Von Willebrand disease (VWD) is the most common congenital bleeding disorder, affecting 1% of the population. Current treatment is suboptimal. Tachyphylaxis limits the use of DDAVP; potential transmissible agents limit the use of Von Willebrand Factor (VWF) concentrate; and both require venous access. Recombinant human IL-11 (rhIL-11, Neumega), a gp-130 signaling cytokine with hematopoietic and anti-inflammatory activity, has recently been shown to increase VWF activity with good tolerance in mice, dogs, and healthy volunteers. We, therefore, initiated a prospective Phase II open label, escalating dose trial of rhIL-11 in subjects with type 1 VWD. VWD was defined by the presence of a bleeding history with at least two of four abnormal tests: F.VIII:C, VWF:RCo, VWF:Ag, PFA-100, and normal distribution of multimers. A total of six subjects completed the study, three each at 25 mcg/kg and 50 mcg/kg dose levels, and all were given rhIL-1 subcutaneously daily for 7 days. On day 4 of rhIL-11, VWF:RCo increased 32% over baseline to 107±9% (mean ± SE) at the 25 mcg/kg dose, and 70% over baseline to 179±55%, at the 50 mcg/kg dose; VWF:Ag levels increased similarly, to 102±38% and 240±120%, respectively; and FVIII:C and VIII:Ag each increased similarly, by up to 143% and 200%. Intravenous DDAVP at a dose of 0.3 mcg/kg given 30 minutes after rhIL-11 on day 7, induced a further increase in VWF:RCo, to 114±48% and 359±152%, and in VWF:Ag, to 113±33% and 277±21%, each respectively at the two rhIL-11 doses; and very high molecular weight VWF multimers were detected by gel elecrophoresis on plasma samples. These data suggest that rhIL-11 acts on other than the DDAVP releasable pool of VWF. The drug was well tolerated. Minor adverse events included hypertension, fluid retention, and hypokalemia, each at less than grade 1 toxicity. There was a mild dilutional decrease in hemoglobin related to fluid retention. There was no significant increase in platelet count. In conclusion, rhIL-11 increases VWF activity to levels in the range associated with clinical hemostasis, suggesting the potential use of rhIL-11 in treatment of clinical bleeding in type 1 VWD.

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Topics:
interleukin-11, von willebrand disease, type 1, gel, desmopressin, fluid retention, hemorrhage, adverse event, anti-inflammatory agents, bleeding diathesis, blood coagulation disorders

Disclosures: Dr. Ragni received drug (rhIL-11) for research studies.

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2006, The American Society of Hematology
2006
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