Pegvaliase-pqpz (Palynziq)

Number: 0933

Policy

Aetna considers pegvaliase-pqpz (Palynziq) injectable medically necessary for the treatment of members with documented diagnosis of phenylketonuria (PKU) and have a baseline blood phenylalanine (Phe) level greater than 600 micromol/L prior to initiation of the requested medication. 

Aetna considers continuation of therapy with pegvaliase-pqpz (Palynziq) medically necessary in a member with documented diagnsosis of phenylketonuria (PKU) who meets at least one of the following criteria:

1. Member has achieved a clinical response as evidenced by a blood phenylalanine concentration of less than or equal to 600 micromol/L; or

2. Members has not achieved a clinical response to treatment with Palynziq (i.e., has not achieved a blood phenylalanine concentration less than or equal to 600 micromol/L) and meets one of the following requirements:

1. Member has not been titrated to the maximum allowed dose of Palynziq of 60 mg once daily; or
2. Member has received less than 16 weeks of continuous treatment with Palynziq at the maximum allowed dose. 

Aetna considers pegvaliase-pqpz (Palynziq) experimental and investigational for all other indications because of insufficient evidence in the peer-reviewed literature.

Notes:

• The FDA requires enrollment in the Risk Evaluation and Mitigation Strategy (REMS) program called the Palynziq REMS Program.
• The REMS program requires that persons be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with Palynziq
• The product labeling states that the initial subcutaneous injection must be administered under supervision of a healthcare provider who has completed training on Palynziq.

Dosing Recommendations

Pegvaliase-pqpz (Palynziq) is available as an injection: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL in a single-dose prefilled syringe.

• Obtain baseline blood phenylalanine concentration before initiating treatment.
• Induction: the recommended initial dosage is 2.5 mg subcutaneously once weekly for 4 weeks administered under supervision of healthcare provider.
• Titration: titrate the dosage in a step-wise manner over at least 5 weeks based on tolerability to achieve a dosage of 20 mg subcutaneously once daily.  See full prescribing information for titration regimen.
• Prior to individual beginning self-injection, confirm person’s competency with self-administration.  Instruct the person and observer (if applicable) on how to recognize the signs and symptoms of anaphylaxis, how to properly administer auto-injectable epinephrine, and to seek immediate medical care upon its use.
• Assess individuals' tolerability, blood phenylalanine concentration, and dietary protein and phenylalanine intake throughout treatment.
• Consider increasing the dosage to a maximum of 40 mg subcutaneously once-daily in persons who have been on 20 mg once daily continuously for at least 24 weeks and who have not achieved a blood phenylalanine concentration less than or equal to 600 micromol/L.
• Consider increasing the 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 and who have not achieved blood phenylalanine control.
• Discontinue Palynziq in persons who have not achieved an adequate response after 16 weeks of continuous treatment with the maximum dosage of 60 mg once-daily.
• Reduce the dosage and/or modify dietary protein and phenylalanine intake, as needed, to maintain blood phenylalanine concentrations within a clinically acceptable range and above 30 micromol/L.

Administration of the initial dose of Palynziq is done under the supervision of a healthcare provider equipped to manage anaphylaxis, and closely observe individuals for at least 60 minutes following injection.

Source: Prescribing Information. Palynziq (pegvaliase-pqpz) injection, for subcutaneous use. 2020.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Palynziq is indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria who have uncontrolled blood phenylalanine concentrations greater than 600 micromol/L on existing management.

Phenylketonuria (PKU) is a rare genetic amino acid metabolism disorder that results in buildup of the essential amino acid, phenylalanine (Phe), in the body.  Elevated Phe leads to increased levels of phenylketones in the blood which are excreted in the urine. Most cases of PKU is caused by mutations in the gene that helps make the hepatic enzyme phenylalanine hydroxylase (PAH), which is needed to convert Phe into tyrosine, a pathway important for the production of key neurotransmitters (e.g., L-dopa, norepinephrine, epinephrine) in the body. The gene encoding PAH has been mapped to human chromosome 12q24.1. When a person with PAH deficiency eats foods that contain protein or aspartame, a dangerous buildup of Phe can occur, leading to neurological problems (e.g. seizures, irreversible brain damage, and intellectual disabilities). The incidence of PKU is 1 in 10,000 to 15,000 births in the United States (FDA, 2018). PKU is inherited in families in an autosomal recessive pattern.

Complete enzyme deficiency is termed “classic PKU”, in which serum Phe concentration exceeds 20 mg/dL (1200 micromol/L). Individuals can develop profound and irreversible intellectual disability without treatment. Residual enzyme activity causes moderate PKU (Phe concentrations 900 to 1200 micromol/L), mild PKU (Phe concentrations 600 to 900 micromol/L), mild hyperphenylalaninemia (HPA; Phe concentrations 360 to 600 micromol/L), and benign mild HPA not requiring treatment (Phe concentrations 120 to 360 micromol/L) (Bodamer, 2016). Affected individuals on an unrestricted diet who have Phe levels above normal but below 1200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment (Bodamer, 2016; Regier and Greene, 2017).

PAH deficiency can be detected by newborn screening in virtually 100% of cases based on the presence of hyperphenylalaninemia (HPA) using tandem mass spectrometry on a blood spot obtained from a heel prick. The diagnosis of PAH deficiency is established in a proband with plasma Phe concentration persistently above 120 µmol/L (2 mg/dL) and altered ratio of Phe to tyrosine in the untreated state with normal BH4 cofactor metabolism; and/or the finding of biallelic pathogenic variants in PAH by molecular genetic testing (Regier and Greene, 2017).

