Incyte Corporation · NASDAQ:INCY
Incyte — Technical Presentation (December 2007)
16 slides from Incyte's technical presentation, December 2007
Slide 1: INCB18424, an Oral, Selective JAK2 Inhibitor, Shows Significant Clinical Activity in Myelofibrosis
INCB18424, an Oral, Selective JAK2 Inhibitor, Shows Significant Clinical Activity in a Phase I/II Study in Patients With Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF) Srdan Verstovsek, MD, PhD11; Hagop Kantarjian, MD11; Animesh Pardana
Slide 2: Disclosures
Disclosures • Srdan Verstovsek, Hagop Kantarjian, Animesh Pardanani, and Ayalew Tefferi are participants of the scientific advisory board for Incyte’s Jak2 inhibitor program • John Redman, Carl-Michael Staschen, Jordan Fridman and Kris Vaddi are employees of Incyte Corporation
Slide 3: Preclinical Summary (abstract #3538)
Preclinical Summary (abstract #3538) • Potent and selective ATP competitive JAK inhibitor INCB18424 JAK1 JAK2 JAK3 Tyk2 IC50 (nM) 2.7 4.5 322 19 • 100-fold selectivity against a broad panel of kinases • Excellent preclinical pharmacokinetic properties • High oral availability • Efficacious and well-
Slide 4: Phase I/II Study Design and Aims
Phase I/II Study Design and Aims • Design: 3+3 dose escalation and expansion of the MTD cohort • Eligibility: Advanced PMF or post-PV/ET MF patients with platelets >100 x 109/L and ANC >1 x 109/L • Primary objectives: safety and determination of MTD • Secondary objectives: PK, PD, safety of extended
Slide 5: Dose Escalation Patient Characteristics
Dose Escalation Patient Characteristics 25 mg BID 50 mg BID Number of patients 6 5 Mean age (years) 63 64 Gender (Male:Female) 4:2 3:2 MPD Diagnosis 4 Post-PV, 2 Post-ET 2 Post-PV, 3 PMF 3 V617F, 1 MplW515K , JAK2 status 5 V617F, 1 Wild Type 1 Wild Type Splenomegaly (mean cm 21 13 below costal margi
Slide 6: Clinical Pharmacokinetics
Clinical Pharmacokinetics • Half-life consistent with once or twice daily dosing • Linear pharmacokinetics over the dose range studied • No accumulation upon repeated dosing • Clearance is predominantly via hepatic metabolism • INCB18424 is a substrate for CYP3A4 • No evidence of induction or inhibi
Slide 7: Clinical Pharmacodynamics
Clinical Pharmacodynamics pSTAT3: A downstream marker for JAK2 activation 25 mg cohort (n=6) Phospho-STAT3 (U/mL) 200 Basal IL6 100 0 Day 1 Day 15 Day 29 Healthy Donor INCB18424 normalizes pSTAT3 levels within 1 month
Slide 8: Dose Escalation Patients: Safety
Dose Escalation Patients: Safety • 25 mg BID: 6 patients – Duration of treatment: 2–6 months – Grade 3 thrombocytopenia in one patient • 50 mg BID: 5 patients – Duration of treatment: 2–4 months – 2 patients developed grade 4 thrombocytopenia at day 14 (dose limiting toxicity) • Overall Safety – No
Slide 9: Dose Escalation Patients: Efficacy
Dose Escalation Patients: Efficacy • All patients have experienced a marked and rapid reduction in splenomegaly (regardless of the mutation status) • IWG-MRT Consensus Criteria for clinical improvement, based on durable reduction in spleen size, achieved in all 6 patients dosed for minimum of 3 mont
Slide 10: Effect of INCB18424 on Splenomegaly (25 mg BID)
Effect of INCB18424 on Splenomegaly (25 mg BID) 35 12* 12* 4* 4* 4* 30 4* 25 Dose Dose Interruption Interruption Spleen Size 20 15 10 5 0 -1 8 15 22 29 57 85 Days on Drug • In patients that received 25 mg BID of INCB18424 without interruption, mean reduction in spleen size was 46%, 58% and 83% at 1,
Slide 11: Effect of INCB18424 on Splenomegaly (50 mg BID)
Effect of INCB18424 on Splenomegaly (50 mg BID) 25 20 Dose Dose Interruption Interruption Spleen Size 15 10 5 Dose Dose Interruption Interruption 0 -1 8 15 22 29 57 85 Days on Drug • In patients that received 50 mg BID of INCB18424 without interruption, mean reduction in spleen size was 66%, 75% and
Slide 12: Effect of INCB18424 on Mutated JAK2 Allele Burden
Effect of INCB18424 on Mutated JAK2 Allele Burden • Ratio of V617F to WT JAK2 assessed by quantitative genotypic analysis V617F Relative to Baseline Peripheral Blood Bone Marrow V617F Relative to Baseline 100 100 90 90 (Percent) (Percent) 80 80 n=8 n=6 P=0.043 n=5 n=5 70 P=0.004 70 P=0.014 P=0.003 6
Slide 13: Effect on Angiogenic Factors & Pro-inflammatory Cytokines
Effect of INCB18424 on Angiogenic Factors & Pro-inflammatory Cytokines 120 120 100 100 80 80 Percent of Baseline N=5 N=3 60 N=5 60 N=2 40 40 20 20 N=2 0 0 Pre-Dose Day 15 Day 28 Day 56 Day 84 Pre-Dose Day 28 IL-6 VEGF Reduced inflammatory and angiogenic cytokines may improve QOL, delay disease progr
Slide 14: Effect on Hematopoietic Growth Factors
Effect of INCB18424 on Hematopoietic Growth Factors N=4 1600 450 N=4 200 N=2 400 180 1400 N=2 350 160 1200 140 Percent of Baseline 300 1000 120 250 800 N=4 100 N=6 200 600 80 150 60 400 100 40 200 50 20 0 0 0 Pre-Dose Day 15 Day 28 Day 56 Day 84 Pre-Dose Day 28 Pre-dose Day 28 Erythropoietin IL-3 GM
Slide 15: Phase II: Expanded MTD Cohort
Phase II: Expanded MTD Cohort • Twenty one patients dosed at 25 mg BID with up to 4 weeks of follow up (all accrued in November 2007) • Rapid clinical responses seen, in reduced spleen size and improved constitutional symptoms • First patient treated for 4 weeks: – spleen 20 cm bcm and liver 9 cm bc
Slide 16: Summary
Summary INCB18424 has significant efficacy as a therapy for patients with PMF or post-PV/ET MF • Marked reduction in spleen size and improvement in quality of life in all patients • Durable transfusion independence achieved in the first patient entered on the study • Very well tolerated • Thrombocyt