Romiplostim FDA Overview

1
RomiplostimFDA Overview

• Oncologic Drugs Advisory Committee Meeting
• Faranak Jamali, MD
• March 12, 2008

2
FDA Overview

• Chronic ITP efficacy and safety
• Faranak Jamali, MD
• Exploratory study in MDS
• Steven Lemery, MD
• Risk management considerations
• Suzanne Berkman, PharmD

3
Proposed indication

• for the treatment of thrombocytopenia in adult
  patients with chronic ITP
• who are non-splenectomized and have an
  insufficient response or are intolerant to
  corticosteroids and/or immunoglobulins.
• who are splenectomized and have an insufficient
  response to splenectomy.

4
Romiplostim Database

• 14 Studies supply data
• Healthy subjects 2 studies
• ITP 2 phase 3 studies, 8 supportive
• MDS 1 study
• CIT 1 study
• Ongoing studies in ITP, MDS, CIT
• Romiplostim exposure in BLA
• n 271 in ITP
• n 121 in other settings

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Phase 3 Studies 20030105 and 20030212

• Study 105 Splenectomy
• Study 212 Spleen intact completed 1 prior
  treatment e.g., prednisone
• Study 213 an open label extension

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Phase 3 Design Features

• R (21), DB, PC, 24 week treatment period with
  12 wk f/u (off med)
• R stratified by con meds (yes/no)
• Starting dose 1 mcg/kg, SC max 15 mcg/kg
• Target plt 50 to 200 K/mcL
• Dose reduction for gt 200K
• Dose held for gt 400K
• Weekly Plt ct regular lab/antibody
• PRO ITP Questionnaire

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Phase 3 study endpoints

• Primary endpoint
• Durable plt response
• Weekly plt ct 50 K/mcL for 6 weeks of the
  last 8 weeks
• Secondary endpoints
• Overall platelet response
• Number of weekly platelet responses
• Patients requiring rescue medication
• Durable plt response on stable dose
• Multiple other supportive endpoints

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• Disposition

Group 105 105 105 212 212
Group Pl Romi-plostim Romi-plostim Pl Romi- plostim
Randomized 21 42 42 21 41
Discontinued 2 2 2 4 2
D/C Cause D/C Cause D/C Cause D/C Cause D/C Cause D/C Cause
Death 2 - - - -
AE - 1 1 1 2
Pregnancy - - 1 1 -
Consent w/d - 1 2 2 -
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• Baseline Characteristics

Cx 105 105 212 212
Cx Pl, n 21 Romi-plastim n 42 Pl n 21 Romi-plastim n 41
Age, med 56 51 46 52
Female () 52 64 76 66
Med Plt (109/L) 14.7 13.5 19.3 18.7
Med Hgb (g/L) 145 137 125 136
Med WBC (109/L) 8.4 8.9 7.7 5.9
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• Prior Therapies

Cx 105 105 212 212
Cx Pl, n 21 Romi- plostim n 42 Pl n 21 Romi- plostim n 41
Subjects w prior ITP Treatment (n) Subjects w prior ITP Treatment (n) Subjects w prior ITP Treatment (n) Subjects w prior ITP Treatment (n) Subjects w prior ITP Treatment (n)
Steroid 20 42 19 37
Anti-D 9 19 6 20
IVIG 20 39 15 26
Vinc/Vinblastin 10 17 0 0
Cyclophos 14 21 7 6
Azathioprine 5 10 1 2
Danazol 10 13 1 6
Rituximab 15 30 5 13
Other 11 21 6 10
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• Primary Endpoint Durable Platelet Response

Study Pl Romi- plostim p- value
105 (splenectomy) 0/21 (0) 16/42 (38) lt 0.01
212 (no splenectomy) 1/21 (5) 25/41 (61) lt 0.01
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• Secondary Endpoints

Outcome Study 105 splenectomy Study 105 splenectomy Study 212 no splenectomy Study 212 no splenectomy
Outcome Pl n 21 Romi- n 42 Pl n 21 Romi- n 41
Overall Plt Resp n () 0 33 (79) 3 (14) 36 (88)
Wks w Plt Resp, mean 0.2 12.3 1.3 15.2
Rescue Med, n () 12 (57) 11 (26) 13 (62) 7 (17)
Dur Plt Resp Stable Dose, n () 0 13 (31) 0 21 (51)
All p-values lt 0.01
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• Safety Data in Phase 3 Studies
• Adverse events
• Specific risks
• Reticulin formation and potential for fibrosis
• Thrombotic events
• Severe thrombocytopenia after discontinuation of
  Romiplostim
• Immunogenicity
• Neoplasia

