Pharmacy Benefit Coverage Criteria

Effective Date………….…………...... 12/1/2020 Next Review Date………………………………. 12/1/2021 Coverage Policy Number ...... P0055

Pegvaliase-pqpz

Table of Contents Related Coverage Resources

Medical Necessity Criteria ...... 1 Sapropterin FDA Approved Indications ...... 2 Recommended Dosing ...... 2 General Background ...... 3 References ...... 3

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Medical Necessity Criteria

Pegvaliase-pqpz (Palynziq®) is considered medically necessary when ALL of the following criteria are met: • Individual is 18 years of age or older • Documented diagnosis of phenylketonuria (PKU) by ONE of the following: o Plasma phenylalanine concentration persistently above 120 μmol/L (2 mg/dL) and altered ratio of phenylalanine to tyrosine in the untreated state with normal BH4 cofactor metabolism o Finding of biallelic pathogenic or likely pathogenic variants in the PAH gene • Uncontrolled blood phenylalanine concentrations of great than 600 micromol/L on existing management (for example, phenylalanine restricted diet, Kuvan) • Individual follows a phenylalanine restricted diet • No concomitant use with Kuvan once stabilized on Palynziq

Initial and reauthorization is up to 12 months unless otherwise stated.

Pegvaliase-pqpz (Palynziq) is considered medically necessary for continued use when the following criteria are met:

• ONE of the following: o Blood Phe levels are being maintained within an acceptable range (120-600 μmol/L) Page 1 of 3 Pharmacy Benefit Clinical Criteria: P0055 o The patient has achieved a greater than or equal to 20% reduction in blood phenylalanine concentration from pre-treatment baseline • No concomitant use with Kuvan

Palynziq is considered experimental, investigational or unproven for any other use.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

FDA Approved Indications

FDA Approved Indication Palynziq is a recombinant enzyme labeled for treating phenylketonuria (PKU) in adults whose phenylalanine concentration remains greater than 600 µmol/L on current therapies.

Recommended Dosing

FDA Recommended Dosing Treatment with Palynziq should be managed by a healthcare provider experienced in the management of PKU. Obtain baseline blood phenylalanine concentration before initiating treatment.

Induction The recommended initial induction dosage for Palynziq is 2.5 mg subcutaneously once weekly for 4 weeks. Administer the initial dose under the supervision of a healthcare provider.

Titration Titrate the Palynziq dosage in a step-wise manner, based on tolerability, over at least 5 weeks, to achieve a dosage of 20 mg subcutaneously once daily according to Table 1.

Maintenance Therapeutic response may not be achieved until the patient is titrated to an effective maintenance dosage of Palynziq. Use the lowest effective and tolerated dosage of Palynziq.

Assess patient tolerability, blood phenylalanine concentrations, and dietary protein and phenylalanine intake throughout treatment.

Individualize the maintenance dosage to achieve blood phenylalanine control (blood phenylalanine concentrations less than or equal to 600 micromol/L), taking into account patient tolerability to Palynziq and dietary protein intake (see Table 1).

Maintain the Palynziq dosage at 20 mg once daily for at least 24 weeks. Consider increasing the Palynziq dosage to 40 mg once daily in patients who have been on 20 mg once daily continuously for at least 24 weeks without achieving blood phenylalanine control. Consider increasing the Palynziq dosage to a maximum of 60 mg once daily in patients who have been on 40 mg once daily continuously for at least 16 weeks without achieving blood phenylalanine control.

Discontinuation Discontinue Palynziq in patients who have not achieved an adequate response after 16 weeks of continuous treatment with the maximum dosage of 60 mg once daily

Table 1: Recommended Dosing Palynziq Dosage Duration* Regimen Treatment Induction 2.5 mg once weekly 4 weeks Titration 2.5 mg twice weekly 1 week 10 mg once weekly 1 week

Page 2 of 3 Pharmacy Benefit Clinical Criteria: P0055 Table 1: Recommended Dosing Palynziq Dosage Duration* Regimen Treatment 10 mg twice weekly 1 week 10 mg four times per week 1 week 10 mg once daily 1 week Maintenance † 20 mg once daily 24 weeks 40 mg once daily 16 weeks Maximum†† 60 mg once daily 16 weeks‡ * Additional time may be required prior to each dosage escalation based on patient tolerability. † Individualize treatment to the lowest effective and tolerated dosage. Consider increasing to a maximum of 40 mg once daily in patients who have not achieved a response with 20 mg once daily continuous treatment for at least 24 weeks. Consider increasing to a maximum of 60 mg once daily in patients who have not achieved a response with 40 mg once daily continuous treatment for at least 16 weeks ‡ Discontinue Palynziq treatment in patients who have not achieved a response after 16 weeks of continuous treatment with the maximum dosage of 60 mg once daily

General Background

Professional Societies/Organizations The American College of Medical Genetics and Genomics (ACMG) published practice guidelines (2014) for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency.2 The guidelines recommend initiating treatment as early as possible, preferably within the first week of life. Dietary restriction of phenylalanine intake is the mainstay of therapy for PKU. Blood phenylalanine levels in all patients should be maintained in the range of 120 to 360 µmol/L. The guidelines state that approximately 25% to 50% of patients with PAH deficiency are responsive to Kuvan™ (sapropterin dihydrochloride tablets and powder for oral solution). A significant decline in blood phenylalanine level is expected in responders once treatment is initiated (with phenylalanine-restricted diet). An improvement in neuropsychiatric symptoms or increase in phenylalanine tolerance without a decrease in blood levels is sufficient reasoning to continue therapy. According to the guidelines, there is strong evidence to support life-long treatment and maintenance of metabolic control in patients with PAH deficiency.

According to the European guidelines for phenylketonuria (2017), there is consensus in the literature that patients with blood phenylalanine concentration > 600 µmol/L should be treated.3 There is also consensus that patients with blood Phe concentration < 360 µmol/L can remain untreated, but should be monitored. Patients with blood Phe concentration between 360 to 600 µmol/L should be treated until 12 years of age. Treatment for life is recommended for any patient with PKU; however, it is also noted that patients ≥ 12 years of age with blood Phe concentration < 600 µmol/L do not require treatment. All adults with PKU should have lifelong systematic follow- ups in specialized metabolic centers, due to specific risks which may occur during adulthood. With regards to target Phe levels, in treated PKU patients up to 12 years of age, the target Phe levels should be 120 to 360 µmol/L; in treated PKU patients ≥ 12 years of age, the target Phe levels should be 120 to 600 µmol/L.

References

1. Palynziq (pegvaliase-pqpz) injection, for subcutaneous use [product information]. BioMarin Pharmaceutical Inc. Novato, CA.October, 2020. 2. van Wegberg AMJ, MacDonald A, Ahring A, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12:162. 3. Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188-200.

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