A Phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of glepaglutide in patients with short bowel syndrome (SBS)

Patients with short bowel syndrome (SBS) are characterized by reduced
intestinal absorptive surface area due to extensive surgical bowel resection or
congenital diseases, such as recurrent Crohn*s disease or mesenteric vascular
disease, resulting in decreased absorptive capacity of the gut. This causes a
reduced uptake of nutrients, fluids, electrolytes, vitamins, and trace
elements, leading to difficulties with maintaining metabolic balances when
receiving a conventional diet. The malabsorption can lead to dehydration,
malnutrition, and weight loss if left untreated.
Whereas less severely affected SBS patients are able to compensate for their
malabsorption by increasing oral intake (hyperphagia) and adapt metabolically
or pharmacologically, more severely affected patients depend upon the safe and
well-adjusted provision of parenteral support of nutrients, fluids,
electrolytes, vitamins, and trace elements to maintain body function, growth,
homeostasis, and health. For those dependent on parenteral support (PS), it is
life-sustaining but at the same time associated with life-threatening
complications. Among those are blood stream infections or sepsis, central vein
thrombosis, liver damage, and renal impairment. In addition, the treatment
burden of parenteral support is substantial. Often 10-18 liters of parenteral
support per week are required. In addition to 10- to 12-hour over-night
parenteral support infusions in such patients, additional hours during daytime
may be required to compensate for losses. While liberating patients during
daytime, night-time infusions disturb sleep and exacerbate the need for
nocturnal urination. Adding to the treatment burden, patients on parenteral
support often need frequent follow-up checks at the hospital, and for many
there is a need for help from a homecare nurse.
Glucagon-like peptide (GLP)-2 is a specific intestinal growth factor that plays
a role in enhancing small intestinal mucosal morphology, function, and
integrity both under normal as well as pathophysiological conditions. Exogenous
GLP-2 induces significant growth of the small intestinal mucosal epithelium via
the stimulation of stem cell proliferation in the crypts and inhibition of
apoptosis on the villi. This trophic effect of GLP-2 has been observed in
numerous species, including humans. Additional effects of GLP-2 include
inhibition of gastric emptying and gastric acid secretion, stimulation of
nutrient absorption, enhancement of intestinal barrier function, and increase
in intestinal blood flow. The short half-life of native GLP-2 of 5-7 minutes in
circulation is a major drawback for its use in a therapeutic setting, and with
the approval of teduglutide (US: Gattex® EU: Revestive® ) for the treatment of
adult patients with SBS to improve intestinal absorption of fluids and
nutrients, the therapeutic relevance of a GLP-2 analog in SBS has been
established.

5.1 Primary Objective
To confirm the efficacy of glepaglutide in reducing PS volume in SBS patients.

5.2 Secondary Objectives
To evaluate the efficacy of glepaglutide on other efficacy endpoints in
patients with SBS.
To evaluate the safety and tolerability of glepaglutide in patients with SBS.

This is a multicenter, placebo-controlled, randomized, parallel-group,
double-blind, fixed dose, Phase 3 trial to demonstrate the superiority of once
weekly and twice weekly subcutaneous (SC) injections of 10 mg glepaglutide
versus placebo in stable SBS patients.
After providing informed consent and initial confirmation of eligibility during
the 2-week Screening period, patients will enter a PS Optimization and
Stabilization Phase before baseline measurements are performed. An individual
drinking menu will be defined by the patient and the Investigator during the
Screening period and until the end of the Optimization Phase. All patients will
be equipped with an electronic diary (eDiary) for recording of trial relevant
data/information.
Unless otherwise specified, baseline is defined as Day 1, prior to first dosing
of trial product.
PS optimization consist of 2 rounds, which limits the Optimization Phase to a
maximum duration of 4 weeks (± 4 days). If optimization cannot be shown during
the 4-week period, a second Optimization Phase of up to 4 weeks (± 4 days) is
allowed. The last Optimization Phase visit can be combined with the first visit
in the Stabilization Phase if the patient is considered optimized.

Optimization Phase
During the Optimization Phase, the Investigator may change the PS volume and
content if the patient is considered unstable or not optimized. Any changes in
PS volume or content will be administered according to institutional standard
practice. The effect of any PS optimizations must be investigated after 2
weeks. Prior to an Optimization Phase visit, the patient must measure his/her
urine over 48 hours, while adhering to the pre-defined drinking menu, and
report the urine volume and oral fluid intake in the eDiary. No more than 2
rounds of PS optimization are allowed to be performed, which limits the
Optimization Phase to a maximum duration of 4 weeks (± 4 days). The second
Optimization Phase visit can be combined with the first visit in the
Stabilization period if the patient is considered optimized.

Stabilization Phase
The Stabilization Phase has a minimum duration of 2 weeks and a maximum
duration of 4 weeks (± 4 days). The last visit of the Optimization Phase can
also be the first visit of the Stabilization Phase. Prior to the Stabilization
Phase visit, the patient must measure his/her urine over 48 hours, while
adhering to the pre-defined drinking menu, and report the urine volume and oral
fluid intake in the eDiary. Patients will be evaluated every 2 weeks during the
Stabilization Phase and will need to fulfill the pre-specified stability
criteria before the patient can be randomized. If stability cannot be shown
during the 4-week period due to unforeseen events such as infections, illness
or similar, a second Stabilization Phase of up to 4 weeks (± 4 days) is
allowed.
A patient will be considered stable if all the following criteria are met:
- Actual PS usage (volume and content) matches prescribed PS (± 10%
deviation in volume is acceptable) and
- 48-hour urine volumes at 2 consecutive visits within a 2-week interval (±
4 days, i.e., visits should be 10 to 18 days apart) are similar (a maximum of ±
25% deviation is acceptable), while the oral fluid intake is constant (the two
48-hour oral intakes differ less than 10%) and maximum 3.5 L per day and
- Urine volume is on average * 1 L and * 2.5 L per day.

