Vyondys 53
golodirsen
Species
MonkeyRatMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse, cynomolgus monkey (adult males) and juvenile rat
“The toxicity of golodirsen was assessed in adult male C57BL/6NCrl mouse and cynomolgus monkey and in male juvenile Sprague Dawley rat.”
Why that species
Human-specific sequence; no in vivo pharmacology, species chosen for exposure/toxicity; rat considered relevant for kidney
“No in vivo nonclinical studies were conducted to assess the extent of exon 53 skipping by golodirsen.”
Surrogate molecule
No surrogate for golodirsen; proof of concept relied on murine exon 23 PMO AVI-4225 from eteplirsen program
“These in vivo studies were conducted using a murine surrogate PMO, AVI-4225, in the mdx mouse, an animal model of DMD.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Title: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”
Pivotal GLP studies
12-wk IV and 26-wk SC mouse; 12-wk IV and 39-wk IV infusion monkey; 10-wk IV juvenile rat
“Toxicology: 12- and 26-week studies in mouse; 12- and 39-week studies in monkey; 4- and 10-week toxicity study in juvenile rat.”
Route in tox
IV (bolus/30-min infusion); SC for 26-week mouse after IV study failed on injection-site reactions
“Golodirsen was administered by weekly injection for 12 weeks (0, 12, 120, or 960 mg/kg IV) or 26 weeks (0, 120, 300, or 600 mg/kg SC); recovery periods were 4 and 8 weeks, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“Golodirsen was negative in an adequately conducted standard battery of in vitro (Ames, chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity
Not conducted pre-approval; dose-ranging done; Tg mouse and 2-year rat as PMRs
“No carcinogenicity studies have been conducted. The sponsor has conducted dose-ranging (DR) studies (reviewed below) to support planned carcinogenicity studies.”
Reproductive & developmental
Not conducted (almost exclusively male population); male reproductive assessments and juvenile rat study
“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male.”
Safety pharmacology
Standalone telemetered monkey CV/CNS study (Latin square, up to 320 mg/kg IV) plus hERG; no effects
“In the only in vivo safety pharmacology study, golodirsen (0, 5, 40, or 320 mg/kg IV) had no effects on CNS, cardiovascular, or respiratory parameters in four male cynomolgus monkeys.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Severe renal toxicity, lethal in juvenile rat at 900 mg/kg; juvenile rat NOAEL 100 mg/kg (2.6x AUC); monkey NOAEL 80 mg/kg
“The NOAEL for this study was the LD of 100 mg/kg. The AUC0-t at this dose was 239,000 ng•hr/mL. This dose provides a safety margin of approximately 2.6X over the recommended human dose of 30 mg/kg, based on plasma exposure.”
Risksopen answer page →
Immune & cytokine safety
Transient complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
“No drug-related findings were observed in the 12-week study, except for transient (Day 8) increases in complement B6 fragment and C3a at the mid and high doses and a dose-related decrease in FSH (Day 80).”
Biodistribution & persistence
Rapid, extensive distribution except CNS; highest in kidney; blood t1/2 1.46 h; ~75% excreted intact in urine
“The drug was rapidly and extensively distributed to most tissues except CNS (brain and spinal cord). Highest levels of radioactivity were observed in kidney.”
Modality-specific risk
Renal toxicity (juvenile deaths, small margin) prompted clinical hold; also monkey femorotibial synovial hyperplasia
“The pivotal nonclinical studies indicate that severe renal impairment (including irreversible renal damage in the juvenile animals) can result from chronic exposure to golodirsen, with only a small safety margin based on exposure.”