Viltepso

“Repeat-dose studies in adult male CD1 mice, and single and repeat-dose studies in adult male cynomolgus monkeys were conducted to evaluate the general toxicology of vitolarsen.”

“In vivo assessment of exon 53 skipping was included in the 12- and 39-week toxicity studies in monkey; viltolarsen is not pharmacologically active in rodents.”

“In male mdx52 mice, IV administration of a mouse surrogate (NDK-73) as well as an additional morpholine oligonucleotide (NDK-33), which targets the Exon 53 3’ end of the mouse dystrophin gene”

“Viltolarsen was administered by IV injection for 12 weeks (+4-week recovery) and 39 weeks (+8-week recovery) at doses of 0, 60, 200, and 600 mg/kg QW and 0, 10, 60, and 360 mg/kg QW, respectively.”

“The pivotal IV toxicity studies were conducted in male CD-1 mouse (13 and 26 weeks) and male cynomolgus monkey (12 and 39 weeks).”

“In the pivotal study, viltolarsen (0, 15, 60, 240, and 1200 mg/kg) was administered weekly by SC injection on PND 7 and by IV injection on PNDs 14 through 70.”

“Viltolarsen was negative in a standard battery of in vitro (Ames, chromosomal aberration in CHL cells) and in vivo (mouse micronucleus) assays.”

“Carcinogenicity studies of viltolarsen were not submitted to the NDA, as agreed to by the Division.”

“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”

“Dedicated single dose studies in rat (CNS) and monkey (cardiovascular and respiratory) did not indicate drug effects on safety pharmacology endpoints, and there was no effect on QT prolongation in CHO cell cultures exposed to up to 3 mg/mL vitolarsen.”

“Based on the 39-week study, the NOAEL for IV administration of vitolarsen in male cynomolgus monkeys was 60 mg/kg (Cmax = 613.9 µg/mL; AUC0-24h = 261.1 µg*h/mL).”

“There were no drug effects on C3 after dosing on Day 0; however, on Day 175, there was an approximate 2-fold elevation in serum C3 24 h after dosing in HDM.”

“With multiple doses (20 mg/kg/week for 8 weeks), highest levels of dose radioactivity were in kidney cortex (819 µg-Eq/g), with concentrations in skeletal muscle of 0.331- 0.479 µg-Eq/g.”

“Kidney toxicity in the pivotal study, which resulted in unscheduled death of two HDM, was characterized by slight increases in urea nitrogen and creatinine, increases in kidney weight in HDM, and histologic findings of intratubular dilation and epithelial vacuolation in the distal tubule and collecting duct in MDM and HDM.”