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.”
Species: general tox
Adult male C57BL/6NCrl mouse, cynomolgus monkey and male juvenile Sprague Dawley rat
“The toxicity of golodirsen was assessed in adult male C57BL/6NCrl mouse and cynomolgus monkey and in male juvenile Sprague Dawley rat.”
Species: DART
Not conducted (patient population almost entirely male); male reproductive organs and sperm assessed in toxicity studies
“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male. Potential effects on male fertility were assessed by histopathological evaluation of male reproductive organs and sperm assessment in toxicity studies.”
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week SC) and male rat (up to 102 weeks IV)
“Administration of golodirsen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 30, 100, or 300 mg/kg) weekly for up to 102 weeks by intravenous injection resulted in no increase in neoplasms.”
Surrogate used in
Proof of concept only: murine surrogate PMO AVI-4225 in mdx mouse, from the EXONDYS NDA; toxicity studies used golodirsen
“Proof of concept for the exon-skipping mechanism was demonstrated in studies originally submitted and reviewed under IND 77429 and NDA 206488 (EXONDYS). 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.”
Genotox: Ames
Negative
“Golodirsen 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
“Golodirsen 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
“Golodirsen 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 (SC) and up to 102-week rat (IV); no increase in neoplasms
“Administration of golodirsen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 30, 100, or 300 mg/kg) weekly for up to 102 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity timing
None before approval; 26-week transgenic mouse and 2-year rat to be conducted after approval
“If the NDA is approved, carcinogenicity studies in two species (26-week in transgenic mouse, 2-year in rat) are to be conducted post-approval, as previously agreed to by the division.”
hERG / QT
hERG IC50 >300 µM; not predicted to cause hERG-mediated cardiotoxicity
“Results of the hERG assay gave an IC50 of greater than 300 µM. Therefore, SRP-4053 is not predicted to result in hERG-mediated cardiotoxicity.”
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 Vyondys 53 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: 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 (FDA pharmacology/toxicology review, p. 113)
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.”
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
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.
Label warnings
- Hypersensitivity Reactions
- Kidney Toxicity
Hypersensitivity & infusion reactionsNephrotoxicity
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 Vyondys 53 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: 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 (FDA pharmacology/toxicology review, p. 113)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week male cynomolgus monkey (IV infusion) with 8-week recovery
“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.”
DART package
Species: DART
Not conducted (patient population almost entirely male); male reproductive organs and sperm assessed in toxicity studies
“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male. Potential effects on male fertility were assessed by histopathological evaluation of male reproductive organs and sperm assessment in toxicity 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.”
PPND / ePPND: when
No PPND or other developmental and reproductive toxicity studies; patient population almost entirely male
“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male.”
Carcinogenicity
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week SC) and male rat (up to 102 weeks IV)
“Administration of golodirsen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 30, 100, or 300 mg/kg) weekly for up to 102 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity model
26-week Tg.rasH2 mouse (SC) and up to 102-week rat (IV); no increase in neoplasms
“Administration of golodirsen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 30, 100, or 300 mg/kg) weekly for up to 102 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity timing
None before approval; 26-week transgenic mouse and 2-year rat to be conducted after approval
“If the NDA is approved, carcinogenicity studies in two species (26-week in transgenic mouse, 2-year in rat) are to be conducted post-approval, as previously agreed to by the division.”
Safety marginopen answer page →
Safety margin at NOAEL
Juvenile rat NOAEL 100 mg/kg ~2.6x human plasma exposure at 30 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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rhabdomyosarcoma cells and immortalized and primary myoblasts from DMD patients; no in vivo exon 53 skipping study with golodirsen
“using a variety of cell types (rhabdomyosarcoma cells and immortalized and primary myoblast from DMD patients). All ASOs demonstrated activity, but golodirsen was selected for development based on “ease and cost of manufacture and IP status (freedom-to-operate) …” No in vivo nonclinical studies were conducted to assess the extent of exon 53 skipping by golodirsen.”
Why that model
Golodirsen sequence is highly specific for the human dystrophin gene
“Golodirsen is believed to be highly specific for the human dystrophin gene sequence and reportedly exhibits no hybridization affinity to any other sequence in the human genome that would present a safety concern for human use.”
Reviewer's view of the efficacy data
No in vivo golodirsen exon-skipping data; proof-of-concept studies accepted from the prior NDA 206488 review, not re-reviewed in detail
“Nonclinical studies demonstrating proof of concept for exon skipping were reviewed by Dr. David Hawver, under NDA 206488. The studies were re-submitted to NDA 211970 but were not re-reviewed in detail here.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; 26-week transgenic mouse and 2-year rat studies deferred post-approval
Why: Seriousness of the indication · Serious disease
“If the NDA is approved, carcinogenicity studies in two species (26-week in transgenic mouse, 2-year in rat) are to be conducted post-approval, as previously agreed to by the division.”
“As previously agreed to by the division, carcinogenicity studies in two species may be conducted post-approval (as PMRs), based on the seriousness of the indication.”
DARTAcceptedBeyond the letter
No fertility or embryo-fetal/pre- and postnatal studies; male fertility assessed by reproductive organ histopathology and sperm in general toxicity studies, plus juvenile rat study
Why: Patient population almost exclusively male · Other reason
“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male.”
“Reproductive and developmental studies (except for the juvenile animal study) were not required because of the intended patient population, which is almost exclusively male.”
Safety marginAccepted with a conditionBeyond the letter
Small margin for renal toxicity: human AUC at 30 mg/kg only 2.6-fold below the juvenile rat NOAEL
Why: Kidney function is monitorable in patients · Other reason
“At the recommended human dose of 30 mg/kg, plasma exposure (AUC of ∼90 µg*hr/mL) is only 2.6-fold lower than that at the no-adverse-effect-level in the most sensitive species (juvenile rat).”
“However, because kidney function is monitorable, the nonclinical data are considered adequate to support approval of golodirsen for the treatment of DMD in patients with mutations amenable to exon 53 skipping therapies.”
Efficacy modelVerdict not stated
No in vivo study of exon 53 skipping with golodirsen; in vitro patient myoblast data only
“No in vivo nonclinical studies were conducted to assess the extent of exon 53 skipping by golodirsen.”
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