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

Trial ID: 2022-502789-26-01
Protocol: AGMB-129-C102
Sponsor: Agomab Spain S.L.U.

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Diseases & Conditions

Crohn's disease

Objectives

The primary objective of this Phase 2a, randomized, placebo-controlled, double-blind study is to evaluate the **safety** and tolerability of AGMB-129 in patients with fibrostenotic Crohn's disease (FSCD), with a comparison to placebo in Part A. This is clinically relevant as it aims to determine the potential adverse effects and overall acceptability of AGMB-129, which is crucial for assessing its viability as a therapeutic option for FSCD, a condition characterized by fibrotic narrowing of the intestines that can lead to significant morbidity.

Secondary objectives include:

Evaluating the **pharmacokinetics** (PK) of AGMB-129, which involves understanding the drug's absorption, distribution, metabolism, and excretion, providing insights into its behavior within the body.
Assessing the **pharmacodynamics** (PD) of AGMB-129, which focuses on the drug's biological effects and mechanisms of action, offering information on its therapeutic potential and efficacy in managing FSCD.

These secondary objectives are essential for comprehensively understanding the drug's profile and optimizing its clinical application.

Participants

The clinical trial involves a total of **23 participants** diagnosed with **fibrostenotic Crohn's disease**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as a confirmed diagnosis of ileal or ileocolonic Crohn's disease established at least three months prior to screening, and the presence of at least one stricture in the terminal ileum. The trial population is characterized by the presence of tolerable obstructive symptoms and a stable weight over the four weeks prior to screening, indicating sufficient food intake even with dietary modifications. Participants are required to maintain stable background therapy for Crohn's disease throughout the study. The trial includes a vulnerable population, ensuring careful consideration of ethical standards in the selection and treatment of participants.

Plans and Procedures

The clinical trial is a **Phase 2a**, randomized, placebo-controlled, double-blind study designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of AGMB-129 in patients with **fibrostenotic Crohn's disease**. The trial will involve the administration of AGMB-129 in capsule form, taken orally, with a placebo group for comparison. The study is expected to run from August 2023 to September 2026, with a maximum treatment period of 60 days for each participant. The trial will include several key phases, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of ileal or ileocolonic Crohn's disease and the presence of at least one stricture in the terminal ileum.

Participants will be randomly assigned to receive either AGMB-129 or a placebo, with neither the participants nor the investigators aware of the group assignments, maintaining the double-blind nature of the study. The primary endpoints include monitoring for adverse events, clinical laboratory tests, electrocardiogram findings, vital signs, physical examination findings, and 2-D echocardiogram findings. Secondary endpoints will assess pharmacokinetic parameters of AGMB-129 and its metabolites in plasma, as well as changes in gene expression at the mRNA level in ileal mucosa.

Study visits will be scheduled at regular intervals to monitor the participants' health and response to the treatment. These visits will include follow-up assessments to ensure the safety and efficacy of the treatment. The end-of-study visit will conclude the trial for each participant, with a comprehensive evaluation of their health status and any changes observed during the study period. Participants are expected to be involved in the study for the duration of the treatment period and follow-up visits, with conditions such as intolerable adverse events or the need for additional therapy potentially leading to early termination from the study.

Treatment

The clinical trial involves the administration of **ORG-129**, an experimental medication developed by Agomab Therapeutics N.V. **ORG-129** is presented in a **capsule** form and is intended for oral administration. The active substance, also named **ORG-129**, is of chemical origin. The trial is designed to evaluate the safety and tolerability of this compound in patients with fibrostenotic Crohn's disease. The maximum treatment period for **ORG-129** is 60 days. The specific dosage and frequency of administration are not detailed in the provided data, and the maximum daily and total dose amounts are indicated as zero, suggesting that these parameters are to be determined during the trial. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, a **placebo** is used as a comparator in this randomized, placebo-controlled, double-blind study. The placebo is referred to as "Placebo to IMP AGMB-129" and does not contain any active substance. The pharmaceutical form and route of administration for the placebo are not specified in the provided data. The placebo serves as a control to assess the effects of **ORG-129** against a non-active treatment, ensuring the reliability of the study outcomes. The trial aims to provide a comprehensive evaluation of the pharmacokinetics and pharmacodynamics of **ORG-129** in the target patient population.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of adverse events (AEs), clinical laboratory tests, electrocardiogram (ECG) findings, vital signs, physical examination findings, and 2-D echocardiogram findings. These parameters will be systematically measured and collected to ensure comprehensive safety and efficacy profiling of the investigational product, **AGMB-129**, in patients with fibrostenotic Crohn's disease.

