Supplemental Table 1. PKUDOS: Recommended Assessments and Schedule

Recommended Assessments / Historical Data Recorded at Screening / Performed/Recorded at Screening / Performed/Recorded Quarterly to Annually
Participant Authorization (required) / X
Demographics / X
Medical History / X / X
Physical Examination / X / X
Neurological evaluation (e.g., tremors, ataxia) / X / X / X
Neurocognitive evaluation / X / X / X
Behavioral Assessment / X / X
Adverse Events a / X
Blood Phe Concentration and history / Last 3 results / X / X
Dietary Phe intake and history / Last 3 reported intakes / X / X
Phe prescription history / Last 3 prescriptions / X / X
Vital signs/weight/height/pregnancy status / X / X
Head circumference for patients < 3 years of age / X / X
Sapropterin dosage / X / X
Clinical laboratory tests / X / X
Concomitant medicationsb / Last 28 days / X / X
Developmental assessmentc / X / X
Genotyping (PAH gene analysis)d / X / X
Blood tyrosine concentrations / Last 3 results / X / X
Osteoporosis screening / X / X / X

a: Adverse events may be reported at any time. Quarterly reporting is recommended.

b: Current medications should be recorded at the screening visit and any changes in medication should be recorded at each follow up visit.

c: Available data including school and/or work performance.

d: Record genotyping once, whenever the data are available

Supplement Table 2. Demographic data for Uninterrupted Use and Short-term Use Populations

Uninterrupted Kuvan Use Population / Short-term Kuvan Use Population
Number of Subjects / 504 / 211
Gender / Male: 253 (50.2%)
Female: 250 (49.6%)
Missing: 1 / Male: 94 (44.5%)
Female: 117 (55.5%)
Missing: 0
Race [b], n (%)
American Indian or Alaska Native / 2 / (0.4%) / 1 / (0.5%)
Asian / 8 / (1.6%) / 2 / (0.9%)
Black or African American / 1 / (0.2%) / 6 / (2.8%)
Native Hawaiian / Pacific Islander / 0 / (0.0%) / 0 / (0.0%)
White / 437 / (86.7%) / 191 / (90.5%)
Other / 8 / (1.6%) / 1 / (0.5%)
Ethnicity, n (%)
Hispanic or Latino / 46 / (9.1%) / 9 / (4.3%)
Not Hispanic or Latino / 455 / (90.3%) / 200 / (94.8%)
Missing / 3 / 2
Age Categories at First Kuvan Dose, n (%)
Birth to < 4 Years / 48 / (9.5%) / 10 / (4.7%)
4 Years to < 13 Years / 206 / (40.9%) / 60 / (28.4%)
13 Years to < 25 Years / 144 / (28.6%) / 86 / (40.8%)
>= 25 Years / 105 / (20.8%) / 55 / (26.1%)
Missing / 1 / (0.2%) / 0 / (0.0%)
Education at Study Entry, n (%)
Not in School a / 223 / (44.2%) / 109 / (51.7%)
Primary (1-2) / 39 / (7.7%) / 21 / (10.0%)
Elementary (3-5) / 62 / (12.3%) / 10 / (4.7%)
Middle (6-8) / 45 / (8.9%) / 15 / (7.1%)
High School (9-12) / 66 / (13.1%) / 25 / (11.8%)
College / 39 / (7.7%) / 17 / (8.1%)
Vocational / 4 / (0.8%) / 3 / (1.4%)
Masters / 1 / (0.2%) / 2 / (0.9%)
Doctoral / 2 / (0.4%) / 0 / (0.0%)
Missing / 23 / 9
Employment at Registry Entry
Currently Not Employed / 316 / (62.7%) / 125 / (59.2%)
Disabled / 11 / (2.2%) / 4 / (1.9%)
Employed <20 Hours per Week / 14 / (2.8%) / 8 / (3.8%)
Employed 20 to 39 Hours per Week / 26 / (5.2%) / 13 / (6.2%)
Employed >39 Hours per Week / 66 / (13.1%) / 36 / (17.1%)
Missing / 71 / 25

a: Subjects in kindergarten are classified as "Not in School."

b: Race categories are not mutually exclusive. Subjects in the ‘Hispanic or Latino’ ethnicity category are not summarized in any of the race categories.

Supplement Table 3. Mean ± SD Blood Phenylalanine (µmol/L), Actual Dietary Phe Intake (mg/day), and Change in Actual Intake from Pre-Sapropterin up to 5 years of exposure for a subgroup of Uninterrupted Use and Short-term Use Populations that had Blood Phe and Dietary Phe measured at the same time points.

