Evaluation of Apraglutide Efficacy and Safety in Steroid-Refractory Gastrointestinal Acute Graft-Versus-Host Disease: A Randomized, Single-Blind Trial

Trial ID: 2023-507960-38-00
Protocol: TA799-101
Sponsor: VectivBio AG

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Diseases & Conditions

Acute graft versus host disease in intestine

Objectives

The primary objective of this study is to assess the **safety** and tolerability of apraglutide in subjects with steroid-refractory lower gastrointestinal acute graft versus host disease (GI-aGVHD) Grade II to IV, as defined by the Mount Sinai aGVHD International Consortium (MAGIC). This evaluation is clinically relevant as it aims to determine the potential of apraglutide to provide a safe treatment option for patients who do not respond to standard steroid therapy, thereby addressing a significant unmet need in the management of GI-aGVHD.

Secondary objectives include:

Evaluating the overall response rate, including partial and complete responses, at various time points on the lower GI tract MAGIC score and total MAGIC score.
Assessing the rate of durable overall response from Day 28 to Day 56 and the duration of response from Day 56 on the total MAGIC score.
Determining the individual durations of lower GI response, particularly in subjects re-treated with apraglutide due to a lower GI-aGVHD flare.
Assessing the time to partial and complete lower GI-aGVHD response as defined by the MAGIC score.
Evaluating the best overall response, failure-free survival, non-relapse mortality, and overall survival.
Assessing the incidence of malignancy relapse, transplantation failure, and the cumulative doses of SS and RUX used.
Evaluating the incidence of infections and sepsis, and the effect of two dose ranges on safety, tolerability, and efficacy.

Participants

The clinical trial involves a total of **8 participants** diagnosed with **acute graft versus host disease (aGVHD)**, specifically focusing on steroid-refractory lower gastrointestinal aGVHD, classified as Grade II to IV according to the Mount Sinai aGVHD International Consortium (MAGIC) criteria. The study population includes both male and female subjects aged 12 years and above, with a minimum weight requirement of 40 kg. However, only individuals aged 18 years and above are eligible in Germany and France. Participants have undergone allogeneic stem cell transplantation from various donor sources and have demonstrated myeloid and platelet engraftment. The trial population was selected based on specific clinical criteria, including the presence of lower GI-aGVHD and prior treatment with systemic steroids. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraceptive guidelines if applicable. The trial includes a vulnerable population, as it involves individuals with a serious medical condition requiring specialized treatment. The selection process ensures that participants meet the necessary health and treatment criteria to assess the safety and tolerability of apraglutide in combination with standard therapies.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and **efficacy** of **apraglutide** in subjects with steroid-refractory gastrointestinal acute graft versus host disease (aGVHD). This is a randomized, single-blind, controlled trial, which will involve participants who have undergone allogeneic stem cell transplantation and are experiencing lower GI-aGVHD. The trial is set to run from March 2022 to August 2025, with an estimated duration of participant involvement of up to 25 weeks. The trial will assess the primary endpoints, including adverse events, incidence of adverse events of special interest, and clinically significant changes in clinical chemistry, vital signs, and electrocardiogram measurements. Secondary endpoints will focus on overall response rates, duration of response, and survival metrics.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and clinical diagnosis of lower GI-aGVHD. Following randomization, participants will receive **apraglutide** via subcutaneous injection, with the treatment period lasting up to 25 weeks. Follow-up visits will occur at regular intervals to monitor safety and efficacy outcomes, including Days 14, 28, 56, 91, 119, 147, and 182. The end-of-study visit will conclude the trial for each participant, assessing long-term outcomes and any adverse events.

Participants are expected to adhere to the trial protocol, including the use of effective contraception for women of childbearing potential and male participants with partners of childbearing potential. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide comprehensive data on the therapeutic potential of **apraglutide** in managing steroid-refractory gastrointestinal aGVHD, contributing to the understanding of its safety and efficacy profile.

