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A phase II prospective open-label escalating dose trial of recombinant interleukin-11 in mild von Willebrand disease

M V Ragni1, R C Jankowitz, H L Chapman

  • 1Department of Medicine/Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ragni@dom.pitt.edu

Haemophilia : the Official Journal of the World Federation of Hemophilia
|August 6, 2008
PubMed

Insights

Recombinant human interleukin-11 (rhIL-11) effectively increased von Willebrand factor (VWF) levels in patients with mild von Willebrand disease (VWD). This novel treatment shows promise for managing VWD, offering an alternative to current therapies.

Area of Science:

  • Hematology
  • Pharmacology
  • Genetics

Background:

  • Von Willebrand factor (VWF) is crucial for platelet adhesion and is deficient in von Willebrand disease (VWD).
  • Current treatments like desmopressin (DDAVP) have limitations including tachyphylaxis and unresponsiveness in some patients.
  • Recombinant human interleukin-11 (rhIL-11) has shown potential in preclinical models to increase VWF levels.

Purpose of the Study:

  • To evaluate the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD.
  • To assess the dose-dependent effects of subcutaneous rhIL-11 on VWF and Factor VIII (FVIII) levels.
  • To explore the potential mechanism of rhIL-11 action compared to DDAVP.

Main Methods:

  • A phase II prospective, open-label trial involving nine subjects with mild VWD.
  • Administration of rhIL-11 at three different doses (10, 25, 50 µg/kg) subcutaneously daily for 7 days.
  • Measurement of VWF antigen, VWF activity, FVIII levels, and platelet VWF mRNA expression.

Main Results:

  • Subcutaneous rhIL-11 administration led to gradual and sustained increases in VWF and FVIII levels (1.5- to 3-fold baseline) over 7 days.
  • A further boost in VWF and FVIII levels was observed after DDAVP administration on day 7, suggesting different mechanisms of action.
  • Platelet VWF mRNA expression increased significantly, indicating potential upregulation of VWF synthesis.
  • rhIL-11 was well-tolerated with no significant adverse events, only mild, transient hypertension, hypokalemia, and fluid retention.

Conclusions:

  • Recombinant human interleukin-11 effectively increases VWF and FVIII levels in humans with mild VWD.
  • The observed increase in VWF mRNA suggests rhIL-11 may upregulate VWF synthesis.
  • rhIL-11 demonstrates a favorable safety profile and warrants further investigation in clinical trials for VWD management.

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