Blood Phenylalanine / Actual Dietary Phenylalanine Intake
Uninterrupted Sapropterin Use Population / Short-term Sapropterin Use Population / Uninterrupted Sapropterin Use Population / Short-term Sapropterin Use Population
Time Interval / Blood Phe
(µmol/L) / D from Baseline
(µmol/L) (percent) / Blood Phe
(µmol/L) / D from Baseline
(µmol/L) / Population Mean Difference
(µmol/L) / Dietary Phe
(mg/day) / D from Baseline
(mg/day) / Dietary Phe
(mg/day) / D from Baseline
(mg/day) / Population Mean Difference
(mg/day)
Baseline
Pre-Sapropterin / 586 ± 363 / - / 854 ± 563 / - / 268
p=0.03 / 1183 ± 1091 / - / 1038 ± 868 / -145
NS
0 £ 1 year / 363 ± 296 / -223 (-38%)
p=0.0001 / 644 ± 421 / -211(-25%)
p=0.08 / 280
p<0.0001 / 1192 ± 936 / 9.1 (1%)
NS / 754 ± 671 / -285 (-27%)
NS / -439
p=0.004
> 1 year to £ 2 years / 386 ± 266 / -200 (-34%)
p=0.0002 / 615 ± 352 / -240 (-28%)
p=0.02 / 228
p<0.0001 / 1145 ± 851 / -38 (-3%)
NS / 601 ± 513 / -437 (-42%)
p=0.005 / -544
p<0.0001
> 2 year to £ 3 years / 414 ± 319 / -172 (-29%)
p=0.005 / 650 ± 352 / -204 (-24%)
p=0.05 / 236
p<0.0001 / 1307 ± 925 / 124 (10%)
NS / 587 ± 578 / -451 (-43%)
p=0.007 / -720
p<0.0001
> 3 year to £ 4 years / 409 ± 265 / -177 (-30%)
p=0.002 / 785 ± 386 / -69 (-8%)
NS / 376
p<0.0001 / 1158 ± 867 / -25 (-2%)
NS / 756 ± 902 / -282 (-27%)
NS / -402
p=0.01
> 4 year to £ 5 years / 401 ± 253 / -185 (-32%)
p=0.004 / 776 ± 370 / 375
p<0.0001 / 1087 ± 669 / -97 (-8%)
NS / 599 ± 756 / -488
p=0.003

NS: not significant

Supplement Table 4 Subjects 0-4 years – Blood Phe and Percent Change from Pre-Sapropterin Baseline up to 3 years Exposure for Uninterrupted Sapropterin Use and Short-term Use Populations a

Time / Blood Phe (mmol/L) Uninterrupted Use Population 0-4 years / Blood Phe (mmol/L) Short-term Use Population 0-4 years
Blood Phe by Venipuncture
Median; Mean ± SD (Nb) / Blood Phe by Filter Paper
Median; Mean ± SD (N) / Overall Mean of Medians / % Change from Baseline
Median; Mean / Blood Phe by Venipuncture
Median; Mean ± SD (N) / Blood Phe by Filter Paper
Median; Mean ± SD (N) / Overall Mean of Medians / % Change from Baseline Median; Mean
Baseline
Pre-Sapropterin Exposure / 227; 283 ± 143 (5) / 290; 335 ± 177 (15) / 259 / - / 490; 490 ± 437 (2) / 248; 297 ± 138 (4) / 369 / -
0 ≤ 1 year / 197; 278 ± 182 (8) / 205; 227 ± 103 (25) / 201 / -22 / 366; 421 ± 186 (4) / 279; 332 ± 128 (7) / 323 / -13
> 1 year to ≤ 2 years / 162; 232 ± 186 (8) / 220; 208 ± 74 (10) / 191 / -26 / 179; 179 ± 110 (2) / 188; 234 ± 133 (3) / 184 / -50
> 2 year to ≤ 3 years / 156; 174 ± 79 (4) / 144; 136 ± 83 (4) / 150 / -42 / - / 224; 224 (1) / 224 / -39

a: If a subject had more than one value during a period, the median was used.

b: Number of subjects (some subjects had multiple samples collected)

Supplement Table 5. Subjects 0-4 years - Prescribed and Actual Dietary Phe (mg/day) and Percent Change in Actual Dietary Phe Intake from Pre-Sapropterin up to 4 years Exposure for Uninterrupted Sapropterin Use and Short-term Use Populations a

Time Interval / Uninterrupted Use Population 0-4 years / Short-term Use Population 0-4 years
Prescribed Dietary Phe
Median; Mean ± SD (N) / Actual Dietary Phe Intake
Median; Mean ± SD (N) / Actual Dietary Phe
Median % Change from baseline
(Mean % Change) / Prescribed Dietary Phe
Median; Mean ± SD (N) / Actual Dietary Phe Intake
Median; Mean ± SD (N) / Actual Dietary Phe
Median % Change from baseline
(Mean % Change)
Baseline
Pre-Sapropterin Exposure / 359; 371 ± 103 (8) / 292; 343 ± 118 (6) / - / 180; 182 ± 43 (3) / 183; 183 ± 60 (2) / -
0-3 months / 525; 524 ± 384 (9) / 472; 450 ± 218 (9) / 62 (31) / 250; 250 ± 0 (1) / 250; 250 ± 0 (1) / 37 (37)
0 £ 1 year / 525; 580 ± 366 (22) / 575; 545 ± 265 (21) / 97 (59) / 285; 345 ± 135 (3) / 385; 380 ± 126 (4) / 110 (108)
> 1 year to £ 2 years / 400; 625 ± 397 (9) / 703; 850 ± 502 (8) / 141 (148) / 413; 413 ± 124 (2) / 364; 364 ± 116 (2) / 99 (99)
> 2 year to £ 3 years / 375; 400 ± 48 (3) / 367; 328± 86 (3) / 26 (-4) / - / 663; 663 ± 0 (1) / 262 (262)
> 3 year to £ 4 years / - / - / - / - / - / -

a: If a subject had more than one value during a period, the median was used.