Slide 1: Safety and efficacy of pegvaliase in adolescents with phenylketonuria: Primary results from PEGASUS
Safety and efficacy of pegvaliase in adolescents with phenylketonuria: Primary results from PEGASUS, a phase 3 open-label randomized controlled study Stephanie Sacharow1, Ashley Andrews2, T. Andrew Burrow 3, Konstantia-Maria Chavele4, Julia Hennermann5, Shaun Jones4, Jasmine Knoll6, Melissa Lah7, La
Slide 2: COI Disclosure
ICIEM 2025 COI Disclosure Stephanie Sacharow Honoraria: N/A Stock or stock options: N/A Royalties or licenses: N/A Lecture fees: N/A Manuscript fees: N/A Research funding: BioMarin, PTC Therapeutics Scholarship fund: N/A Belonging to endowed chair by business: N/A Advisory board with travel expenses
Slide 3: Background
Background Phenylketonuria (PKU) • PKU is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase, resulting in accumulation of phenylalanine (Phe) in the blood and tissues1 • High Phe levels in the brain are associated with neurological, neurocognitive, and psychological s
Slide 4: Pegvaliase for the Treatment of PKU
Pegvaliase for the Treatment of PKU • Pegvaliase is a pegylated recombinant phenylalanine ammonia lyase that metabolizes Phe • The safety and efficacy of pegvaliase as an enzyme substitution therapy for adults with PKU were demonstrated in the phase 3 PRISM clinical development program1–3 • Pegvalia
Slide 5: PEGASUS Study Design
PEGASUS Study Design Part 1 Part 2 Primary Treatment Phase Extension Phase 72 weeks ≤142 weeks Pegvaliase Continue pegvaliase 4-week Randomize screening/run-in 2:1 Diet only Initiate pegvaliase • Change from baseline in blood Phe after 72 weeks • Phase 3, multicenter, open-label, randomized Primary
Slide 6: PEGASUS Study Design
PEGASUS Study Design Part 1 Part 2 Primary Treatment Phase Extension Phase 72 weeks ≤142 weeks Pegvaliase Continue pegvaliase 4-week Randomize screening/run-in 2:1 Diet only Initiate pegvaliase Results from the Primary Treatment Phase are presented here 6
Slide 7: Participant Disposition
Participant Disposition Randomized N=55 ITT and Pegvaliase Diet only Safety Population N=36 N=19 Discontinued, n=4a • AE (n=1) Discontinued, n=2 • Physician decision (n=1) • Withdrawal (n=2) • Withdrawal (n=2) Completed Part 1 Pegvaliase Diet only (Primary Treatment Phase) N=32 N=17 Entered Part 2 P
Slide 8: Baseline Demographics and Clinical Characteristics
Baseline Demographics and Clinical Characteristics Pegvaliase Diet Only Total (N=36) (N=19) (N=55) Age at baseline, years Mean (SD) 14.4 (1.27) 14.1 (1.29) 14.3 (1.27) 12–15 30 (83.3%) 17 (89.5%) 47 (85.5%) 16–17 6 (16.7%) 2 (10.5%) 8 (14.5%) Mean age: Gender 14.3 years Female 22 (61.1%) 11 (57.9%)
Slide 9: Change from Baseline in Blood Phe Following 72 Weeks on Study
Change from Baseline in Blood Phe Following 72 Weeks on Study Primary Efficacy Endpoint Treatment N Baseline Average of Change from Baseline at Differencea P Value Mean (SD), Weeks 69 Average of Weeks 69 and 73 in LS Mean (95% CI), µmol/L and 73 µmol/L Mean (SD), Mean (SD), LS Mean (95% CI), µmol/L
Slide 10: Change from Baseline in Blood Phe Following 72 Weeks on Study
Change from Baseline in Blood Phe Following 72 Weeks on Study Mean % Change from Baseline 1500 100 Pegvaliase (N=31) Pegvaliase Diet Only Diet Only (N=17) –49.7% 0.3% 83.9% Mean (SD) Blood Phe (μmol/L) 80 Percentage of Participants 67.7% 1000 60 45.2% 40 500 20 11.8% 11.8% 5.9% n=36 n=31 n=19 n=17 0
Slide 11: Change from Baseline in Blood Phe Concentration over Time
