A Phase 2b, Randomized, Placebo-controlled, Double-blind, Dose-ranging Trial to Assess the Efficacy and Safety of Ontunisertib in Patients With Fibrostenosing Crohn's Disease

Main inclusion criteria:

• Adults, ≥18 years of age  

• Diagnosis of ileal or ileocolonic CD based on clinical and endoscopic or radiological evidence established at least 12 weeks prior to signing the ICF.  

• Presence of at least 1 endoscopically non-passable ileal stricture, caused by CD, confirmed by a centrally-read SES-CD ileal narrowing score of 3.  

• Present stricture(s) can be naïve or anastomotic, and will be confirmed by centrally read MRE.  

• Presence of (sub)obstructive symptoms, e.g., postprandial pain, bloating, or cramping, AND/OR dietary restrictions.  

• Participants should be on stable anti-inflammatory background therapy for CD and agree to maintain stable background therapy for the duration of the trial. Pts on stable corticosteroids prior to screening should be willing to undergo forced tapering as early as Week 6 to be off steroids by the Week 12 visit. 

• Not expected in the investigator’s opinion to require hospitalization, endoscopic balloon dilation, surgical resection, or optimized anti-inflammatory therapy during the first 4 weeks of the trial.  

Main Exclusion Criteria  

• History or current diagnosis of ulcerative colitis 

• CD-related complications:  

  • Short bowel syndrome (<200 cm small bowel remaining).  

  • Ileostomy (diverting or end), colostomy, small bowel stoma, or ileoanal pouch.  

  • Internal fistulae and sinus tracts deriving from the area of stenosis. Participants with perianal fistulae could be included if not septic.

  • Anal and perianal stricture.  

  • Suspected or diagnosed active intra-abdominal or perianal abscess that has not been appropriately treated and abscess in relation to the stricture.  

  • Toxic megacolon.  

  • Blind-ending sinus could be included.  

• Endoscopic balloon dilation or surgical treatment of the index small bowel stricture within the last 6 months prior to screening.  

• Current or history of vasculitis or large blood vessel disorder.  

• Current or history of valvulopathy,  

• Hereditary xanthinuria or molybdenum cofactor deficiency.  

• Any other severe acute or chronic medical condition, psychiatric disorder, laboratory abnormality, or systemic or opportunistic infection that may increase the risk associated with trial participation or trial treatment administration, or may interfere with the interpretation of trial results, as determined by the investigator.  

• Prior exposure to ontunisertib.  

• Concomitant or prior use of the following systemically administered medications:  

  • JAK inhibitor from 4 weeks prior to screening.  

  • Cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil from 8 weeks prior to screening.  

  • Requiring continued treatment with strong or moderate inhibitors of CYP3A4.  

• Clinically significant abnormal vital signs, physical examination, or abnormalities at 12-lead ECG at screening or baseline, or any other abnormal changes on the ECG that would interfere with measurement of the QT interval.