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Previous Clinical Experience

Previous Clinical Experience. Victor Sandor, MD VP Global Oncology Drug Development Incyte Corporation. The RESPONSE Trial CINC424B2301. Outline. INC424 clinical experience in healthy volunteers Key findings from: Single and multiple ascending dose studies Drug interaction studies

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Previous Clinical Experience

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  1. Previous Clinical Experience Victor Sandor, MD VP Global Oncology Drug Development Incyte Corporation The RESPONSE TrialCINC424B2301

  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

  3. Clinical Evaluation of INC424 in Phase I

  4. INC424 Phase I Clinical Summary

  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

  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

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

  8. Phase II Study in Advanced PV and ET Polycythemia Vera (N=34) 10 mg BID* (n=7) 25 mg BID* (n=8) 50 mg QD (n=7) 10 mg BID (n=12) • 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 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

  9. PV Patient Characteristics

  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. Overall Safety in PV INC424 (N=34) *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

  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 by palpation Mean ± SE 8 5 4 4 3 Reduction in Palpated Spleen Length Reduction in Palpated Spleen Length Through Week 36 • 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 • Response Durability • 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. 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 Symptomatic Improvement Mean Symptom Severity Scores Through Week 36 Pruritus Bone pain Night sweats 0 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 *Same subject

  18. 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 Starting Dose Selection in PV

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

  20. ET Patient Characteristics

  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. Overall Safety in ET INC424 (N=39) *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

  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: Myelofibrosis

  26. Phase I / II Study Design in MF • 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 INCB018424 (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). INCB018424 (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;363:1117-1127.

  27. Non-hematologic Toxicities in MF 75% of randomized patients remain on study after 2+ years of follow-up *AEs thought to be at least possibly related to study medication occurring in >2% of the study population.

  28. Hematologic Toxicities in MF 60% had dose reduction / interruption 35% had dose escalation to 20 or 25 mg *Among patients who were transfusion-independent at baseline.

  29. Serious Adverse Events • Use of gradual dose tapering or short-term courses of corticosteroids have been used in MF patients requiring treatment discontinuation

  30. 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)

  31. 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)

  32. Phase III Program in MF Progressing US Registration Study: COMFORT-I • Agreement with FDA on SPA • Design: • Blinded, randomized 1:1 • INCB018424 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 • INCB018424 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. 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 INC424 Clinical Summary

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