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NDA 22-291 PROMACTA® (Eltrombopag)

NDA 22-291 PROMACTA® (Eltrombopag). FDA Review Andrew Dmytrijuk, MD. Proposed Indication. Eltrombopag is indicated for the short-term treatment of previously-treated patients with chronic idiopathic thrombocytopenic purpura (ITP) to increase platelet counts and reduce or prevent bleeding .

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NDA 22-291 PROMACTA® (Eltrombopag)

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  1. NDA 22-291 PROMACTA® (Eltrombopag) FDA Review Andrew Dmytrijuk, MD

  2. Proposed Indication Eltrombopag is indicated for the short-term treatment of previously-treated patients with chronic idiopathic thrombocytopenic purpura (ITP) to increase platelet countsandreduce or prevent bleeding. Underlines added for emphasis

  3. Eltrombopag Background • Tablet, administered daily • Binds to transmembrane portion of TPO receptor • Preclinical testing of Eltrombopag: • stimulated platelets only in chimpanzees • in other animals (in high doses): • Chronic progressive nephropathy • Liver abnormalities • Cataracts • Preclinical testing of another TPO receptor agonist: marrow fibrosis

  4. Clinical Database Eltrombopag (E) exposure n = 1088 • Chronic ITP: • n = 330 • Thrombocytopenia in hepatitis C: • n = 56 • Chemotherapy-induced thrombocytopenia: • n = 134 • Clinical pharmacology: • N = 568

  5. ITP Program • “Short term”: 6 week exposure - Completed: placebo controlled - 773A - 773B - On-going, single arm: “REPEAT” • “Long term”: ≥ 6 month exposure - On-going: placebo controlled: “RAISE” - On-going: single arm: “EXTEND”

  6. Major Review Topics: “Short Term” • Efficacy: • increase platelet counts • reduce or prevent bleeding • Safety: • bleeding risks following drug discontinuation • hepatotoxicity • “short term” indication but long term usage - more hepatotoxicity? - potential marrow fibrosis?

  7. Data Presentation • Completed studies (short-term): • 773A • 773B • On-going studies/interim: • REPEAT (cycles of short-term) • EXTEND • RAISE

  8. “Short Term” Rationale: Protocols “Short term treatment may increase platelet counts in patients with chronic ITP scheduled for surgical or dental procedures, where a low platelet count can be a hindrance or even prohibitive of the procedure due to the risk of excessive bleeding.” Underlines added for emphasis

  9. Studies 773A and 773B: Design Features • DB, PC, multi-national • Eligibility: - platelets < 30K despite at least 1 prior therapy - did not select patients scheduled for procedures • Randomization: - 773A: placebo or active drug at 30 mg, 50 mg or 75 mg daily - 773B: placebo or active drug at 50 mg daily

  10. 773A and 773B: Design Features, continued • Dose adjustment: - dosing terminated for Plt ct > 200K - 773B: could increase dose to 75 mg at day 22 • Major baseline and follow-up evaluations: - CBC, clinical chemistry - WHO bleeding score • Endpoints: - Primary: Plt ct ≥ 50K at day 43 or drug d/c due to Plt ct > 200K (“response”) - Other: change in WHO bleeding score

  11. 773A and 773B Baseline Characteristics All randomized subjects

  12. 773A and 773B Disposition

  13. 773A and 773B Primary Endpoint Results, n (%) *P < 0.01 for Eltrombopag 50 mg versus placebo

  14. Primary Endpoint in Splenectomy Subsets, n (%)

  15. 773A and 773B Maximum Platelet Responses

  16. WHO Bleeding Scores • Focused upon change from baseline bleeding score • Unclear clinical meaningfulness of changes in score (e.g., 2 to 1) “A method for objective quantification of bleeding symptoms in ITP has not been established.” Br J Haematol 2007;138(2)245-8 • Investigators: • subjectively assigned WHO score • aware of platelet counts

  17. WHO Bleeding Scale

  18. WHO Bleeding Scores in 773A and 773BDistribution of Change from Baseline Score to “No Bleeding” Score at End of Therapy Pooled placebo and 50 mg Eltrombopag groups

  19. “Hemostatic Challenges” in 773A and 773B

  20. Adverse Events: 773A and 773BPlacebo and 50 mg Eltrombopag cohorts *no ITP rescue medication reported

  21. Death in Study 773A • 66 year old man, hx pneumonectomy • Day 15: increased ALT/AST • Day 21: hospitalized for COPD exacerbation with liver and renal test abnormalities • Died ~ day 26 of “cardiac failure caused by pulmonary failure” • Autopsy: thromboemboli in lung and liver, R and L ventricular hypertrophy • Eltrombopag-associated liver/renal test abnormalities?

