A Phase 4 interventional study of Pegvaliase and Methotrexate in Phenylketonuria, sponsored by BioMarin Pharmaceutical. Recruiting at 12 sites in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-11-10.
Sponsored by BioMarin Pharmaceutical · Phase 4, Interventional, and Treatment
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.
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:
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:
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
191 studies on the registry are indexed under Phenylketonurias; 40 are open to participants now.
This study's planned enrollment of 12 is below the median of 27 across 122 interventional studies indexed under Phenylketonurias.
Browse Phenylketonurias studies →BioMarin Pharmaceutical is the lead sponsor of 112 studies on the registry; 13 are open to participants now.
Of its 17 completed or terminated interventional studies of FDA-regulated products, 12 (71%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 · Drug: Methotrexate
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 · Drug: Methotrexate
Pegvaliase (Palynziq) administered by subcutaneous injection. Dosing follows U.S. Prescribing Information and investigator judgement.
Also known as: Palynziq
Oral methotrexate 15 mg administered once weekly during the Tolerability Period and the Combination Treatment Period.
Also known as: MTX
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
Time frame: 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
Time frame: Baseline to Week 5, Week 9, Week 25, and Week 49
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
Time frame: Baseline through Week 49
Trough Palynziq plasma PK
To characterize the PK of Palynziq during co-administration with MTX in adults with PKU
Time frame: Baseline through Week 49
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)
Time frame: 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
Time frame: Baseline to Week 24 and Week 48
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Studies of the drug tested here: Pegvaliase