Phase 3 Study to Evaluate the Efficacy & Safety of Self-Administered Injections of BMN165 by Adults With PKU

Study Overview
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Brief Summary
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The BMN 165 clinical development program has been designed to demonstrate the safety and efficacy of BMN 165 in reducing blood Phe concentrations in adults with PKU.

Detailed Description
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165-302 is a Phase 3, 4 Part, Randomized, Double-Blind, Placebo-Controlled, Discontinuation Study to Evaluate the Efficacy and Safety of Self Administered Subcutaneous Injections of BMN 165 by Adults With PKU. This study is open only to adults who have been exposed to BMN165 in a previous study. Study BMN 165-302 is a four-Part, Phase 3 study. Part 1: Open-label period Part 2: A Randomized, double-blind, placebo-controlled period of 8 weeks Part 3: Two sub-Parts to Part 3:- Part 3A - BMN 165 administered using vial and syringe during this open label period. Part 3B - BMN 165 administered using prefilled syringe during this open-label period. Part 4: A long-term, open-label extension period.

Official Title
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A Four-Part, Phase 3, Randomized, Double-Blind, Placebo- Controlled, Four-Arm, Discontinuation Study to Evaluate the Efficacy and Safety of Subcutaneous Injections of BMN 165 Self-Administered by Adults With Phenylketonuria (PKU)

Conditions
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Phenylketonuria (PKU)

Intervention / Treatment
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* Drug: BMN165 20mg/day
* Drug: BMN165 40mg/day
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Individuals eligible to participate in this study must meet all of the following criteria: Have completed a prior BMN 165 study (PAL-003, 165-205, or 165-301) prior to screening Have had a stable BMN 165 dose regimen for at least 14 days prior to screening Are at least 18 y/o and no older than 70 y/o at screening Subjects who are < 18 y/o and are already enrolled into Study 165-301 under Amendment #1 (10JAN2014) may enroll into this study Has identified a person who is > 18 y/o who has the neurocognitive and linguistic capacities to comprehend and complete the Profile of Mood States (POMS)-Observer rated scale Has identified a competent person(s) > 18 y/o who can observe the subject during study drug administration at certain points in the study A home healthcare nurse may perform the study drug observations 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; for minors, parent or guardian provides written consent and assent may be requested Are willing and able to comply with all study procedures For females of childbearing potential, a negative pregnancy test at screening and willing to have additional pregnancy tests during the study If sexually active, willing to use two acceptable methods of contraception during and for 4 weeks after the study Males post vasectomy for 2 years with no known pregnancies do not need to use any other forms of contraception 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 dietitian confirming that the subject is capable of maintaining their diet Have neurocognitive and linguistic capacities to comprehend and answer investigator's prompts for the Attention Deficit Hyperactivity Disorder Rating Scale (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 ≥8 weeks prior to enrollment and willing to maintain stable dose throughout study unless a change is medically indicated General good health, as evidenced by physical examination, clinical laboratory evaluations, and ECG tests 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 (except BMN 165) 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 (except BMN 165) intended to treat PKU, including the use of large neutral amino acids, within 2 days prior to the administration of study drug Have known hypersensitivity to Dextran® or components of Dextran Use or planned use of any injectable drugs containing PEG (except for BMN 165), including medroxyprogesterone injection, within 3 months prior to screening and during study participation Current use of levodopa A positive test for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody A history of organ transplantation or taking chronic immunosuppressive therapy A history of substance abuse in the past 12 months or current alcohol or drug abuse Current participation in the Kuvan registry study (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. 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 at least 2x the upper limit of normal Creatinine at least 1.5x the upper limit of normal

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BMN165 20mg/day<br>BMN165 20mg/day self-administered daily | Drug: BMN165 20mg/day<br>* BMN165 20mg/day self-administered daily<br>* Other names: PEG-PAL;|
| Placebo Comparator: 20 mg/day Placebo<br>20 mg/day Placebo self-administered daily | Drug: Placebo<br>* Non-drug placebo, self-administered daily<br>* Other names: Dextran 40;|
| Active Comparator: BMN165 40mg/day<br>BMN165 40mg/day self-administered daily | Drug: BMN165 40mg/day<br>* BMN165 40mg/day self-administered daily<br>* Other names: PEG-PAL;|
| Placebo Comparator: 40 mg/day Placebo<br>40 mg/day Placebo self-administered daily | Drug: Placebo<br>* Non-drug placebo, self-administered daily<br>* Other names: Dextran 40;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Blood Plasma Phenylalanine (Phe) Concentration at Part 2 | Blood phe concentration in subjects previously exposed to BMN165 who were administered BMN165 20 or 40 mg/day compared with those who were administered a matching placebo. | At Part 2 baseline and change from baseline at Part 2 week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Cognitive and Mood Symptoms Measured by ADHD Rating Scale (RS)-IV Inattention Subscale at Part 2 | Attention deficit hyperactivity disorder rating scale IV (ADHD RS-IV) is investigator-rated, 9-item, inattention subscale score ranges from 0 to 27, with higher scores indicative of a greater degree of impairment and a baseline score >9 indicative of a presence of symptoms. | At Part 2 baseline and change from baseline at Part 2 week 8 | 
| Change From Baseline in the Blood Plasma Phenylalanine (Phe) Concentration at Part 4 | The long term effect of multiple dose levels of BMN165 on blood phe concentration in subjects who are administered BMN165 using pre-filled syringes. | At Part 4 week 57, 105, 161, 209 and 249 | 
| Change From Baseline in the Cognitive and Mood Symptoms Measured by PKU POMS TMD at Part 2 | Phenylketonuria (PKU) Total Mood Disturbance (TMD) Profile of Mood States (POMS) PKU POMS TMD is self-rated, each item in the tool is rated using a five-point Likert scale: 0 (not at all), 1 (a little), 2 (moderately), 3 (quite a bit), and 4 (extremely). | At Part 2 baseline and change from baseline at Part 2 week 8 | 
| Change From Baseline in the Cognitive and Mood Symptoms Measured by PKU POMS Confusion Subscale at Part 2 | PKU POMS confusion mood domain (referred to as the confusion subscale) is self-rated, each item in the tool is rated using a five-point Likert scale: 0 (not at all), 1 (a little), 2 (moderately), 3 (quite a bit), and 4 (extremely). | At Part 2 baseline and change from baseline at Part 2 week 8 | 
| Change From Baseline in the Cognitive and Mood Symptoms Measured by POMS TMD at Part 2 | Full-length POMS TMD is self-rated, each item in the tool is rated using a five-point Likert scale: 0 (not at all), 1 (a little), 2 (moderately), 3 (quite a bit), and 4 (extremely). | At Part 2 baseline and change from baseline at Part 2 week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PKU, PEG-PAL, Prism, BioMarin, rAvPAL-PEG, BMN165