STENOVA - A Study to Evaluate Safety, Tolerability, PK and PD of AGMB-129 in Patients With Fibrostenotic Crohn's Disease

A Phase 2a, Randomized, Placebo-controlled, Double-blind Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of AGMB-129 in Patients With Fibrostenotic Crohn's Disease

Many patients with Crohn's disease develop fibrotic narrowing (strictures) in their bowel, causing obstructive symptoms such as abdominal pain, cramping, or vomiting after meals. Because of these symptoms, patients often require bowel resection surgery. The objective of this clinical trial is to evaluate the safety, pharmacokinetics, and pharmacodynamics of AGMB-129 (Ontunisertib) in patients with Crohn's disease and symptomatic strictures, and whether it can have a beneficial effect on intestinal strictures.

The participants will be in the Part A for a duration of up to 19 weeks including a 5 week screening period, a 12-week double-blind, placebo-controlled treatment period, and 2 week safety follow up period. Participants who continue to Part B can receive treatment for up to an additional 48 weeks, with a safety follow-up visit 2 weeks after the last dose of treatment.

Part A is a randomized, placebo-controlled, double-blind, parallel, multicenter, phase 2a study in participants with Crohn's disease and symptomatic intestinal strictures.

Part A consists of 3 periods (a screening period, a placebo-controlled, double-blind treatment period, and safety follow-up). After signing informed consent, eligibility will be assessed during a 5-week screening period. The presence of qualifying intestinal strictures will be assessed by ileocolonoscopy and magnetic resonance enterography (MRE). The presence of obstructive symptoms will be also evaluated.

Eligible participants will be randomized 1:1:1 to receive AGMB-129 high dose, low dose or placebo for 12 weeks.

During Screening and Week 12 visits, participants will undergo ileocolonoscopy with biopsy collection for exploring pharmacodynamics. Participants will have blood sample collection at Weeks 2, 4, 8, and 12 to assess safety, pharmacokinetics, and pharmacodynamics.

Throughout the study, participants will undergo routine safety assessments at study visits, which will include physical examination, vital signs, clinical laboratory assessment, electrocardiogram (ECG), and recording of AEs.

Part B is an open-label treatment extension for participants who have completed the double-blind treatment period in Part A.

Inclusion Criteria (Part A):

1. Diagnosis of ileal or ileocolonic CD based on supporting guideline criteria (eg, clinical, endoscopic, and histologic evidence) established at least 3 months prior to screening.

2. Presence of at least 1 stricture in the terminal ileum within reach of an endoscope (passable or nonpassable).Strictures should be noncritical, naïve or anastomotic stricture(s), caused by CD and confirmed centrally by MRE according to the following criteria:

   • Localized luminal narrowing (luminal diameter ≤50% relative to normal adjacent bowel); AND
   • Bowel wall thickening (≥25% relative to adjacent bowel; AND
   • Either prestenotic dilation (defined as a luminal diameter ≥3 cm) or nonpassable with adult colonoscope

3. Presence of tolerable obstructive symptoms, as defined by a screening S-PRO severity score ≥2, and not expected to require hospitalization, endoscopic balloon dilation, surgical resection, or additional therapy during the study. Participant should have sufficient food intake, even with diet modification.

4. Stable background therapy for CD and agree to maintain background therapy for the study duration

Exclusion criteria (Part A):

1. History or current diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, nonsteroidal anti-inflammatory drug-induced colitis, idiopathic colitis (ie, colitis not consistent with CD), radiation colitis, microscopic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption.
2. CD-related complications (previous extensive small bowel resection, ileorectal anastomosis, proctocolectomy, short bowel syndrome, ileostomy [diverting or end], colostomy, small bowel stoma, ileoanal pouch, inactive fistulae in or adjacent to an ileal stricture, anal and perianal stricture, active intra-abdominal or perianal abscess that has not been appropriately treated, abscess in relation to the stricture, toxic megacolon, very severe inflammation, or presence of deep ulceration in the colon or terminal ileum).
3. Ileitis not associated with CD (eg, ileitis associated with infections, spondyloarthropathies, ischemia, etc.).
4. Endoscopic balloon dilation or surgical treatment of the same small bowel stricture within the last 6 months prior to screening
5. Receiving cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 8 weeks of screening or Janus kinase inhibitor therapy within 4 weeks of screening.
6. Requiring continued treatment with systemically administered medications that are sensitive CYP3A4/5 substrates with a narrow therapeutic index or strong inhibitors of aldehyde oxidase or xanthine oxidase.
7. Current or history of vasculitis, valvulopathy or large vessel disorder or major abnormalities documented by cardiac echocardiography with Doppler

Inclusion Criteria (Part B):

1. Completion of the 12-week treatment period (Part A) and participant is willing and able to continue treatment.
2. Per investigator judgment, participant is able to continue or resume treatment following completion of the Week 12 visit in Part A.

Exclusion criteria (Part B):

1. More than 24 weeks since completion of the Week 12 visit in Part A.
2. Experienced any AE leading to permanent treatment discontinuation during treatment with study drug in the double blind treatment period (Part A).
3. Have undergone endoscopic balloon dilation or bowel surgery (resection surgery or strictureplasty) for any intestinal stricture since the Week 12 visit in Part A.
4. Developed any condition which meets the Part A exclusion criteria, as per investigator judgment.
5. Any condition which in the opinion of the investigator affects the safety or ability to participate in Part B.
6. Participation in any other clinical trial since the completion of the Week 12 visit in Part A.