  22. Subject 144 in Study 773A Liver/renal test abnormalities

  23. Major Safety Signals from 773A and 773B 1. Risk for liver toxicity 2. Hemorrhage risk following Eltrombopag D/C

  24. Risk for liver toxicity: • Eltrombopag undergoes liver metabolism • Preclinical data show liver toxicity at high doses • One death with liver test abnormalities and small imbalances in liver test abnormalities in general population

  25. Liver Tests, Max Toxicity Grade: 773A & 773B

  26. Hemorrhage risk following Eltrombopag D/C • Compared to baseline, worsened thrombocytopenia following TPO-mimetic drug D/C • Worsened thrombocytopenia, compared to baseline: 10% Eltrombopag vs 6% placebo • Imbalance in serious hemorrhages following drug D/C

  27. Serious Hemorrhage Adverse Events: with use of rescue medications * 75 mg Eltrombopag

  28. On-going: REPEAT • Design: • eligible: platelets ≥ 20K and ≤ 50K & 1 prior tx • 3 cycles of 6 weeks separated by up to 30 days “off therapy” • Primary endpoint: proportion of subjects with platelet response, given a response in cycle 1 • Limitations: • “off therapy” period can be shortened • Uncontrolled, interim data

  29. REPEAT: Platelet Response

  30. REPEAT: Hemostatic challenges

  31. REPEAT: Major Safety Findings • 1 Serious hemorrhage: epistaxis and ear hemorrhage, off therapy • 25/66 (38%) required Eltrombopag at a time point before 30 days “off therapy” due to platelets < 20K or bleeding symptoms • ~ 15% rate of liver test abnormalities: grade 1 or 2

  32. On-going: EXTEND • Design: • Eligible: completed prior study • Long term exposure with Eltrombopag dose adjustment and attempt to reduce/eliminate concomitant meds • Bone marrow reports after one year • Primary endpoint: safety • Limitations: uncontrolled, interim data • Platelet data n = 109 • Overall safety n = 207

  33. EXTEND: Exposure: median of 98 days

  34. Safety Data: EXTEND Hemostatic challenges in 13 subjects: • Pre-procedure rescue medications in 2 subjects • No bleeding complications

  35. Safety Data: EXTEND • 4 Deaths - MVA - GI hemorrhage ~ 55 days after last dose - Bronchiectasis/possible sepsis/DVT - Unwitnessed death/few details • 20 subjects with SAE - 3 PE - 3 hemorrhage - 2 increased liver tests - isolated other events • ~ 15% rate of liver test abnormalities: mainly grade 1 or 2

  36. Bone Marrow Data: EXTEND • Other TPO-mimetic molecules cause marrow fibrosis in animals • No marrow SAE in short term Eltrombopag studies • All subjects in EXTEND to have marrow exam after one year Eltrombopag • Marrows examined by site pathologists/reports summarized • no central/adjudicated review • terms/definitions variable

  37. Bone Marrow Data: EXTEND • To date: 19 subjects with marrow reports • 17 obtained ≥ 10 months exposure (other after 2 and 8 months exposure) • 7/19 had “reticulin” documented in report • 1 had “reticulin and trichrome stains show moderate fibrosis, moderate increase in type 3 collagen (reticulin) and mild increase in type 1 collagen” • 1 had “myelofibrosis grade 2/3”

  38. On-going: RAISE • R, DB, PC, six month exposure • Remains blinded, to date 197 enrolled • 1 death to date (CNS hemorrhage/nonresponder) • 26 subjects with SAE “on therapy” • 5 hemorrhage • 4 cataract • 3 liver test abnormalities • 2 thromboses • other isolated events • 3 subjects with “post-therapy SAE” (bronchitis, PE, CNS hemorrhage)

  39. Summary: Efficacy • Increased platelet counts in 60 – 70% subjects • Bleeding assessed with scores at each visit • Incremental changes of ? meaningfulness • Investigators unblinded to platelet counts • Change predominantly from score of 1 to 0 • Hemostatic challenges reported in only 7 subjects • 4 Eltrombopag group: no rescue medication • 3 Placebo group: rescue medication

  40. Summary: Safety • Imbalance in serious hemorrhagic events requiring rescue ITP medications • 7 Eltrombopag group vs 1 placebo group • Most serious hemorrhage followed Eltrombopag discontinuation: 5/7 • Imbalance in liver test abnormalities • small imbalance in predominantly grade 1 and 2 • one death in a patient with rising liver test abnormalities

  41. Summary: Eltrombopag in long term evaluation program • Interim data/studies on-going • Controlled data still blinded • Continued signals of predominantly grade 1 & 2 liver test abnormalities • Bone marrow effects signaled by reticulin presence in 7/19 biopsies

  42. Major Discussion Considerations: • Efficacy: • increase platelet counts • reduce or prevent bleeding • Safety: • bleeding risks following drug discontinuation • hepatotoxicity • “short term” indication but long term usage - more hepatotoxicity? - potential marrow fibrosis?

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