CurrentmhnPolicy CP.PHAR.140

Clinical Policy: Pegvaliase-pqpz (Palynziq)

Defines medical necessity criteria, initial and continued therapy requirements, dosing limits, concomitant-use exclusions, approval durations, and coding implications for Palynziq (pegvaliase-pqpz) for adult members with PKU across Commercial, HIM, and Medicaid lines of business.

Policy Summary

Payermhn

PolicyClinical Policy: Pegvaliase-pqpz (Palynziq)

Policy CodePolicy CP.PHAR.140

Change TypeAddition / Clarification

Effective DateDec 1, 2018

Next Review Date

Key ActionProvider must submit documentation (office chart notes, lab results or other clinical information) supporting that member meets all approval criteria.

SourceLink

POLICY UPDATE CHANGES

Added Sephience as an agent that should not be used concomitantly with Palynziq.

Added C9399 as HCPCS code.

Differentiation of approval duration by line of business added for Commercial.

Exclusion against concomitant use with sapropterin (Kuvan) added to Continued Therapy to mirror Initial Approval Criteria.

1FDA approved indication(s)

18Minimum age (years)

600 µmol/LPhe threshold for initiation/response

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Maximum dose allowed

REMSREMS required (anaphylaxis risk)

Coverage Summary & Scope

Scope: Defines medical necessity criteria, initial and continued therapy requirements, dosing limits, concomitant-use exclusions, approval durations, and coding implications for Palynziq (pegvaliase-pqpz) for adult members with PKU. Coverage stance: covered with criteria. Indication: Palynziq (pegvaliase-pqpz) for adults with phenylketonuria (PKU). Policy number: CP.PHAR.140. Payer: mhn. Effective date: 2018-12-01. Status: CURRENT.

Initial Therapy Criteria

Initial Therapy - Phenylketonuria (must meet all)

Covered when ALL of the following are met:

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Initial Therapy - Other diagnoses/indications

If use is not covered by main criteria or policy not updated for label change (must meet one):

ANY of the following

Label change handling: If this drug has recently (within the last 6 months) undergone a label change that is not yet reflected in this policy, follow applicable formulary/no-coverage or non-formulary policy per line of business (CP.CPA.190, HIM.PA.33, CP.PMN.255, HIM.PA.103, CP.PMN.16 as applicable)
Off-label referral: If requested use is not specifically listed under section III and criterion 1 above does not apply, refer to off-label use policy per line of business (CP.CPA.09, HIM.PA.154, CP.PMN.53)

Continuation Therapy Criteria

Continued Therapy - Other diagnoses/indications

If use is not covered by main continued therapy criteria (must meet one):

ANY of the following

Label change handling: If this drug has recently (within the last 6 months) undergone a label change that is not yet reflected in this policy, follow applicable formulary/no-coverage or non-formulary policy per line of business (CP.CPA.190, HIM.PA.33, CP.PMN.255, HIM.PA.103, CP.PMN.16 as applicable)
Off-label referral: If requested use is not specifically listed under section III and criterion 1 above does not apply, refer to off-label use policy per line of business (CP.CPA.09, HIM.PA.154, CP.PMN.53)

Unproven Uses / Exclusions

Diagnoses/Indications NOT authorized

Not covered unless meet off-label policy or evidence of coverage:

Non-FDA approved indications not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off-label use policies (CP.CPA.09, HIM.PA.154, CP.PMN.53) or evidence of coverage documents

Concomitant-use exclusions: Palynziq must not be prescribed concurrently with sapropterin (Kuvan) or Sephience (Sephience was added to the exclusion list per material change with P&T approval 11.25.2025). Safety requirements: Palynziq carries a boxed warning for anaphylaxis and enrollment in the REMS program is required; REMS-related requirements (supervised initial dosing and availability of auto-injectable epinephrine) are safety requirements and are not listed as concomitant-use exclusions.

Applicable Codes

HCPCS codes (informational)HCPCS

J3590	Unclassified drugs or biologics
C9399	Unclassified drugs or biologics

Provider Actions & Billing Rules

Prior Authorization

Prior authorization required with specified criteria

Prior authorization is required. Approval will be granted only when all initial or continued therapy criteria in the policy are met. Key required items include: prescription by or in consultation with an endocrinologist, metabolic disease specialist, or genetic disease specialist; patient age ≥ 18 years; member on and continuing a phenylalanine-restricted diet; failure of generic sapropterin (Kuvan) at maximally indicated doses unless contraindicated or not tolerated; recent phenylalanine (Phe) blood level > 600 µmol/L for initiation (and Phe control targets for continuation); and dose limits (initial request ≤ 20 mg/day; dose escalation limits up to 60 mg/day per policy).

