Immune Modulation During Palynziq® Treatment in Adults (IMPALA)

A Phase 4 Study of Immune Modulation During Palynziq® Treatment in Adults With Phenylketonuria (PKU)

Study 165-401 is a Phase 4, open-label study designed to examine the concomitant use of methotrexate (MTX) to suppress immune responses to Palynziq and improve tolerability and efficacy in adults with PKU.

Study Overview

• Status: Not yet recruiting
• Conditions: Phenylketonuria
• Intervention / Treatment: Biological: Pegvaliase; Drug: Methotrexate

Detailed Description

The overall objective of the study is to evaluate the ability of MTX, when co-administered with Palynziq, to suppress immune responses to Palynziq and thus improve the tolerability and efficacy of Palynziq in adults with phenylketonuria (PKU). Up to 12 participants will be enrolled into the study across 2 cohorts, with a target enrollment of 6 participants into each cohort:

• Cohort A: Individuals with uncontrolled blood phenylalanine (Phe) > 600 μmol/L on existing management who have never been treated with Palynziq (Palynziq naïve)
• Cohort B: Individuals who have uncontrolled blood Phe > 600 μmol/L after ≥ 24 consecutive weeks of treatment with Palynziq, are on a current dose of≥ 20mg/day, and are unable to further dose escalate (Palynziq experienced)

Palynziq will be initiated (Cohort A) or will continue (Cohort B) as indicated in the Palynziq United States Prescribing Information (USPI) and as prescribed by the participant's treating physician. The decision to initiate or continue Palynziq must be made independently of participation in this study. Palynziq and MTX will not be supplied by BioMarin as part of participation in this study.

All participants will be administered MTX at an oral dose of 15 mg/week concurrent with Palynziq:

• Cohort A participants will have a 4-week Screening Period, followed by a 4-week MTX Tolerability Period during which only MTX will be administered. If MTX is tolerated during the MTX Tolerability Period, the participant will then enter the 24-week Combination Treatment Period during which MTX + Palynziq will be administered concurrently.
• Cohort B participants will have a 4-week Screening Period. Participants will then have 24 weeks of concurrent MTX + Palynziq treatment (Combination Treatment Period): participants will be assessed for MTX tolerability during the first 4 weeks of MTX + Palynziq (MTX Tolerability Period) and then receive another 20 weeks of MTX + Palynziq.

After completion of Week 24 (Combination Treatment Period), MTX will be discontinued for both cohorts and Palynziq only will continue for another 24 weeks (to Week 49; Follow-up Period).

Participants will be assessed for safety and MTX tolerability. If a participant in either Cohort A or B is unable to tolerate MTX, the participant will be discontinued from MTX treatment. Participants who discontinue from MTX early should continue to complete the remaining study assessments until as long as such continued participation will not detrimentally affect the health, safety, and welfare of the participant per investigator determination

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Trial Specialist; Phone Number: 1-800-983-4587; Email: medinfo@bmrn.com

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Dept. of Human Genetics
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Tampa, Florida, United States, 33613
      • University Of South Florida Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical School
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center (URMC)
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University (OHSU) - PARENT
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pittsburgh Medical Center (UPMC) - Children's Hospital of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
      • Contact: Markey McNutt
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults between 18 and 65 years old
• Have a confirmed diagnosis of phenylketonuria (PKU)
• Are in generally good health based on medical evaluation
• Are willing and medically eligible to receive Palynziq and methotrexate (MTX) Cohort A: Have never taken Palynziq before and are willing to start it during the study Cohort B: Have blood > 600 μmol/L after taking Palynziq for at least 24 weeks, are on a daily dose of at least 20mg and unable to increase the dose further
• Agree to use required contraception if they or their partner could become pregnant
• Are willing to carry two epinephrine devices at all times during Palynziq treatment

Exclusion Criteria:

