Clinical Policy: Odevixibat (Bylvay) Form

CENTENE
Corporation

Clinical Policy: Odevixibat (Bylvay)
Reference Number: CP.PHAR.528
Effective Date: 07.20.21
Last Review Date: 05.26
Line of Business: Commercial, HIM/ICHRA, Medicaid                                 Revision Log

See Important Reminder at the end of this policy for important regulatory and legal
information.

Description
Odevixibat (Bylvay™) is a non-systemic ileal bile acid transport inhibitor.

FDA Approved Indication(s)
Bylvay is indicated for the treatment of:
• Pruritus in patients 3 months of age and older with progressive familial intrahepatic
  cholestasis (PFIC)
• Cholestatic pruritus in patients 12 months of age and older with Alagille syndrome (ALGS)

Limitation(s) of use: Bylvay may not be effective in a subgroup of PFIC type 2 patients with
specific ABCB11 variants resulting in non-functional or complete absence of bile salt export
pump protein (BSEP-3).



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Approval duration: 12 months

C. Other diagnoses/indications (must meet 1 or 2):
1. If this drug has recently (within the last 6 months) undergone a label change (e.g.,
   newly approved indication, age expansion, new dosing regimen) that is not yet
   reflected in this policy, refer to one of the following policies (a or b):
   a. For drugs on the formulary (commercial, health insurance marketplace/ICHRA)
      or PDL (Medicaid), the no coverage criteria policy for the relevant line of
      business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance
      marketplace/ICHRA, and CP.PMN.255 for Medicaid; or
   b. For drugs NOT on the formulary (commercial, health insurance
      marketplace/ICHRA) or PDL (Medicaid), the non-formulary policy for the
      relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health
      insurance marketplace/ICHRA, and CP.PMN.16 for Medicaid; or
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed
   under section III (Diagnoses/Indications for which coverage is NOT authorized) AND
   criterion 1 above does not apply, refer to the off-label use policy for the relevant line
   of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance
   marketplace/ICHRA, and CP.PMN.53 for Medicaid.



Approval duration: 12 months



Approval duration: 12 months

C. Other diagnoses/indications (must meet 1 or 2):
1. If this drug has recently (within the last 6 months) undergone a label change (e.g.,
   newly approved indication, age expansion, new dosing regimen) that is not yet
   reflected in this policy, refer to one of the following policies (a or b):
   a. For drugs on the formulary (commercial, health insurance marketplace/ICHRA)
      or PDL (Medicaid), the no coverage criteria policy for the relevant line of
      business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance
      marketplace/ICHRA, and CP.PMN.255 for Medicaid; or
   b. For drugs NOT on the formulary (commercial, health insurance
      marketplace/ICHRA) or PDL (Medicaid), the non-formulary policy for the
      relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health
      insurance marketplace/ICHRA, and CP.PMN.16 for Medicaid; or
2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed
   under section III (Diagnoses/Indications for which coverage is NOT authorized) AND
   criterion 1 above does not apply, refer to the off-label use policy for the relevant line
   of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance
   marketplace/ICHRA, and CP.PMN.53 for Medicaid.

III. Diagnoses/Indications for which coverage is NOT authorized:
A. Non-FDA approved indications, which are not addressed in this policy, unless there is
   sufficient documentation of efficacy and safety according to the off label use policies –
   CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace/ICHRA, and
   CP.PMN.53 for Medicaid, or evidence of coverage documents.

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IV. Appendices/General Information
Appendix A: Abbreviation/Acronym Key
ABCB11: ATP binding cassette
     subfamily B member 11
ALGS: Alagille syndrome
BSEP-3: bile salt export pump 3
FDA: Food and Drug Administration
IBAT: ileal bile acid transporter
ObsRO: observer-reported outcome
PFIC: progressive familial intrahepatic
     cholestasis
sBA: serum bile acid
ULN: upper limit of normal

Appendix B: Therapeutic Alternatives
This table provides a listing of preferred alternative therapy recommended in the approval
criteria. The drugs listed here may not be a formulary agent for all relevant lines of business
and may require prior authorization.

| Drug Name | Dosing Regimen | Dose Limit/
Maximum Dose |
|-----------|---------------|----------------|
| ursodeoxycholic acid (Ursodiol®)* | 15-30 mg/kg/day | 30 mg/kg/day |
| Example of therapies for pruritus: | Varies | Varies |
| antihistamine, rifampin, cholestyramine |  |  |

Therapeutic alternatives are listed by brand name® (generic) when the drug is available by brand name only
and generic (Brand name®) when the drug is available by both brand and generic.
*Off-label

