Table 2 Guidance statements and evidence grades: treatment goals and patient-/system-related considerations prior to initiating therapy
Guidance statement(s) | Evidence grade |
|---|---|
Goal of pegvaliase treatment | |
1. The goal of pegvaliase treatment is to provide life-long maintenance of blood Phe concentrations as low as possible while normalizing diet (protein intake) | B (Consistent level 2 or 3 studies) |
Patient-/system-related considerations prior to initiating therapy | |
2. Pegvaliase should be considered for all adult patients with PKU who have the ability to give informed consent to treatment and whom the clinician considers able to adhere to pegvaliase treatment, including requirements for monitoring of adverse events | B (Based on data from pegvaliase clinical trials, which include two phase 2 and two randomized controlled phase 3 studies) |
3. Caution should be exercised before recommending pegvaliase for use in adult patients who: a. Are unable to communicate issues associated with adverse events b. Are experiencing severe anxiety and/or other mental health problems that might limit their ability to inject and manage pegvaliase, or to communicate adverse events c. Do not have a trained observera to accompany them for at least 1 hour following each injection during introduction and initial up-titration of pegvaliase d. Are unable to inject (either by self-injection or with the help of their trained observer) even after education/training e. Do not have access to emergency services | D (Opinion of the SC, based on their experience in the clinical trial program) |
4. The decision to discontinue sapropterin dihydrochloride and administer pegvaliase should be at the discretion of the treating clinician and based on individual patient preference | D (Opinion of the SC, based on their experience in the clinical trial program; more data/research are required) |
5. Pegvaliase is not currently recommended for use in women who are planning to become pregnant in the immediate future a. Based on pharmacokinetic data, a 4-week period is sufficient to wash out pegvaliase; therefore, women who are taking pegvaliase should be advised to discontinue pegvaliase at least 4 weeks prior to a planned pregnancy and should be counseled to achieve a controlled blood Phe concentration within the desired range through other treatment strategies, including dietary restriction and/or sapropterin, prior to conception, as per ACMG guidelines b. In women who present pregnant while taking pegvaliase; consideration should be given on a case-by-case basis to the benefits–risks of continuing pegvaliase therapy versus the teratogenic effects of hyperphenylalaninemia | D (Opinion of the SC, based on their experience in the clinical trial program; more data are required before use of pegvaliase in this population can be recommended, however, the risks of hyperphenylalaninemia on pregnancy outcomes are well documented) |
Patient education required prior to initiation | |
6. Treating clinicians should discuss the risks and benefits of pegvaliase therapy with patients to make an informed, shared decision on the appropriateness of its use | D (Opinion of the SC, based on their experience in the clinical trial program) |
7. The treating clinician should set expectations regarding the potential adverse events associated with pegvaliase | D (Opinion of the SC, based on their experience in the clinical trial program) |
8. Patients shouldb identify an observer(s) who is (are) willing to undergo training and accompany them for at least 1 hour after injection during the introduction and initial titration of pegvaliase a. The trained observer should be able to recognize signs of acute systemic hypersensitivity/anaphylaxis, administer an epinephrine autoinjector, and call emergency services if necessary b. Both the patient and their observer should receive specific face-to-face education (via telemedicine or in person) on the appropriate use of the epinephrine autoinjector | D (Opinion of the SC, based on their experience in the clinical trial program) |
9. Health-care providers should provide easy-to-understand, clear instructions on self-injection (including how to use the prefilled syringe) and on appropriate dosing, to ensure pegvaliase is correctly self-administered | C (Based on extrapolations from level 2 or 3 studies in other therapy areas) |
10. The treating clinician should set expectations that while some patients may show a response early on, in others, it may take 1 year or more from initiation of treatment before a reduction in blood Phe concentration is observed | D (Opinion of the SC, based on their experience in the clinical trial program) |
Definition of treatment efficacy | |
11. The definition of a “clinically meaningful” efficacy benefit should be determined by the treating clinician and should be based on individual patient goals a. Primarily, the efficacy benefit of treatment should be determined by a significant reduction of blood Phe concentration from baseline OR maintenance of blood Phe concentration within an acceptable range, with progression towards normalization of diet within 1 year of initiation of pegvaliase b. Additional benefits to consider may include an observed reduction in disease burden and/or an improvement in QoL, psychosocial well-being, and/or cognitive function | D (Opinion of the SC, based on their experience in the clinical trial program) |
