Pariglasgene brecaparvovec

Pariglasgene brecaparvovec should not be used during pregnancy. There is no data on the use of pariglasgene brecaparvovec in pregnant women. It is not known whether pariglasgene brecaparvovec can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

Pregnant C57BL/6 mice administered pariglasgene brecaparvovec-opnr intravenously (IV) at 1.3 × 10¹⁴ gc/kg of maternal body weight on gestation day 6 showed no adverse maternal effects or fetal abnormalities. While vector DNA was detected in the blood and placenta of pregnant mice, it was not detected in the liver of the fetuses.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There is no information regarding the presence of pariglasgene brecaparvovec in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pariglasgene brecaparvovec and any potential adverse effects on the breastfed child from pariglasgene brecaparvovec or from the underlying maternal condition.

Carcinogenicity studies have not been conducted with pariglasgene brecaparvovec.

Liver samples collected from offspring of C57BL/6N mice administered pariglasgene brecaparvovec-opnr at a dose of 1.3 × 10¹⁴ gc/kg showed no differences in integration patterns (using target enrichment sequencing) in the F1 offspring of treated vs untreated mice and therefore and correspondingly provide no evidence of germline transmission, despite vector DNA detection in the ovaries and testes of adult mice. At this dose level, there were no adverse effects on mating, fertility, pregnancy, lactation, or litter viability. Administration of pariglasgene brecaparvovec-opnr showed the presence of vector DNA in the blood (males only), liver, testes, and ovaries of treated mice; however, no vector DNA was observed in the blood and liver from the offspring, indicating no germline transmission to F1 offspring.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described in this section reflects exposure to pariglasgene brecaparvovec in two clinical studies.

Study 1 was a randomized, double-blind, placebo-controlled study in 46 patients aged 8 years and older with GSDIa. During the Primary Efficacy Analysis Period (PEAP, Weeks 1–48), 21 patients received pariglasgene brecaparvovec at the recommended dose of 1.0 × 10¹³ gc/kg and 25 received placebo. After Week 48, 19 placebo-treated patients subsequently received pariglasgene brecaparvovec up to Week 96.

Study 2 was a single-arm, open-label study of pariglasgene brecaparvovec in 12 adults with GSDIa with follow up duration of 52 weeks.

Seven serious adverse events (SAEs) were observed in PEAP of Study 1, including anaphylaxis/infusion reaction (2), adrenal insufficiency (2), high lactate level (2), and hypoglycemia (1).

The most common adverse reactions in the PEAP (occurring in ≥10% of patients) with higher frequency in pariglasgene brecaparvovec compared to placebo during PEAP in Study 1 are shown in the following table.

Adverse Reactions: Study 1:

Abbreviations: ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase.
¹ All events were mild to moderate (<5.0× ULN), except one severe (Grade 3) asymptomatic event (peak ALT: 253 U/L).
ALT/AST elevations peaked between 4 and 12 weeks post-pariglasgene brecaparvovec administration and resolved within 15 weeks.
² All adverse events were mild to moderate.
³ Two SAEs were reported.
⁴ All adverse events were mild.
⁵ Two Serious adverse reactions with onset within minutes of pariglasgene brecaparvovec administration.

Safety evaluations during the Crossover Period of Study 1 and in Study 2 did not identify any additional adverse reactions.