Appendix C: Contraindications/Boxed Warnings
• Contraindication(s): patients with prior or active hepatic decompensation events (e.g.,
  variceal hemorrhage, ascites, hepatic encephalopathy)
• Boxed warning(s): None reported

Appendix D: General Information
• Initial care for patients with PFIC targets symptoms and nutritional problems, including
  fat-soluble vitamin supplementation.
• Off-label conventional treatment for PFIC pruritus includes antihistamines, rifampin, and
  cholestyramine. In the pivotal PEDFIC 1 study, 85% of placebo and 57.1% of Bylvay
  patients are already receiving rifampicin.
• Ursodiol is usually considered first line therapy for all PFIC types and has been proven to
  improve liver function and pruritus. Use of Ursodiol is supported by expert opinion;
  additionally, in the pivotal PEDFIC 1 study, 90% of placebo and 76.2% of Bylvay
  patients were already receiving Ursodiol.
• Other PFIC options include surgical options such as nasobiliary drainage, partial external
  biliary diversion, and liver transplant.
• The PEDFIC 1 study only enrolled patients with PFIC type 1 or 2. PEDFIC 2 is an
  ongoing open-label extension of PEDFIC 1 and includes patients with other types of
  PFIC; however, results are not yet available.
• Bylvay will not work on PFIC type 2 with ABCB11 variants that encode for absence of
  BSEP-3 since Bylvay acts on the bile acid transporter. Therefore, in patients missing the
  BSEP-3 transporter, Bylvay may not inhibit the bile salt export pump.

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Appendix E: Observer-Reported Outcome (ObsRO) Instrument for Pruritus
• Used to measure patients’ scratching as observed by their caregiver twice daily (once in
  the morning and once in the evening)
• Scratching was assessed on a 5-point scale (0-4):
  ◦ 0: no scratching
  ◦ 1: a little scratching
  ◦ 2: medium scratching
  ◦ 3: a lot of scratching
  ◦ 4: worst possible scratching

Appendix F: Genetic Confirmation of PFIC
• PFIC 1
  ◦ Protein deficiency: FIC1
  ◦ Mutated gene: ATP8B1
• PFIC 2
  ◦ Protein deficiency: BSEP
  ◦ Mutated gene: ABCB11

Appendix G: Classic Criteria, Based on Five Body Systems, for a Diagnosis of ALGS
| Classic Criteria | Description |
|------------------|-------------|
| Liver/cholestasis | Usually presenting as jaundice with conjugated hyperbilirubinemia in the neonatal period, often with pale stools |
| Dysmorphic faces | Broad forehead, deep-set eyes, sometimes with upslanting palpebral fissures, prominent ears, straight nose with bulbous tip, and pointed chin giving the face a somewhat triangular appearance |
| Heart disease | Most frequently peripheral pulmonary artery stenosis, but also pulmonary atresia, atrial septal defect, ventricular septal defect, and Tetralogy of Fallot |
| Axial skeleton/vertebral anomalies | Characteristic ‘butterfly’ vertebrae may be seen on an antero-posterior radiograph, and occasionally hemivertebrae, fusion of adjacent vertebrae, and spina bifida occulta |
| Eye/posterior embryotoxon | Anterior chamber defects, most commonly posterior embryotoxon, which is prominence of Schwalbe’s ring at the junction of the iris and cornea |

V. Dosage and Administration
| Indication | Dosing Regimen* | Maximum Dose |
|------------|----------------|--------------|
| ALGS | The recommended dose is 120 mcg/kg PO AM with a meal. | 120 mcg/kg/day |
|          | Recommended dosage/quantity for 120 mcg/kg/day: |              |
|          | Body weight (kg) | Total daily dose (mcg) |
|          | ≤ 7.4 | 600 (1 oral pellet) |
|          | 7.5 to 12.4 | 1,200 (2 oral pellets) |
|          | 12.5 to 17.4 | 1,800 (3 oral pellets) |

