Kidney Week

Abstract: PO1938

Reduction of Globotriaosylceramide Inclusions in Renal Peritubular Capillaries in Patients with Fabry Disease Following Treatment with Pegunigalsidase Alfa

Session Information

• Renal Pathology: From Laboratory to Bedside
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1600 Pathology and Lab Medicine

Authors

• Barisoni, Laura, Duke University School of Medicine, Durham, North Carolina, United States

Laura Barisoni, MD

• Jennette, J. Charles, University of North Carolina System, Chapel Hill, North Carolina, United States

J. Charles Jennette,

• Holida, Myrl D., The University of Iowa Healthcare, Iowa City, Iowa, United States

Myrl D. Holida,

• Goker-Alpan, Ozlem, Lysosomal Disorders Research and Treatment Unit, Fairfax, Virginia, United States

Ozlem Goker-Alpan,

• Maegawa, Gustavo, University of Florida, Gainesville, Florida, United States

Gustavo Maegawa,

• Giraldo, Pilar, Hospital de Dia Quiron, Zaragoza, Spain

Pilar Giraldo,

• Gonzalez, Derlis Emilio, Instituto Privado del Nino y Adolescente, Asuncion, Gran Asunción, Paraguay

Derlis Emilio Gonzalez,

• Tuffaha, Ahmad M., University of Kansas Medical Center, Kansas City, Kansas, United States

Ahmad M. Tuffaha,

• Alon, Sari, Protalix Biotherapeutics, Carmiel, Northern, Israel

Sari Alon,

• Almon, Einat, Protalix Biotherapeutics, Carmiel, Northern, Israel

Einat Almon,

• Chertkoff, Raul, Protalix Biotherapeutics, Carmiel, Northern, Israel

Raul Chertkoff,

• Hughes, Derralynn, Royal Free London NHS Foundation Trust, London, London, United Kingdom

Derralynn Hughes,

Background

Fabry disease (FD) is a rare genetic disorder characterized by reduced activity of the lysosomal enzyme α-galactosidase A (α-Gal A), leading to accumulation of sphingolipids such as globotriaosylceramide (Gb₃) and globotriaosylsphingosine (lysoGb₃), and organ dysfunction. Gb₃ inclusions form in various renal cell types and Gb₃ clearance from renal peritubular capillaries (PTCs) has been used as a surrogate endpoint in trials of approved FD therapies. The objective of this analysis was to quantify the reduced burden of Gb₃ inclusions in PTCs in patients with FD participating in a phase 1/2 trial of pegunigalsidase alfa (recombinant α-Gal A) enzyme replacement therapy.

Methods

In a phase 1/2 dose-ranging study (NCT01678898), 18 adults with FD received 0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg of pegunigalsidase alfa by intravenous infusion every 2 weeks for up to 12 months. Kidney biopsies were taken at baseline and after 6 months of treatment. Levels of Gb₃ inclusions in renal PTCs were determined using the Barisoni Lipid Inclusions Scoring System (BLISS) protocol (Barisoni L et al. Arch Pathol Lab Med. 2012;136:816–824).

Results

Of 14 evaluable patients with available kidney biopsies at baseline and 6 months, 12 patients (85.7%) had ≥20% reduction, 11 patients (78.6%) had ≥50% reduction, and 3 patients (21.4%) had ≥90% reduction in Gb₃ inclusions. In the analysis (n=13; excluding 1 male patient due to minimal renal involvement), the mean BLISS score 6 months from baseline was lowered for all doses (reduced by 75.5%, 86.5%, and 39.5% in the 0.2 mg/kg, 1.0 mg/kg, and 2.0 mg/kg treatment groups, respectively). The magnitude of reduction of Gb₃ inclusions was greater in males (n=7; reduction: 85.0%) vs females (n=6; reduction: 47.7%). Overall, mean BLISS score was reduced from 4.23 at baseline to 0.83 at 6 months (67.8% ± 8.9%). Reduction in Gb₃ inclusions at 6 months was correlated with a reduction in plasma lysoGb₃ at 12 months (R=0.905).

Conclusion

Results from this phase 1/2 study demonstrated that pegunigalsidase alfa reached the affected tissue and effectively reduced the number of Gb₃ inclusions in renal PTCs at 6 months in adults with FD.