Redemplo
plozasiran
Species
MonkeyRat
Longest study
37 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat (off-target toxicity) and cynomolgus monkey (pharmacologically relevant)
“Monkeys were deemed the most pharmacologically relevant species to evaluate on-target safety profile of plozasiran.”
Why that species
Antisense strand fully complementary to monkey and human ApoC-III mRNA, 7 mismatches to rodent; rat only suitable for off-target toxicity
“The antisense strand of plozasiran is fully complementary to monkey and human ApoC-III mRNAs, whereas plozasiran has seven sequence mismatches to the rodent ApoC-III mRNA transcript.”
Surrogate molecule
Yes: rodent-specific surrogate AD06313 used in rat embryo-fetal/repro studies; clinical molecule in general tox
“A follow-up EFD study was conducted with single dose SC administration of plozasiran or the rodent-specific surroga”
Species: general tox
Rat (24-week) and cynomolgus monkey (37-week), SC Q4W
“Q4W in rats (15, 30, and 120 mg/kg) and monkeys (30, 90, and 180 mg/kg) for durations up to 24- and 37-weeks, respectively”
Species: DART
Rat (FEED, EFD, PPND) and rabbit (EFD)
“Plozasiran was tested in a complete battery of nonclinical reproductive and developmental toxicity studies, including a fertility and early embryonic development (FEED) study in rats, embryo-fetal development (EFD) studies in rats and rabbits, and a pre/postnatal development (PPND) study in rats.”
Species: carcinogenicity
6-month transgenic mouse and 2-year rat
“Carcinogenic potential of plozasiran was tested in a 6-month transgenic mouse and a 2-year rat carcinogenicity study, the latter of which was submitted in the second round of the procedure.”
Surrogate used in
Yes: rat surrogate siRNA AD06313 in rat FEED and EFD studies
“Due to sequence mismatch between plozasiran and rat ApoC-III mRNA, animals treated with a rat surrogate anti-ApoC-III siRNA (AD06313) were included in the FEED and EFD studies to assess the on-target reproductive and developmental effects.”
Study lengthopen answer page →
Longest pivotal study
37 weeks
“Q4W in rats (15, 30, and 120 mg/kg) and monkeys (30, 90, and 180 mg/kg) for durations up to 24- and 37-weeks, respectively”
Pivotal GLP studies
24-week rat and 37-week monkey SC Q4W repeat-dose toxicity studies
“Repeat-dose general toxicology studies with plozasiran were conducted with SC administration (consistent with the clinical route) Q4W in rats”
Route in tox
Subcutaneous, Q4W
“Repeat-dose general toxicology studies with plozasiran were conducted with SC administration (consistent with the clinical route) Q4W in rats”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, in vitro chromosomal aberration (TK6), in vivo mouse micronucleus; not genotoxic
“Plozasiran was not genotoxic when tested in the in vitro bacterial mutation (Ames) assay, in vitro chromosomal aberration assay in cultured TK6 lymphoblastoid cells, and in vivo micronucleus assay in mice.”
Carcinogenicity
Conducted: 26-week Tg.rasH2 mouse negative; 2-year rat study ongoing
“In the 26-week study in Tg.rasH2 mice, administration of plozasiran by the SC route Q8W up to 120 mg/kg (~50-fold clinical dose, based on AUC) did not increase the incidence of tumors in male or female mice.”
Reproductive & developmental
Conducted in rat: fertility (NOAEL 50 mg/kg), EFD (NOAEL 60 mg/kg), PPND (pup survival reduced at 24 mg/kg and above); no rabbit
“The NOAEL for male and female fertility was 50 mg/kg (19-fold the human dose, based on BSA).”
Safety pharmacology
Standalone monkey CV study (single SC dose up to 300 mg/kg); hERG not warranted
“Plozasiran had no adverse effect on cardiovascular function in conscious cynomolgus monkeys following a single dose of SC injection up to 300 mg/kg.”
Genotox: Ames
Negative (Ames)
“Plozasiran was not genotoxic when tested in the in vitro bacterial mutation (Ames) assay, in vitro chromosomal aberration assay in cultured TK6 lymphoblastoid cells, and in vivo micronucleus assay in mice.”
