A 104-Week, Multicenter, Single-Arm, Long-Term, Phase 3 Extension Trial Investigating the Safety and Efficacy of Glepaglutide in Adult Patients with Short Bowel Syndrome (SBS) Completing the EASE SBS 2 Trial

Glepaglutide is a glucagon-like peptide (GLP) -2 which is being investigated
for treatment of patients with short bowel syndrome (SBS) to improve intestinal
absorption of fluids and nutrients. This trial investigates the long-term
safety and efficacy of glepaglutide in adult patients with SBS. For information
regarding glepaglutide, please see the current version of the Investigator's
Brochure.

This study has been transitioned to CTIS with ID 2024-513373-43-00 check the CTIS register for the current data.

The objectives of this extension trial are to assess the long-term safety and
maintenance of efficacy beyond 2 to 2.5 years of treatment with glepaglutide in
adult patients with SBS.

Primary Objective:
To evaluate the long-term safety of glepaglutide treatment

Secondary Objectives:
To evaluate the maintenance of response with regards to efficacy endpoints with
glepaglutide 10 mg once weekly (OW)
To assess the long-term immunogenicity of glepaglutide and its impact on
pharmacokinetics (PK), safety, and efficacy maintenance

This is an open-label, multicenter, single-arm, phase 3 extension trial
investigating glepaglutide 10 mg administered OW by an auto-injector (AI) in
adult patients with SBS completing the EASE SBS 2 trial.
Patients receiving OW or twice weekly (TW) glepaglutide in the EASE SBS 2 trial
will receive glepaglutide 10 mg OW in this extension trial.
Treatment in addition to glepaglutide will be according to standard of care.
Pauses in trial drug are allowed.
Relevant data collected during the lead-in pivotal trial ZP1848-17111 (Efficacy
and Safety Evaluation of Glepaglutide in Treatment of SBS 1 [EASE SBS 1]), and
data from the last visit of EASE SBS 2 trial will be transferred to this trial.
The Investigator will record in the electronic case report form (eCRF) the
type, content, and volume of the prescribed parenteral support (PS) on an
ongoing basis. Changes to the prescribed volume and content of PS during the
104-week treatment phase are left to the discretion of the Investigator based
on institutional practice. The changes and the reason for changes in
volume/content should be documented in the eCRF. The Investigator may arrange
unscheduled visits during the trial to assess patient safety and PS
volume/content needs. Intake of enteral liquid/food will be according to
clinical practice per Investigator clinical judgment.
Following exposure to glepaglutide OW or TW for 2 or 2.5 years in the lead-in
trial EASE SBS 1 and the extension trial EASE SBS 2, the treatment for this
extension trial is glepaglutide 10 mg OW, administered by AI in addition to
standard of care. Duration of treatment is 104 weeks. If deterioration in PS
needs is observed, the dose of glepaglutide may be increased to 10 mg TW as
judged by the Investigator. The reason for TW dosing must be entered in the
eCRF.

All patients will undergo the following interventions:
- ECG
- Vital signs, including weight
- Physical examination (full physical examination at Visit 1; SBS
symptom-driven at all other visits)
- Colonoscopy or CT/MRI (In case a remnant colon is not connected to the
passage of foods and thereby dormant, a CT-scan or MRI (if standard of care at
site) will suffice at the discretion of the investigator.)
- Urine collection
- Pregnancy test for females of childbearing potential3
- Blood draws for safety (hematology and biochemistry)
- Blood draws for Citrulline
- Blood draws for PK
- Blood draws for anti-drug antibodies
- Administration of IP via auto-injector

Benefits:
The completed dose-finding phase 2 trial ZP1848-15073 tested glepaglutide in
patients with SBS with or without the need of PS; the primary endpoint of
change in wet weight of ostomy/diarrhea output (*wet weight output*) was chosen
as the most direct measure of the impact of glepaglutide on intestinal
absorption. The trial met its primary efficacy endpoint by showing
statistically significant and clinically relevant reductions in wet weight of
ostomy/diarrhea output (*wet weight output*) with glepaglutide dosed 1 mg/day
(estimated reduction of 592 g/day; p=0.002) and 10 mg/day (estimated reduction
of 833 g/day; p=0.0002). Results for wet weight absorption and urine weight
supported the results for the primary endpoint, with statistically significant
improvements demonstrated for 1 mg/day and 10 mg/day glepaglutide. In addition,
improved macronutrient absorption was seen for the 1 mg/day and 10 mg/day
glepaglutide dose level, and improvements were observed for absolute absorption
of sodium and potassium at the higher
glepaglutide dose levels. In conclusion, the phase 2, dose-finding trial of
glepaglutide in SBS patients showed consistent and clinically relevant benefit
for 1 mg/day and 10 mg/day glepaglutide in improving intestinal function.
Patients receiving glepaglutide treatment in this extension trial are likely to
experience maintenance of intestinal function, with reduced dependence on PS as
a result.

