ModifiedCignaPolicy IP0764

Phenylketonuria - Sephience

Defines prior authorization and medical necessity criteria for coverage of Sephience (sepiapterin oral powder) for treatment of hyperphenylalaninemia in patients with sepiapterin-responsive phenylketonuria across Cigna lines of business, including initial and continuation therapy, employer and individual/ family plan specific requirements, and not-covered conditions.

Policy Summary

PayerCigna

PolicyPhenylketonuria - Sephience

Policy CodePolicy IP0764

Change TypeTitle update; continuation criteria added; employer product requirements added

Effective Date

Next Review Date

Key ActionPrior Authorization is required for benefit coverage of Sephience; initial approvals require prescription by or in consultation with a metabolic disease specialist.

SourceLink

POLICY UPDATE CHANGES

New policy created (Summary of Changes = New policy).

Policy title updated from 'Phenylketonuria - Sephience for Individual and Family Plans' to 'Phenylketonuria - Sephience'.

For patients currently receiving Sephience, 'patient has achieved a blood phenylalanine concentration < 360 micromol/L' was added as an option for demonstrating clinical response.

Added Employer Plans preferred product requirements.

1FDA-approved indication

12Initial approval (weeks)

1 yearContinuation duration (current users)

Coverage Summary

Scope: Defines prior authorization and medical necessity criteria for coverage of Sephience (sepiapterin oral powder) for treatment of hyperphenylalaninemia in patients with sepiapterin‑responsive phenylketonuria across Cigna lines of business, including initial and continuation therapy, employer and individual/family plan requirements, dosing/titration, and not‑covered conditions.

Policy stance: Coverage is covered_with_criteria — Sephience is covered when the specified prior authorization and clinical criteria are met.

FDA‑approved indication summary: Sephience is indicated for treatment of hyperphenylalaninemia in adult and pediatric patients 1 month of age and older with sepiapterin‑responsive PKU and should be used in conjunction with a phenylalanine‑restricted diet. Biochemical responsiveness should generally be determined by a therapeutic trial.

Key thresholds, dosing limits, and approval durations

Blood Phe percent reduction (widely accepted)≥30%

Policy continuation threshold (allowed)≥20% reduction from baseline

Blood Phe absolute target for response/continuation< 360 micromol/L

Maximum daily dose60 mg/kg

Initial approval duration12 weeks

Continuation approval duration (current users)1 year

Medical Necessity Criteria

Conditions Not Covered (Not Medically Necessary)

Coding

Policy Identifiermixed

IP0764

Coverage Policy Number

Provider Actions

Prior Authorization

Prior authorization required

Prior Authorization is required for benefit coverage of Sephience. Initial approvals require the medication to be prescribed by or in consultation with a metabolic disease specialist.

Documentation Required

Documentation to support prior authorization

Provide chart notes, laboratory tests (including baseline and on-treatment blood phenylalanine [Phe] levels), claims records, or other information as documentation where indicated (for example, to support prior sapropterin failure/intolerance or response on therapy).

Background, Evidence & Definitions

Sephience is indicated for treatment of hyperphenylalaninemia in patients ≥1 month of age with sepiapterin‑responsive phenylketonuria and is to be used in conjunction with a phenylalanine‑restricted diet. Per the prescribing information, biochemical responsiveness cannot generally be predicated by laboratory or molecular testing and is determined through a therapeutic trial of Sephience. A reduction in blood phenylalanine (Phe) concentration of ≥ 30% is widely accepted as demonstrating responsiveness, though smaller reductions (for example, ≥ 20%) may be sufficient in selected individual circumstances; this is reflected in policy continuation options. For infants and young children, starting doses are age‑based with a maximum daily dose of 60 mg/kg, and for patients <2 years blood Phe should be checked within 2 weeks and therapy discontinued if no decrease after 2 weeks at the maximum dose.

The pivotal phase 3 trial (APHENITY) consisted of a two‑part design. In the 2‑week fixed‑dose assessment (part one), of 156 patients assessed for responsiveness, 103 (66%) had a ≥ 30% decrease in blood Phe. In the randomized part two efficacy analysis (patients with ≥30% response), the primary endpoint (mean change in blood Phe from baseline to Week 6) favored Sephience with a 63% mean reduction versus +1% with placebo (P < 0.0001).

Revision History

11/15/2025policy_created

New policy created

01/15/2026title_updated

Policy title updated from 'Phenylketonuria - Sephience for Individual and Family Plans' to 'Phenylketonuria - Sephience' (non-material)

01/15/2026criteria_added

For patients currently receiving Sephience, 'patient has achieved a blood phenylalanine concentration < 360 micromol/L' was added as an option for demonstrating clinical response