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• Adverse Events in Phase 3 Studies, n ()

Adverse event Pl n 41 Romi- n 84
Any 39 (95) 84 (100)
Any serious 8 (20) 14 (17)
Fatal 3 (7) 1 (1)
Any bleed 25 (61) 48 (57)
Any serious bleed 4 (10) 5 (6)
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• Adverse Events in Phase 3 Studies ()

Term Pl n 41 Romi- n 84
Arthralgia 20 26
Dizziness 0 17
Insomnia 7 16
Myalgia 2 14
Extremity pain 5 13
Abdominal pain 0 11
Shoulder pain 0 8
Dyspepsia 0 7
Paresthesia 0 6
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Specific Safety Risks Safety Database

• ITP n 271
• 6 months phase 3 and other studies
• Extension study 213 SOC study 131
• Median exposure 37 weeks
• 36 subjects exposed for 2 years
• Healthy n 56
• MDS n 44
• CIT n 21

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1) Reticulin Formation and Risk for Fibrosis

• Reticulin in marrow reticulin fibrosis
• identified with silver stain
• associated with benign and malignant conditions
• thought to be reversible
• Collagen in marrow collagen fibrosis
• identified with trichrome stain
• less likely reversible
• myelofibrosis/cytopenias
• Could long term Romiplostim exposure result in
  marrow fibrosis/cytopenia?

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Romiplostim and Reticulin Formation

• Repeat Romiplostim dose studies in rats
• marrow fibrosis on H and E stains
• reversible after drug discontinuation
• Prior study in rats with a TPO (Yanagida)
• repeat dose resulted in myelofibrosis
• predominance of reticulin
• marrow TGFß content paralleled reticulin
• suggested megakarycocyte TGFß may stimulate
  reticulin formation

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Increased Reticulin in ITP Studies

• Phase 3 (controlled) studies
• One Romiplostim group/none Placebo
• Uncontrolled studies
• Nine patients
• Follow-up information
• 2 patients had marrows improved with
  Romiplostim discontinuation 2 others stable
  
• 2 remained on Romiplostim or dose interrupted
• Not available or pending as of 120 day update

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Patient Features from Detailed Review of Six AE
with Increased Reticulin

• All had nucleated RBC in peripheral blood
• All had undergone splenectomy
• All received high doses 7 to 18 mcg/kg
• 5 had no collagen on trichrome 1 had localized
  collagen assessed as inconsistent with chronic
  idiopathic myelofibrosis

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Aplastic Anemia

• 75 y o female with ITP, DM, CAD breast cancer
  history
• Six months Romiplostim
• Marrow at time of AA diagnosis only focal
  erythropoiesis and myelopoiesisconvincing marrow
  megakaryocytes not identified
• No JAK2 V617F point mutation detected
• Con meds azathioprine, carvedilol, amlodipine,
  losartan, acyclovir, ezetimibe and fenfibrate
• Died 54 days later

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2) Thrombotic Events

• Phase 3 (controlled) studies
• Placebo group PE
• Romi group CVA and arterial embolus
• Other studies 12 patients
• DVT (3), PE (3)
• MI (2), Portal V thrombosis (2), Superficial
  thrombophlebitis (2), Thrombosis (2)

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3) Severe Thrombocytopenia after Romiplostim
Discontinuation

• Potential risk suppression of TPO
• Early phase studies
• 4/57 patients experienced decreased plts
• Approximated baseline within 14 days
• Notable case
• 80 y o male received six months Romiplostim
• CVA 3 days after Romiplostim discontinuation
• (plt count 107K/mcL), aspirin therapy
• 7 days later ICH (plt ct 5K/mcL)
• Plt transfusion and died next day

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4) Immunogenicity
Developed ITP subjects tested n 225
Binding Abs Binding Abs
Romiplostim 23 (10)
TPO 12 (5)
Neutralizing Abs Neutralizing Abs
Romiplostim 1
TPO 0
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5) Neoplasia
Phase 3 Studies, Pooled
Subjects with neoplasms, n Pl n 41 Romi n 84
Any 5 2
B cell lymphoma 0 1
Basal cell ca 0 1
M myeloma 1 0
Liver metastasis 1 0
Benign lung neoplasm 1 0
Fibroma (arm) 1 0
Benign ovarian tumor/ Uterine leiomyoma 1 0
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Romiplostim in Chronic ITPSummary

• Increases and sustains platelet counts in
  patients who have failed prior therapies
• Long term safety data limited
• marrow events/reticulin/potential fibrosis
• thrombotic events
• severe thrombocytopenia after discontinuation
• immunogenicity
• neoplasia