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.”
Species: general tox
mdx and C57BL mouse, cynomolgus monkey and juvenile Sprague-Dawley rat
“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).”
Species: DART
Not conducted (patient population almost entirely male); male reproductive organs assessed in toxicity studies
“No developmental and reproductive toxicity studies were conducted with eteplirsen because the patient population is almost entirely male. Potential effects on male fertility were assessed by histopathological evaluation of male reproductive organs in toxicity studies.”
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week) and male rat (96-week)
“Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg) weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks resulted in no increase in neoplasms.”
Surrogate used in
Yes: mouse surrogate PMO AVI-4225 in 3-month and 26-week mdx/C57BL mouse toxicity 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.”
Genotox: Ames
Negative
“Eteplirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Eteplirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Eteplirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity model
26-week Tg.rasH2 mouse and 96-week rat; no increase in neoplasms
“Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg) weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks resulted in no increase in neoplasms.”
Carcinogenicity timing
26-week transgenic mouse and 2-year rat studies planned after approval; none conducted before the marketing application
“The sponsor plans to conduct a 26-week study in transgenic mice and a 2-year study in rats to assess the carcinogenicity of eteplirsen.”
hERG / QT
No toxicologically important effects in monkey safety pharmacology study up to 320 mg/kg SC or IV
“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
Why it's blank
The public FDA and EMA reviews of Exondys 51 don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA pharmacology/toxicology review, p. 91)
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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Anti-eteplirsen IgG in 1/129 patients (0.78%); IgE in 3/21 (14.3%)
“With administration of 30 mg/kg/week of EXONDYS 51, during the 192-week treatment duration in three clinical studies, 1 out of 129 patients (0.78%) was positive for anti-eteplirsen IgG and 3 out of 21 patients with non-missing samples (14.3%) were positive for anti-eteplirsen IgE.”
Label warnings
- Hypersensitivity Reactions
Hypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Exondys 51 don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
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 (FDA pharmacology/toxicology review, p. 91)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV male cynomolgus monkey with 8-week recovery
“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.”
DART package
Species: DART
Not conducted (patient population almost entirely male); male reproductive organs assessed in toxicity studies
“No developmental and reproductive toxicity studies were conducted with eteplirsen because the patient population is almost entirely male. Potential effects on male fertility were assessed by histopathological evaluation of male reproductive organs in toxicity studies.”
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.”
PPND / ePPND: when
Not conducted: no female fertility, embryofetal or early postnatal development studies, as the DMD population is almost entirely male
“Assessments of the effects of eteplirsen on female fertility, embryofetal development, and early postnatal development were not conducted because the DMD patient population is almost entirely male.”
Carcinogenicity
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week) and male rat (96-week)
“Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg) weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks resulted in no increase in neoplasms.”
Carcinogenicity model
26-week Tg.rasH2 mouse and 96-week rat; no increase in neoplasms
“Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg) weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks resulted in no increase in neoplasms.”
Carcinogenicity timing
26-week transgenic mouse and 2-year rat studies planned after approval; none conducted before the marketing application
“The sponsor plans to conduct a 26-week study in transgenic mice and a 2-year study in rats to assess the carcinogenicity of eteplirsen.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL exposure 3.4x human in monkey and <1x in mdx mouse (surrogate); highest doses 17-20x
“Safety margins based on plasma (AVI-4225 or eteplirsen) exposures at the NOAELs in adult animals are low (<1 in mdx mouse, 3.4 in monkey); however, plasma exposures at the highest doses tested, which were associated with minimal-to-slight toxicity (except for moderate dilatation of lateral ventricles), were 17 and 20 times the anticipated human exposure.”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Exon 51 skipping in human muscle cell cultures, DMD patient muscle explants, transgenic hDMD mice (IM) and cynomolgus monkey (IV)
“The ability of eteplirsen to induce exon 51 skipping in human dystrophin mRNA has been demonstrated in the following: human muscle cell cultures; muscle explants from a DMD patient; gastrocnemius muscle of transgenic hDMD mice (after direct IM injection); quadriceps muscle, heart, and diaphragm of cynomolgus monkey (after 12 weeks of once weekly IV infusions); and EDB muscle of 7 DMD patients (after direct IM injection).”
Why that model
Human product cannot be tested in mdx mouse (different dystrophin mutation), requiring a mouse-specific exon 23 PMO
“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.”
Reviewer's view of the efficacy data
Supportive: greater than dose-proportional exon 51 skipping in monkey and dose-related mdx muscle pathology improvement with surrogate AVI-4225
“The sponsor’s studies demonstrate a greater than dose-proportional increase in exon 51 skipping with eteplirsen in monkey and a dose-related improvement in muscle pathology with a mouse-specific surrogate (AVI-4225) in the mdx mouse.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; transgenic mouse and rat studies deferred to postmarketing requirements
Why: DMD is life-threatening and severely disabling with no satisfactory alternative therapy · Serious disease · Rare disease / unmet need
“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.”
“4) DMD is a life-threatening and severely disabling disease for which no satisfactory alternative therapy exists. The sponsor’s justification is acceptable.”
DARTAcceptedBeyond the letter
No standard reproductive and developmental studies; male fertility assessed by reproductive organ histopathology in toxicity studies
Why: Patient population is primarily male · Other reason
“Because the patient population is primarily male, standard reproductive and developmental studies were not required. To assess male fertility, the sponsor conducted a histopathological evaluation of male reproductive organs in the pivotal toxicity studies,”
SpeciesAcceptedBeyond the letter
Pharmacology and toxicity in mdx mouse required a mouse-specific exon 23 surrogate PMO (AVI-4225)
Why: Human product cannot be tested in mdx mouse because of differences in the dystrophin gene mutation · No relevant species
“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.”
“Overall, the nonclinical studies of eteplirsen and the mouse surrogate (AVI-4225) are adequate to support approval of the NDA, with appropriate labeling and PMRs for carcinogenicity studies in two species.”
Safety marginAcceptedBeyond the letter
Low NOAEL exposure margins: below one in mdx mouse (surrogate) and 3.4 in monkey
Why: Highest doses tested, with minimal-to-slight toxicity, gave 17 and 20 times the anticipated human exposure · Pharmacology or kinetics
“Safety margins based on plasma (AVI-4225 or eteplirsen) exposures at the NOAELs in adult animals are low (<1 in mdx mouse, 3.4 in monkey); however, plasma exposures at the highest doses tested, which were associated with minimal-to-slight toxicity (except for moderate dilatation of lateral ventricles), were 17 and 20 times the anticipated human exposure.”
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