekM.D., Ph.D.Associate ProfessorDepartment of LeukemiaUniversity of TexasMD Anderson Cancer CenterHouston, Texas, USA

JAK-STAT Signaling• A well characterized signalingpathway involved in normalhematopoiesis (blood making),inflammation, and immune functionblood• Four members of JAK family– JAK1, JAK2, JAK3 and Tyk2– Promiscuous signaling (!)cell• JAK2 specifically mediatescytokine signaling for red bloodcells and platelets (its inhibitioncauses anemia and low platelets)Shuai, K. & Liu,B. (2003) Nature Reviews Immunology 3:900

JAK2V617F in MPD: 2005• Acquired mutation in a gene• Results in constitutivelyactive JAK2 tyrosinekinase (always activeenzyme)• Causes disease in mice(PV → MF)• Present in ~50% of ET andMF patients, ~97% PVJAK2V617FQuintás-Cardama A, Nat Rev Drug Discov. 2011 Feb;10(2):127-40.

JAK2V617F in MPD: 2011• Other mutations identified (about 10 so far);clonal hyerarchy → “multiclonal” state• JAK2 mutation is not a cause for the diseasepresence in humans; just contributor to thedisease existence• JAK-STAT pathway dysregulation, regardlessof JAK2 mutational status, is a key pathologicfeature of MPDsQuintás-Cardama A, Nat Rev Drug Discov ;10(2):127-40.Anand S, Blood 2011;118(6): 1610-21

JAK2 Inhibitors• Not selective for mutated JAK2V617Fenzyme• Lowering of platelets and red bloodcells is expected side effect due toinhibition of normal JAK2• Elimination of the disease unlikely• However: may benefit patient with andwithout JAK2V617F mutation

Evaluation ofJAK2 Inhibitors in MFEfficacy:• Splenomegaly• Quality of life/Performance status• AnemiaToxicity:• Lowering of blood count, other ?

Evaluation ofJAK2 Inhibitors in MFSplenomegaly

Splenomegaly in MF Patient Pre-Therapy

Splenomegaly after 2 Months of Therapy

Spleen Response to SB1518Baseline spleen size (cm below left costal margin)≥ 16; 11-15; 5-10• 15 of 34 (44%) patients had response of ≥ 50% reductionMesa et. al. EHA 2011 (a1022) Oral Sunday

Spleen Response to CYT38746% had 50% reductionPardanani et. al. ASCO 2011

Spleen Response to SAR302503(TG101348)Pardanani et. al. JCO 2011;29(7):789-796

Spleen length, cmRapid and Durable Impact on Spleen Size inPatients With and Without JAK2V617F Mutation22.520.017.515.0JAK mutation POSITIVE; N = 33JAK mutation NEGATIVE; N = 612.510.07.55.02.500 56 112 168 224 280 336Time on Therapy (days)Ruxolitinib phase I/II

Percent Change From Baseline in SpleenVolume in Individual Patients at Week 24% Change From Baseline604020Ruxolitinib (n = 139)Placebo (n = 106)0-20-4035% decrease-60-80-100Ruxolitinib phase III (COMFORT-1 study): at week 24, ruxolitinib-treatedpatients had a median 33.0% decrease in spleen volume, and placebo-treatedpatients had a median 8.5% increase (P < 0.0001)

Evaluation ofJAK2 Inhibitors in MFQuality of life/Performance status

2008 2011

Symptom Response to CYT387YM/Cytopia phase I/II

Symptom Response to SAR302503(TG101348)Early SatietyFatigueNight SweatsPardanani et. al. JCO 2011;29(7):789-796

Change in 6MWT Performance (meters)Change in Body Weight, kgImproved Exercise Capacity and Body Weight• 6-minute walk test (6MWT) is well established measure of exercise capacity• MF patients walk 60-90 meters less than age-matched healthy volunteers807060N=26N=2171 meters12.510.58.5Mean Lowest Quartile5057 meters6.54.540N=272.5302034 Meters0.5-1.5-3.528 56 84 112 140 168Days on Study10-5.5-7.501 Month 3 Months 6 MonthsTime on Study-9.5Ruxolitinib phase I/II

Evaluation ofJAK2 Inhibitors in MFAnemia

Red Blood Cell TransfusionsNewlytransfusionindependent byIWG criteria*JAK2inhibitor #1JAK2inhibitor #2Placebo41% 58% 47%*Patients receiving at least 2 units PRBC during the 4weeks prior to therapy and no transfusions for at least8 weeks while receiving treatmentCONCLUSION: response criteria is not good

Hemoglobin improvement• In general no significant improvementYM/Cytopia phase I/II