Genotox: in vitro mammalian
Chromosomal aberration in TK6 lymphoblastoid cells: negative
“Plozasiran was not genotoxic when tested in the in vitro bacterial mutation (Ames) assay, in vitro chromosomal aberration assay in cultured TK6 lymphoblastoid cells, and in vivo micronucleus assay in mice.”
Genotox: in vivo
Mouse micronucleus: negative
“Plozasiran was not genotoxic when tested in the in vitro bacterial mutation (Ames) assay, in vitro chromosomal aberration assay in cultured TK6 lymphoblastoid cells, and in vivo micronucleus assay in mice.”
Carcinogenicity model
26-week transgenic (Tg.rasH2) mouse completed; 2-year rat study to follow postmarketing
“The carcinogenic potential of plozasiran was assessed in the completed 26-week transgenic mouse carcinogenicity study. The Agency agreed that a 2-year rat carcinogenicity study should be conducted postmarketing considering the unmet medical need associated with the FCS clinical indication.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, completion to be submitted postmarketing
“The 2-year rat carcinogenicity study is ongoing, and the Agency recommends that completion of this study should be submitted postmarketing (after approval) considering the unmet medical need associated with the FCS clinical indication.”
hERG / QT
No effect on hERG tail current at 6.4 μM (100 μg/mL); large margin to human unbound Cmax
“At a concentration of 6.4 μM (100 μg/mL), plozasiran did not affect hERG tail current amplitude in vitro. This represents a large safety margin to the human unbound Cmax (15.6 ng/mL) at the proposed therapeutic dose.”
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 Redemplo 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: Rat NOAEL 120 mg/kg Q4W (47x MRHD); monkey NOAEL 180 mg/kg (140x, top dose); liver, kidney, lymph node, injection-site changes (FDA integrated review, p. 247)
NOAEL / key findings
Rat NOAEL 120 mg/kg Q4W (47x MRHD); monkey NOAEL 180 mg/kg (140x, top dose); liver, kidney, lymph node, injection-site changes
“The NOAEL was considered 180 mg/kg/Q4W (140-fold MRHD, BSA), the highest dose tested, based on the absence of significant toxicity.”
Risksopen answer page →
Immune & cytokine safety
Proinflammatory cytokines induced in human whole blood in vitro at high concentrations; none in rat/monkey studies
“No induction of proinflammatory cytokines or inflammation were noted in the completed rat and monkey toxicity studies at doses higher than the plasma concentrations expected at MRHD”
Biodistribution & persistence
High liver concentration (>100-fold other sites), liver half-life ~4-5 days in rats
“revealed high liver concentration (>100-fold) compared to other sites and a prolonged liver elimination half-life (~4 to 5 days)”
Modality-specific risk
Hybridization-independent off-target toxicity from siRNA tissue accumulation: liver, lymph nodes, injection sites; no on-target toxicity
“All toxicology findings with chronic SC administration of plozasiran in rats and monkeys were associated with hybridization”
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
No treatment-induced or treatment-boosted ADA in 50 FCS patients over 12 months
“In Trial 1, none of the 50 FCS-patients treated with REDEMPLO over a period of 12 months developed treatment-induced or treatment-boosted ADAs.”
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 Redemplo 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: Rat NOAEL 120 mg/kg Q4W (47x MRHD); monkey NOAEL 180 mg/kg (140x, top dose); liver, kidney, lymph node, injection-site changes (FDA integrated review, p. 247)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
37-week cynomolgus monkey (SC, monthly) with 4-week recovery (control and high dose)
“Monkey (cyno) 37w, 10 monthly doses +4w SC injection GLP SR-00804 Main: 7 M/F Recovery: 2 M/F (control and high dose)”
Pivotal GLP studies
24-week rat and 37-week monkey SC Q4W repeat-dose toxicity studies
“Repeat-dose general toxicology studies with plozasiran were conducted with SC administration (consistent with the clinical route) Q4W in rats”
DART package
Species: DART
Rat (FEED, EFD, PPND) and rabbit (EFD)
“Plozasiran was tested in a complete battery of nonclinical reproductive and developmental toxicity studies, including a fertility and early embryonic development (FEED) study in rats, embryo-fetal development (EFD) studies in rats and rabbits, and a pre/postnatal development (PPND) study in rats.”