Risks:
Overal Risk Profile:
The results from clinical and non-clinical studies and the safety profile
described to date do not give rise to specific safety concerns. Specifically,
the completed non-clinical chronic toxicity program raises no concerns in
relation to the extended treatment period of the present trial. The evaluation
of chronic toxicity included a study in Wistar rats receiving up to 1, 3, and
10 mg/kg/day glepaglutide for 26 weeks and a study in Beagle dogs receiving
0.25, 1, and 5 mg/kg/day glepaglutide for 39 weeks. In both studies,
glepaglutide caused a range of findings in the intestinal tract that were
attributable to its pharmacological action. In the study in rats, changes
occurred in the liver and kidney, which were likely physiological adaptations
to high dose levels of the test material. The systemic
no-observed-adverse-effect-level (NOAEL) in this study was therefore determined
to be 10 mg/kg/day. In the study in Beagle dogs, reduced weight gain was noted
in females receiving the highest dose level of 5 mg/kg/day glepaglutide, and
the systemic NOAEL in this study was therefore determined to be 5 mg/kg/day in
males and 1 mg/kg/day in females. Local irritation at the injection sites
occurred at all dose levels in both studies. The identified NOAEL exposure
level in rats and dogs is >=86 and >=48 times higher, respectively, than the
expected maximum exposure level in this trial. The carcinogenic potential of
glepaglutide has been tested in a mouse
and a rat carcinogenicity study. Subcutaneous administration of glepaglutide to
CD-1 mice for up to 104 weeks at doses up to 1.0 mg/kg/day, caused a range of
findings in the intestinal tract that were attributable to its pharmacological
action. There were no neoplastic findings due to
treatment demonstrating that ZP1848 was not carcinogenic to the CD-1 mouse.
Subcutaneous administration of glepaglutide to Wistar rats at doses up to 2.0
mg/kg/day for 104 weeks caused a range of findings in the intestinal tract that
were attributable to its pharmacological action.
Mucosal hypertrophy/hyperplasia is a part of the continuum leading to adenoma
and adenocarcinoma formation, and this was considered the cause for the
presence of such tumors in the duodenum in a few males given 2.0 mg/kg/day (at
exposure approx. 25 times higher than the expected maximum exposure level in
this extension trial). Chronic inflammatory changes at the injection sites seen
in both the mouse and the rat carcinogenicity study, resulting from repeated
daily subcutaneous injection, occurred at all dose levels, and led to an
increased incidence of
cutaneous pleomorphic fibrosarcomas in males. Pleomorphic fibrosarcomas are
considered a group of largely undifferentiated or primitive sarcomas and are
the most common type induced in rodents by repeated subcutaneous injection of
agents not considered carcinogens (solutions of glucose and other sugars,
sodium chloride, certain water-soluble food colourings and surfactants,
carboxymethycellulose and macromolecular dextrans). Glepaglutide was well
tolerated at daily doses of up to 10 mg in the phase 2 Trial ZP1848-15073
conducted in SBS patients. Consistent with the clinical setting, the most
frequently reported adverse events (AEs; reported in >20% of patients) in the
phase 2 trial were injection site
reactions, nausea, abdominal pain, abdominal distension, vomiting, stoma
complication, fatigue, dizziness, polyuria, decreased appetite, peripheral
edema, and cough. Treatment-emergent serious adverse events (SAEs) comprised 8
events in 2 patients in the 0.1 mg glepaglutide dose
group and 8 events reported in 6 patients in the 10.0 mg glepaglutide dose
group, with no dose dependency or clustering of events being observed.
Injection site reactions were dose dependent, mild to moderate in severity and
transient by nature. The most frequently reported symptoms
were itching and redness. No deaths were reported in this or any other trials
with glepaglutide.
No specific safety issues were raised from the phase 1 clinical trial program;
for further details please see the Investigator*s Brochure.
In addition to the gastrointestinal tract, there are also GLP-2 receptors in
the lung, brain, and hypothalamus. So far, clinically significant
off-intestinal targeted effects resulting from these additional receptor sites
have not been seen.
Studies with teduglutide suggest that expected common AEs for this class of
compounds include abdominal pain and distension, injection site reactions,
nausea, headache, upper respiratory tract infection, and (in some studies)
vomiting, and fluid overload.

Immunogenicity:
Based on the current non-clinical and clinical knowledge of glepaglutide, the
risk of immunogenicity (development of anti-drug antibodies [ADA]) following
administration of glepaglutide is considered high. However, longer-term
clinical treatment is required to investigate whether such a response will be
transient or persistent. As no acute or non-acute AEs or effects on
pharmacokinetics (PK) or pharmacodynamics have been linked to the immune
response towards glepaglutide in the completed clinical trials, the effects,
and potential consequences of the anti-glepaglutide response are so far
considered of minor criticality. Glepaglutide ADA will be monitored in this
trial, including their glepaglutide neutralizing
potential, reactivity to the main glepaglutide metabolite (ZP18481-34) as well
as potential crossreactivity to native GLP-2.

Cardiovascular Safety:
No cardiovascular safety issues have been identified for glepaglutide. A
concentration-response analysis of the potential of glepaglutide to cause QT
prolongation ruled out any clinically concerning effects at the intended dose
level, on which grounds a waiver for a dedicated thorough QT study was granted
by the Food and Drug Administration in April 2018.

Neoplasms:
GLP-2 and GLP-2 analogs stimulate development of colonic adenomas in rodent
models. Increases in plasma citrulline concentrations as seen with GLP-2 analog
treatment indicate an intestinotrophic effect with increases in enterocyte mass
and intestinal surface area. Consequently, it cannot be excluded that treatment
with glepaglutide could promote growth of existing tumors in patients during
long-term treatment. Although the risk of malignancy is hypothetical in humans
and colonoscopy can be difficult in these patients, a baseline colonoscopy has
been suggested for patien