Combination Ruxolitinib + Sonidegib in Myelofibrosis New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from Amgen, Celgene Corporation, Merck, Incyte, Seattle Genetics, and Takeda Oncology.

Ruxolitinib + Sonidegib in MF: Background Ruxolitinib: JAK1/2 inhibitor approved to treat MF-related symptoms and splenomegaly Sonidegib: Hedgehog pathway inhibitor targeting SMO[1] Addition of sonidegib to ruxolitinib improved splenomegaly and bone marrow fibrosis in murine MF model[2] Current trial evaluates combination of ruxolitinib and sonidegib in pts with intermediate- or high-risk MF Phase Ib results established recommended phase II dose of sonidegib 400 mg/day + ruxolitinib 20 mg BID[3] Updated safety/efficacy for 27 pts who received the recommended phase II dose presented here[4] MF, myelofibrosis; SMO, smoothened. 1. Pan S, et al. ACD Med Chem Lett. 2010;1:130-134. 2. Bhagwat N, et al. ASH 2013. Abstract 666. 3. Gupta V, et al. ASH 2014. Abstract 714. 4. Gupta V, et al. ASH 2015. Abstract 825. Slide credit: clinicaloptions.com

Ruxolitinib + Sonidegib in MF: Study Design Open-label phase Ib/II trial Analysis performed 24 wks after last enrollment at recommended phase II dose (RP2D) Endpoints: Safety/tolerability, pharmacokinetics, efficacy (splenomegaly/bone marrow fibrosis reduction, JAK2 V617F) Dose Escalation[1] Determine MTD/RP2D Dose Expansion[2] Treat additional pts at RP2D IPSS, International Prognostic Scoring System; MF, myelofibrosis; MTD, maximum tolerated dose; PET-MF, postessential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; SMO, smoothened. PMF, PPV-MF, or PET-MF; int- or high-risk IPSS; palpable splenomegaly; JAK/SMO inhibitor naive (N = 50) Sonidegib 400 mg PO QD + Ruxolitinib 10, 15, or 20 mg PO BID (n = 23) Sonidegib 400 mg PO QD + Ruxolitinib 20 mg PO BID (n = 27) 1. Gupta V, et al. ASH 2014. Abstract 712. 2. Gupta V, et al. ASH 2015. Abstract 825. Slide credit: clinicaloptions.com

Ruxolitinib + Sonidegib in MF: Key Baseline Characteristics MF classification, % Primary MF Post polycythemia vera MF Post essential thrombocythemia MF 59.3 14.8 25.9 Median palpable spleen length, cm (range) 10 (1-29) Median spleen volume by MRI/CT, cm3 (range) 2093 (530-4792) IPSS risk, % Low Intermediate-1 Intermediate-2 High 3.7 66.7 JAK2 V617F +, % 85.2 IPSS, International Prognostic Scoring System; MF, myelofibrosis. Slide credit: clinicaloptions.com Gupta V, et al. ASH 2015. Abstract 825. Reproduced by permission.

Ruxolitinib + Sonidegib in MF: Safety 26% pts discontinued treatment: treatment-related AEs (n = 3), other AEs (n = 2), death (n = 1), pt decision (n = 1) AEs in > 20% Pts, % All Grades (n = 27) Grade 3/4 (n = 27) Hematologic Anemia Thrombocytopenia 52 26 33 11 Nonhematologic Muscle spasms* Elevated creatine phosphokinase* Myalgia* Dysgeusia* Diarrhea Fatigue Pyrexia Alopecia* 48 37 30 22 4 19 7 - AE, adverse event; MF, myelofibrosis. *AE not typically observed with ruxolitinib. Slide credit: clinicaloptions.com Gupta V, et al. ASH 2015. Abstract 825. Reproduced by permission.

Ruxolitinib + Sonidegib in MF: Reduction in Splenomegaly Spleen Length Response at Week 24 +400% 100 Maximum Change From Baseline in Spleen Length by Palpation, % 60 20 -20 -60 50% reduction -100 Sonidegib 400 mg QD + Ruxolitinib 20 mg BID (n = 21) Spleen Volume Response at Week 24 20 MF, myelofibrosis; tx, treatment. Change From Baseline in Spleen Volume by MRI/CT at Week 24, % -20 -40 35% reduction -60 -80 -100 Slide credit: clinicaloptions.com Gupta V, et al. ASH 2015. Abstract 825. Reproduced with permission.

Ruxolitinib + Sonidegib in MF: Efficacy 55.6% pts achieved ≥ 50% reduction in palpable spleen length at end of Wk 24; 92.6% at any time on treatment 55.6% achieved nonpalpable spleen at any time on treatment 44.4% pts achieved ≥ 35% reduction in MRI/CT spleen volume at end of Wk 24; 55.6% at any time during treatment JAK2 V617F allele burden absolute changes from baseline to Wk 24 ranged from -56.5% to 7.0% with mean of -9.0% Bone marrow fibrosis change from baseline to Wk 24: improved (n = 2), stable (n = 8), worsened (n = 3) Pharmacokinetics of combination tx similar to individual agents Bone marrow sonidegib concentrations comparable to plasma MF, myelofibrosis; tx, treatment. Slide credit: clinicaloptions.com Gupta V, et al. ASH 2015. Abstract 825.

Ruxolitinib + Sonidegib in MF: Conclusions Combination of ruxolitinib and sonidegib generally well tolerated with no observable PK interactions Early efficacy results similar to ruxolitinib monotherapy Majority of pts achieved resolution of palpable splenomegaly, ≥ 35% reduction in spleen volume JAK2 V617F allele burden and bone marrow fibrosis improved in some patients Wk 24 efficacy failed to attain predetermined benchmark for additional patient enrollment Study will pursue longer-term follow-up of current patients MF, myelofibrosis; PK, pharmacokinetic. Slide credit: clinicaloptions.com Gupta V, et al. ASH 2015. Abstract 825.

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