Specialist prescriber: endocrinologist, metabolic disease specialist, or genetic disease specialist
Age ≥ 18 years
On and will continue a phenylalanine-restricted diet during treatment
Failure of generic sapropterin (Kuvan) at up to maximally indicated doses unless contraindicated or intolerant
Initiation Phe threshold: recent (within 90 days) Phe > 600 µmol/L
Initial dosing limit: does not exceed 20 mg/day
Maximum dosing limit for escalation/continuation: does not exceed 60 mg/day

Clinical Evidence & Rationale

Evidence: Palynziq Prescribing Information (BioMarin; Nov 2020; references updated through 2025) and key clinical trials including the PRISM phase 3 trial and the pivotal double-blind randomized discontinuation phase 3 trial (2018) are cited as primary evidence sources informing this policy.

Background & Definitions

Background: Palynziq is a PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine to ammonia and trans-cinnamic acid to reduce blood phenylalanine concentrations. It is indicated to reduce blood Phe in adults with PKU who have uncontrolled Phe > 600 µmol/L. The product carries a boxed warning for anaphylaxis and requires REMS enrollment with supervised initial dosing by a healthcare professional and the need for the patient to have access to auto-injectable epinephrine while using Palynziq.

Term	Definition
Phe	Phenylalanine
PKU	Phenylketonuria
PAH	Phenylalanine hydroxylase
PAL	Phenylalanine ammonia lyase

Policy Revision History

11.25.20254Q 2025 annual review (P&T Approval Date)Latest

Added Sephience as an agent that should not be used concomitantly with Palynziq. (material change)

11.244Q 2024 annual review (P&T Approval Date = 11.24)

Added exclusion against concomitant use with sapropterin (Kuvan) for Continued Therapy to mirror Initial Approval Criteria.

11.234Q 2023 annual review (P&T Approval Date = 11.23)

Policy Summary

Payermhn

PolicyClinical Policy: Pegvaliase-pqpz (Palynziq)

Policy CodePolicy CP.PHAR.140

Change TypeAddition / Clarification

Effective DateDec 1, 2018

Next Review Date

Key ActionProvider must submit documentation (office chart notes, lab results or other clinical information) supporting that member meets all approval criteria.

SourceLink

On This Page

Documentation Required

Submit supporting documentation

Submit supporting documentation with the prior authorization request, such as office chart notes, laboratory results, and other clinical information, to demonstrate that the member meets all approval criteria.

Documentation Required

Phe level monitoring and timing

Provide recent phenylalanine (Phe) blood levels and timing: for initial approval, a Phe level obtained within 90 days showing > 600 µmol/L is required. For continued therapy, submit documentation of blood Phe control (≤ 600 µmol/L) or the member's dosing history and response per the policy's escalation and continuation criteria.

Initial: Phe within 90 days > 600 µmol/L
Continued: evidence of Phe control (≤ 600 µmol/L) or documented dosing history and response per escalation rules

Documentation Required

REMS and safety monitoring

Ensure REMS enrollment and document safety monitoring: enrollment in the Palynziq REMS is required, the initial dose must be administered under supervision of a healthcare professional, and the member must have access to auto-injectable epinephrine given the boxed warning for anaphylaxis.

Enroll patient in Palynziq REMS
Document supervised initial dosing by a healthcare professional
Document plan for access to auto-injectable epinephrine

Billing Rule

Dose limit enforcement

Dose limits are enforced per policy: initial approval requests exceeding 20 mg/day should be denied. Any request for a dose that exceeds the maximum allowed (60 mg/day) or increases above permitted escalation thresholds should be denied unless documentation demonstrates adherence to the stepwise escalation/duration criteria.

Doses > 20 mg/day for initial approval should be denied
Requests exceeding 60 mg/day should be denied
Dose increases require documentation that escalation timing and prior-dose duration criteria were met

Documentation Required

Concomitant therapy exclusion

Document that Palynziq is not being used concurrently with sapropterin (Kuvan) or Sephience; requests will not meet criteria if concomitant therapy with these agents is present.

Confirm no concurrent prescription of sapropterin (Kuvan)
Confirm no concurrent prescription of Sephience

Denial Risk

Non-FDA use denial risk

Requests for non‑FDA indications not addressed in this policy will be denied unless the provider supplies sufficient documentation of efficacy and safety consistent with the applicable off‑label use policies or evidence of coverage documents.

Differentiation of approval duration by line of business added for Commercial: approval duration specified as 6 months or to member's renewal date, whichever is longer.

11.214Q 2021 annual review (P&T Approval Date = 11.21)

Added C9399 as HCPCS code; references reviewed and updated.