Secondary endpoints focus on pharmacokinetic (PK) parameters of AGMB-129 and its metabolites in plasma, as well as changes in gene expression at the mRNA level in ileal mucosa. These assessments will be conducted in both Part A and Part B of the study. The trial is designed to provide a detailed understanding of the drug's pharmacodynamics and its impact on the disease at a molecular level. The data collection will be performed at specified intervals throughout the study duration, ensuring a robust analysis of the efficacy parameters.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.
Presence of at least 1 stricture in the terminal ileum within reach of an endoscope (passable or nonpassable).* Strictures should be noncritical or anastomotic stricture(s), caused by CD and confirmed centrally by MRE according to the following criteria: 1. localized luminal narrowing (luminal diameter ≤50% relative to normal adjacent bowel); AND 2. bowel wall thickening (≥25% relative to adjacent bowel); AND 3. either prestenotic dilation (defined as a luminal diameter ≥3cm) or nonpassable with adult colonoscope *Note: The terminal ileum is defined as the last 15 cm of ileum proximal to the ileocecal valve or ileocolonic anastomosis. Other small bowel strictures will be considered on a case-by-case basis following discussion with the sponsor. Two strictures within 3 cm are considered the same stricture, and a long segment with multiple areas of narrowing or multiple strictures, that have inflammation between them, is counted as 1 stricture.
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. Participants should have sufficient food intake, even with diet modification, defined as a stable weight over the 4 weeks prior to screening.
Stable background therapy for CD and agree to maintain background therapy for the duration of Part A.
For Part B: Completion of the 12-week treatment period (AGMB-129 or placebo) and the Week 12 visit in the double blind treatment period (Part A) and participant is willing and able to continue treatment.
For Part B: Per investigator judgment, participant is able to continue or resume treatment following completion of the Week 12 visit in Part A.

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Exclusion Criteria

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, untreated colonic mucosal dysplasia, or untreated bile acid malabsorption.
Current or history of valvulopathy or large vessel disorder.
Major abnormalities documented by cardiac echocardiography with Doppler: 1. Moderate or severe heart function defect, including moderate to severe valve stenosis or regurgitation. 2. Left ventricular ejection fraction <50% of the lower limit of normal.
For Part B: More than 24 weeks since completion of the Week 12 visit in Part A.
For Part B: Experienced any AE leading to permanent treatment discontinuation during treatment with study treatment in the double-blind treatment period (Part A).
For Part B: Have undergone endoscopic balloon dilation or bowel surgery (resection surgery or strictureplasty) for any intestinal stricture since the Week 12 visit in Part A.
For Part B: Developed any condition which meets the Part A exclusion criteria.
For Part B: Any condition which in the opinion of the investigator affects the safety or ability to participate in Part B.
For Part B: Participation in any other clinical trial since the completion of the Week 12 visit in Part A.
Hereditary xanthinuria or molybdenum cofactor deficiency.
Any severe acute or chronic medical condition, psychiatric disorder, laboratory abnormality, or systemic or opportunistic infection that may increase the risk associated with study participation or study treatment administration, or may interfere with the interpretation of study results, as determined by the investigator.
Clinically significant vital signs, physical examination, or 12-lead ECG at screening or Baseline (PR ≥220 msec, QRS ≥120 msec and prolonged QTcF >450 msec for males or >470 msec for females), bradycardia (<50 bpm) or clinically significant ST wave changes, bundle branch block, or any other abnormal changes on the ECG that would interfere with measurement of the QT interval.
Receiving cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 8 weeks of screening or Janus kinase inhibitor therapy within 4 weeks of screening.
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.
CD-related complications (previous extensive small bowel resection, ileorectal anastomosis, proctocolectomy, short bowel syndrome [<200 cm remaining small bowel], ileostomy [diverting or end], colostomy, small bowel stoma, ileoanal pouch, inactive fistulae in or adjacent to an ileal stricture, anal and perianal stricture [only if not passable by scope], 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).
Ileitis not associated with CD (eg, ileitis associated with infections, spondyloarthropathies, ischemia, etc.).
Endoscopic balloon dilation or surgical treatment of the same small bowel stricture within the last 6 months prior to screening.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	01 Aug 2023	14
Denmark	Not Recruiting	01 Aug 2023	10
Germany	Not Recruiting	01 Aug 2023	8
Italy	Not Recruiting	01 Aug 2023	11
Poland	Not Recruiting	01 Aug 2023	16
Spain	Not Recruiting	01 Aug 2023	4