AG-181 safety and tolerability in people with phenylketonuria

A Phase 1b, Open-label, Multicenter, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of AG-181 in Subjects With Phenylketonuria

This trial will test AG-181 for safety and tolerability in people with PKU who have high blood phenylalanine and at least one R408W PAH mutation.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 69 Years
• Sex: All
• Sponsor: Agios Pharmaceuticals, Inc. (Industry-sponsored)
• Locations: 1 site (Dallas, Texas)
• Trial ID: NCT07241234 on ClinicalTrials.gov

What this trial studies

This Phase 1 interventional study will administer AG-181 to participants with genetically confirmed phenylketonuria and monitor safety, tolerability, pharmacokinetics, and pharmacodynamics. Eligible participants must have two mutant PAH alleles with at least one R408W variant and persistently elevated plasma phenylalanine (>600 μmol/L) during screening. The protocol includes central genotyping confirmation, repeated blood Phe measurements, and dietitian-supervised stabilization of protein and Phe intake. All dosing and follow-up visits are conducted at the University of Texas Southwestern Medical Center with close monitoring for adverse events and drug-related effects.

Who should consider this trial

Good fit: People with genetically confirmed PKU (two PAH mutations with at least one R408W), average plasma Phe >600 μmol/L during screening (no individual assessment <360 μmol/L after Day -20), BMI 18–35 kg/m², weight ≥50 kg, and dietitian approval to maintain consistent protein/Phe intake are ideal candidates.

Not a fit: Patients without the R408W mutation, those with well-controlled Phe below the required thresholds, pregnant people, or individuals outside the BMI/weight limits are unlikely to qualify or receive benefit from this Phase 1 safety study.

Why it matters

Potential benefit: If safe and showing favorable PK/PD, AG-181 could become a new option to help lower phenylalanine levels or improve metabolic control for PKU patients with the R408W mutation.

How similar studies have performed: Other approved PKU therapies such as sapropterin and pegvaliase have shown clinical benefit by different mechanisms, but AG-181 is an early-phase investigational therapy with limited prior clinical data in this specific drug.

Eligibility criteria

Key Inclusion Criteria:

* Diagnosis of PKU, defined as documented presence of 2 mutant alleles in the phenylalanine hydroxylase (PAH) gene, of which at least 1 is the R408W mutation, as determined during Screening per the genotyping performed by the study central genotyping laboratory.
* At least 1 plasma Phe concentration greater than (\>) 600 micromoles per liter (μmol/L) in the 52 weeks before providing informed consent.
* Average concentration of plasma Phe \> 600 μmol/L in Phe samples taken during Screening, with no individual assessment below 360 μmol/L. Any Phe samples taken after Day -20 will not be included.
* Body mass index (BMI) greater than or equal to (≥) 18.0 kilograms per meter square (kg/m\^2) to lesser than or equal to (≤) 35.0 kg/m\^2 and weight ≥ 50 kilograms (kg) at any time during the Screening Period.
* Documented approval from a dietitian confirming that the subject can maintain their diet consistent in protein and Phe intake throughout the study as outlined in the Diet Manual.

Key Exclusion Criteria:

* Prior exposure to AG-181.
* Receiving inhibitors of P-glycoprotein (P-gp) that have not been stopped for ≥ 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) before administration of the first dose of study drug.
* Receiving products that are strong inhibitors or strong inducers of cytochrome P450 CYP1A2, CYP2C8, or CYP3A that have not been stopped for ≥ 28 days before administration of the first dose of study drug.
* Receiving treatment with an acid-reducing agent, including but not limited to proton pump inhibitors and H2 blockers. Short-acting acid-reducing agents such as calcium carbonate are permitted.
* Any preexisting condition that could (in the opinion of the Investigator) interfere with gastrointestinal anatomy or motility that may disrupt the absorption, metabolism, and/or excretion of the study drug.
* Any preexisting condition that could (in the opinion of the Investigator) interfere with hepatic or renal function that may disrupt the absorption, metabolism, and/or excretion of the study drug.
* Inability to tolerate oral medication.
* Unwillingness to washout from tetrahydrobiopterin (BH4) supplementation (eg, sapropterin dihydrochloride, Kuvan), pegvaliase-pqpz (Palynziq), or any other PKU therapy by Day -30 during Screening.

Where this trial is running

Dallas, Texas

• University of Texas Southwestern Medical Center (UTSW) — Dallas, Texas, United States (Recruiting)

Study contacts

• Study coordinator: Agios Medical Affairs

Conditions Phenylketonuria