PhenylketonuriaPhase 4NCT07477691
Immune Modulation During Palynziq® Treatment in Adults (IMPALA)
A Phase 4 study testing Pegvaliase and Methotrexate in people with Phenylketonuria, run by BioMarin Pharmaceutical at 12 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Phenylketonuria
- What is being tested?
- Pegvaliase and Methotrexate
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 12 sitesUnited States
- Study dates
- 29 May 2026to 30 Sep 2027
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
12 sites in 1 country. Contact the study team or a site near you to ask about taking part.
12 sites in 1 country
United States12 sites, 12 recruiting
- Not yet recruiting
Children's Hospital Colorado
Aurora, Colorado, 80045
- Not yet recruiting
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611
- Recruiting
UT Southwestern Medical Center
Dallas, Texas, 75390
Markey McNutt
- Not yet recruiting
Indiana University School of Medicine
Indianapolis, Indiana, 46202
- Not yet recruiting
UCLA Dept. of Human Genetics
Los Angeles, California, 90095
- Not yet recruiting
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, 53226
- Not yet recruiting
University of Minnesota Medical School
Minneapolis, Minnesota, 55455
- Not yet recruiting
University of Pittsburgh Medical Center (UPMC) - Children's Hospital of Pittsburgh
Philadelphia, Pennsylvania, 19104
- Not yet recruiting
Oregon Health & Science University (OHSU) - PARENT
Portland, Oregon, 97239
- Not yet recruiting
University of Rochester Medical Center (URMC)
Rochester, New York, 14642
- Not yet recruiting
University of Utah Hospital
Salt Lake City, Utah, 84108
- Not yet recruiting
University Of South Florida Medical Center
Tampa, Florida, 33613
About this study
Official title: 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.
Read the 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
- Conditions
- Phenylketonuria
- Being tested
- Pegvaliase, Methotrexate
- Keywords
- PKU, Phenylketonuria, Pegvaliase, Palynziq, Methotrexate, Immune Response, Safety, Immune Modulation, BMN 165-401, Hyperphenylalaninemia, Enzyme Substitution Therapy, Pharmacologic Immunosuppression
- Medical subject headings
- Phenylketonurias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PegvaliaseBiological
Also called Palynziq
Pegvaliase (Palynziq) administered by subcutaneous injection. Dosing follows U.S. Prescribing Information and investigator judgement.
MethotrexateDrug
Also called MTX
Oral methotrexate 15 mg administered once weekly during the Tolerability Period and the Combination Treatment Period.
| Study group | Role | What they receive |
|---|---|---|
| Palynziq naïve | Experimental | 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). Receives: Biological: Pegvaliase; Drug: Methotrexate |
| Palynziq experienced | Experimental | 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). Receives: Biological: Pegvaliase; Drug: Methotrexate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: Baseline to Week 5, Week 9, Week 25, and Week 49
Secondary outcomes (2)
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
Measured: Baseline through Week 49
Trough Palynziq plasma PK
To characterize the PK of Palynziq during co-administration with MTX in adults with PKU
Measured: Baseline through Week 49
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2026
- Study start29 May 2026
- Primary completion30 Sep 2027 (estimated)
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PhenylketonuriaStudies of the same condition, open and under way.
- More trials run by BioMarin PharmaceuticalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- BioMarin Pharmaceutical
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, MD, Study director, BioMarin Pharmaceutical
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07477691
- Sponsor's protocol ID
- 165-401
- Other IDs
- 2021-005058-27
- Status last verified
- Jun 2026
- First submitted
- 13 Mar 2026
- Last updated
- 17 Jun 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 4 Study of Immune Modulation During Palynziq® Treatment in Adults With Phenylketonuria (PKU)
- ClinicalTrials.gov ID
- NCT07477691
- Acronym / sponsor ID
- 165-401
- Conditions
- Phenylketonuria
- Keywords
- PKU, Phenylketonuria, Pegvaliase, Palynziq, Methotrexate, Immune Response, Safety, Immune Modulation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- BioMarin PharmaceuticalIndustry (pharma, biotech, devices)
- Study start
- 29 May 2026 (actual)
- Primary completion
- 30 Sep 2027 (estimated)
- Study completion
- 30 Sep 2027 (estimated)
- First posted
- 17 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Palynziq naïve | Experimental | Biological: Pegvaliase, Drug: MethotrexateIndividuals 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). |
| Palynziq experienced | Experimental | Biological: Pegvaliase, Drug: MethotrexateIndividuals 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). |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PegvaliaseAlso: PalynziqPegvaliase (Palynziq) administered by subcutaneous injection. Dosing follows U.S. Prescribing Information and investigator judgement. | Biological | Palynziq experienced, Palynziq naïve |
| MethotrexateAlso: MTXOral methotrexate 15 mg administered once weekly during the Tolerability Period and the Combination Treatment Period. | Drug | Palynziq experienced, Palynziq naïve |
Primary outcome
Change in blood Phe levels from baseline to Week 25 and Week 49
Time frame: Baseline to Week 25 and Baseline to Week 49
To evaluate blood Phe response in adults with PKU co-administered Palynziq with MTX for 6 months
Anti-PEG IgG, IgM, anti-PAL IgG, IgM levels at Weeks 5, 9, 25, and 49
Time frame: Baseline to Week 5, Week 9, Week 25, and Week 49
To evaluate the ability of MTX to modulate the immune response to Palynziq in adults with PKU
2 secondary outcomes
Incidence of TEAEs
Time frame: Baseline through Week 49
Trough Palynziq plasma PK
Time frame: Baseline through Week 49
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Medical Director, MD study director
BioMarin Pharmaceutical
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Pegvaliase and Methotrexate in people with Phenylketonuria, run by BioMarin Pharmaceutical at 12 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 17 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Trial Specialist (1-800-983-4587, medinfo@bmrn.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in blood Phe levels from baseline to Week 25 and Week 49 (time frame: Baseline to Week 25 and Baseline to Week 49). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2026.