Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency

George A Diaz, Andreas Schulze, Markey C McNutt, Elisa Leão-Teles, J Lawrence Merritt 2nd, Gregory M Enns, Spyros Batzios, Allison Bannick, Roberto T Zori, Leslie S Sloan, Susan L Potts, Gillian Bubb, Anthony G Quinn, George A Diaz, Andreas Schulze, Markey C McNutt, Elisa Leão-Teles, J Lawrence Merritt 2nd, Gregory M Enns, Spyros Batzios, Allison Bannick, Roberto T Zori, Leslie S Sloan, Susan L Potts, Gillian Bubb, Anthony G Quinn

Abstract

Hyperargininemia in patients with arginase 1 deficiency (ARG1-D) is considered a key driver of disease manifestations, including spasticity, developmental delay, and seizures. Pegzilarginase (AEB1102) is an investigational enzyme therapy which is being developed as a novel arginine lowering approach. We report the safety and efficacy of intravenously (IV) administered pegzilarginase in pediatric and adult ARG1-D patients (n = 16) from a Phase 1/2 study (101A) and the first 12 weeks of an open-label extension study (102A). Substantial disease burden at baseline included lower-limb spasticity, developmental delay, and previous hyperammonemic episodes in 75%, 56%, and 44% of patients, respectively. Baseline plasma arginine (pArg) was elevated (median 389 μM, range 238-566) on standard disease management. Once weekly repeat dosing resulted in a median decrease of pArg of 277 μM after 20 cumulative doses (n = 14) with pArg in the normal range (40 to 115 μM) in 50% of patients at 168 hours post dose (mean pegzilarginase dose 0.10 mg/kg). Lowering pArg was accompanied by improvements in one or more key mobility assessments (6MWT, GMFM-D & E) in 79% of patients. In 101A, seven hypersensitivity reactions occurred in four patients (out of 162 infusions administered). Other common treatment-related adverse events (AEs) included vomiting, hyperammonemia, pruritus, and abdominal pain. Treatment-related serious AEs that occurred in five patients were all observed in 101A. Pegzilarginase was effective in lowering pArg levels with an accompanying clinical response in patients with ARG1-D. The improvements with pegzilarginase occurred in patients receiving standard treatment approaches, which suggests that pegzilarginase could offer benefit over existing disease management.

Trial registration: ClinicalTrials.gov NCT02488044 NCT03378531.

Keywords: ARG1-D; arginase 1 deficiency; human enzyme; hyperammonemia; hyperargininemia; pegzilarginase; spasticity.

Conflict of interest statement

G. A. D. has performed as a consultant and received travel and clinical study support from Aeglea. A. Schulze has received funds from Aeglea for the clinical study and for investigator‐initiated research. M. C. McNutt has received funds from Aeglea for clinical studies, honoraria, and travel reimbursement. E. Leão‐Teles has received financial support for educational activities and consulting and has received funds from Aeglea for the clinical study. J. L. Merritt II has received funds from Aeglea for the clinical study. G. M. Enns has received funds from Aeglea for the clinical study. S. Batzios has received funds from Aeglea for the clinical study, acted as a speaker on behalf of Aeglea. A. Bannick has received funds from Aeglea for the clinical study. R. T. Zori has performed as a consultant and received travel support and clinical study funding from Aeglea. L. S. Sloan, S. L. Potts, G. Bubb, and A. G. Quinn are employees of Aeglea BioTherapeutics Inc.

© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Figures

FIGURE 1
FIGURE 1
Flowchart diagram of the 101A Phase 1/2 study and the 102A long‐term open label extension. *Two patients withdrew for personal reasons
FIGURE 2
FIGURE 2
Box plot demonstrating the minimum, first quartile, median, third quartile, and maximum values for, A, plasma arginine at baseline, 7 days after doses 1 and 8 in 101A part 2 and 7 days after doses 1 and 12 in 102A. B, Plasma GC levels for GAA (guanidinoacetic acid), NAA(N‐α‐acetyl‐L‐arginine), GVA (α‐keto‐δ‐guanidinovaleric acid), and ArgA (argininic acid) at baseline and dose 8 in 102A, and as median in open‐label extension study. Note: For arginine, Dose 20 (if available) or Dose 19 (if D20 was not available) was used for 102A. Ten patients had D20 and 4 patients had D19. For GC, the mean of all OLE visits from 102, that is, Doses 9 to 20 was used. ArgA, R,S‐argininic acid; BL, baseline; D, dose; GAA, guanidinoacetic acid; GVA, α‐keto‐δ‐guanidinovaleric acid; NAArg, Nα‐acetyl‐L‐arginine; OLE, mean of doses in 102A (open‐label extension); ULN, upper limit of normal, determined from study of GCs in healthy adults (n = 12), equal to 0.2, 3.7, 0.3, and 0.17 μM for ArgA, GAA, GVA, and NAArg, respectively
FIGURE 3
FIGURE 3
Heat map of baseline deficits in clinical outcomes assessments in all patients & overall clinical responses and individual assessment responses using three key complementary mobility assessments
FIGURE 4
FIGURE 4
Patient profiles outlining baseline deficits, therapeutic & disease history, and occurrence of hypersensitivity and ADA

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