A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Odevixibat (A4250) in Children with Biliary Atresia Who Have Undergone a Kasai Hepatoportoenterostomy (BOLD)

There is no approved drug treatment for Biliary Atresia (BA) and the only
available option is surgical Kasai Hepatoportoenterostomy (HPE). The chance of
re-establishing bile flow strongly correlates with timing of the procedure.
Even with a successful surgery that established drainage, children*s disease
progressed and they developed portal fibrosis, cirrhosis, and portal
hypertension. About half of the patients required a liver transplantation
during the first 2 years of life. Approximately 80% of patients needed a
transplant within the first 2 decades of life.There is clearly a need for new
therapies to treat BA. Although Kasai HPE has become a lifesaver since its
introduction, most patients with BA continue to experience gradual liver injury
from excessive bile acids, and there are currently no approved treatments to
limit this damage. Primarily, treatments are needed to prevent or reverse the
damage to the bile ducts. However, therapies that directly target the cause of
BA-associated liver damage, such as agents lowering bile acid levels, also have
the potential to benefit patients. Liver damage in BA is characterized by rapid
progression. By inhibiting the IBAT with high selectivity and potency,
odevixibat may have the potential to relieve cholestasis and improve liver
function in patients with BA. Early intervention is critical in slowing or
preventing the complications of the disease. Therefore, the study aims to
enroll patients as soon as possible after Kasai HPE (i.e. within 3 weeks).

Odevixibat has been tested in two Phase 3 studies in over 60 children with
Progressive Familial Intrahepatic Cholestasis (PFIC). One study lasting for 6
months is completed, and one 72-week open-label study is ongoing. In the
completed study, one patient stopped the study early due to an adverse event of
diarrhea that was considered related to odevixibat. In the ongoing open-label
study, three patients discontinued treatment due to adverse events of
cholestasis (gallstones), acute pancreatitis (inflamed pancreas) and
splenomegaly (enlarged spleen), hypophgia (decreased appetite), weight decrease
and jaundice (yellowing of the skin). None of the events that led to treatment
discontinuation were related to odevixibat. Odevixibat has also been tested in
a 4-week Phase 2 study in 20 children with chronic liver disease and impaired
bile flow and severe itch, including three patients with Biliary Atresia. No
patients treated with odevixibat have died. In all studies described above,
nine patients treated with odevixibat have been hospitalized. In all cases, the
reason for hospitalization was unrelated to odevixibat.

Infants with BA have elevated serum bile acids. These levels remain high or
continue to rise in patients with poor long-term outcomes but decrease over
time in patients with better long-term outcomes. Serum bile acids are an
indicator of elevated bile acids within the liver, which in turn are thought to
play a contributory role in hepatic oxidative stress and fibrosis. Harpavat et
al. have shown that serum bile acid levels can predict long-term outcomes in
patients with BA; even in patients with successful Kasai HPE procedures
(defined as serum total bilirubin levels <1.5 mg/dL at 6 months post
Kasai-HPE), elevated serum bile acids may persist and can predict continued
loss of hepatic function. This clinical observation, along with the preclinical
data demonstrating the adverse impact of elevated bile acids on the liver,
provides support for the hypothesis that lowering serum bile acids may be of
benefit in the long-term outcome of patients with BA. By reducing the bile acid
load, odevixibat has the potential to ameliorate or slow hepatic injury or
fibrosis and to improve the long-term outcomes of patients with BA. The
risk/benefit profile of odevixibat in patients with BA is considered
acceptable.

This study has been transitioned to CTIS with ID 2024-512086-14-00 check the CTIS register for the current data.

Primary Objective:
The primary objective is to evaluate the efficacy of repeated once-daily doses
of odevixibat versus placebo in children with biliary atresia (BA) post Kasai
hepatoportoenterostomy(HPE) based native liver survival (NLS) of up to 104
weeks.

Secondary Objectives:
• To evaluate the effect of odevixibat compared to placebo on the time to onset
of sentinel events.
• To evaluate the effect of odevixibat compared to placebo on total bilirubin
after 13, 26, 52, and 104 weeks.
• To evaluate the effect of odevixibat compared to placebo on serum bile acids
after 13, 26, 52, and 104 weeks.
• To assess the long-term safety and tolerability of repeated daily doses of
odevixibat compared to placebo for 104 weeks in children with BA post. Kasai HPE

Exploratory Objectives
• To evaluate the effect of odevixibat compared to placebo on measures of
overall hepatic health and function throughout the study treatment period
• To evaluate the effect of odevixibat compared to placebo on overall health of
the patients throughout the study treatment period

This is a double-blind, randomized, placebo-controlled study to evaluate the
efficacy and safety of odevixibat compared to placebo in children with BA who
have undergone a Kasai HPE. The study includes a Screening Period of up to 3
weeks followed by a 104-week double-blind, placebo-controlled Treatment period.

The study will consist of 2 parts, a Sentinel Cohort of up to 40 patients
followed by the Primary Cohort. The Sentinel Cohort will consist of up to the
first 40 patients and will be characterized by a different starting dose than
the Primary Cohort, if dose escalation is recommended by the DMC. Initially,
the first 20 patients will be randomized to odevixibat 40 µg/kg/day, or placebo
in a ratio of 1:1. After one month of treatment, short-term safety will be
assessed by the Medical Monitor and the Investigator to determine if the
patient can dose escalate to 120 µg/kg/day. Patients randomized to placebo will
remain on placebo.
After the initial 20 patients enrolled have received one month of therapy and
the decision on dose escalation has been made for each individual patient, the
cumulative data will be reviewed by the Data Monitoring Committee (DMC). If the
DMC agrees that short-term safety has been demonstrated, subsequent patients
randomized into the active treatment arm will receive 120 µg/kg/day of
odevixibat as their initial dose and enrollment into the Primary Cohort will
begin. If the DMC does not agree to increase the initial dose of the active
treatment arm to 120 µg/kg/day, enrollment into the Sentinel Cohort will
continue for another 20 patients.
Randomization will be stratified by age of the infant at the time of the Kasai
HPE (<30 days, 30 to 60 days, and >60 to <=90 days) and by the presence or
absence of splenic malformation syndrome. A patient may be dose-reduced due to
adverse events (AEs) as per individual patient safety monitoring guidelines

Study subject*s participation will last about 2 years and contains a screening
period of up to 3 weeks, a treatment period of 2 years, and a 4-week follow-up
period. Study subject will need to come to the study center at least 11 times
over this period. There will also be an additional follow-up telephone call
near study completion. Subjects are expected to undergo procedures/assessments
as described in the section 8.1.4. of the protocol, which include: Physical
exam, vital signs, growth parameters, demographics and medical/surgical
history, abdominal ultrasound, neurocognitive tests, blood and urine tests
(including optional testing for Gilbert*s syndrome) and collection of stool
samples.

Odevixibat has been tested in two Phase 3 studies in over 60 children with
Progressive Familial Intrahepatic Cholestasis (PFIC). One study lasting for 6
months is completed, and one 72-week open-label study is ongoing. In the
completed study, one patient stopped the study early due to an adverse event of
diarrhea that was considered related to odevixibat. In the ongoing open-label
study, three patients discontinued treatment due to adverse events of
cholestasis (gallstones), acute pancreatitis (inflamed pancreas) and
splenomegaly (enlarged spleen), hypophgia (decreased appetite), weight decrease
and jaundice (yellowing of the skin). None of the events that led to treatment
discontinuation were related to odevixibat. Odevixibat has also been tested in
a 4-week Phase 2 study in 20 children with chronic liver disease and impaired
bile flow and severe itch, including three patients with Biliary Atresia. No
patients treated with odevixibat have died. In all studies described above,
nine patients treated with odevixibat have been hospitalized. In all cases, the
reason for hospitalization was unrelated to odevixibat. The most common adverse
effects considered related to odevixibat seen in children are listed below (of
note these adverse effects were seen in patients with PFIC that participated in
the Phase 3 studies).

