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A Phase 3, Open-Label, Multi-Center Study to Assess the Safety and Efficacy of BMN 165 in Japanese Subjects 18 Years of Age and Older With Phenylketonuria

A Phase 3 Study to Assess the Safety and Efficacy of BMN 165 in Japanese Adults With Phenylketonuria

12

A total of 12 participants were enrolled into the study at 3 clinic sites in Japan. On Day 1 of the study and study treatment, the participants' age ranged from 20 to 46 years. Eight participants were males and 4 were females. All participants were Japanese. The mean (SD) blood Phe concentration at naive baseline was 1032.33 (166.21) micro mol/L.

The study comprised of a 4-week Screening period, a 52-week Part 1 which included an Induction/Titration/Maintenance Phase, and a 168-week Part 2 which was a Long-term Extension Phase. All participants completed the induction and titration dosing regimen, and 11 participants completed Part 1. One participant withdrew from the study at Week-28.

Overall, all 12 participants reported at least 1 treatment-emergent adverse event and all 12 reported at least 1 Adverse Event (AE) assessed by the investigator as related to BMN 165. The most common (>= 40% of the participants) AEs by preferred term (PT) overall were injection site erythema and injection site swelling (each 83.3%) of participants, arthralgia (75.0%), nasopharyngitis (66.7%), malaise (66.7%), dermatitis allergic (58.3%), injection site pruritus, and urticaria (each 50.0%), injection site pain, pyrexia, headache, COVID-19, complement factor C3 levels decreased and complement factor C4 levels decreased (41.7% for each). Three participants (25.0%) experienced AEs with a CTCAE severity Grade of >= 3 (diverticulitis intestinal haemorrhagic, fall, arthritis allergic [2 events], and anaphylactic reaction). Except for the two Grade 3 events of arthritis allergic, all other Grade 3 events were assessed as unrelated to the study drug. Overall, 4 participants reported 6 treatment-emergent SAEs: 2 Grade 2 SAEs of nasopharyngitis and uterine polyp, and 4 Grade 3 SAEs of arthritis allergic, anaphylactic reaction, diverticulitis intestinal haemorrhagic, and fall. Except for the Grade 3 SAE of arthritis allergic which was assessed as related to treatment with BMN 165, no other SAEs were assessed as related to treatment. None of the SAEs lead to study drug discontinuation. Overall, 7 participants (58.3%) reported at least 1 AE leading to study drug interruption or dose reduction. All events leading to dose reduction or interruption were non-serious, of mild to moderate severity, and assessed by the investigator as related to the study drug. During the study, 1 participant experienced a Grade 3 event of anaphylactic reaction. No action was taken with BMN 165 due to the event. A skin prick test for peach was performed and the result was positive. BMN 165 was continued, and there was no recurrence of an anaphylactic reaction. The causality of the anaphylactic reaction was assessed by the investigator as related to peach protein and not suspected to be related to BMN 165. Six (50.0%) participants experienced 7 AESIs including: dermatitis allergic, alopecia (2 events), hypersensitivity, impetigo, rash, and anaphylactic reaction. All 12 participants had hypersensitivity AEs. No deaths or AEs leading to discontinuation were reported.

The primary efficacy results confirm the efficacy of BMN 165 in reducing blood Phe concentrations in Japanese participants. A mean (SD) percent change from naive baseline (overall) from Years 1 to 4 ranged from -42.9% (68.37%) to -77.0% (32.01%), demonstrating a reduction on blood Phe levels over 4 years of treatment. No clear trend in change in blood Phe concentration from treatment naive baseline was observed across the dosing categories. A high proportion of participants were able to achieve substantial blood Phe reductions with increased BMN 165 treatment duration and dose. Three participants experienced hypophenylalaninemia during the Maintenance Phase. The intake of medical formula protein (without Phe) was reduced and/or the intake from protein intact food was increased, but blood Phe remained < 30 micro mol/L. In 2 of the 3 participants, reduction of BMN 165 treatment dose resulted in resolution of the event. The third participant also experienced increased levels of AST and ALT, for which treatment dose was reduced, but this resulted only in resolution of the increased AST and ALT; the hypophenylalaninemia event was continuing at study completion. The mean (SD) ADHD-RS IV Inattention score at baseline was 5.0 (4.67) which is below the level for observable symptoms. The mean (SD) change from baseline at Year 1 was -1.0 (1.61) which showed improvement over time with mean (SD) change from baseline of -3.0 (2.58) at Year 4. This result should be interpreted in view of the mean baseline ADHD-RS IV score of 5.0, which indicates the majority of patients were asymptomatic (having scores < 9 in the normative range) on the ADHD-RS IV inattention scale.