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| Indication | Dosing Regimen* | Maximum Dose |
|------------|----------------|--------------|
|          | Body weight (kg) | Total daily dose (mcg) |
|          | 17.5 to 25.4 | 2,400 (2 capsules) |
|          | 25.5 to 35.4 | 3,600 (3 capsules) |
|          | 35.5 to 45.4 | 4,800 (4 capsules) |
|          | 45.5 to 55.4 | 6,000 (5 capsules) |
|          | ≥ 55.5 | 7,200 (6 capsules) |
| PFIC | The recommended dose is 40 mcg/kg PO AM with a meal. If there is no improvement in pruritus after 3 months, the dosage may be increased in 40 mcg/kg increments up to 120 mcg/kg PO QD not to exceed a total daily dose of 6 mg. | 6 mg/day |
|          | Recommended dosage/quantity for 40 mcg/kg/day: |              |
|          | Body weight (kg) | Total daily dose (mcg) |
|          | ≤ 7.4 | 200 (1 oral pellet) |
|          | 7.5 to 12.4 | 400 (2 oral pellets) |
|          | 12.5 to 17.4 | 600 (1 oral pellets) |
|          | 17.5 to 25.4 | 800 (2 oral pellets) |
|          | 25.5 to 35.4 | 1,200 (1 capsule) |
|          | 35.5 to 45.4 | 1,600 (2 capsules) |
|          | 45.5 to 55.4 | 2,000 (3 capsules) |
|          | ≥ 55.5 | 2,400 (2 capsules) |

*Bylvay oral pellets are intended for use by patients weighing < 19.5 kg, while the capsules are intended for use by patients weighing ≥ 19.5 kg.

VI. Product Availability
• Oral pellets: 200 mcg, 600 mcg
• Capsules: 400 mcg, 1,200 mcg



| Reviews, Revisions, and Approvals | Date | P&T
Approval Date |
|--------------------------------|------|----------------|
| 2Q 2022 annual review: modified rifampicin references to rifampin as there are no rifampicin products currently marketed; references reviewed and updated. | 02.04.22 | 05.22 |
| Template changes applied to other diagnoses/indications and continued therapy section. | 10.04.22 |  |
| 2Q 2023 annual review: no significant changes; references reviewed and updated. | 02.05.23 | 05.23 |
| RT4: added newly FDA-approved indication for ALGS. | 06.27.23 | 05.24 |
| 2Q 2024 annual review: added exclusions for portal hypertension and history of a hepatic decompensation event for both PFIC and ALGS per competitor analysis; references reviewed and updated. | 01.10.24 | 05.24 |
| 2Q 2025 annual review: for initial and continued therapy, added exclusion for concurrent use with other IBAT inhibitors; for exclusion of pathologic variations of the ABCB11 gene that predict complete absence of the BSEP protein, clarified this is specific to PFIC type 2; references reviewed and updated. | 03.06.25 | 05.25 |
| Added step therapy bypass for IL HIM per IL HB 5395. | 09.08.25 |  |
| 2Q 2026 annual review: no significant changes; revised initial approval durations for both PFIC and ALGS to 12 months; references reviewed and updated. | 04.10.26 | 05.26 |
| Added ICHRA line of business. |  |  |

Important Reminder
This clinical policy has been developed by appropriately experienced and licensed health care
professionals based on a review and consideration of currently available generally accepted
standards of medical practice; peer-reviewed medical literature; government agency/program
approval status; evidence-based guidelines and positions of leading national health professional

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organizations; views of physicians practicing in relevant clinical areas affected by this clinical
policy; and other available clinical information. The Health Plan makes no representations and
accepts no liability with respect to the content of any external information used or relied upon in
developing this clinical policy. This clinical policy is consistent with standards of medical
practice current at the time that this clinical policy was approved. “Health Plan” means a health
plan that has adopted this clinical policy and that is operated or administered, in whole or in part,
by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a
component of the guidelines used to assist in making coverage decisions and administering
benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage
decisions and the administration of benefits are subject to all terms, conditions, exclusions, and
limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy,
contract of insurance, etc.), as well as to state and federal requirements and applicable Health
Plan-level administrative policies and procedures.

This clinical policy is effective as of the date determined by the Health Plan. The date of posting
may not be the effective date of this clinical policy. This clinical policy may be subject to
applicable legal and regulatory requirements relating to provider notification. If there is a
discrepancy between the effective date of this clinical policy and any applicable legal or
regulatory requirement, the requirements of law and regulation shall govern. The Health Plan
retains the right to change, amend or withdraw this clinical policy, and additional clinical
policies may be developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is
not intended to dictate to providers how to practice medicine. Providers are expected to exercise
professional medical judgment in providing the most appropriate care, and are solely responsible
for the medical advice and treatment of members. This clinical policy is not intended to
recommend treatment for members. Members should consult with their treating physician in
connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent
judgment and over whom the Health Plan has no control or right of control. Providers are not
agents or employees of the Health Plan.

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and
distribution of this clinical policy or any information contained herein are strictly prohibited.
Providers, members, and their representatives are bound to the terms and conditions expressed
herein through the terms of their contracts. Where no such contract exists, providers, members
and their representatives agree to be bound by such terms and conditions by providing services to
members and/or submitting claims for payment for such services.

Note:
For Medicaid members, when state Medicaid coverage provisions conflict with the coverage
provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please
refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

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