Rebisufligene etisparvovec

Rebisufligene etisparvovec is an adeno-associated virus serotype 9 (AAV9)-based gene therapy designed to deliver a functional copy of the human N-sulfoglucosamine sulfohydrolase (SGSH) gene to cells. Intravenous infusion of rebisufligene etisparvovec results in production of the lysosomal enzyme sulfamidase in target tissues with subsequent breakdown of heparan sulfate (HS) in lysosomes.

In Study 1, the mean (standard deviation [SD]) baseline cerebrospinal fluid heparan sulfate (CSF HS) concentration in the modified intention-to-treat (mITT) population (N=17) was 335.3 (156.9) nmol/L. The mean percent change from baseline (SD) in CSF HS concentration in the mITT population was -58.5% (13.84) at Month 1 post-rebisufligene etisparvovec infusion, -73.6% (11.12) at Month 6, -66.7% (13.46) at Month 12, and -57.1% (22.48) at Month 24 (n=16).

CSF HS exposure represents the time-normalized area under the curve (AUC) of the percent change from baseline in CSF HS concentration. In Study 1, the mean (SD) change from baseline in CSF HS exposure was -29.25% (6.92) at Month 1, -60.17 (9.43) at Month 6, -65.02 (9.42) at Month 12, and -63.78% (11.56) at Month 24 in the mITT population (N=17).

At Month 24, 93.8% of patients (15 of 16) in the mITT population maintained a reduction in CSF HS exposure of at least 50%.

Vector Distribution and Vector Shedding

Nonclinical Data

Biodistribution of vector genome DNA was evaluated following a single intravenous administration in healthy C57BL/6 mice at dose levels of 5.0 × 10¹³ vg/kg and 2.0 × 1014 vg/kg. At 26 weeks post administration of 5.0 × 10¹³ vg/kg to adult mice, vector genome DNA was detected in all major organs analyzed, with the highest quantities detected in the liver followed by lower levels in the heart, uterus with cervix, kidney, lung, brain, lymph node, spleen, and gonads. At 90 days post administration of 2.0 × 1014 vg/kg to adolescent and neonatal mice, vector genome DNA was detected in all major organs analyzed, with the highest quantities detected in the liver and heart followed by lower levels in the lung and kidney. Human SGSH mRNA transcripts were measured in the liver and brain, with highest expression in the liver.

Clinical Data

Biodistribution of vector genome DNA in plasma and vector shedding in stool, urine, and saliva were assessed at multiple time points in 22 patients following a single intravenous administration of rebisufligene etisparvovec at a dose of 3.0 × 10¹³ vg/kg in Study 1. In general, peak levels of vector genome DNA occurred within a median duration of 3 days for plasma, urine, saliva and stool after infusion. Peak vector genome DNA concentrations were highest in plasma followed by stool, saliva, and urine. After reaching the maximum in a matrix, the vector genome DNA concentration declined steadily.

Clearance of vector DNA was defined as measurement of at least 2 consecutive results below the lower limit of quantification (LLOQ; 5000 vg/mL for urine, saliva, plasma and 4000 vg/mL for stool samples). Based on this definition, vector genome DNA was cleared from urine, saliva, and stool within median values of 15, 30, and 84 days post-infusion, respectively. All patients achieved clearance of vector DNA in saliva, while 96% and 82% of the patients cleared the vector DNA in urine and stool, respectively, based on available data.

Pharmacokinetics in Specific/Special Populations

No dedicated pharmacokinetic studies using rebisufligene etisparvovec have been conducted in special populations.

Animal toxicology studies were conducted in healthy C57BL/6 mice at dose levels up to 2.0 x 10¹⁴ vg/kg. No adverse rebisufligene etisparvovec-related toxicological findings were observed.