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ph-91067

Phenylketonuria Prior Authorization Program Summary

Policy Number: PH-91067

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx, SourceRx-Performance, and Health Insurance Marketplace formularies.

POLICY REVIEW CYCLE

Effective Date	Date of Origin
01-01-2026

FDA LABELED INDICATIONS AND DOSAGE

Agent(s)	FDA Indication(s)	Notes	Ref#
Kuvan® (sapropterin) Powder for oral solution* Tablet*	Reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin-(BH4-) responsive phenylketonuria (PKU). Kuvan is to be used in conjunction with a Phe-restricted diet.	*generic available	1
Palynziq® (pegvaliase-pqpz) Subcutaneous injection	To reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management		2
Sephience™ (sepiapterin) Oral powder	Treatment of hyperphenylalaninemia (HPA) in adult and pediatric patients 1 month of age and older with sepiapterin-responsive phenylketonuria (PKU). Sephience is to be used in conjunction with a phenylalanine (Phe)-restricted diet.		6

See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

Phenylketonuria

Phenylketonuria (PKU), also known as phenylalanine hydroxylase (PAH) deficiency, is a rare autosomal recessive error of phenylalanine (Phe) metabolism caused by variants in the gene encoding PAH. PAH deficiency leads to accumulation of Phe in the blood and brain. Untreated, PKU is characterized by irreversible intellectual disability, microcephaly, motor deficits, eczematous rash, autism, seizures, developmental problems, aberrant behavior, and psychiatric symptoms. Since the initiation of newborn screening, almost all cases of PAH deficiency are diagnosed following a positive newborn screening test.(3,4,5)

Treatment is recommended to be taken as early as possible, preferably within the first week of life with a goal of having blood Phe in the treatment range within the first 2 weeks of life.(4,5) Dietary therapy, involving dietary Phe restriction and supplementation with reduced or Phe-free amino acid mixtures (medical foods, formulas), is the mainstay of therapy and effective in preventing severe mental retardation association with untreated classical PAH deficiency.(3,4,5)

Treatment for life is recommended, even though it is acknowledged that dietary management is associated with significant patient burden.(3,4,5) Over time, subtle intellectual and neuropsychiatric issues may manifest even with treatment.(4) In addition, patients treated from the early weeks of life with initial good metabolic control, but who lose control later in childhood or adult life, may experience both reversible and irreversible neuropsychiatric consequences. Even severely intellectually disabled adults with late-diagnosed PAH deficiency show improvements in challenging behavior with lowering of blood Phe levels.(3,4)

Since neurocognitive and neuropsychiatric symptoms, as well as clinically evident neurologic abnormalities including tremor and gait disturbance, are associated with rising Phe levels, the ACMG recommends that treatment for PAH deficiency should be lifelong for individuals with untreated Phe levels greater than 360 microl/L, and that Phe should be maintained less than or equal to 360 micromol/L for life.(4)

Sapropterin is a synthetic form of naturally occurring cofactor, tetrahydrobiopterin (BH4) which activates PAH. Some patients with PAH deficiency who have some residual enzyme activity respond to administration of sapropterin with an increase in the metabolism of Phe to tyrosine.(3) Approximately 25-50% of patients with PAH deficiency are sapropterin responsive. A significant decline in blood Phe is expected in responders with the assumption that diet remains stable with sapropterin therapy. Most sapropterin-responsive patients have a rapid decline in blood Phe level, but occasionally a delay of 2-4 weeks is seen.(4) Clinical judgment is required to determine what constitutes as a significant or beneficial blood Phe decline in an individual patient, but 30% is often cited as evidence of effective Phe reduction since clinical trials for sapropterin identified responders as greater than or equal to 30% decrease in blood Phe from baseline.(1,4) Sapropterin treatment is not recommend in patients with two null variants, as response is limited by an absence of residual PAH protein.(3)

Sepiapterin is a precursor of the enzymatic cofactor BH4 which activates PAH. Clinical judgment is required to determine what constitutes as a significant or beneficial blood Phe decline in an individual patient, but 30% is often cited as evidence of effective Phe reduction since clinical trials for sepiapterin identified responders as greater than or equal to 30% decrease in blood Phe from baseline.(6)

Pegvaliase-pqpz is a phenylalanine-metabolizing enzyme. In adults being treated with pegvaliase, achieving a blood Phe level below 360 micromol/L allows for the possibility of dietary liberalization. After an individual reaches control of blood Phe concentration (less than 360 micromol/L), intact protein is added incrementally while medical food protein is decreased by similar amounts, until dietary reference intake (DRI) is met or exceeded, considering individual needs and preferences.(5,7) Patients should discontinue pegvaliase if they have not achieved an adequate response (i.e., blood phenylalanine concentration less than or equal to 600 micromol/L) after 16 weeks of continuous treatment with the maximum dosage of 60 mg once daily.(2)

Safety

Kuvan (sapropterin) has no FDA labeled contraindications for use.(1)

