Rapid Drug Desensitization Study in Adults Experiencing Hypersensitivity Reactions to Palynziq

This is a Phase 4 study to evaluate the impact of RDD on adult (≥18 years old) participants with PKU who have experienced HSRs leading to treatment interruption or reduction of dose or dosing frequency while receiving commercial Palynziq. This is not a blinded study. All participants will undergo the same assessments: Screening, the RDD in clinic on Day 1, in clinic dosing on Day 2, followed by remote visits in weeks 2-24 post-RDD to monitor for HSRs and changes in Palynziq dosing. Remote visits will occur every other week from Week 2 through Week 12, then monthly until Week 24.

The total duration of participation in the trial will be approximately 30 weeks: up to 6 weeks for screening, followed by RDD and 24 weeks of post-RDD follow-up.

No Data Monitoring Committee (DMC) will be used for this trial.

Inclusion criteria

• Age:

1.Participants must be 18 years of age or older inclusive, at the time of signing the informed consent.

• Type of Participant and Disease Characteristics 2. Participants must have phenylketonuria and must have been receiving commercial Palynziq and enrolled in the REMS.

• Participants must have developed HSRs leading to treatment interruption or reduction of dose or dosing frequency (Graade 2 or above) while on Palynziq, and must be able to undergo RDD within 6weeks from the reactive HSR and last Palynziq dose.
• Sex and Contraceptive/Barrier Requirement 4. Males and females are eligible to participate in this clinical study. Contraceptive use is not required during the study. Please refer to the Pregnancy section of USPI for further information.
• Informed Consent 5. Participants must be capable of giving written informed consent as described in Section 10.1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria

• Medical Conditions:

• Participant may not have any kind of disorders that, in the opinion of the investigator, may compromise the ability of the participant to give written informed consent and/or comply with any aspect of the study, and/or where any aspect of participation would be medically inadvisable for the underlying disorder.
• Participant must not be pregnant on the day of the RDD.
• Participants with uncontrolled asthma, active upper respiratory infection or other active infections, or cardiovascular disease. Asthma control will be assessed using the Asthma Control Test at screening.
• Prior/Concomitant Therapies:

• Participants were not using antihistamine premedication(s) at the time of reactive HSRs.

• Participants are willing and able to resume and tolerate Palynziq at the reactive dose prior to the RDD.

• Participant must not be receiving concurrent injectables containing PEG with the exception of PEG-containing vaccines, such as COVID-19 vaccinations (see Section 6.7).

7.Participants receiving beta blockers.

• Prior/Concurrent Clinical Study Experience 8. Participants may not be currently participating in an interventional study of any investigational product, device, or procedure, or any other BioMarin clinical trial or post-marketing study.

Other Exclusions 9. Participants must not be experiencing reactions that are not appropriate for RDD, including severe cutaneous adverse reactions (SCAR) as defined by the American Academy for Allergy, Asthma, and Immunology.