A Clinical Study on the Safety and Tolerability of PL54 Injection in Adult Patients With Phenylketonuria (PKU)

This is a multicenter, open-label, dose-escalation Phase I clinical study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of single or multiple subcutaneous injections of PL54 injection in adult patients with phenylketonuria (PKU). The trial is divided into Phase Ia and Phase Ib.

Phase Ia:

A single subcutaneous injection will be administered. The phase includes a 2-week screening period, a single administration on Day 1 (D1), and a 4-week follow-up period, totaling approximately 6 weeks. Approximately 30 subjects will be enrolled across five dose groups: 0.01 mg/kg, 0.04 mg/kg, 0.1 mg/kg, 0.25 mg/kg, and 0.5 mg/kg, with 6 subjects per group (including 1 sentinel). The first subject in each dose group will receive a single subcutaneous injection of PL54, and the remaining subjects in the same dose group will be enrolled only after the first subject has completed at least 14 days of safety assessment. Dose escalation to the next group will proceed only after all subjects in the previous dose group have completed at least 14 days of visit assessments and the Safety Monitoring Committee (SMC) determines that the dose escalation termination criteria have not been met.

Phase Ib:

Approximately 18 subjects will be enrolled. Subcutaneous injections will be administered once weekly for 4 consecutive weeks (the dosing period for subsequent dose groups may be adjusted based on observed anti-drug antibody [ADA], pharmacokinetic [PK], and pharmacodynamic [PD] results from previous dose groups). Three dose groups are planned: 0.04 mg/kg, 0.1 mg/kg, and 0.25 mg/kg, with 6 subjects per group (the actual dose groups and dosing regimen will be adjusted based on Phase Ia results). Dose escalation to the next group will proceed only after all subjects in the previous dose group have completed at least 28 days of visit assessments and the SMC determines that the dose escalation termination criteria have not been met.

Key Inclusion Criteria:

• Adult patients aged 18 to 55 years, inclusive, regardless of sex.
• Subjects with a prior diagnosis of phenylketonuria (PKU) meeting the following criteria:

• Blood Phe concentration ≥600 µmol/L at screening;
• Average blood Phe concentration ≥600 μmol/L within the 12 months prior to screening (with at least two test results available);
• Genetic test report confirming the presence of phenylalanine hydroxylase (PAH) gene defects.
• Ability to maintain dietary stability from 3 days prior to screening through the end of the trial.
• Subjects (including partners) capable of practicing effective contraception during the trial period, with no plans for conception within 3 months after trial completion.
• Voluntarily sign the informed consent form and, in the investigator's judgment, able to comply with all study requirements.

Key Exclusion Criteria:

• Known hypersensitivity to PL54 injection or any of its excipients.
• Medical conditions or history assessed by the investigator that may increase the risk of severe allergic reactions (e.g., acute exacerbation of allergic asthma, atopic constitution, history of anaphylaxis, etc.).
• Use of any medication for PKU (including large neutral amino acids) within 14 days prior to study drug administration or within 5 half-lives of the drug (whichever is longer).
• Use or planned use of any injectable medication containing polyethylene glycol (PEG) (except the investigational drug) within 3 months prior to screening or during the study period, including medroxyprogesterone acetate injection.
• Prior use of Pegvaliase (PALYNZIQ®).
• History of any of the following manifestations associated with prior PEG-containing product use: systemic symptoms (e.g., respiratory or gastrointestinal symptoms, hypotension, angioedema, allergic reactions). The investigator will determine eligibility based on the severity of previous symptoms.
• Clinically significant abnormal vital signs, physical examination, laboratory tests, or other relevant findings at screening, deemed by the investigator to render the subject unsuitable for enrollment.
• Significant medical history of immunological, cardiovascular, respiratory, gastrointestinal, endocrine, renal, hematological, neurological, psychiatric, or malignant diseases (except basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been excised with no evidence of recurrence) assessed by the investigator prior to screening.
• Stable use of immunosuppressants (e.g., cyclosporine, azathioprine) within 4 weeks prior to screening, with inability to discontinue use during the study period.
• Vaccination within 4 weeks prior to screening or planned vaccination during the study period.
• Positive serology for Treponema pallidum-specific antibodies, human immunodeficiency virus (HIV) antibodies, hepatitis C virus (HCV) antibodies, or hepatitis B virus (HBV) surface antigen.
• Serum creatinine ratio > 1.5 × upper limit of normal (ULN).
• Alanine aminotransferase (ALT) > 2 × ULN.
• Pregnant or breastfeeding women.
• Participation in any investigational drug trial and receipt of an investigational product within 3 months prior to screening.
• Prior use of any gene therapy for phenylketonuria (including participation in clinical studies).
• Any other condition deemed by the investigator to preclude participation in the trial.