Reproductive & developmental
Conducted in rat: fertility (NOAEL 50 mg/kg), EFD (NOAEL 60 mg/kg), PPND (pup survival reduced at 24 mg/kg and above); no rabbit
“The NOAEL for male and female fertility was 50 mg/kg (19-fold the human dose, based on BSA).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“FEED and PPND were conducted in rats, EFD in rats and rabbits.”
Carcinogenicity
Species: carcinogenicity
6-month transgenic mouse and 2-year rat
“Carcinogenic potential of plozasiran was tested in a 6-month transgenic mouse and a 2-year rat carcinogenicity study, the latter of which was submitted in the second round of the procedure.”
Carcinogenicity model
26-week transgenic (Tg.rasH2) mouse completed; 2-year rat study to follow postmarketing
“The carcinogenic potential of plozasiran was assessed in the completed 26-week transgenic mouse carcinogenicity study. The Agency agreed that a 2-year rat carcinogenicity study should be conducted postmarketing considering the unmet medical need associated with the FCS clinical indication.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, completion to be submitted postmarketing
“The 2-year rat carcinogenicity study is ongoing, and the Agency recommends that completion of this study should be submitted postmarketing (after approval) considering the unmet medical need associated with the FCS clinical indication.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 180 mg/kg Q4W (highest dose): 140-fold MRHD by BSA
“The NOAEL was considered 180 mg/kg/Q4W (140-fold MRHD, BSA), the highest dose tested, based on the absence of significant toxicity.”
NOAEL / key findings
Rat NOAEL 120 mg/kg Q4W (47x MRHD); monkey NOAEL 180 mg/kg (140x, top dose); liver, kidney, lymph node, injection-site changes
“The NOAEL was considered 180 mg/kg/Q4W (140-fold MRHD, BSA), the highest dose tested, based on the absence of significant toxicity.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human ApoC-III transgenic (dyslipidemic) mouse, healthy cynomolgus monkey and dyslipidemic rhesus macaque
“In vivo pharmacological characterization of plozasiran was conducted in a transgenic mouse expressing human ApoC-III (human ApoC-III mouse), healthy cynomolgus monkey, and dyslipidemic rhesus macaque monkeys.”
Why that model
Antisense strand fully complementary to monkey and human ApoC-III mRNA but has seven mismatches to rat
“The antisense strand of plozasiran is designed to be fully complementary to the monkey and human ApoC-III mRNA transcripts whereas seven sequence mismatches exist with the rat ApoC-III mRNA sequence.”
Reviewer's view of the efficacy data
EMA: in vivo PD response demonstrated by liver APOC3 suppression, lower serum APOC3 and lipid-lowering effects
“Regarding the primary pharmacology of plozasiran, it can be concluded that the in vivo PD response of plozasiran was shown by the suppression of liver APOC3 expression, reduction in serum APOC3 protein concentrations and lipid-lowering effects in serum.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
2-year rat carcinogenicity study ongoing at approval; completion to be submitted postmarketing
Why: Unmet medical need associated with familial chylomicronemia syndrome · Rare disease / unmet need
“The 2-year rat carcinogenicity study is ongoing, and the Agency recommends that completion of this study should be submitted postmarketing (after approval) considering the unmet medical need associated with the FCS clinical indication.”
SpeciesAcceptedBeyond the letter
Rat lacks full ApoC-III sequence homology (seven mismatches), so suitable only for off-target toxicity; monkey the pharmacologically relevant species
Why: Monkeys deemed the most pharmacologically relevant species for on-target safety · No relevant species
“The antisense strand of plozasiran is fully complementary to monkey and human ApoC-III mRNAs, whereas plozasiran has seven sequence mismatches to the rodent ApoC-III mRNA transcript. Moderate pharmacodynamic activity was observed in rats only at toxic doses; however, the lack of full rat mRNA sequence homology makes this species suitable only for assessing off-target toxicity.”
“Monkeys were deemed the most pharmacologically relevant species to evaluate on-target safety profile of plozasiran.”
DARTVerdict not stated
Rat embryo-fetal study tested a rodent-specific surrogate siRNA (AD06313) alongside plozasiran
“In pregnant rats, daily treatment with plozasiran or a rodent-specific surrogate (AD06313) during the period of organogenesis did not result in fetal malformations or teratogenicity at any dose up to 60 mg/kg/day plozasiran (23-fold MRHD), the highest dose tested.”
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