An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165
Condition: Phenylketonuria
MeSH terms: Phenylketonurias
Intervention: BMN 165
Intervention description: After informed consent, eligible subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day. All subjects will initiate IP at a fixed-dose of 2.5 mg/week for 4 weeks (Induction). After the Induction Period, subjects will enter the Titration Period (Weeks 5 up to 34) where they will increase their weekly BMN 165 dose to a daily dose regimen of 20 mg/day or 40 mg/day. The Titration Period will be individualized to each subject based on a minimum of 6 weeks (the amount of time it takes to reach a dose regimen of 20 mg/day with no dose interruptions) and up to 30 weeks (accounts for dose reduction or interruption due to AEs). Subjects will stop titration once they have achieved either the 20 mg/day or 40 mg/day dose regimen. The majority of subjects will maintain the 20 or 40 mg/day dose regimen for at least an additional 2 weeks until a minimum of approximately 26 weeks or a maximum of 36 weeks in the study.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Masking description: All subjects receive Study Drug. Subjects will be randomized (1:1) to titrate up to one of two dose regimens: 20 mg/day or 40 mg/day.Eligible subjects will be randomized 1:1 using an IWRS to titrate to one of two dose regimens:
20 mg/day or 40 mg/day. The randomization will be stratified by blood Phe levels of 600 to 900 µmol/L and >900 µmol/ using the last available blood Phe concentration prior to Day 1 of the study.
Enrollment: 261.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: PKU; PEG-PAL; BioMarin; rAv-PAL PEG; BMN 165; open label; Prism301; Pegvaliase

Summary:

      The BMN 165 clinical development program has been designed to demonstrate the safety and
      efficacy of BMN 165 in reducing blood Phe concentrations in patients 18 to 70 years old with
      hyperphenylalaninemia due to PKU. Study BMN 165-301 is a Phase 3, open-label, randomized
      study designed to further characterize the safety of BMN 165 during two induction, titration,
      and maintenance dose regimens in adults with PKU who have not had previous exposure to BMN
      165 (naive). Subjects will be randomized (1:1) to titrate up to one of two dose regimens.
      Other key features of this study are the dose regimens chosen for induction and titration;
      the study duration; self administration of study drug; and the chosen tertiary objectives.
    

Eligibility criteria:

        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.