The main purpose of this study is to evaluate the long-term safety of PTC923 in participants with phenylketonuria, and to evaluate the changes from baseline in dietary phenylalanine (Phe)/protein consumption.

Eligible participants are:

Feeder participants: those who have completed a Phase 3 PTC Therapeutics (PTC) sponsored feeder study.

Non-feeder controlled participants: those who have not completed a feeder study and have blood Phe levels <360 μmol/L at study entry.

Non-feeder uncontrolled participants: those who have not completed a feeder study and have blood Phe levels ≥360 μmol/L at study entry.

Inclusion Criteria:

• Clinical diagnosis of PKU with hyperphenylalaninemia (HPA) documented by past medical history of at least 2 blood Phe measurements ≥600 μmol/L.
• Women of childbearing potential must have a negative pregnancy test at screening and agree to abstinence or the use of at least one highly effective form of contraception for the duration of the study, and for up to 90 days after the last dose of the study drug.
• Males who are sexually active with women of childbearing potential who have not had a vasectomy must agree to use a barrier method of birth control during the study and for up to 90 days after the last dose of study drug. Males must also refrain from sperm donations during this time period.
• Willing to continue current diet unchanged while participating in the study (unless specifically instructed to change diet during the study by the investigator).

Exclusion Criteria:

• Inability to tolerate oral medication.
• A female who is pregnant or breastfeeding, or considering pregnancy.
• Serious neuropsychiatric illness (for example, major depression) not currently under medical control, that in the opinion of the investigator or PTC, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant.
• Past medical history and/or evidence of renal impairment and/or condition including moderate/severe renal insufficiency (glomerular filtration rate [GFR] <60 milliliters [mL]/minute [min] min as estimated most recently during qualifying participation in a feeder study) and/or under care of a nephrologist.
• Any other condition that in the opinion of the investigator or PTC, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant.
• Requirement for concomitant treatment with any drug known to inhibit folate synthesis (for example, methotrexate).
• Concomitant treatment with tetrahydrobiopterin (BH4) supplementation (for example, sapropterin dihydrochloride, KUVAN) or pegvaliase-pqpz (PALYNZIQ).

Additional criteria for non-feeder participants who did not participate in a feeder study:

• Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, and peptic ulcer disease, etc) that could affect the absorption of study drug.
• History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy.
• History of allergies or adverse reactions to synthetic BH4 or sepiapterin.
• Any clinically significant laboratory abnormality as determined by the investigator.
• Any abnormal physical examination and/or laboratory findings indicative of signs or symptoms of renal disease, including calculated GFR <60 milliliters (mL)/minute/1.73 square meter (m^2).

Confirmed diagnosis of a primary BH4 deficiency as evidenced by biallelic pathogenic mutations in 6-pyruvoyltetrahydropterin synthase, recessive GTP cyclohydrolase I, sepiapterin reductase, quinoid dihydropteridine reductase, or pterin-4-alphacarbinolamine dehydratase genes.