Change from Baseline in Blood Phe Concentration over Time 200 100 Mean (SE) Change from Baseline 0 in Blood Phe (μmol/L) Diet Only –100 –200 –300 –400 –500 Pegvaliase –600 0 2 3 4 5 6 7 8 9 11 13 15 17 19 21 25 29 33 37 41 45 49 53 57 61 65 69 73 Week Phe, phenylalanine; SE, standard error 11
Slide 12: Change from Baseline in Blood Phe Following 72 Weeks on Study
Change from Baseline in Blood Phe Following 72 Weeks on Study 1800 Pegvaliase Diet Only 1500 Blood Phe at Weeks 69–73 (μmol/L) Blood Phe Levels in Pegvaliase Arm n (%) 1200 at Average of Weeks 69 and 73a (N=31) 900 ≤600 µmol/L 16 (51.6%) ≤360 µmol/L 12 (38.7%) 600 ≤120 µmol/L 6 (19.4%) aLOCF imputat
Slide 13: Dietary Protein Intake
Dietary Protein Intake Secondary Efficacy Endpoint Total protein intake was relatively stable over time in both groups Mean Pegvaliase Diet Only Diet Only (N=19) Baseline 1.06 g/kg/day 1.10 g/kg/day 1.4 Mean (SE) Total Protein Intake (g/kg/day) Pegvaliase (N=36) Average of 1.2 1.09 g/kg/day 1.15 g/k
Slide 14: Dietary Protein Intake
Dietary Protein Intake Protein intake from intact food increased and intake from medical food decreased among pegvaliase-treated participants 1.2 Diet Only (N=19) Mean Pegvaliase Diet Only from Intact Food (g/kg/day) 1.0 Mean (SE) Protein Intake Pegvaliase (N=36) Baseline 0.30 g/kg/day 0.24 g/kg/day
Slide 15: Part 1 Safety Summary – Pegvaliase Arm
Part 1 Safety Summary – Pegvaliase Arm All participants in the pegvaliase Common AEs group (n=36) experienced ≥1 AE SAEs Injection site (anaphylactic 5.6% 77.8% Headache 66.7% erythema reaction) AEs leading to Injection study drug 5.6% Arthralgia 75.0% 61.1% site pain discontinuationa a1 of 2 partic
Slide 16: AEs Occurring During the Primary Treatment Phase
AEs Occurring During the Primary Treatment Phase Participants with AE, n (%) Pegvaliase Diet Only (N=36) (N=19) Any AE 36 (100%) 17 (89.5%) AEs assessed by investigator as related to 36 (100%) 0 study drug AEs leading to dose reduction 9 (25.0%) 0 AEs leading to dose interruption 19 (52.8%) 0 AEs le
Slide 17: Conclusions
Conclusions Pegvaliase treatment for 72 weeks in adolescents with PKU Significant reduction ~100% in protein from intact food Safety profile consistent with in mean blood Phe ~30% in protein from medical food that seen in adults1 Total protein intake unchanged Results from the Primary Treatment
Slide 18: Acknowledgments
Acknowledgments • The authors would like to thank the study participants and their families for their contributions to this research. • The authors acknowledge medical writing assistance provided by Rebecca Lew, PhD, CMPP, of Envision Ignite, a part of Envision Pharma Group, and funded by BioMarin P
Slide 19: Back-up
Back-up 19
Slide 20: Pegvaliase Exposure in the Primary Treatment Phase
Pegvaliase Exposure in the Primary Treatment Phase • Overall mean (SD) daily dose was 21.4 (9.60) mg • Overall mean (SD) duration of treatment was 460.8 (150.73) days • During the Primary Treatment Phase, 34 participants titrated up to ≥20 to <40 mg/day, 26 participants titrated up to ≥40 to <60 mg/
Slide 21: Adherence to Pegvaliase in the Primary Treatment Phase
Adherence to Pegvaliase in the Primary Treatment Phase The rate of study drug use was calculated as the total amount of study drug used (as reported by participants in workbooks) divided by the total amount of study drug dispensed Pegvaliase (N=36) Dosage usage Mean (SD), % 97.0 (15.02) Median (min,