• Pregnant, breastfeeding, planning to become pregnant, planning to father a child, or not using effective birth control if applicable
• Have a known severe allergy or hypersensitivity reaction to methotrexate (MTX), Palynziq, or other PEG-containing medications
• Have a serious active infection or a history of severe or recurrent infections
• Have significant medical conditions that may affect safety or participation (such as serious heart, lung, liver, kidney, immune, neurological, psychiatric, or cancer-related conditions)
• Have a history of substance or alcohol abuse within the past 12 months
• Have had an organ transplant or are taking chronic immunosuppressive medications
• Are currently taking medications that are not allowed in the study, including other PKU treatments besides Palynziq
• Are using, or plan to use, injectable PEG-containing medications other than Palynziq during the study
• Have major surgery planned during the study participation period
• Are currently participating in another clinical study involving Palynziq
• In the opinion of the study doctor, are not a suitable candidate for the study or may have difficulty complying with study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Palynziq naïve; Individuals with uncontrolled blood phenylalanine (Phe) > 600 μmol/L on existing management who have never been treated with Palynziq. Participants will have a 4-week Screening Period, followed by a 4-week MTX Tolerability Period during which only MTX will be administered. If MTX is tolerated during the MTX Tolerability Period, the participant will then enter the 24-week Combination Treatment Period during which MTX + Palynziq will be administered concurrently. After completion of Week 24 (Combination Treatment Period), MTX will be discontinued for both cohorts and Palynziq only will continue for another 24 weeks (to Week 49).	Biological: Pegvaliase; Pegvaliase (Palynziq) administered by subcutaneous injection. Dosing follows U.S. Prescribing Information and investigator judgement.; Other Names: Palynziq; Drug: Methotrexate; Oral methotrexate 15 mg administered once weekly during the Tolerability Period and the Combination Treatment Period.; Other Names: MTX
Experimental: Palynziq experienced; Individuals who have uncontrolled blood Phe > 600 μmol/L after ≥ 24 consecutive weeks of treatment with Palynziq, are on a current dose of ≥ 20mg/day and are unable to further dose escalate (Palynziq experienced). Participants will have a 4-week Screening Period. Participants will then have 24 weeks of concurrent MTX + Palynziq treatment (Combination Treatment Period): participants will be assessed for MTX tolerability during the first 4 weeks of MTX + Palynziq (MTX Tolerability Period) and then receive another 20 weeks of MTX + Palynziq. After completion of Week 24 (Combination Treatment Period), MTX will be discontinued for both cohorts and Palynziq only will continue for another 24 weeks (to Week 49).	Biological: Pegvaliase; Pegvaliase (Palynziq) administered by subcutaneous injection. Dosing follows U.S. Prescribing Information and investigator judgement.; Other Names: Palynziq; Drug: Methotrexate; Oral methotrexate 15 mg administered once weekly during the Tolerability Period and the Combination Treatment Period.; Other Names: MTX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in blood Phe levels from baseline to Week 25 and Week 49	To evaluate blood Phe response in adults with PKU co-administered Palynziq with MTX for 6 months	Baseline to Week 25 and Baseline to Week 49
Anti-PEG IgG, IgM, anti-PAL IgG, IgM levels at Weeks 5, 9, 25, and 49	To evaluate the ability of MTX to modulate the immune response to Palynziq in adults with PKU	Baseline to Week 5, Week 9, Week 25, and Week 49

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of TEAEs	To evaluate the safety of co-administration of Palynziq with MTX in adults with PKU. A TEAE is defined as any AE that newly appeared, increased in frequency, or worsened in severity following initiation of the study drugs (MTX or Palynziq) administration. Incidence of TEAEs will be defined as (number of TEAEs)/(total exposure time in person-years) *100	Baseline through Week 49
Trough Palynziq plasma PK	To characterize the PK of Palynziq during co-administration with MTX in adults with PKU	Baseline through Week 49

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in IgG-C3d CIC, C3, C4 levels from baseline to Weeks 9, 25, and 49	To evaluate formation of CIC and activation of complement pathway. Change from baseline to time t for each participant will be defined as (blood level at time t) - (blood level at baseline)	Baseline to Weeks 9, 25, and 49
Percentage of participants in Cohort B that have escalated from dose at enrollment	To evaluate ability to dose escalate in Cohort B participants following co-administration of Palynziq with MTX	Baseline to Week 24 and Week 48

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: Medical Director, MD, BioMarin Pharmaceutical

Study record dates

Study Major Dates

• Study Start (Estimated): March 31, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: March 13, 2026
• First Submitted That Met QC Criteria: March 13, 2026
• First Posted (Actual): March 17, 2026

Study Record Updates

• Last Update Posted (Actual): March 17, 2026
• Last Update Submitted That Met QC Criteria: March 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Safety; Methotrexate; Immune Response; Phenylketonuria; PKU; Hyperphenylalaninemia; Pegvaliase; Immune Modulation; Palynziq; BMN 165-401; Enzyme Substitution Therapy; Pharmacologic Immunosuppression
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Amino Acid Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Phenylketonurias; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pterins; Pteridines; Aminopterin; Methotrexate; pegvaliase
• Other Study ID Numbers: 165-401; 2021-005058-27 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No