Background: We aimed to assess the tolerability, pharmacokinetics, safety, and efficacy of sargramostim in Japanese patients with active Crohn's disease (CD).
Methods: Patients with moderately to severely active CD were enrolled. Step 1 was an open-label, phase 1 study of 2 microg/kg per day sargramostim administered subcutaneously (SC) for 4 weeks, with an optional 8-week extension with 6 microg/kg per day. Step 2 was an open-label, phase 1-2 study of the tolerability and pharmacokinetics of SC sargramostim 6 microg/kg per day over 4 weeks and of 8-week efficacy and safety. Efficacy variables were the proportion of patients achieving a clinical response [> or =100-point decrease from baseline in the CD activity index (CDAI)] and the proportion achieving clinical remission (CDAI < or = 150 points).
Results: Six patients participated in Step 1; five in Step 2. Serum concentrations of sargramostim peaked within 1 h of administration; mean terminal half-life was 2 h. Maximal serum concentrations increased with the dose. Mean accumulation ratios were 0.998 in Step 1 and 0.673 in Step 2. One of the six patients in the Step-1 extension and none of the five in Step 2 achieved a clinical response. Clinical remission was reported in one patient in each step. A notable decrease in median CDAI scores was observed in the extension and Step 2. In responders, improvement tended to be maintained through the 30-day follow-up. Drug-related adverse events included injection-site reaction, pyrexia, back pain, and bone pain.
Conclusion: The systemic exposure of sargramostim increased dose-dependently. No accumulation in systemic exposure was associated with the repeated once-daily administration. SC sargramostim at 6 microg/kg per day improved median CDAI scores. A minority of patients experienced clinical remission or clinical response.