Randomized Phase III Trial of Avatrombopag a Novel

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Randomized Phase III Trial of Avatrombopag, a Novel Oral Thrombopoietin Receptor Agonist, in Previously

Randomized Phase III Trial of Avatrombopag, a Novel Oral Thrombopoietin Receptor Agonist, in Previously Treated Chronic ITP Integrating New Hematology Findings Into Practice: Independent Conference Coverage of ASH 2017, * December 9 -12, Atlanta, Georgia *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 activity is supported by educational grants from Abb. Vie; Astra. Zeneca; Celgene Corporation; Genentech; Janssen Biotech, Inc administered by Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals; Novartis Pharmaceuticals Corporation; Pharmacyclics Inc; Seattle Genetics; and Takeda Oncology.

Phase III Avatrombopag: Background § Conventional first-line therapies for ITP reduce clearance of autoantibody-coated

Phase III Avatrombopag: Background § Conventional first-line therapies for ITP reduce clearance of autoantibody-coated platelets[1] – Pts failing splenectomy or second-line agents (eg, rituximab) often treated with TPO-RAs, which directly induce platelet production § Avatrombopag: small-molecule TPO-RA shown to significantly increase platelet response vs placebo by Day 28 in phase II study; generally well tolerated[2 -4] § Current phase III trial evaluated efficacy and safety of avatrombopag vs placebo in pts with refractory chronic ITP[5] References in slidenotes Slide credit: clinicaloptions. com

Phase III Avatrombopag: Study Design § Randomized, double-blind, placebo-controlled phase III trial conducted at

Phase III Avatrombopag: Study Design § Randomized, double-blind, placebo-controlled phase III trial conducted at Wk 26 27 sites in 11 countries Adult pts with ITP ≥ 12 mos, mean PLT count < 30 x 109/L, and ≥ 1 prior therapy for ITP but no splenectomy or rituximab within 12 wks of randomization (N = 49) Avatrombopag 20 mg/day* PO (n = 32) Open-label extension Placebo (n = 17) *Dose titration (5 -40 mg/day) permitted after Day 5 based on individual responses. § Primary endpoint: cumulative wks of PLT response (PLT count ≥ 50 x 109/L) in absence of rescue therapy § Secondary endpoints: PLT response at Day 8, reduction in concomitant ITP therapies, durable PLT response rate lasting ≥ 6 of 8 last wks of treatment Jurczak W, et al. ASH 2017. Abstract 17. Slide credit: clinicaloptions. com

Phase III Avatrombopag: Baseline Characteristics Characteristic Avatrombopag (n = 32) Placebo (n = 17)

Phase III Avatrombopag: Baseline Characteristics Characteristic Avatrombopag (n = 32) Placebo (n = 17) 46. 4 (14. 2) 29 (90. 6) 41. 2 (14. 7) 16 (94. 1) Female, n (%) 23 (71. 9) 8 (47. 1) White, n (%) 31 (96. 9) 15 (88. 2) 80. 3 80. 0 Mean BL PLT count x 109/L (SD) § ≤ 15 x 109/L, n (%) § 15 -30 x 109/L, n (%) § ≥ 30 x 109/L, n (%) 14. 1 (8. 6) 18 (56. 3) 13 (40. 6) 1 (3. 1) 12. 7 (7. 8) 10 (58. 8) 7 (41. 2) 0 Splenectomy, n (%) 11 (34. 4) 5 (29. 4) Concomitant ITP agents, n (%) 15 (46. 9) 7 (41. 2) Mean age, yrs (SD) § < 65 yrs, n (%) Median weight, kg Jurczak W, et al. ASH 2017. Abstract 17. Slide credit: clinicaloptions. com

Phase III Avatrombopag: Pt Disposition § Nearly 70% of pts completed 6 mos of

Phase III Avatrombopag: Pt Disposition § Nearly 70% of pts completed 6 mos of avatrombopag Avatrombopag (n = 32) Placebo (n = 17) Completed treatment, n (%) 22 (68. 8) 1 (5. 9) Discontinued treatment, n (%)* § Inadequate therapeutic effect § Adverse events § Withdrawal of consent 10 (31. 3) 7 (21. 9) 3 (9. 4) 0 16 (94. 1) 15 (88. 2) 0 1 (5. 9) Mean duration of exposure, wks 22. 8 8. 9 Pt Disposition *Criteria for treatment d/c: PLTs dangerously low after 7 days of treatment at max dose, rescue therapy required > 3 times or continuously for > 3 wks. Jurczak W, et al. ASH 2017. Abstract 17. Slide credit: clinicaloptions. com