BMN 165 in Japanese participants with elevated blood Phe concentrations dosed according to an I/T/M dosing regimen demonstrated efficacy in reducing blood Phe concentrations and was generally well tolerated. No new safety issues were identified.

No

CMIC Co., Ltd.

Hamamatsucho Bldg., 1-1-1 Shibaura, Minatoku, Tokyo

ClinicalTrialInformation@cmic.co.jp

CMIC Co., Ltd.

Hamamatsucho Bldg., 1-1-1 Shibaura, Minatoku, Tokyo

+81-3-6779-8000

ClinicalTrialInformation@cmic.co.jp

completed

June. 13, 2019

Interventional

Screening :4 weeks in duration Part 1 : Phase 3, Open-Label, Multi-Center Study which is 52 weeks consisting of Induction/Titration period and Maintenance period. Part 2 : Long-term Extension period (up to 156 weeks).

treatment purpose

3

(Main items only)
1.Current diagnosis of PKU with 2 blood Phe concentrations > 600 micromole per liter during the Screening period (2 to 3 weeks between Phe assessments).
2.Average blood Phe concentration of > 600 micromole per liter over the past 6 months (per available data).
3.18 or more years of age and 70 or less years of age at the start of the Screening period (Day -28).
4.Has identified a competent adult 20 or more years of age who can observe the subject during study drug administration and for a minimum of 1 hour following administration for first 6 months of dosing, upon return to dosing after an AE, if dosing is increased, or per investigator determination. A home healthcare nurse may perform the study drug observations as acceptable by local regulatory and site requirements.
5.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 to have 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.
6.If sexually active must agree to either not have sex during this study or must use 2 acceptable methods of contraception while participating in the study beginning at Screening and for 4 weeks after discontinuing study drug.

(Main items only)
1. Previous treatment with BMN 165.
2. History of hypersensitivity to components of BMN 165.
3. Use of any investigational product or investigational medical device within 30 days prior to Screening (Day-28) or requirement for any investigational agent prior to completion of all scheduled study assessments.
4. Use of sapropterin (Biopten) treatment within 14 days prior to Day 1 (ie, first dose of BMN 165) or any other medication that is intended to treat PKU within 2 days prior to Day 1.
5. Use or planned use of any injectable drugs containing PEG (other than BMN 165), including medroxyprogesterone injection, within 3 months prior to Screening (Day-28) and during study participation.
6. Positive test for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, or hepatitis C antibody.
7. Pregnant or breastfeeding at Screening (Day -28) or planning to become pregnant (self or partner) or breastfeed at any time during the study.

Both

Phenylketonuria

investigational material(s)
Generic name etc : BMN 165
INN of investigational material : pegvaliase
Therapeutic category code : 399 Agents affecting metabolism, n.e.c.
Dosage and Administration for Investigational material : BMN 165 will be administered SC at dose levels of 2.5 to 60 mg. The minimum dose is a single weekly dose of 2.5 mg (for a total weekly dose of 2.5 mg). The maximum allowable daily dose is 40 mg/day (for a maximum weekly dose of 280 mg) after a minimum of 24 weeks on 20 mg/day during Part 1. Subjects may increase dose up to 60 mg/day in Part 2 (for a maximum weekly dose of 420 mg) after a minimum of 16 weeks on 40 mg/day.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

efficacy
The primary objective of the study is to evaluate the efficacy and safety of BMN 165.
The primary efficacy evaluations are observed blood Phe concentration,and change in blood Phe concentration and percentage change in blood Phe concentration from treatment naive baseline. Safety variables will be assessed for AEs, clinical laboratory tests, vital signs, physical examination, ECG and immunogenicity tests.

pharmacokinetics
The secondary objective of the study is to characterize the PK of BMN 165. Through and intensive plasma BMN 165 concentrations will be summarized.

+81-6-6645-2121

Jan. 31, 2019

+81-562-93-2111

Jan. 31, 2019

+81-3-3293-1711

Jan. 31, 2019