OC 21.4 - Effect of Growth on AAV-mediated Expression of FIX-R338L in Juvenile Hemophilia B Dogs

Sunday, July 10, 2022

3:30 PM – 3:45 PM

Location: ExCel Center, S11A

Presentation Format: Virtual

Co-Author(s)

TN

Timothy C. Nichols

Professor
Department of Medicine and Pathology and Lab Medicine, UNC
Chapel Hill, North Carolina, United States
SR

Swapnil Rakhe

Senior Scientist
Rare Disease Research, Pfizer Inc.
Cambridge, Massachusetts, United States
VA

Valder Arruda, MD, PhD

Associate Professor of Pediatrics
Perelman School of Medicine, University of Pennsylvania
Philadelphia, Pennsylvania, United States
BS

Benjamin J. Samelson-Jones, PhD

Assistant Professor of Pediatrics
Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
MC

Melissa Caughey

Assistant Professor
UNC Biomedical Engineering
Chapel Hill, North Carolina, United States
EM

Elizabeth Merricks

Research Operations Manager
UNC Department of Pathology and Lab Medicine (FOBRL)
Chapel Hill, North Carolina, United States
JM

John E. Murphy

Vice President
Rare Disease Research, Pfizer Inc.
Cambridge, Massachusetts, United States

Presenting Author(s)

DP

Debra D. Pittman, MS

Senior Research Director
Rare Disease Research, Pfizer Inc.
Windham, New Hampshire, United States

Background: The human liver doubles in mass 8-9 months from birth and again by 3-4 years. Liver growth and expanding blood volume may reduce FIX levels in pediatric recipients of hemophilia B (HB) gene therapy. HB dogs exhibit a similar phenotype and have proven to be highly predictive of the human experience with gene therapy. HB dogs with severe spontaneous bleeding can be monitored post-gene therapy to assess the effect of normal growth on FIX transgene levels and bleeding phenotype.

Aims: To determine the effect of growth on FIX levels in male juvenile HB dogs following treatment with an AAV-delivered, high-activity canine FIX-R338L.

Methods: Twelve HB dogs received an AAV encoding FIX-R338L variant under a liver specific promoter at age 3 or 6 months to model 2-6-year- or 6-12-year- old children, respectively. Six dogs per age group, were dosed at 5E+11 (2 dogs), 2.5E+12 (3 dogs) or 5E+12 (1 dog) vg/kg. Body weights, liver size (ultrasound), clinical chemistries and hemostatic activity were monitored by whole blood clotting (WBCT), thromboelastography (TEG) and activated partial thromboplastin time (aPTT).

Results: Dogs were followed for ≥12 months, during a period of liver growth (right lateral lobe: 35.7±5.4 to 93.5±10.6 mm, Figure 1) and blood volume expansion (estimated ~0.1 L to ~2 L). Treatment was well tolerated. To date, no spontaneous bleeds have occurred post-treatment. Increasing vector dose was associated with progressive shortening of clotting times (Figure 2). Stable, durable reductions of the aPTT, WBCT and TEG R values were observed in all dogs, indicative of FIX activity.

Conclusion(s): AAV-mediated gene therapy is associated with long-term correction of the laboratory and clinical phenotype of HB. This durable efficacy was observed in growing juvenile HB dogs treated at an early age (3 or 6 months) and was sustained for ≥ 1 year (ongoing observation) despite liver growth and blood volume expansion.