Long-term Safety and Efficacy of Odevixibat in Patients With Alagille Syndrome

An Open Label Study to Evaluate the Long-term Safety and Efficacy of Odevixibat (A4250) in Patients With Alagille Syndrome (ASSERT-EXT)

The purpose of this study is to assess the long-term safety and effectiveness of odevixibat in participants with Alagille syndrome (ALGS).

The participants of this study will have ALGS a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth and severe itching (pruritis).

The drug used for the study is odevixibat and was authorized for the treatment of cholestatic pruritus in infants with ALGS over 12 months of age by the United States Food and Drug Administration on 13 June 2023.

This Phase 3, open-label, multi-center extension study will have two groups of participants: Cohort 1 (participants who participated in Study A4250-012 [NCT04674761; ASSERT] and meet the entry criteria for this study) and Cohort 2 (infants under 12 months of age) with ALGS.

The study will consist of 2 or 3 periods:

1. A 'Treatment period' of 72 weeks (cohort 1) or 12 weeks (cohort 2). Participants will visit the clinic every 4 to 12 weeks and will receive a dose of 120 μg/kg odevixibat daily.
2. An 'Optional extension period' where participants who wish to continue receiving odevixibat after the 'treatment period' will have the opportunity to remain on treatment with visits every 16 weeks until the drug is commercially available. The optional extension is available provided continued use is supported by the risk-benefit profile, the participant has not been previously withdrawn or discontinued from the study, and the study is not terminated by the Sponsor.
3. A 'Safety follow-up period' of 4 weeks (cohort 1) or 2 weeks (cohort 2). The Safety Follow-up Period will not occur for those who remain on treatment in the optional extension period.

Participants will need to complete an e-diary and questionnaires throughout the study (cohort 1 only). Participants will undergo blood samplings, urine collections (cohort 1 only), physical examinations, and clinical evaluations. They may continue some other medications, but the details need to be recorded.

Inclusion Criteria:

Cohort 1 :

1. Completion of the 24-week Treatment Period of Study A4250-012
2. Signed informed consent and assent as appropriate. Patients who turn 18 years of age (or legal age per country) during the study will be required to re-consent to remain on the study
3. Caregivers (and age-appropriate patients) must be willing and able to use an electronic diary (eDiary) device as required by the study
4. Sexually active males and females must agree to use a reliable contraceptive method with ≤1% failure rate (such as hormonal contraception, intra-uterine device, or complete abstinence) from signed informed consent through 90 days after last dose of study drug.

Cohort 2 :

1. Infant with clinically confirmed ALGS , ≤11 months of age at Study Day 1
2. Body weight ≥2 kg at Study Day 1
3. Gestational age ≥36 weeks. For children born with gestational age between 32 and 36 weeks, a postmenstrual age of ≥36 weeks is required .
4. Signed parent/legal guardian informed consent.

Exclusion Criteria:

Cohort 1 :

1. Decompensated liver disease, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy
2. Patients who were not compliant with study drug treatment or procedures in Study A4250-012
3. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the safety of the patient, or interfere with the patient participating in or completing the study
4. Known hypersensitivity to any components of odevixibat

Cohort 2 :

1. Patient with past medical history or ongoing presence of other types of liver disease including, but not limited to, the following:

   1. Biliary atresia of any kind
   2. Progressive familial intrahepatic cholestasis (PFIC)
   3. Benign recurrent intrahepatic cholestasis

2. Patient with a past medical history or ongoing presence of any other disease or condition known to interfere with the absorption, distribution, metabolism (specifically bile acid metabolism), or excretion of drugs in the intestine, including but not limited to, inflammatory bowel disease

3. Patient with past medical history or ongoing chronic diarrhea requiring intravenous fluid or nutritional intervention for treatment of the diarrhea and/or its sequelae

4. Patient has a confirmed past diagnosis of infection with human immunodeficiency virus or other present and active, clinically significant chronic infection

5. Recent infection requiring hospitalization or treatment with parenteral anti-infective within 4 weeks of Study Day 1 or completion of oral anti-infective treatment within 2 weeks prior to the Screening Visit

6. Cancer diagnosis (except for basal cell carcinoma)

7. Chronic kidney disease with an impaired renal function and a glomerular filtration rate <70 mL/min/1.73 m2

8. Patient with surgical history of disruption of the enterohepatic circulation (biliary diversion surgery) within 6 months prior to the Screening Visit

9. Patient has had a liver transplant, or a liver transplant is planned within 6 months of Study Day 1

10. Decompensated liver disease, history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy

11. International normalized ratio (INR) >1.4 (the patient may be treated with Vitamin K, and if INR is ≤1.4 at resampling the patient may be enrolled)

12. Serum alanine aminotransferase (ALT) >10 × upper limit of normal (ULN) at Screening

13. Serum ALT >15 × ULN at any time point during the last 6 months unless an alternate etiology was confirmed for the elevation

14. Total bilirubin >15 × ULN at Screening

15. Patient suffers from uncontrolled, recalcitrant pruritic condition other than ALGS. Examples include, but not limited to, refractory atopic dermatitis or other primary pruritic skin diseases.

16. Patient exposed to alcohol or substance abuse in utero

17. Bile acid or lipid binding resins and medications that slow gastrointestinal motility

18. Patient has had investigational exposure to a drug, biologic agent, or medical device within 30 days prior to the Screening Visit, or 5 half-lives of the study agent, whichever is longer

19. Any other conditions or abnormalities which, in the opinion of the investigator may compromise the safety of the patient, or interfere with the patient participating in or completing the study