Impact on Blood and Bone MarrowIn general:• High white blood cells and high plateletsdecrease to normal levels• Percent blast in blood stays stable• Bone marrow fibrosis does not change, staysstable• JAK2V617F allele burden may decrease

JAK2 Inhibitor Side Effects fromPhase II StudiesGI Anemia Platelets LiverNeuropathyXXXXXXXXXX

What happens if the therapy with JAK2inhibitor is interrupted?Number of patients:34 33 33 34 34 33 33 33 36 37 39 40 40 40 34 29 26 23 24 24 22 22 22 20 21 20 18 17 15Days Around Dose Change• Return of the symptoms within 7 days

Serious Adverse Events After Therapy InterruptionAdverse EventRuxolitinib(n = 155)Placebo(n = 151)Total with interruption, n 49 54Total SAEs, n (%) 3 (6.1) 3 (5.6)Febrile neutropenia 1 (2.0) 0GI hemorrhage 1 (2.0) 0Urosepsis 1 (2.0) 0Fatigue 1 (2.0) 0Anemia 0 1 (1.9)Hepatic encephalopathy 0 1 (1.9)Pulmonary edema 0 1 (1.9)Gout 0 1 (1.9)Overall:•Percent of patients that discontinued ruxolitinib due to side effects was 11%•Percent of patient that discontinued placebo due to side effects was 11%

JAK2 Inhibitors for MF• Not selective for JAK2V617F (patients withand without JAK2 mutation benefit)• Toxicity profiles differ• Efficacy:• MF: spleen size reduction and significantimprovement in quality of life = bettercontrol of MF• improved survival – YES! (retrospectiveand prospective analyses)

Overall Survival: MDACC Phase 1-2Study Cohort vs. Historical ControlRuxolitinibN=107Hazard ratio=0.6195% CI: 0.41–0.89p-value=0.022ControlN=310Number of Patients at Risk—MDACC Study 251107 105 99 84 81 53 15Number of Patients at Risk—Historical Control300 257 226 180 146 118 9329

Overall Survival Update: COMFORT-1HR=0.50 (0.25–0.98)P=0.04Number of Patients at Risk—Ruxolitinib155 155 155 154 153 152 148 144 143 143 140 134 102 68 52 37 18 8 3Number of Patients at Risk—Placebo154 152 151 148 147 147 142 139 132 131 123 115 83 58 45 35 20 9 3• Overall survival analysis conducted at the time of a preplanned safety update with data cutoff4 months after primary analysis cutoff date• After a median follow up of 51 weeks, 13 (8.4%) deaths in ruxolitinib group and 24 (15.7%) deathsin placebo group30

Clinical Trials in MPD at MD AndersonAgent (Company) Diseases and studies Type of therapySAR302503 (Sanofi) MF: phase III JAK2 inhibitorLY2784544 (Lilly) ET/PV/MF: phase I JAK2 inhibitorCYT387 (Cytopia/YM) MF: phase I JAK2 inhibitorRuxolitinib(Incyte/Novartis)MF low platelets: phase IMF: combination with revlimidPV: phase IIIJAK1 and JAK2inhibitorNS-018 (NS Pharma) MF: phase I JAK2 inhibitorBMS911543 (BMS) MF: phase I JAK2 inhibitorAB0024 (Gilead) MF: phase II LOXL2 antibodyIPI-926 (Infinity)Pomalidomide + predMF: phase IIMF: phase IIHedgehog inhibitorIMID

SAR302503 Phase III Study DesignMultinational, multicenter, double blind, placebo-controlled randomized study- Intermediate-2 or Highrisk Primary MF-Post-Polycythemia VeraMyelofibrosis-Post-EssentialThrombocythemiaMyelofibrosisNo StratificationfactorRandomization 1/1/1RANDOMIZATION75 pts75 pts75 ptsQ 4 weeksSAR302503 500mgDaily oral dosesQ 4 weeksSAR302503 400mgDaily oral dosesQ 4 weeksPlaceboDaily oral doses• 225 pts, Sites ~125, Recruitment: 9 months, 25 countries• Safety data monitored by DMC (~Q 6 months)• Cross over possibleEndof C6Crossover 1/1End of C6or PDEOT| 32

Phase II study of ruxolitinib in PV (n=34)• Response Criteria - European LeukemiaNet:– CR:– Hct < 45% without phlebotomy– platelet count < 400,000– WBC < 10,000– normal spleen– no disease-related symptoms– PR: Hct < 45% OR response in > 3 of the other criteria• 97% overall response– 50% CR– 47% PR• Phase 3 study for approval of ruxolitinib for PV is underway

THANK YOUsverstov@mdanderson.org