Table 3 Guidance statements and evidence grades: dosing considerations

From: Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria

Guidance statement(s)

Evidence grade

Introduction and titration of pegvaliase

 1. Blood Phe and Tyr concentrations should be monitored every 1–4 weeks (2–4 hours postprandial) during treatment introduction or when adjusting diet and/or dose

D (Opinion of the SC, based on their experience in the clinical trial program)

 2. Pegvaliase should be initiated and titrated as per the prescribing informationa, with consideration of the following:

     a. Titration to target maintenance dose should be performed in a stepwise manner based on individual patient tolerability

     b. Some patients may require additional time prior to each dose escalation and may therefore take longer to reach an effective maintenance dose

     c. Some patients require a dose of less than 20 mg/day to achieve an adequate response; in these patients, early reductionb of Phe concentration during the titration phase may indicate that the patient does not require further dose increases

     d. Consider discontinuing pegvaliase in individuals who do not show an efficacy benefit at any point within 52 weeks of initiation of pegvaliase

B (Based on data from the pegvaliase clinical trial program)

 3. Based on clinical trial experience, the expert SC recommends initiating and titrating pegvaliase per the prescribing information;a however, the decision to increase the dose to 40 mg/day could be made sooner than after 24 weeks on 20 mg/day, depending on patient tolerability

D (Opinion of the SC, based on their experience in the clinical trial program)

Adjusting diet/dose

 4. Blood Phe concentrations should be controlled by balancing adjustments in diet and dose, with the goal of maintaining blood Phe concentration as low as possible while normalizing diet

D (Opinion of the SC, based on their experience in the clinical trial program)

 5. When blood Phe reaches <120 µmol/L (based on two consecutive blood Phe results):

     a. In patients on a restricted diet (i.e., with <Dietary Reference Intake [DRI] from intact protein) and/or who are receiving medical food, consider adding 10–20 g intact protein and reduce protein from medical food by 10–20 g until diet normalization, and adjust dose as necessary to maintain blood Phe control

     b. In patients on an unrestricted diet with intact protein providing ≥DRI, maintain the current pegvaliase dose and continue to monitor blood Phe concentration to avoid hypoPhe

D (Opinion of the SC, based on their experience in the clinical trial program)

 6. When blood Phe reaches <30 µmol/L (based on two consecutive blood Phe results):

     a. In patients on a restricted diet (i.e., with <DRI from intact protein) and/or who are receiving medical food, consider adding 10–20 g intact protein and reduce protein from medical food by 10–20 g until diet normalization, and adjust dose as necessary to maintain blood Phe control

     b. In patients on an unrestricted diet with intact protein providing ≥DRI, decrease the total weekly pegvaliase dose by 10–20%

D (Opinion of the SC, based on their experience in the clinical trial program)

Resuming pegvaliase treatment following dose interruption

 7. Following treatment interruption (not related to an anaphylaxis event), pegvaliase can be resumed; however, recommendations for the dose of pegvaliase at reintroduction vary according to the length of the dose interruption

     a. There is some evidence from clinical trials to suggest that after treatment interruption of up to 8 weeks, pegvaliase therapy can be resumed at the previous dose

     b. After treatment interruption of more than 8 weeks, pegvaliase therapy can be resumed at a lower dose and then escalated weekly at the discretion of the treating clinician

C (Based on a small patient population from the pegvaliase randomized discontinuation trial)

 8. Consider resuming premedications and trained observer (if appropriate)c when reintroducing pegvaliase following prolonged treatment interruption of greater than 8 weeks until the previous dose (prior to interruption) is achieved

Premedications: C (based on nonrandomized comparison of AE rates before/after a change of protocol to the phase III clinical trial)

Trained observer: D (opinion of the SC, based on their experience in the clinical trial program)

 9. Following dose interruption, consultation with a metabolic dietitian is recommended to counsel on dietary management to assist with blood Phe control

D (Opinion of the SC, based on their experience in the clinical trial program)

  1. AE adverse event, SC Steering Committee.
  2. Postconsensus comments by the SC in response to recent FDA approval of pegvaliase:
  3. aThese recommendations are based on the FDA prescribing information, but it is important to note that the prescribing information from other countries may differ.
  4. bThe PALYNZIQ prescribing information defines first response as at least a 20% reduction in blood phenylalanine concentration from pretreatment baseline or a blood phenylalanine concentration ≤600 µmol/L suggesting that further blood Phe lowering may be achieved with continued treatment.21 The recommendation is to reach maintenance dose before adjusting diet.
  5. cPALYNZIQ was not licensed when the consensus program was conducted, and this recommendation was drafted based on experience from the clinical trial program, during which the presence of an observer was required. Postapproval, use of a trained observer is not considered mandatory.
Back to article page