Prsentation PowerPoint

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New perspectives of TPO agonists in the treatment
of ITP Bertrand Godeau Service de Médecine
Interne CHU Mondor, Créteil, France bertrand.godea
u_at_hmn.aphp.fr
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ITP Pathophysiology

• Accelerated platelet destruction
• Impaired platelet production

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TPO (MGDF)

• Ligand for c-Mpl
• 60 - 70 kDa glycosylated polypeptide
• 332 amino acids
• Synthetised mainly by liver
• Negatively regulated by
• - Platelet count
• - Megacaryocyte mass

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Recombinant human TPO
Neutralizing Ab cross-reacting with endogenous
TPO
High risk of severe and prolonged thrombocytopenia
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TPO agonists
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Newland A et al An open-label, unit dose-finding
study evaluating the safety and platelet response
of a novel thrombopoietic protein (AMG531) in
thrombocytopenic adult patients with ITP Blood
2004 104 567 a (abstract 2058).

• Phase 1 study
• 16 adult patients
• 13/16 splenectomized
• ITP duration gt 3 mths
• Platelet count lt 30x109/L (or 50x109/L if
  steroids)

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Newland A et al An open-label, unit dose-finding
study evaluating the safety and platelet response
of a novel thrombopoietic protein (AMG531) in
thrombocytopenic adult patients with ITP Blood
2004 104 567 a (abstract 2058).
AMG531
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Newland A et al An open-label, unit dose-finding
study evaluating the safety and platelet response
of a novel thrombopoietic protein (AMG531) in
thrombocytopenic adult patients with ITP Blood
2004 104 567 a (abstract 2058).
Response 67
  evaluation of the response after conversion
of the unit (µg) dose to µg/kg demonstrated that
received dose-equivalent of gt 1µg/kg, 8/12 (67)
achieved the platelet response criterion 
 Platelet response not related to splenectomy
status 
No anti-AMG531 or anti-TPO Ab was detected
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Kuter D et al A phase 2 placebo controlled study
evaluating the platelet response and safety of
weekly dosing with a novel thrombopoietic protein
(APG531) in thrombocytopenic adult patients with
ITP. Blood 2004 104 148a.

• Multicenter, randomized, double blind placebo
  controlled phase 2 study
• Weekly dose of 1 µg/kg and 3 µg/kg, 6-weeks of
  treatment
• Adult patients, ITP duration gt 3 mths
• Objectives Platelet reponse and safety profile

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Kuter D et al A phase 2 placebo controlled study
evaluating the platelet response and safety of
weekly dosing with a novel thrombopoietic protein
(APG531) in thrombocytopenic adult patients with
ITP. Blood 2004 104 148a.
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Kuter D et al A phase 2 placebo controlled study
evaluating the platelet response and safety of
weekly dosing with a novel thrombopoietic protein
(APG531) in thrombocytopenic adult patients with
ITP. Blood 2004 104 148a.
Median time to response day 8
No anti-AMG531 or anti-TPO Ab was detected
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Kuter D et al A phase 2 placebo controlled study
evaluating the platelet response and safety of
weekly dosing with a novel thrombopoietic protein
(APG531) in thrombocytopenic adult patients with
ITP. Blood 2004 104 148a.
13
Kuter D et al A phase 2 placebo controlled study
evaluating the platelet response and safety of
weekly dosing with a novel thrombopoietic protein
(APG531) in thrombocytopenic adult patients with
ITP. Blood 2004 104 148a.
Transient thrombocytopenia, n 1
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Bussel J et al Long-term dosing of AMG531 is
effective and well tolerated in thrombocytopenic
patients with ITP Blood 2005 106 (abstract 220)

• Open-label study
• AMG531 starting dose 1 µg/kg with dose
  adjustment
• 26 pts treated for up to 24 weeks

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Bussel J et al Long-term dosing of AMG531 is
effective and well tolerated in thrombocytopenic
patients with ITP Blood 2005 106 (abstract 220)
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Bussel J et al Long-term dosing of AMG531 is
effective and well tolerated in thrombocytopenic
patients with ITP Blood 2005 106 (abstract 220)
Response 80 ? Mean AMG 531 dose 3.7
µg/kg ? Durable response 46
No anti-AMG531 or anti-TPO Ab was detected
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Bussel J et al Long-term dosing of AMG531 is
effective and well tolerated in thrombocytopenic
patients with ITP Blood 2005 106 (abstract 220)
Response 80 ? Mean AMG 531 dose 3.7
µg/kg ? Durable response 46
No anti-AMG531 or anti-TPO Ab was detected
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Jenkins J et al An oral, non-peptide, small
molecule thrombopoietic receptor agonist
increases platelet count in healthy subjects
Blood 2004 104 797 a (abstract 2919)

• Single blind placebo-controlled phase I study
• 72 healthy male subjects
• Eltrombopag, orally, once daily for 10 days,
  various doses

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Jenkins J et al An oral, non-peptide, small
molecule thrombopoietic receptor agonist
increases platelet count in healthy subjects
Blood 2004 104 797 a (abstract 2919)
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Bussel et al Eltrombopag, a novel, oral platelet
growh factor, increases platelet counts in
thrombocytopenic patients and healthy subjects
ASCO 2006, poster 8602
Results after 6 weeks
All starting platelet count lt 30 000
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Eltrombopag Adverse events
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Comments

• TPO agonists a new therapeutic strategy for ITP
  ?
• Only transient effect, not curative
• Safety ? (myelofibrosis ?)

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TPO agonistsPotential indications ?

• Refractory patients ? YES
• Before splenectomy or invasive procedure ?
•  Waiting treatment  after the initial phase of
  ITP ?

Why not but steroids effective and not expensive