An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165

Primary and Secondary Outcomes:

The primary objective of the study is the following:

- To characterize the safety and tolerability during induction, titration, and maintenance
dosing in BMN 165-naïve subjects who self administer BMN 165 at dose levels of 20 mg/day
and 40 mg/day

The secondary objective of the study is the following:

- To evaluate blood Phe concentration during induction, titration, and maintenance dosing
in BMN 165-naïve subjects who self administer BMN 165 at dose levels of 20 mg/day and 40
mg/day

The tertiary objectives of the study are the following:

- Percentage of daily recommended intake for age of natural protein intake

- Dietary protein intake from medical food and intact food

- The ADHD-RS score (-Investigator Rated; inattentive subscale score, total score, and
hyperactivity/impulsivity subscale score)

- POMS scores (-Observer Rated and -Subject Rated)

- Trough plasma concentrations of BMN 165

Primary Analysis:

All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The
incidence of AEs will be summarized by system organ class, preferred term, relationship to
study drug, and severity for the subjects who are randomized to the 40 mg/day dose, the 20
mg/day dose, and overall. A by-subject listing will be provided for those subjects who
experience an SAE, including death, or experience an AE associated with early withdrawal from
the study or study drug. Hypersensitivity AEs and AEs that result in dosing interruption or
dose reduction are of interest, and the percentage of subjects who report these AEs will be
presented.

Clinical laboratory data will be summarized by the type of laboratory test for the subjects
who are randomized to the 40 mg/day dose, the 20 mg /day dose, and overall. Frequency and
percentage of subjects who experience abnormal (ie, outside of reference range) and/or
clinically significant abnormalities after study drug administration will be presented for
each clinical laboratory test. For each clinical laboratory test, descriptive statistics will
be provided for baseline and all subsequent post-baseline visits. Changes from baseline to
the post-baseline visits will also be provided. Descriptive statistics, including clinically
significant changes from baseline, of vital signs, physical examination results, ECG test
results, and immunogenicity test results will also be provided in a similar manner.
Additionally, antibodies and titers will be summarized at the scheduled time point.

Detailed statistical methods will be provided in the Statistical Analysis Plan (SAP).

Secondary Analysis:

The secondary efficacy endpoint is change from baseline to end of study in blood Phe
concentration.

Baseline is defined as the average of blood Phe concentrations collected prior to dosing at
the Screening Visit and on Day 1.

The primary analysis method for the secondary endpoint will use a repeated measures model,
with change from baseline Phe as the dependent variable and dose (40 mg/day or 20 mg/day),
study week, and baseline Phe as independent variables.

A responder analysis will be presented as a cumulative distribution function. The percentage
of subjects with blood Phe concentration below "X" umol/L at the end of the study will be
plotted and summarized for various "X" as a cumulative distribution function for each of the
2 doses and overall.

Detailed statistical methods will be provided in the SAP.

Tertiary Analyses:

The statistical analysis method for tertiary endpoints (protein intake; the ADHD-RS IV score)
will be descriptive. More details regarding the analysis methods for the tertiary endpoints
will be provided in the SAP.

Trough plasma concentrations of BMN 165 will be evaluated.

DMC The Data Monitoring Committee (DMC) will act in an advisory capacity to

BioMarin to monitor subject safety and the efficacy of BMN 165 in subjects who participate in
Study BMN 165-301 .The DMC responsibilities may include the following:

- Review the study protocol, informed consent and assent documents, and plans for data
monitoring

- Evaluate the progress of the trial; study data quality; timeliness; subject recruitment,
accrual and retention; subjects' risk versus benefit; and other factors that could
affect the study outcome

- Consider relevant information that may have an effect on the safety of the participants
or the ethics of the study

- Protect the safety of the study participants in accordance with the stopping rules as
defined in study protocol

- Make recommendations to BioMarin concerning continuation or termination of the study or
other modifications of the study based on their observations

- If appropriate, conduct interim analysis of safety and efficacy

INCLUSION CRITERIA

Individuals eligible to participate in this study must meet all of the following criteria:

- A current diagnosis of PKU with the following:

- Current blood Phe concentration >600 µmol/L at screening and

- 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 and ≤70 years of age at the time of screening

- Subjects who are < 18 years of age but are already enrolled into the study may
continue to participate

- If taking Kuvan, 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 capacities to comprehend and complete the POMS-Observer-rated scale

- Has identified 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.

- 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 2 acceptable methods of contraception while
participating in the study and 4 weeks after the study.

- 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.

- 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 dietician confirming that the subject
is capable of maintaining their diet in accordance with dietary information presented
in the protocol.

- Have neurocognitive and linguistic capacities to comprehend and answer investigator's
prompts for the ADHD RS- Investigator rated instrument and to complete the
POMS-Subject rated scale.

- If applicable, maintained stable dose of medication for attention deficit
hyperactivity disorder (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 and ECG tests performed at screening

EXCLUSION CRITERIA

Individuals who meet any of the following exclusion criteria will not be eligible to
participate in the study:

- Use of any investigational product or investigational medical device within 30 days
prior to screening or requirement for any investigational agent prior to completion of
all scheduled study assessments.

- Use of any medication that is intended to treat PKU (except Kuvan), including the use
of large neutral amino acids, within 2 days prior to administration of study drug Day
1 (first dose of BMN 165). Note: Kuvan treatment must be stopped ≥14 days before Day 1

- Use or planned use of any injectable drugs containing PEG (other than BMN 165),
including medroxyprogesterone injection, within 3 months prior to screening and during
study participation

- Known hypersensitivity to any components of BMN 165

- Current use of levodopa

- A positive test for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody

- A history of organ transplantation or on chronic immunosuppressive therapy

- A history of substance abuse (as defined by the Diagnostic and Statistical Manual of
Mental Disorders [DSM IV]) in the past 12 months or current alcohol or drug abuse

- Current participation in the Kuvan registry study (PKU Demographics, Outcomes and
Safety [PKUDOS]). Patients may discontinue the PKUDOS registry trial to allow
enrollment in this study

- Pregnant or breastfeeding at screening or planning to become pregnant (self or
partner) or breastfeed at any time during the study

- Concurrent disease or condition that would interfere with study participation or
safety (eg, history or presence of clinically significant cardiovascular, pulmonary,
hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,
neurological, oncologic, or psychiatric disease)

- Major surgery planned during the study period

- Any condition that, in the view of the investigator, places the subject at high risk
of poor treatment compliance or terminating early from the study

- Alanine aminotransferase (ALT) concentration ≥2 times the upper limit of normal

- Creatinine >1.5 times the upper limit of normal.