Phase III Avatrombopag: Primary Endpoint § Significantly longer duration of PLT response with avatrombopag

Phase III Avatrombopag: Primary Endpoint § Significantly longer duration of PLT response with avatrombopag vs placebo 25 Cumulative Wks of PLT Count ≥ 50 x 109/L P <. 0001 Wks 20 15 12. 0 10 5 0 0. 1 Avatrombopag (n = 32) Jurczak W, et al. ASH 2017. Abstract 17. Reproduced with permission. Placebo (n = 17) Slide credit: clinicaloptions. com

Phase III Avatrombopag: Secondary Endpoints Outcome, % (95% CI) Avatrombopag (n = 32) Placebo

Phase III Avatrombopag: Secondary Endpoints Outcome, % (95% CI) Avatrombopag (n = 32) Placebo (n = 17) P Value PLT count ≥ 50 x 109/L at Day 8 65. 6 (49. 2 -82. 1) 0 <. 05 Durable PLT response* 34. 4 (17. 9 -50. 8) 0 <. 05 Reduction of concomitant ITP medications 33. 3 (9. 5 -57. 2) 0 NS *PLT response lasting ≥ 6 of 8 last wks of treatment. Jurczak W, et al. ASH 2017. Abstract 17. Slide credit: clinicaloptions. com

Phase III Avatrombopag: PLT Counts Over Time (Exploratory Endpoint) Median PLT Count (x 109/L)

Phase III Avatrombopag: PLT Counts Over Time (Exploratory Endpoint) Median PLT Count (x 109/L) § Median PLT count higher with avatrombopag vs placebo beginning at Day 8 (80. 5 vs 8. 0 x 109/L) 200 Avatrombopag Placebo 180 160 140 120 100 80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Wks Jurczak W, et al. ASH 2017. Abstract 17. Reproduced with permission. Slide credit: clinicaloptions. com

Phase III Avatrombopag: Safety § Avatrombopag generally well tolerated, with only 3 pts (9.

Phase III Avatrombopag: Safety § Avatrombopag generally well tolerated, with only 3 pts (9. 4%) discontinuing treatment for TEAEs Avatrombopag (n = 32) Placebo (n = 17) TEAE in ≥ 10% of Pts, n (%) Any 31 (96. 9) 10 (58. 8) Treatmentrelated 20 (62. 5) 3 (17. 6) Grade 3/4 6 (18. 8) 0 TEAE, n (%) Leading to study drug withdrawal 3 (9. 4) Jurczak W, et al. ASH 2017. Abstract 17. 0 Avatrombopag (n = 32) Placebo (n = 17) Headache 12 (37. 5) 2 (11. 8) Contusion 10 (31. 3) 4 (23. 5) URTI 6 (18. 8) 1 (5. 9) Arthralgia 4 (12. 5) 0 Epistaxis 4 (12. 5) 3 (17. 6) Fatigue 4 (12. 5) 1 (5. 9) Gingival bleeding 4 (12. 5) 0 Petechiae 4 (12. 5) 1 (5. 9) Slide credit: clinicaloptions. com

Phase III Avatrombopag: Conclusions § In pts with previously treated chronic ITP, avatrombopag superior

Phase III Avatrombopag: Conclusions § In pts with previously treated chronic ITP, avatrombopag superior to placebo for cumulative duration of PLT response ≥ 50 x 109/L without rescue therapy – 12. 0 vs 0. 1 wks, respectively (P <. 0001) § PLT response at Day 8 and during last 8 wks of treatment also improved with avatrombopag vs placebo § Avatrombopag well tolerated with few (9. 4%) d/c for TEAEs – Headache, contusion, upper respiratory tract infection among most commonly reported TEAES § Study investigators conclude that avatrombopag may provide a new TPO-RA treatment option for adults with refractory chronic ITP Jurczak W, et al. ASH 2017. Abstract 17. Slide credit: clinicaloptions. com

Go Online for More CCO Coverage of ASH 2017! Short slideset summaries of all

Go Online for More CCO Coverage of ASH 2017! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: § § § Leukemias Lymphomas/CLL Myeloma Nonmalignant hematology Hot topics in hematology clinicaloptions. com/oncology