Clinical safety data
Odiparcil has undergone phase I and II clinical studies in post-operative deep-vein thrombosis and was found to be safe and well tolerated. 648 healthy volunteers received odiparcil in 29 completed phase I clinical pharmacology and pharmacokinetics studies. In these studies, employing single-doses and multiple-doses administered for up to 14 days, odiparcil was safe with low toxicity observed and was well tolerated. Three phase IIb trials in the prevention of thromboembolism after hip arthroplasty or knee surgery and in patients at risk of a stroke were conducted using multiple-doses (250 to 1,000 mg/day) administered to 1,161 patients for up to 16 weeks and confirmed odiparcil’s safety and tolerability.
A non-interventional study has been conducted to develop a quantitative method to measure glycosaminoglycan (GAG) storage levels in leukocytes as a disease activity biomarker in MPS VI. This new method allows to quantify levels of chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) in leukocytes (leukoGAG) and will be an important tool to measure the effect of odiparcil on MPS VI patients during the iMProveS trial.
Six MPS VI patients and six age-matched healthy volunteers participated in the study. All six MPS patients have been treated with galsulfase between 6 and 14 years. Urinary GAGs (uGAG) and leukoGAGs were measured and the results demonstrate that all MPS VI patients had uGAG levels above the upper limit of normal and leukoGAG levels above the level of the healthy volunteers.
In MPS VI patients receiving ERT, the most abundant GAG components are DS and CS in urine and CS in leukocytes. These two forms of GAGs are reduced in vitro in MPS VI patient cells treated with odiparcil (see mechanism of action).
Finally, data on arylsulfatase B activity (the deficient enzyme in MPS VI) in leukocytes, showed that one hour after completion of galsulfase infusion, enzyme activity is increased nearly ten fold but that CS content in leukocytes remains more than 12-fold above basal level. These results demonstrate room for improvement in the therapeutic concept and suggest the possibility to reduce GAG levels with new treatments such as odiparcil.