The Investigator and Medical Monitor must both agree and approve that the
patient has met the criteria to be considered stable after completing the
Stabilization Phase.
The baseline PS volume (L/week) will be defined as the actual PS volume
received during the 7-day period prior to Visit 1 (Day 1). The baseline daily
urine volume (L per day) will be defined as the average of the last two 48-hour
urine volume measures from the Stabilization Phase.

Main trial period
Visit 1 is done within 2 weeks after the last Stabilization Phase visit. If
done on the same day, Visit 1 lab samples should be drawn. All eligible
patients who complete the Optimization and Stabilization Phases will be
randomized in a 1:1:1 manner to receive either: a) glepaglutide 10 mg twice
weekly, b) glepaglutide 10 mg once weekly and placebo once weekly, or c)
placebo SC for the following 24 weeks.
During the 24-week Treatment Phase, PS need will be evaluated by 48-hour
balance periods involving urine measurements and during which patients will be
required to keep to an individually pre-defined drinking menu (timing, volume,
and content) and document this in the eDiary.
The actual volume of PS will be recorded on an ongoing basis in electronic
diaries (eDiaries) by the patients. The Investigator will record the type,
content, and volume of the PS being used. Once trial drug treatment is
initiated, PS volume can be adjusted at trial visits (at Weeks 1, 2, 4, 8, 12,
16, 20, and 24) if the criteria for adjustment are met and according to a
predefined algorithm.
Algorithm for PS volume reduction:
IF: daily urine volume of the current visit is at least 10% higher than
baseline urine volume.
THEN: New PS volume (weekly) = Current PS volume (weekly) * 7 x absolute
increase in daily urine volume from baseline

The Investigator may arrange unscheduled visits (preceded by a 48-hour balance
period) if he or she considers the visits to be needed based on medical
judgement to assess PS volume needs.
It is acknowledged that intake of oral liquids and PS might have to be changed
between scheduled visits to avoid edema, especially if treatment is effective.
In such cases changes to the PS is at the discretion of the Investigator and
the reason needs to be documented in the eCRF.
Any changes to the content of PS are left to the discretion of the Investigator
and the reason is documented in the eCRF.
After completing the Treatment Phase, all patients (patients in all 3 treatment
groups) will be eligible to enter an Extension Trial and receive glepaglutide.
In addition, patients who were dosed but discontinued from trial treatment due
to reasons other than an unacceptable adverse event (AE) related to the trial
product or withdrawal of consent may be invited to enter the Extension Trial
when completing the 24-week Treatment Phase schedule. For patients not entering
the Extension Trial, a Follow-up Visit will be conducted 4 weeks after
completion of the Treatment Phase.

All patients will receive the following interventions:
- ECG
- Vital signs and physical examination
- Colonoscopy or CT/MRI
- Urine collection
- Pregnancy test (for females of childbearing potential only)
- Blood draws for safety (hematology and chemistry)
- Blood draws for citrulline, anti-drug antibodies and bone markers
- Blood draws for HIV, hepatitis B and hepatitis C testing
- Blood draws for PK
- eDiary and questionnaires
- SC injections with IP or placebo (2x per week)

4.3.1 Benefits
For the conducted dose-finding trial ZP1848-15073 testing glepaglutide in SBS
patients with or without the need of parenteral support, the primary endpoint
of change in wet weight of ostomy/diarrhea output (*wet weight output*) was
chosen as the most directly 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,
absorption of macronutrients increased in the combined 1+10 mg and 1 mg dose
groups, 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. For further efficacy results please see the
Investigator*s Brochure for glepaglutide.
Patients receiving glepaglutide treatment in the present Phase 3 trial are
likely to experience similar improvements in intestinal function, with reduced
dependence on parenteral support as result. Trial patients completing the trial
period (including those receiving placebo and patients who were dosed but
discontinued from trial treatment due to reasons other than an AE related to
the trial product or withdrawal of consent) will receive the opportunity to
receive long-term glepaglutide treatment in an Extension Trial to the present
trial.

4.3.2 Risks
Overall 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 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 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 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.
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 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, 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 in 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.
Experiences with native GLP-2 and 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 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 and cross-reactivity to the main glepaglutide metabolite
(ZP1848 [1-34]) as well as 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 effect at the intended dose
level, on which grounds a waiver for a dedicated TQT study was granted by the
FDA in April 2018.
Patients with severe and acute cardiac disease are excluded from trial
participation.

Neoplasms
GLP-2 stimulates development of colonic adenomas in rodent models. Increases in
plasma citrulline concentrations as seen with GLP-2 analog treatment might
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
patients taking GLP-2 analogs who have residual colons. Therefore a screening
colonoscopy (within 6 months prior to screening) is a requirement for patients
in the present trial, and patients with a pre-existing recent history of cancer
(except for select, treated, and highly curable in situ cancers) are excluded
from the trial. These are considered adequate precautionary measures. Neoplasms
(malignant and benign) are defined as AEs of special interest (AESIs) for the
trial.

Risk of underdosing
The PK results and exposure-response analyses for glepaglutide substantiates
that both once weekly and twice-weekly dosing of 10 mg glepaglutide result in
glepaglutide concentrations within the therapeutically effective dose range.
Regardless, a risk of inadequate dosing in individual patients receiving 10 mg
glepaglutide once-weekly cannot be excluded.

4.4.3 Overall Benefit-risk Conclusion for the Trial
In conclusion, the benefit-risk ratio for the proposed glepaglutide treatment
regimens is considered favorable for the intended trial population, and
potential risks are considered appropriately handled and mitigated.