A Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-181 in Subjects With Phenylketonuria

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

The primary purpose of this study is to assess the safety and tolerability of AG-181 in subjects with Phenylketonuria (PKU).

Study Overview

• Status: Recruiting
• Conditions: Phenylketonuria
• Intervention / Treatment: Drug: AG-181

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Agios Medical Affairs; Phone Number: 833-228-8474; Email: medinfo@agios.com

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • University of Texas Southwestern Medical Center (UTSW)

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: AG-181; Subjects will receive AG-181 from Day 1 to Day 28.	Drug: AG-181; AG-181 film-coated tablets
Experimental: Cohort 2 (Optional Cohort): AG-181; Subjects will receive AG-181.	Drug: AG-181; AG-181 film-coated tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) by Type, Severity, and Relationship to the Study Drug	Up to Day 42

Secondary Outcome Measures

Outcome Measure	Time Frame
Plasma Concentration of AG-181	Up to Day 28
Maximum Concentration (Cmax) of AG-181	Up to Day 28
Time to Maximum (Peak) Concentration (Tmax) of AG-181	Up to Day 28
Area Under the Concentration-Time Curve (AUC) of AG-181	Up to Day 28
Apparent Total Body Clearance (CL/F) of AG-181	Up to Day 28
Apparent Volume of Distribution in the Terminal Phase (Vz/F) of AG-181	Up to Day 28
Change From Baseline in Phenylalanine (Phe) Concentration	Baseline up to Day 28

Collaborators and Investigators

• Sponsor: Agios Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2026
• Primary Completion (Estimated): January 17, 2028
• Study Completion (Estimated): January 17, 2028

Study Registration Dates

• First Submitted: November 17, 2025
• First Submitted That Met QC Criteria: November 17, 2025
• First Posted (Actual): November 21, 2025

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• 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
• Other Study ID Numbers: AG181-C-002; 2025-522630-31-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No