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Table 18FDA documentation used for Kuvan approval process

Document Title“Clinical Team Leader Summary Review of NDA 22-181 Kuvan for the treatment of PKU; 12-3-2007“Clinical Team Leader Summary Review of NDA 22-181 Kuvan for the treatment of PKU; 12-3-2007“Clinical Team Leader Summary Review of NDA 22-181 Kuvan for the treatment of PKU; 12-3-2007
Trial NumberPKU-001 / PKU-003PKU-004PKU-006, Part 2
Patient Characteristics
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# screened for BH4 responsiveness

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# at enrollment

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# per protocol

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Age range

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Sex

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489 screened for BH4

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89 responders (≥30% blood Phe decrease from baseline to day 8), 88 participants randomized

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8-49 years, mean 20

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51M, 37F

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Extension study of PKU-003

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80 participants who completed PKU-003 (39 who had received BH4, 41 who had received placebo)

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8-49, mean 20

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47M, 33F

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Part 1 tested 90 PKU patients

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45 responders(≥30% blood Phe decrease from baseline, and a blood Phe ≤300 on day 8)

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4-12 yrs old (mean 7yrs)

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26 (58%) male

Study Drug ComparisonBH4 vs. placebo (double blind)Forced-dose titrationBH4 vs. placebo (double blind, placebo controlled)
Type of Randomization (x:x; #patients per drug vs. placebo)1:1; 41 and 47NA3:1; 33 and 12
Drug Dosing Protocol
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BH4 10mg/kg/day once a day

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6 week open label forced dose-titration: 5mg/kg/day for 2 weeks, then 20 mg/kg/day for 2 weeks, then 10mg/kg/day for 2 weeks. Then maintained on 10mg/kg/day for 4 weeks. Then 12 weeks of BH4 dosed at 5 (N=6), 10 (N=37), or 20 (N=37) mg/kg/day based on individual patient's blood Phe from the forced dose-titration

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BH4 20 mg/kg/d

Length of Study6 weeks22 weeks total BH4 use (with PKU-003 data)10 weeks of treatment
Diet Controlled/NotNo dietary changes madeNo dietary changesNo change for first 3 weeks of tx; at week 3, increased dietary Phe 5 mg/kg/day for 2 weeks if blood Phe ≤300. Further increase of dietary Phe at weeks 5, 7, and 9 with specific blood Phe levels while maintaining blood Phe at <360 micromol/L
Pretreatment Phe Levels Micromol/L (SD)G1: 848 (300)
G2: 888 (323)
844 (398)G1: 314 (107)
G2: 303 (74)
Outcomes MeasuredPrimary: Mean change in blood Phe from baseline at week 6
Secondary: Mean change from baseline in weekly blood Phe levels; proportion of patients who had blood Phe <600 μmol/L at week 6; AEs during tx
Primary: Change in blood Phe from baseline to weeks 10, 12, 16, 20, and 22
Secondary: Blood Phe at week 2, 4, 6. Safety and AEs
Primary: Mean dietary Phe tolerated after 10 weeks of double-blind treatment for each treatment group.
Secondary: Difference in blood Phe from baseline to pre-Phe supplement; comparison of tx groups in amount of Phe supplement tolerated
Publication of Matched DataLevy 2007113Lee 2008114Trefz 2009115

AE = adverse events; EU = European Union; FDA = Food and Drug Administration; NDA = New Drug Application; Phe = phenylalanine; PKU = phenylketonuria; tx = treatment

G1: BH4; G2: Placebo.

From: Results

Cover of Adjuvant Treatment for Phenylketonuria (PKU)
Adjuvant Treatment for Phenylketonuria (PKU) [Internet].
Comparative Effectiveness Reviews, No. 56.
Lindegren ML, Krishnaswami S, Fonnesbeck C, et al.

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