A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease.
BACKGROUND
Intestinal inflammation associated with Crohn's disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)-12. We report our clinical experience with a novel oral IL-12/IL-23 inhibitor (STA 5326) for the treatment of active Crohn's disease.


METHODS
We conducted an open-label, dose-escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohn's disease (Crohn's disease activity index [CDAI] 220-450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohn's disease endoscopic index of severity.


RESULTS
STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug-related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42%-82% of patients); 100 points or greater decrease in CDAI (range 38%-64% of patients), and CDAI <150 (range 15%-36%).


CONCLUSIONS
Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohn's disease. Clinical activity was observed at qd doses of 28 mg and above.
Burakoff
Robert
R
Brigham & Women's Hospital, Boston, Massachusetts, USA.
Barish
Charles F
CF
Riff
Dennis
D
Pruitt
Ronald
R
Chey
William Y
WY
Farraye
Francis A
FA
Shafran
Ira
I
Katz
Seymour
S
Krone
Charles L
CL
Vander Vliet
Martha
M
Stevens
Christopher
C
Sherman
Matthew L
ML
Jacobson
Eric
E
Bleday
Ronald
R
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D006835:Hydrazones; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines; D012074:Remission Induction; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*
D006835:Hydrazones; D053759:Interleukin-23; D009025:Morpholines; D011743:Pyrimidines; D014227:Triazines; D018664:Interleukin-12; C504227:apilimod