• A current diagnosis of PKU with the following
o Current blood Phe concentration > 600 μmol/L at screening and
o Average blood Phe concentration of > 600 μmol/L over the past 6 months (per available data)
• Have no previous exposure to BMN 165.
• Are ≥ 18 years of age and ≤ 70 years of age at the time of screening.
If taking Kuvan® treatment, have a treatment end date ≥ 14 days prior to Day 1 (ie, first dose of BMN 165).
• Are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures.
• Are willing and able to comply with all study procedures.
• Has identified a person who is ≥ 18 years of age who has the neurocognitive and linguistic capabilities to comprehend and complete the POMS-Observer-rated scale.
• Has identifed a competent person or persons who are ≥ 18 years of age who can observe the subject during study drug administration and for a minimum of 1 hour following administration until dose titration has completed and if needed upon return to dosing after an AE and per investigator determination.
o A home healthcare nurse may perform the study drug observations.
• For females of childbearing potential, must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. (Females are considered not of childbearing potential if they have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy.)
• If sexually active, must be willing to use two acceptable methods of contraception while participating in the study.
o Males post vasectomy 2 years with no known pregnancies for at least 2 years do not need to use any other forms of birth control during the study.
o Females who have been in menopause for at least 2 years, have had a tubal ligation at least 1 year prior to screening, or have had a total hysterectomy do not need to use any other forms of contraception during the study.
• Have received documented approval from a study dietitian confirming that the subject is capable of maintaining their diet in accordance with Section 9.6.
• Have neurocognitive and linguistic capacities to comprehend and answer investigator's prompts for the ADHD-RS IV scale and POMS scales.
• If applicable, maintained stable dose of medication for ADHD, depression, anxiety, or other psychiatric disorder for > 8 weeks prior to enrollment and willing to maintain stable dose throughout study unless a change is medically indicated.
• Are in generally good health, as evidenced by physical examination, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and ECG tests performed at screening.