A 90 Day, Phase 4,Open Labeled Exploratory Study of RELiZORB

Project Summary/Abstract

Short bowel syndrome (SBS) is often due to the loss of large amounts of small intestine that
compromises digestive absorption. The treatments include (1) a high-calorie diet that
includes vitamins, minerals, carbohydrates, proteins and fats; (2) injections of vitamins and
minerals; (3) administration of drugs to slow the normal movement of the intestine or to
increase the surface area of the intestinal lining; and (4) feeding through the vein (i.e.,
parenteral nutrition or PN). Many patients cannot wean from PN due to reduced intestinal
length or function. Patients on long-term PN frequently experience serious metabolic
complications, sepsis, hepatic biliary disorders including cholestasis, and fibrosis and can
progress to liver failure. Full intestinal feeding (enteral nutrition) without PN is the
optimal way to prevent the above complications.

Enterally administered long chain triglycerides in patients with SBS, especially those with
hepatic dysfunction, are not well tolerated due to bile acid malabsorption, which leads to
decreased micelle formation and fat digestion. The dietary fat is unable to be emulsified by
the bile acids and acted on by lipases before exiting the patient as stool. Switching to
other forms of fat such as medium-chain triglycerides (MCTs) that do not require micelles for
absorption may be better tolerated in patients with bile acid or pancreatic insufficiency but
are not optimal as they increase the osmotic load in the intestine. This may increase the
chance of stool dumping; moreover, MCTs do not contain essential fatty acids (FAs). The
ability to provide the essential FAs such as those present in enteral formulas in a form that
does not require the formation of micelles for absorption, would allow patients with SBS and
those who are no longer PN dependent to receive adequate nutrition and continue to maintain
the same growth trajectory as when they received the majority of their nutrition
parenterally.

RELiZORB is a digestive enzyme cartridge connected in-line with enteral feed tubing sets
designed to mimic the function of pancreatic lipase. It is hypothesized that by using an
external lipase device (RELiZORB) enteral nutrition will be better absorbed, and PN
dependence reduced as enteral autonomy is increased. This product uniquely eliminates the
need for intestinal emulsification and lipase activity and eliminates the risk of drugs,
including lipases, allowing absorption at the time the diet enters the gut. The device has
been shown to digest >90% of fat in most enteral formulas.

This is a phase 4, open label single center clinical trial to determine the safety,
tolerability, and bioavailability of the RELiZORB enzyme cartridge with enteral nutrition
when used daily for 90 days in pediatric subjects with SBS, aged 5 years - 18 years, who are
PN dependent. The change in PN calories from baseline, assessed at Day 7, 14, 28, 60, and 90,
will be assessed by area under the curve and presented with a 95% confidence interval. The
number (percent) of treatment-emergent adverse events, grade 2 or above, will be tabulated.
Changes in growth, fecal fat/protein, plasma FAs, PN volume, and enteral/oral nutrition will
be described.

Inclusion Criteria:

1. Male or female patients, aged 5 years - 18 years, inclusively.

2. Diagnosed with SBS, as determined by medical history or PN dependence (i.e. need for
PN for >60 days after intestinal resection or a bowel length <25% of expected).

3. Congenital or acquired gastrointestinal disease requiring surgical intervention that
has occurred at least 3 months prior to screening.

4. Subject is receiving no more than 40% calories from enteral fat.

5. At least 30% of daily caloric and fluid intake has been provided by PN for at least 6
months prior to screening.

6. Stable PN nutrition requirement, determined by less than 10% reduction in PN nutrition
for at least 1 month prior to screening, or at the discretion of the investigator.

7. Screening direct bilirubin that is in the normal range for age and is not determined
to be clinically significant by the investigator.

8. The patient has an existing feeding tube and is able to tolerate at least 20 ml/kg/day
enteral nutrition.

9. The patient or a parent or legal guardian of the patient is able to read, understand,
and is willing to provide informed consent (or assent, if applicable) for the patient.

10. The patient (if assent is applicable) or a parent or legal guardian is able to
understand the requirements of the study and is willing to bring the patient to all
clinic visits and complete all study related procedures (as determined by the
investigator).

11. A parent or legal guardian is willing to provide written authorization for the use and
disclosure of protected health information.

Exclusion Criteria:

1. Had a bowel lengthening procedure performed.

2. Other causes of chronic liver disease other than SBS (i.e. hepatitis C, cystic
fibrosis, biliary atresia, alpha 1 anti-trypsin deficiency, and Alagille syndrome).

3. Any serum triglyceride concentration greater than 400 mg/dL at screening.

4. Pancreatic insufficiency as defined as the use of pancreatic enzymes within 30 days
prior to screening.

5. Use of enteral bile salt sequestering agents (e.g., cholestyramine, colestipol,
colesevelam) within 3 months prior to screening.

6. Evidence of untreated intestinal obstruction or active stenosis, as determined by the
investigator.

7. Unstable absorption due to cystic fibrosis or known DNA abnormalities (i.e., familial
adenomatous polyposis, Fanconi syndrome) as determined by the investigator.

8. History of microvillus inclusion disease, as determined by medical history.

9. Severe known dysmotility syndrome (i.e., pseudo-obstruction, gastroschisis-related
motility disorders), as determined by the investigator.

10. Use of teduglutide growth hormone, or supplemental glutamine within 3 months prior to
screening.

11. Active clinically significant pancreatic or biliary disease, as determined by the
investigator.

12. Determined by the investigator to be unsuitable for participation in this trial for
any reason.