Palynziq (pegvaliase-pqpz) has no FDA labeled contraindications for use, but does have a boxed warning. Anaphylaxis has been reported after administration of pegvaliase-pqpz and may occur at any time during treatment. Auto-injectable epinephrine is prescribed to all patients treated with pegvaliase-pqpz, and the patient (and observer, if applicable) are instructed in recognizing signs and symptoms of anaphylaxis. Due to this, pegvaliase-pqpz is available only through a restricted program called Palynziq REMS.(2)

Sephience (sepiapterin) has no FDA labeled contraindications for use.(6)

REFERENCES

Number	Reference
1	Kuvan prescribing information. BioMarin Pharmaceutical Inc. August 2024.
2	Palynziq prescribing information. BioMarin Pharmaceutical Inc. November 2020.
3	Van Wegberg AMJ, MacDonald A, Ahring K, et al. European guidelines on diagnosis and treatment of phenylketonuria: First revision. Mol Genet Metab. 2025 Jun;145(2):1-41. doi: 10.1016/j.ymgme.2025.109125
4	Smith WE, Berry SA, Bloom K, et al. Phenylalanine hydroxylase deficiency diagnosis and management: A 2023 evidence-based clinical guideline of the American College of Genetics and Genomics (ACMG). Genet Med. 2025 Jan;27(1):1-10. doi: 10.1016/j.gim.2024.101289
5	Genetic Metabolic Dietitians International (GMDI) and Southeast Regional Genetics Network (SERN): PKU nutrition management guidelines. March 2022, v.2.5. Last updated June 2022. Available at: https://managementguidelines.net/guidelines.php/136/overview/0/0/PKU%20Nutrition%20Guidelines/Version%202.5
6	Sephience prescribing information. PTC Therapeutics, Inc. July 2025.
7	Cunningham A, Rohr F, Splett P, et al. Nutrition management of PKU with pegvaliase therapy: Update of the web-based PKU nutrition management guideline recommendations. Orphanet J Rare Dis. 2023 Jun;13:155. doi: 10.1186/s13023-023-02751-0

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Available MSC	Final Age Limit	Preferred Status

Palynziq	pegvaliase-pqpz subcutaneous soln pref syringe	10 MG/0.5ML ; 2.5 MG/0.5ML ; 20 MG/ML	M ; N ; O ; Y	N
Sephience	sepiapterin powder packet	1000 MG ; 250 MG	M ; N ; O ; Y	N
Kuvan	sapropterin dihydrochloride powder packet ; sapropterin dihydrochloride tab	100 MG ; 500 MG	M ; N ; O ; Y	O ; Y

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Kuvan	sapropterin dihydrochloride powder packet ; sapropterin dihydrochloride tab	100 MG ; 500 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance
Palynziq	pegvaliase-pqpz subcutaneous soln pref syringe	10 MG/0.5ML ; 2.5 MG/0.5ML ; 20 MG/ML	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance
Sephience	sepiapterin powder packet	1000 MG ; 250 MG	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx ; SourceRx-Performance

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
PA	Initial Evaluation Target Agent(s) will be approved when ALL of the following are met: The patient has a diagnosis of phenylketonuria (PKU) AND If the patient has an FDA labeled indication, then ONE of the following: The patient’s age is within FDA labeling for the requested indication for the requested agent OR There is support for using the requested agent for the patient’s age for the requested indication AND ONE of the following: BOTH of the following: Phenylalanine levels cannot be maintained within the recommended maintenance range with dietary intervention (phenylalanine-restriction) despite strict compliance AND The Phe-restricted diet will continue while being treated with the requested agent OR If the requested agent is Palynziq, the patient’s current phenylalanine level is less than 360 micromol/L AND ONE of the following: If the requested agent is Kuvan, sapropterin, or Sephience, the patient has a baseline (prior to therapy for the requested indication) blood Phe level greater than 360 micromol/L OR If the requested agent is Palynziq, the patient has a baseline (prior to therapy for the requested indication) blood Phe level greater than 600 micromol/L AND If the request is for a brand agent, then ONE of the following: The patient has tried and had an inadequate response to generic sapropterin despite monitored adherence to treatment OR The patient has an intolerance or hypersensitivity to generic sapropterin that is NOT expected to occur with the requested brand agent OR The patient has an FDA labeled contraindication to generic sapropterin that is NOT expected to occur with the requested brand agent OR There is support for use of the requested brand agent over generic sapropterin (e.g., presence of two null mutations) AND The prescriber is a specialist in the area of the patient’s diagnosis (e.g., metabolic disorders), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND The patient will NOT be using the requested agent in combination with another phenylketonuria agent (e.g., Kuvan, Palynziq, sapropterin, Sephience) for the requested indication AND The patient does NOT have any FDA labeled contraindications to the requested agent AND The requested quantity (dose) is within FDA labeled dosing for the requested indication Length of Approval: Kuvan (sapropterin): Approve for 2 months if initial dose is 5 mg/kg/day to less than 20 mg/kg/day, and for 1 month if initial dose is 20 mg/kg/day Palynziq (pegvaliase-pqpz): 9 months Sephience (sepiapterin): Approve for 2 months if initial dose is 7.5 mg/kg/day to less than 60 mg/kg/day, and for 1 month if initial dose is 60 mg/kg/day Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required. Renewal Evaluation* Target Agent(s) will be approved when ALL of the following are met: The patient has been previously approved for the requested agent through the plan’s Prior Authorization process (Note: patients not previously approved for the requested agent will require initial evaluation review) AND The patient has had clinical benefit with the requested agent AND ONE of the following: The patient is currently on a phenylalanine (Phe) restricted diet and will continue while being treated with the requested agent OR If the requested agent is Palynziq, the patient’s phenylalanine level is less than 360 micromol/L AND If the request is for a brand agent, then ONE of the following: The patient has tried and had an inadequate response to generic sapropterin despite monitored adherence to treatment OR The patient has an intolerance or hypersensitivity to generic sapropterin that is NOT expected to occur with the requested brand agent OR The patient has an FDA labeled contraindication to generic sapropterin that is NOT expected to occur with the requested brand agent OR There is support for use of the requested brand agent over generic sapropterin (e.g., presence of two null mutations) AND The prescriber is a specialist in the area of the patient’s diagnosis (e.g., metabolic disorders), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND The patient will NOT be using the requested agent in combination with another phenylketonuria agent (e.g., Kuvan, Palynziq, sapropterin, Sephience) for the requested indication AND The patient does NOT have any FDA labeled contraindications to the requested agent AND The requested quantity (dose) is within FDA labeled dosing for the requested indication Length of Approval: 12 months