Treatment

The clinical trial involves the administration of **apraglutide**, an investigational medicinal product, to evaluate its safety and efficacy in subjects with Grade II to IV steroid-refractory gastrointestinal acute graft versus host disease. **Apraglutide** is provided in the form of a **powder for solution for injection**. The active substance, **apraglutide**, is a protein-based compound with the chemical structure H-HIS-GLY-ASP-GLY-SER-PHE-SER-ASP-GLU-NLE-D-PHE-THR-ILE-LEU-ASP-LEU-LEU-ALA-ALA-ARG-ASP-PHE-ILE-ASN-TRP-LEU-ILE-GLN-THR-LYS-ILE-THR-ASP-NH2. The pharmaceutical form is designed for **subcutaneous injection**. The maximum daily dose is 10 mg, with a total maximum dose of 250 mg over a treatment period of 25 days. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to the experimental treatment, participants will receive the best available therapy as standard-of-care, which may include supportive treatments such as steroids and ruxolitinib (RUX). These non-experimental treatments are administered according to the standard medical guidelines for managing acute graft versus host disease. The trial is conducted in a single-blind manner, ensuring that the participants are unaware of the specific treatment allocation, while the investigators are informed. This design helps to minimize bias and allows for an objective assessment of the investigational product's safety and efficacy.

Efficacy

The efficacy of apraglutide in the clinical trial will be assessed using both primary and secondary endpoints. Primary endpoints focus on safety-related parameters, including the incidence and severity of adverse events (AEs) and adverse events of special interest (AESIs) related to apraglutide, such as injection site reactions and gastrointestinal obstructions. Additionally, clinically significant changes from baseline in clinical chemistry, hematology, vital signs, and electrocardiogram (ECG) measurements will be evaluated. The occurrence and titer of anti-drug antibodies (ADAs) will also be monitored.

Secondary endpoints will assess the overall response rate, defined as partial response (PR) and complete response (CR), at various time points, including Days 14, 28, 56, 91, 119, 147, and 182, using the lower GI tract MAGIC score. The duration of response from Day 56 and Day 28, time to partial and complete lower GI-aGVHD response, and best overall response up to Day 91 will be measured. Additional secondary endpoints include failure-free survival, non-relapse mortality, incidence of malignancy relapse, overall survival, graft failure, and incidence of lower GI-aGVHD flare. The cumulative doses of SS and RUX, incidence of infections and sepsis, and the effect of two dose groups on safety, tolerability, and efficacy will also be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent for this trial prior to any trial specific assessment. A signed assent form will also be required for all subjects under the age of 18 years
Male or female subjects aged 12 years or above at the time of consent and who weigh a minimum of 40.0kg. Only subjects of 18 years and above will be included in Germany and France
Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are eligible
Evident myeloid and platelet engraftment (confirmed prior to trial medication start): a) Absolute neutrophil count >1000/mm3 and b) Platelets ≥20,000/mm3. Use of growth factor supplementation (granulocyte-colony stimulating factor and granulocyte-macrophage-colony stimulating factor) and transfusion support is allowed
Clinical diagnosis of lower GI-aGVHD, MAGIC Stage 1–4 prior to randomization. Suitable diagnostic procedures should be implemented to exclude alternative reasons for diarrhea; these include (but not limited to) fecal cultures and lower gut biopsy with histological assessment for infectious diseases
Clinically confirmed SR lower GI-aGVHD defined as subjects administered SS, given alone, or combined with CNIs and either: a) Disease progression based on organ assessment after 3 days of treatment with MP ≥2 mg/kg/day ([or prednisone dose ≥2.5 mg/kg/day] or equivalent) +/- CNIs or b) Did not improve after 7 days of treatment with systemic MP ≥2 mg/kg/day ([or prednisone dose ≥2.5 mg/kg/day] or equivalent) or c) Progressed to a new organ after treatment with systemic MP ≥2 mg/kg/day6 ([or prednisone dose ≥2.5 mg/kg/day} or equivalent) for skin and upper GI-aGVHD, or d) Recurred during or after a steroid taper. Initial dose should be ≥2 mg/kg/day systemic MP ([or prednisone dose ≥2.5 mg/kg/day] or equivalent)
Treatment with SS plus RUX (RUX started concomitantly to apraglutide or a maximum of 72 hours before apraglutide initiation)
Women of childbearing potential must agree to use a highly effective method of contraception and refrain from donating eggs during the trial and for 4 weeks after the EOT visit. Effective contraceptive methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner. In Germany, oral methods of hormonal contraception are to be combined with another accepted method of contraception. To be considered sterilized or infertile, females must have undergone surgical sterilization (bilateral tubectomy, hysterectomy, or bilateral ovariectomy) or be post-menopausal (defined as at least 12 months amenorrhea without an alternative medical cause, may be confirmed with follicle-stimulating hormone test in case of doubt). Women who do not engage in heterosexual intercourse will be allowed to join the trial without contraception following a thorough discussion with the Investigator to determine if this is feasible for the subject. The following methods are not considered acceptable methods of contraception: calendar, ovulation, symptothermal, post-ovulation methods, withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method
Male subjects with a female partner of childbearing potential must commit to practice methods of contraception and abstain from sperm donation during the trial and for 2 weeks after the EOT visit. Nevertheless, if their partners are women of childbearing potential, they must agree to practice contraception and use a highly effective method of contraception during the trial and for 4 weeks after the EOT visit. Such methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion

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Exclusion Criteria

Treatment with any systemic GVHD therapy (other than SS and RUX) including methotrexate and mycophenolate mofetil at the time of randomization/Day 0. Graft versus host disease prophylaxis (ciclosporin A, tacrolimus, sirolimus, everolimus, or anti-thymocyte globulin) is allowed.
History of chronic gall bladder or bile duct inflammation or biliary obstruction unless a cholecystectomy was performed before screening.
Presence or history of GI tumors (including the hepatobiliary system and pancreas) within the last five years before randomization; presence of colonic polyps that are not removed.
Evidence of chronic renal disease as demonstrated by inadequate renal function, which is defined as estimated glomerular filtration rate (eGFR) <20 mL/min/1.73m2 (using the Chronic Kidney Disease Epidemiology [CKD-EPI] formula) and is confirmed within 48 hours prior to randomization/Day 0)
Subjects that present or have a history of familial adenomatous polyposis.
Presence of an active clinically uncontrolled infection or evidence of active tuberculosis (clinical diagnosis per local practice). Cytomegalovirus reactivation is permitted as long as no evidence of pulmonary disease is present.
Central venous catheter sepsis requiring systemic antibiotics within the previous 7 days prior to randomization/Day 0.
Presence of decompensated liver cirrhosis Child Pugh Classes B and C.
Clinically significant or uncontrolled cardiac disease including acute myocardial infarction within 6 months prior to randomization/Day 0, uncontrolled hypertension, congestive heart failure New York Heart Association Class III or IV
Requirement for vasopressor or inotropic support within 30 days prior to randomization/Day 0.
Presence of uncontrolled cholestatic disorders or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to aGVHD and ongoing organ dysfunction)
Failed alloSCT due to relapse of underlying malignant disease.
Presence of relapsed primary malignancy or treatment for relapse after alloSCT.
Requirement for unplanned immune suppression withdrawal as treatment of early malignancy relapse or low donor chimerism. Unclear remission states will be discussed with the Sponsor
Concomitant treatment with Janus kinase inhibitor therapy other than RUX at the time of randomization.
Known cGVHD.
Known active GI inflammation not related to GI-aGVHD (e.g., active inflammatory bowel disease such as Crohn's and ulcerative colitis)
History of progressive multifocal leuko-encephalopathy.
Known pregnant or nursing (lactating) women.
Known major abdominal surgery in the last 6 months prior to randomization/Day 0 (surgical feeding tube placement or other minimally invasive surgery is allowed)
History of clinically significant intestinal adhesions increasing the risk of GI obstruction or GI contrast examination findings suggesting subacute intestinal obstruction or stricture within 6 months prior to randomization/Day 0
Liver enzymes meeting any of the following criteria within 48 hours prior to trial medication start: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 x upper limit of normal (ULN), b. Alanine aminotransferase or AST >5 x ULN AND international normalized ratio >3
Presence of SR GI-aGVHD occurring after donor lymphocyte infusion for pre-emptive treatment of malignancy recurrence
Ongoing participation in an interventional trial or administration of any investigational drug in less than its five half-lives prior to randomization/Day 0. Participation in observational or interventional trials involving supportive care such as probiotics or antiemetics, graft manipulation or transplant procedures, new combinations or new dosing of approved therapies for conditioning, prophylaxis , pre- or post-alloSCT and treatment of the underlying malignant disease are allowed after consultation with the Sponsor
Known or suspected hypersensitivity to GLP-1 or GLP-2 analogs or apraglutide excipients.
Any use of enteral glutamine or growth factors such as native GLP-2, GLP-1, GLP-2 and GLP-1 analogs or known ADA within 6 months prior to randomization/Day 0
Inability to understand or unwillingness to adhere to the trial visit schedules and other protocol requirements, including subjects not willing to comply owing to drug/alcohol abuse or any condition that would interfere with full participation in the trial, including administration of trial medication and attending required trial visits; pose a significant risk to the subject; or interfere with interpretation of trial data
Presence of newly diagnosed malignancies at screening or prior to randomization/Day 0.
Less than 2 weeks anticipated survival at screening.