Sargramostim in patients with Crohn's disease: results of a phase 1-2 study.
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.


CONCLUSIONS
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.
Department of Internal Medicine, Social Insurance Central General Hospital, Tokyo, Japan.
Masakazu
M
Takazoe
Toshiyuki
T
Matsui
Satoshi
S
Motoya
Takayuki
T
Matsumoto
Toshifumi
T
Hibi
Mamoru
M
Watanabe
D000328:Adult; D003424:Crohn Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D055103:Hypodermoclysis; D007155:Immunologic Factors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins
D007155:Immunologic Factors; D011994:Recombinant Proteins; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor