This study is an international, multi-center, randomized, double-blind, placebo-controlled, two-treatment, two-period cross-over study to evaluate the pharmacodynamics, safety, tolerability and pharmacokinetics of a single oral dose of CDX-6114 in patients with phenylketonuria (PKU).

• Inclusion criteria

  1. Male and female patients between the ages of 18 and 55 years (inclusive) with a diagnosis of classical PKU by either a historical blood Phe concentration of > 1200 mol/L at any time or a genetic diagnosis of PKU.

  2. Patients capable of following dietary instructions to maintain protein intake stable throughout the study duration based on principal investigator and dietician assessment.

  3. Patients with a blood Phe concentration < 1200mol/L at screening.

  4. Have a body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.

  5. Patients must be in good general health, as determined by the PI or delegate, based on a medical evaluation including detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead electrocardiogram (ECG) and clinical laboratory tests.

  6. Male patients (unless surgically sterilised) and their female spouse/partner(s) who are of childbearing potential:

     1. Must agree to stay abstinent (where abstinence is the preferred and usual life-style of the patient), starting at screening and continuing throughout the clinical study period, and for 90 days after last study drug administration.

        Or

     2. Must be using highly effective contraception starting at screening and continuing throughout the clinical study period, and for 90 days after last study drug administration. Highly effective contraception is defined as follows:

     i. Injectable or implantable hormones ii. Intrauterine device iii. Surgical sterilisation iv. Sterilisation implant device v. Combined oral contraceptives vi. Use of a condom plus oral or injectable or implantable or intrauterine contraception

     c. These requirements do not apply to participants in a same sex relationship.

  7. Male patients must agree not to donate sperm starting at screening and continuing throughout the clinical study period, and for 90 days after last study drug administration.

  8. Female patients of childbearing potential and their spouse/partner(s):

     1. Must agree not to become pregnant during the clinical study period and for 30 days after last study drug administration.
     2. Must have a negative serum pregnancy test at screening.
     3. If heterosexually active, must agree to consistently use a form of highly effective contraception, starting at screening and continuing throughout the clinical study period, and for 30 days after last study drug administration. Highly effective contraception is defined as follows:

     i. Injectable or implantable hormones ii. Intrauterine device iii. Surgical sterilisation iv. Sterilisation implant device v. Surgical sterilisation of the male partner vi. Combined oral contraceptives vii. Use of a condom plus oral or injectable or implantable or intrauterine contraception

     Or

     d. Must agree to stay abstinent (where abstinence is the preferred and usual life-style of the patient), starting at screening and continuing throughout the clinical study period, and for 30 days after last study drug administration.

     e. These requirements do not apply to participants in a same sex relationship.

  9. Female patients of non-childbearing potential:

     1. Must have a confirmed clinical history of sterility (e.g. the patient is without a uterus).

        Or

     2. Must be postmenopausal as defined as amenorrhea for at least 1 year prior to screening and a laboratory confirmed serum follicle stimulating hormone (FSH) level ≥ 40mIU/mL or similar value considered to be in the menopausal range.

  10. Female patients must agree not to breastfeed from screening, throughout the clinical study period, and until 90 days after last study drug administration.

  11. Female patients must agree not to donate ova from screening, throughout the clinical study period, and until 90 days after last study drug administration.

  12. Patient must be competent to understand the nature of the study and capable of giving written informed consent. Be willing to report for the scheduled study visits and communicate to study personnel about adverse events and concomitant medication use.

  13. Patient agrees not to participate in another interventional study while participating in the present clinical study.

Exclusion criteria

1. Female patient who has been pregnant within the 6 months prior to screening or breastfeeding within the 3 months prior to screening.
2. Evidence or history of clinically significant haematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies and childhood asthma) at time of screening.
3. Current or chronic history of gastrointestinal illness or conditions interfering with normal gastrointestinal anatomy or motility. Examples include gastrointestinal bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS) or celiac sprue.
4. Evidence or history of gastrointestinal symptoms that could lead to the assumption of an underlying gastrointestinal impairment.
5. Treatment with any anti-platelet and/or anticoagulant medication.
6. Evidence or history of specific food intolerance. Examples include coeliac disease, severe lactose or dairy food intolerance or a severe intolerance to any food/ingredient included in the standard breakfast.
7. Any positive result, on screening, for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCV) or antibodies to human immunodeficiency virus type 1 (HIV-1) and/or type 2 (HIV-2).
8. A positive drug/alcohol result.
9. Patient has a history of exceeding > 21 units of alcohol/week for male patients or > 14 units of alcohol/week for female patients within the 3 months prior to screening. One unit of alcohol is equivalent to 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of spirits.
10. Patient has a history of regular smoking (daily or most days in a week) or the use of nicotine products (3 or more nicotine-containing products) who would be unable to abstain from smoking during the confinement periods in the Phase 1 Unit.
11. Patient has used any recreational drugs of abuse within the 3 months prior to screening.
12. Patient has a pulse rate ≤ 50 or ≥ 100 bpm; mean systolic blood pressure (SBP) > 140 mmHg; mean diastolic blood pressure (DBP) > 90 mmHg at screening (excluding white-coat hypertension; therefore, a repeat test showing results within range will be acceptable).
13. Patient has any clinically significant abnormalities at screening in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the PI or delegate, which may interfere with the interpretation of QTc interval changes including abnormal ST-T wave morphology.
14. Patient has prolonged QTcF (QT interval corrected for heart rate using Fridericia's formula) > 450 ms for male patients or > 470 ms for female patients, or a shortened QTcF < 300 ms or a family history of prolonged QT syndrome, at screening.
15. Patient has any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis at screening as judged by the PI or delegate, including: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) or Total bilirubin (TBL) more than 2.0 times above the Upper Limit of Normal (ULN).
16. Plasma donation within the 14 days prior to screening or any whole blood donation/significant blood loss > 500 mL during the 3 months prior to screening.
17. Treatment with any Investigational Drug or Device/Treatment within the 30 days prior to the first administration of study drug.
18. Use of any prescribed or non-prescribed medication including herbal medicines, antacids and analgesics (other than anti-hypertensive drugs, oral contraceptives, paracetamol or multi-vitamins) for the two weeks prior to the initial administration of the study medication or up to a minimum of 5 times the half-life of the medication if it has a long half-life.
19. Known allergy or adverse reaction history to any of the oral dose formulation components e.g. mannitol.
20. Use of Sapropterin (KUVAN) or pegylated phenylalanine ammonia lyase (Palinzyk) or SYNB1618 or any Phenylalanine-lowering drug within the last 4 weeks.