Exondys 51
eteplirsen
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
Cynomolgus monkey and juvenile rat (eteplirsen); mdx/C57BL mouse incl. mouse surrogate
“The pivotal toxicity studies were conducted in mdx or C57BL mice (12-week, 3-month, and 26-week), cynomolgus monkey (12- and 39-week), and juvenile Sprague-Dawley rat (10-week).”
Why that species
Human-sequence-specific PMO; no pharmacologically relevant species, monkey used for exposure/exon-skipping, mdx mouse needs exon 23 surrogate
“For mdx mouse, the pharmacological activity of the human product cannot be tested because of differences in the dystrophin gene mutation, requiring use of a mouse-specific PMO, exon 23 skipping AON and, therefore, resulting in a different truncated dystrophin.”
Surrogate molecule
Yes: mouse-specific exon 23 PMO (AVI-4225) used in 3-month and 26-week mdx/C57BL mouse studies
“In the 3-month and 26-week studies, the mouse surrogate, AVI-4225, was administered to mdx and C57BL mice according to the same study design.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“39-Week Intravenous Injection Toxicity and Toxicokinetic Study of Eteplirsen in Sexually Mature Male Cynomolgus Monkeys with an 8-Week Recovery”
Pivotal GLP studies
39-week IV male monkey; 10-week IV juvenile rat (PND14-77); 26-week IV mdx mouse with surrogate AVI-4225
“Pivotal toxicology studies of eteplirsen were conducted in male monkeys (39-week study) and juvenile male rats (10-week study). A 26-week study was conducted with a mouse-specific surrogate (AVI-4225) in male transgenic mdx mice.”
Route in tox
IV weekly (clinical route); SC arms in 12-week mouse and monkey studies
“In the pivotal studies, eteplirsen was administered weekly at doses of 0, 5, 40, and 320 mg/kg IV; the 12-week study also included a group receiving 320 mg/kg SC.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“Eteplirsen was negative in a standard battery of genetic toxicology (Ames, in vitro chromosomal aberration in CHO, in vivo mouse micronucleus) assays.”
Carcinogenicity
Not conducted pre-approval; Tg.rasH2 mouse and 2-year rat as PMRs (later negative per label)
“Carcinogenicity studies have not been conducted for eteplirsen. As agreed to by the division, carcinogenicity studies in two species would be conducted post approval as PMRs.”
Reproductive & developmental
Not conducted (almost entirely male population); male reproductive organ histopathology in tox studies; juvenile rat study
“No developmental and reproductive toxicity studies were conducted with eteplirsen because the patient population is almost entirely male.”
Safety pharmacology
Standalone telemetered monkey CV/respiratory/CNS study (SC and IV up to 320 mg/kg); no findings
“No toxicologically important effects were observed in a safety pharmacology study in cynomolgus monkeys given single injections of eteplirsen at up to 320 mg/kg SC or IV.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Kidney tubular degeneration in all species; monkey NOAEL 320 mg/kg (~20x AUC); juvenile rat NOAEL 300 mg/kg (6x); bone density loss
“As shown in the table below, safety margins based on AUCs at the NOAELs in the pivotal toxicity studies in monkey and juvenile rat are 20-fold and 6-fold, respectively, compared to the mean AUC observed in DMD patients”
Risksopen answer page →
Immune & cytokine safety
No effects on TDAR or immunophenotyping in juvenile rat; lymphoid necrosis in spleen/thymus at high dose in mouse
“No drug-related effects were observed on TDAR, immunophenotyping, physical development, neurobehavioral development, or on the male reproductive system.”
Biodistribution & persistence
Rapid, widespread distribution; highest in kidney, low in brain; ~60% urinary excretion; only kidney retained at 56 days
“Widespread tissue distribution was detected by QWBA, with highest peak levels in kidney (165000 ng-eq/g). At 56 days postdose, radioactivity was detected only in kidney and urine.”
Modality-specific risk
Renal tubular toxicity (PMO kidney accumulation); also lateral ventricle dilatation (mdx mouse) and juvenile bone density loss
“Regarding toxicity, the primary toxicities observed with eteplirsen were renal tubule degeneration/necrosis in all species tested (mdx mouse, juvenile rat, cynomolgus monkey), dilatation of lateral ventricles in mdx mouse, and decreases in bone mineral content and density in juvenile rat.”