Module

Clinical Criteria for Approval

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

The patient has a diagnosis of phenylketonuria (PKU) AND
If the patient has an FDA labeled indication, then ONE of the following:
1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
2. There is support for using the requested agent for the patient’s age for the requested indication AND
ONE of the following:
1. BOTH of the following:
  1. Phenylalanine levels cannot be maintained within the recommended maintenance range with dietary intervention (phenylalanine-restriction) despite strict compliance AND
  2. The Phe-restricted diet will continue while being treated with the requested agent OR
2. If the requested agent is Palynziq, the patient’s current phenylalanine level is less than 360 micromol/L AND
ONE of the following:
1. If the requested agent is Kuvan, sapropterin, or Sephience, the patient has a baseline (prior to therapy for the requested indication) blood Phe level greater than 360 micromol/L OR
2. If the requested agent is Palynziq, the patient has a baseline (prior to therapy for the requested indication) blood Phe level greater than 600 micromol/L AND
If the request is for a brand agent, then ONE of the following:
1. The patient has tried and had an inadequate response to generic sapropterin despite monitored adherence to treatment OR
2. The patient has an intolerance or hypersensitivity to generic sapropterin that is NOT expected to occur with the requested brand agent OR
3. The patient has an FDA labeled contraindication to generic sapropterin that is NOT expected to occur with the requested brand agent OR
4. There is support for use of the requested brand agent over generic sapropterin (e.g., presence of two null mutations) AND
The prescriber is a specialist in the area of the patient’s diagnosis (e.g., metabolic disorders), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
The patient will NOT be using the requested agent in combination with another phenylketonuria agent (e.g., Kuvan, Palynziq, sapropterin, Sephience) for the requested indication AND
The patient does NOT have any FDA labeled contraindications to the requested agent AND
The requested quantity (dose) is within FDA labeled dosing for the requested indication

Length of Approval:

Kuvan (sapropterin): Approve for 2 months if initial dose is 5 mg/kg/day to less than 20 mg/kg/day, and for 1 month if initial dose is 20 mg/kg/day

Palynziq (pegvaliase-pqpz): 9 months

Sephience (sepiapterin): Approve for 2 months if initial dose is 7.5 mg/kg/day to less than 60 mg/kg/day, and for 1 month if initial dose is 60 mg/kg/day

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

The patient has been previously approved for the requested agent through the plan’s Prior Authorization process (Note: patients not previously approved for the requested agent will require initial evaluation review) AND
The patient has had clinical benefit with the requested agent AND
ONE of the following:
1. The patient is currently on a phenylalanine (Phe) restricted diet and will continue while being treated with the requested agent OR
2. If the requested agent is Palynziq, the patient’s phenylalanine level is less than 360 micromol/L AND
If the request is for a brand agent, then ONE of the following:
1. The patient has tried and had an inadequate response to generic sapropterin despite monitored adherence to treatment OR
2. The patient has an intolerance or hypersensitivity to generic sapropterin that is NOT expected to occur with the requested brand agent OR
3. The patient has an FDA labeled contraindication to generic sapropterin that is NOT expected to occur with the requested brand agent OR
4. There is support for use of the requested brand agent over generic sapropterin (e.g., presence of two null mutations) AND
The prescriber is a specialist in the area of the patient’s diagnosis (e.g., metabolic disorders), or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
The patient will NOT be using the requested agent in combination with another phenylketonuria agent (e.g., Kuvan, Palynziq, sapropterin, Sephience) for the requested indication AND
The patient does NOT have any FDA labeled contraindications to the requested agent AND
The requested quantity (dose) is within FDA labeled dosing for the requested indication

Length of Approval: 12 months

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.