The mainstay of therapy in PKU is dietary restriction of phenylalanine (e.g., low-protein diet and use of a Phe-free medical formula). A proportion of individuals with PKU benefit from adjuvant therapy with sapropterin, a cofactor for PAH. Treatment of phenylalanine hydroxylase deficiency "must be life long" (Vockley et al, 2014). The NIH Consensus Development Conference on PKU recommended maintaining a blood concentration of 120 to 360 micromol/L for affected children through 12 years of age and 120 to 900 micromol/L after 12 years of age. However, although data are limited, higher blood Phe concentrations appear to adversely affect brain function, even in adults. Thus, maintenance of lower levels (2 to 10 mg/dL, 120 to 600 micromol/L) is strongly encouraged during adolescence or even beyond (Bodamer, 2016). Pegylated phenylalanine ammonia lyase (PEG-PAL) has been under investigation as a treatment option for PKU. PEG-PAL is an enzyme, derived from the prokaryote Anabaena variabilis, which degrades phenylalanine.

On May 24, 2018, the U.S. Food and Drug Administration (FDA) approved Palynziq (pegvaliase-pqpz) (BioMarin Pharmaceutical Inc.) subcutaneous injection to reduce blood phenylalanine (Phe) levels in adults with phenylketonuria (PKU), who have uncontrolled Phe levels >600 µmol/L on existing management. Palynziq is a PEGylated phenylalanine ammonia lyase enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. It substitutes for the deficient phenylalanine hydroxylase enzyme activity in patients with PKU and reduces blood phenylalanine concentrations. Treatment with Palynziq consists of induction, titration, and maintenance phases; periodic blood Phe monitoring is recommended (FDA, 2018; MPR, 2018). 

FDA approval was based the PRISM program evaluating Palynziq in PKU patients, which included two Phase 3 clinical trials: PRISM-1 (NCT01819727), PRISM-2 (NCT01889862), and an open-label extension trial (NCT03694353) that followed about 40 patients from prior trials who received Palynziq at doses greater than 40 mg a day. PRISM-1 was an open-label, randomized, multicenter trial that evaluated subcutaneous pegvaliase for the treatment of adults with phenylketonuria (PKU). Pegvaliase-naïve participants with blood Phe >600 μmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants from this study continued pegvaliase treatment in PRISM-2, which was an 8-week, placebo-controlled, randomized withdrawal trial in patients who were previously treated with pegvaliase (Palynziq). Study participants were randomized (2:1) to either continue maintenance pegvaliase 20mg or 40mg once daily or to receive matching placebo for a total of 8 weeks. The data showed that of 261 participants who received pegvaliase, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 μmol/L, 60.7% of participants achieved blood Phe ≤360 μmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 μmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. The authors concluded that these studies support the efficacy of pegvaliase for the treatment of adults with PKU, and that most participants had a manageable safety profile. The PRISM-2 extension study is continuing to assess long-term effects of pegvaliase treatment (MPR, 2018; Thomas et al, 2018).

The most common adverse events reported in the Palynziq trials (at least 20% in either treatment phase) included injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and diarrhea. Hypersensitivity reactions occurred in most patients, likely due to formation of antibodies to the product (BioMarin Pharmaceutical, 2018; FDA, 2018). 

The most serious adverse reaction in the Palynziq trials was anaphylaxis, which occurred most frequently during upward titration of the dose within the first year of treatment. Because of this serious risk, the labeling for Palynziq includes a Boxed Warning and the product is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Palynziq REMS Program. Notable requirements of the Palynziq REMS Program include the following (FDA, 2018):

• Prescribers must be certified by enrolling in the REMS program and completing training
• Prescribers must prescribe auto-injectable epinephrine with Palynziq
• Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive Palynziq
• Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with Palynziq
• Patients must have auto-injectable epinephrine available at all times while taking Palynziq.

Subsequently, in October 2020, the FDA increased the maximum Palynziq dose for treating adults with phenylketonuria (PKU) from 40 mg to 60 mg. The 60 mg dose may be prescribed to patients who have been on 40 mg once daily continuously for at least 16 weeks, but have to control the levels of phenylalanine in the blood. If phenylalanine levels are still not controlled after 16 weeks on the 60 mg dose, prescribers are instructed to discontinue the treatment. The approval was based on data from the PRISM Phase 3 studies, which showed that 19% of participants required a 60 mg dose to achieve an adequate response to Palynziq. Irrespective of the dose used, Palynziq lowered phenylalanine to target levels in two thirds (66%) of the 86 patients who received treatment for at least two years. Among those treated for three years, 66% also reached phenylalanine concentrations of 360 umol/L or lower. Of the patients who achieved their first response at a dose of 60 mg once daily, a majority (67%) did so within 16 weeks of treatment. Safety data from patients followed for more than six years in the open-label trial also showed that Palynziq’s safety profile was consistent with previous studies, irrespective of the dose. The rate and types of adverse events (side effects) were similar among patients receiving 20 mg, 40 mg, and 60 mg. 

Appendix

Blood Phenylalanine Monitoring and Diet

• Obtain blood phenylalanine concentrations every 4 weeks until a maintenance dosage is established.
• After a maintenance dosage is established, periodically monitor blood phenylalanine concentrations.
• Counsel patients to monitor dietary protein and phenylalanine intake, and adjust as directed by their healthcare provider.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
84030	Phenylalanine (PKU), blood
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
Pegvaliase-pqpz (Palynziq) - no specific code:
ICD-10 codes covered if selection criteria are met:
E70.0	Classical phenylketonuria

The above policy is based on the following references: