Amondys 45
casimersen
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
Adult male mouse and cynomolgus monkey; juvenile male rat
“The pivotal (GLP) general toxicity studies were conducted in adult male C57BL/6NCrl mouse and cynomolgus monkey.”
Why that species
No relevant animal models for species-/mutation-specific PMO; pharmacology in human cells only, tox species for exposure
“The pharmacological activity of casimersen was tested in vitro using human rhabdomyosarcoma cells and normal primary myoblasts, as there are no relevant animal models due to the species- and mutation-specific nature of PMO ASOs.”
Surrogate molecule
No surrogate for casimersen; proof of concept from murine exon 23 PMO AVI-4225 (eteplirsen IND)
“Proof of concept for the exon-skipping mechanism was demonstrated in studies conducted under IND 77429 using the MDX mouse model of muscular dystrophy.”
Species: general tox
Adult male C57BL/6NCrl mouse and cynomolgus monkey
“The pivotal (GLP) general toxicity studies were conducted in adult male C57BL/6NCrl mouse and cynomolgus monkey.”
Species: DART
Not conducted (patient population extremely rare in females)
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval, as previously agreed to by the division, because of the seriousness of the indication.”
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week SC) and male rat (up to 104 weeks IV)
“Administration of casimersen 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, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”
Surrogate used in
Proof of concept only: murine surrogate AVI-4225 in mdx mouse (exon 23 mutation); toxicity studies used casimersen
“In that model, the mutation is located in exon 23 of the dystrophin gene; therefore, a surrogate murine antisense oligonucleotide was developed (AVI-4225) to demonstrate the pharmacology of the exon-skipping activity.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Title: SRP-4045: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”
Pivotal GLP studies
12-wk IV, 22-wk IV (terminated) and 26-wk SC mouse; 12-wk and 39-wk IV monkey; 10-wk IV juvenile rat
“general toxicology (12-, 22-, and 26-week IV in mouse; 12- and 39-week IV in monkey) studies”
Route in tox
IV bolus/30-min infusion; SC for 26-week mouse because chronic IV infeasible (injection-site toxicity)
“Although the clinical route of administration is IV, the adverse effects at the injection site in the 22-week mouse IV study, indicated that the IV route for the 26-week duration is not feasible.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“Casimersen was tested in a standard battery of in vitro (bacterial reverse mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) genetic toxicology assays. The studies were adequately conducted and negative.”
Carcinogenicity
Not conducted pre-approval (deferred to PMR); Tg mouse and rat dose-ranging studies done
“Carcinogenicity assessments are deferred to post-marketing for the DMD indication.”
Reproductive & developmental
Not conducted (patients extremely rare in females); male reproductive endpoints in tox studies; juvenile rat
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval”
Safety pharmacology
Standalone monkey CV/neurological study (4 weekly IV doses up to 320 mg/kg) plus hERG; no adverse effects
“Cynomolgus monkeys received IV injections of SRP-4045 weekly for 4 total doses of 0, 5, 40, or 320 mg/kg.”
Genotox: Ames
Negative
“Casimersen was negative in in vitro (bacterial reverse mutation assay and chromosomal aberration assay in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Casimersen was negative in in vitro (bacterial reverse mutation assay and chromosomal aberration assay in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Casimersen was negative in in vitro (bacterial reverse mutation assay and chromosomal aberration assay in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity model
26-week Tg.rasH2 mouse (SC) and up to 104-week rat (IV); no increase in neoplasms
“Administration of casimersen 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, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies deferred to postmarketing requirements; not conducted before approval
“Carcinogenicity assessments were not conducted. PMRs covering the carcinogenicity assessments are recommended.”
hERG / QT
hERG IC50 >3 mM
“The ICso for the inhibitory effect of SRP-4045 on the hERG current was greater than 3 mM.”
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 Amondys 45 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 basophilia/vacuolation, degeneration; juvenile rat NOAEL 300 mg/kg (4x AUC); no kidney no-effect dose in mouse/rat (FDA pharmacology/toxicology review, p. 75)
NOAEL / key findings
Kidney tubular basophilia/vacuolation, degeneration; juvenile rat NOAEL 300 mg/kg (4x AUC); no kidney no-effect dose in mouse/rat
“Due to the observation of degeneration and necrosis in renal tubular epithelium in a significant number of HD animals, the NOAEL for this study was the MD of 300 mg/kg”
Risksopen answer page →
Immune & cytokine safety
Dose-related complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
“Activation of complement, dose-related in magnitude, was observed in all SRP-4045 dose groups, as evidenced by increases in Bb and C3a.”
Biodistribution & persistence
Extensive tissue distribution; highest kidney, lowest brain; urinary elimination complete by 336 h; low protein binding
“Protein binding was low (<37%) in animal and human plasma, and there was extensive tissue distribution, with highest and lowest levels of radioactivity in kidney and brain, respectively”
Modality-specific risk
Renal tubular toxicity (class PMO effect, monitorable); less severe than golodirsen
“The pivotal nonclinical studies indicate that renal impairment can result from chronic exposure to casimersen . However, because kidney function is monitorable, the nonclinical data are considered adequate”
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 Amondys 45 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 basophilia/vacuolation, degeneration; juvenile rat NOAEL 300 mg/kg (4x AUC); no kidney no-effect dose in mouse/rat (FDA pharmacology/toxicology review, p. 75)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV study in male cynomolgus monkeys with 8-week recovery
“SRP-4045: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”
Pivotal GLP studies
12-wk IV, 22-wk IV (terminated) and 26-wk SC mouse; 12-wk and 39-wk IV monkey; 10-wk IV juvenile rat
“general toxicology (12-, 22-, and 26-week IV in mouse; 12- and 39-week IV in monkey) studies”
DART package
Species: DART
Not conducted (patient population extremely rare in females)
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval, as previously agreed to by the division, because of the seriousness of the indication.”
Reproductive & developmental
Not conducted (patients extremely rare in females); male reproductive endpoints in tox studies; juvenile rat
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval”
PPND / ePPND: when
No PPND study: reproductive and developmental studies not required because patients are extremely rare in females
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females)”
Carcinogenicity
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week SC) and male rat (up to 104 weeks IV)
“Administration of casimersen 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, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity model
26-week Tg.rasH2 mouse (SC) and up to 104-week rat (IV); no increase in neoplasms
“Administration of casimersen 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, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies deferred to postmarketing requirements; not conducted before approval
“Carcinogenicity assessments were not conducted. PMRs covering the carcinogenicity assessments are recommended.”
Safety marginopen answer page →
Safety margin at NOAEL
Juvenile rat no-effect dose (300 mg/kg) ~4x human AUC at 30 mg/kg/week
“At the overall no-effect dose (300 mg/kg), plasma exposure (AUC) was 4 times that in humans at the recommended human dose of 30 mg/kg/week.”
NOAEL / key findings
Kidney tubular basophilia/vacuolation, degeneration; juvenile rat NOAEL 300 mg/kg (4x AUC); no kidney no-effect dose in mouse/rat
“Due to the observation of degeneration and necrosis in renal tubular epithelium in a significant number of HD animals, the NOAEL for this study was the MD of 300 mg/kg”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro only: human rhabdomyosarcoma cells and normal primary myoblasts
“The pharmacological activity of casimersen was tested in vitro using human rhabdomyosarcoma cells and normal primary myoblasts, as there are no relevant animal models due to the species- and mutation-specific nature of PMO ASOs.”
Why that model
No relevant animal models due to species- and mutation-specific nature of PMO ASOs
“The pharmacological activity of casimersen was tested in vitro using human rhabdomyosarcoma cells and normal primary myoblasts, as there are no relevant animal models due to the species- and mutation-specific nature of PMO ASOs.”
Reviewer's view of the efficacy data
Class proof of concept accepted from prior mdx mouse studies with murine surrogate AVI-4225 (IND 77429)
“Proof of concept studies for the exon skipping activity of the oligonucleotide drugs such as SRP-4045 was demonstrated in studies originally submitted and reviewed under IND 77429 in which the murine surrogate PMO, AVI-4225, was used in the mdx mouse”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Why: Intended patient population is extremely rare in females · Other reason
“Reproductive toxicology studies are typically not conducted for the DMD indication. Therefore, detailed examination of male reproductive organs and sperm evaluations were conducted as part of the chronic toxicity studies.”
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval, as previously agreed to by the division, because of the seriousness of the indication.”
CarcinogenicityAccepted with a conditionBeyond the letter
Mouse and rat carcinogenicity studies not conducted before approval; deferred to postmarketing requirements
Why: Seriousness of the indication; post-approval conduct previously agreed by the division · Serious disease
“Carcinogenicity assessments were not conducted. PMRs covering the carcinogenicity assessments are recommended.”
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval, as previously agreed to by the division, because of the seriousness of the indication.”
Efficacy modelVerdict not stated
No in vivo efficacy model for casimersen; pharmacology tested in vitro in human rhabdomyosarcoma cells and primary myoblasts
Why: No relevant animal models due to the species- and mutation-specific nature of PMO ASOs · No relevant species
“The pharmacological activity of casimersen was tested in vitro using human rhabdomyosarcoma cells and normal primary myoblasts, as there are no relevant animal models due to the species- and mutation-specific nature of PMO ASOs.”
Similar precedents
Exondys 51Oligos · eteplirsen · DMD exon 51 (PMO)Monkey + rodent · 39 wkQalsodyOligos · tofersen · SOD1 (ASO)Monkey + rodent · 39 wkSpinrazaOligos · nusinersen · SMN2 (ASO)Monkey + rodent · 53 wkViltepsoOligos · viltolarsen · DMD exon 53 (PMO)Monkey + rodent · 39 wkVyondys 53Oligos · golodirsen · DMD exon 53 (PMO)Monkey + rodent · 39 wkZanvastroOligos · zilganersen · GFAP (ASO)Monkey + rodent · 39 wk