The most common related adverse effects seen in research studies with
odevixibat are listed below.
Very common (may affect more than 1 in 10 people):
• Blood bilirubin increased (an orange-yellow pigment formed in the liver by
the breakdown of hemoglobin and excreted in bile) (14%)
Common (may affect up to 1 in 10 people):
• Alanine aminotransferase (ALT) increased (a substance produced by the liver
that can be measured with a blood test) (10%)
• Aspartate aminotransferase (AST) increased (a substance produced by the liver
that can be measured with a blood test) (6%)
• Diarrhea (6%)
• Pruritis (itchiness) (3%)
• International normalized ratio (INR) increased (test to see how well your
blood clots and can be related to Vitamin K levels or function of the liver)
(3%)
• Hepatic enzyme increased (a substance produced by the liver that can be
measured with a blood test) (3%)
• Blood creatine phosphokinase increased (3%)
• Abdominal (stomach) pain (3%)

The adverse effects considered related to odevixibat seen in healthy adult
volunteers in Albireo sponsored trials are listed below:
Very common (may affect more than 1 in 10 people):
• Diarrhea (45%)
• Abdominal (stomach) pain (29%)
Common (may affect up to 1 in 10 people):
• Upper abdominal (stomach) pain (10%)
• Nausea (Feeling like you might vomit) (9%)
• Headache (6%)
• Abdominal discomfort (discomfort in the stomach) (5%)
• Lower abdominal pain (pain in the lower part of the stomach) (3%)
• Abdominal distension (swollen belly) (2%)
• Constipation (difficulty passing stools) (2%)
• Dyspepsia (indigestion or upset stomach) (2%)
• Vomiting (2%)
• Anorectal discomfort (slight pain in rectum and/or anus) (2%)
• Feces discoloured (stool color different than usual) (2%)
• Feces soft (stool softer than usual) (2%)
• Feeling hot (2%)
• Decreased appetite (2%)
• Dizziness (2%)

RISKS RELATED TO STUDY PROCEDURES:
Placebo risk: Some participants in this study will receive a placebo. Taking a
placebo is the same as not taking any active medicine. Study participant*s
symptoms of BA may get worse, stay the same, or improve, just as it may do if
he/she does not participate in the study.
Blood draws: A blood draw may cause faintness, inflammation of the vein, pain,
bruising, swelling, or bleeding at the site of puncture. There is also a slight
risk of infection. In very rare cases, there is a risk of blood clot or nerve
injury after blood draw. Fasting: Fasting could cause dizziness, headache,
stomach discomfort, or fainting.

There is no approved drug treatment for Biliary Atresia (BA) and the only
available option is surgical Kasai Hepatoportoenterostomy (HPE). The chance of
re-establishing bile flow strongly correlates with timing of the procedure.
Even with a successful surgery that established drainage, children*s disease
progressed and they developed portal fibrosis, cirrhosis, and portal
hypertension. About half of the patients required a liver transplantation
during the first 2 years of life. Approximately 80% of patients needed a
transplant within the first 2 decades of life.There is clearly a need for new
therapies to treat BA. Although Kasai HPE has become a lifesaver since its
introduction, most patients with BA continue to experience gradual liver injury
from excessive bile acids, and there are currently no approved treatments to
limit this damage. Primarily, treatments are needed to prevent or reverse the
damage to the bile ducts. However, therapies that directly target the cause of
BA-associated liver damage, such as agents lowering bile acid levels, also have
the potential to benefit patients. Liver damage in BA is characterized by rapid
progression. By inhibiting the IBAT with high selectivity and potency,
odevixibat may have the potential to relieve cholestasis and improve liver
function in patients with BA. Early intervention is critical in slowing or
preventing the complications of the disease. Therefore, the study aims to
enroll patients as soon as possible after Kasai HPE (i.e. within 3 weeks).

Infants with BA have elevated serum bile acids. These levels remain high or
continue to rise in patients with poor long-term outcomes but decrease over
time in patients with better long-term outcomes. Serum bile acids are an
indicator of elevated bile acids within the liver, which in turn are thought to
play a contributory role in hepatic oxidative stress and fibrosis. Harpavat et
al. have shown that serum bile acid levels can predict long-term outcomes in
patients with BA; even in patients with successful Kasai HPE procedures
(defined as serum total bilirubin levels <1.5 mg/dL at 6 months post
Kasai-HPE), elevated serum bile acids may persist and can predict continued
loss of hepatic function. This clinical observation, along with the preclinical
data demonstrating the adverse impact of elevated bile acids on the liver,
provides support for the hypothesis that lowering serum bile acids may be of
benefit in the long-term outcome of patients with BA. By reducing the bile acid
load, odevixibat has the potential to ameliorate or slow hepatic injury or
fibrosis and to improve the long-term outcomes of patients with BA. The
risk/benefit profile of odevixibat in patients with BA is considered
acceptable.