Rivfloza
nedosiran
Species
MonkeyMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (relevant) plus mouse (nedosiran inactive; off-target assessment)
“Nedosiran is inactive in the mouse because the LDHA mRNA sequence is different from humans, and hence, the toxicology of nedosiran was studied in the mouse to assess off-target hybridization effects.”
Why that species
LDHA mRNA target sequence 100% homologous in monkey; not conserved in mouse
“The monkey is considered a pharmacologically relevant model because the LDHA mRNA target sequence has 100% homology with humans.”
Surrogate molecule
Yes: mouse-active analog DCR-m355 used in pharmacology and mouse reproductive studies
“The effects of knockdown of LDHA mRNA were also assessed in genetically or chemically induced mouse models of PH using the pharmacologically active mouse-specific analog DCR-m355.”
Species: general tox
Mouse (juvenile, off-target) and cynomolgus monkey (juvenile and adult)
“Repeat dose toxicology studies were conducted in mice for up to 26 weeks and monkeys for up to 39 weeks.”
Species: DART
Mouse (fertility, EFD, PPND; plus mouse-active analog) and rabbit (EFD)
“In an embryo-fetal development study in mice, no maternal or developmental toxicities were observed with nedosiran at doses up to 2000 mg/kg/dose (58x the maximum recommended human dose (MRHD) or with the mouse active analog DCR-m355.”
Species: carcinogenicity
Not conducted pre-approval; 2-year study in one rodent species required postmarketing
“Complete a long-term (2-year) GLP carcinogenicity study of nedosiran by subcutaneous injection in one rodent species.”
Surrogate used in
Yes: mouse-specific analog DCR-m355 in mouse PH disease models, fertility, EFD and PPND studies
“The effects of knockdown of LDHA mRNA were also assessed in genetically or chemically induced mouse models of PH using the pharmacologically active mouse-specific analog DCR-m355.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“General toxicity studies were conducted for durations up to 26 weeks in juvenile mice and 39 weeks in juvenile and adult monkeys.”
Pivotal GLP studies
26-week juvenile mouse and 39-week juvenile/young adult cynomolgus monkey, SC once every 4 weeks
“Repeat dose toxicology studies were conducted in mice for up to 26 weeks and monkeys for up to 39 weeks.”
Route in tox
Subcutaneous, once every 4 weeks (mimicking clinical monthly dosing)
“The animals were dosed once every 4 weeks to mimic the clinical monthly dosing frequency.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, in vitro micronucleus, in vivo mouse micronucleus)
“Nedosiran was negative in the bacterial reverse mutation assay and did not induce micronuclei in mammalian cells in vitro or in vivo (Table 48).”
Carcinogenicity
Not conducted pre-approval; deferred to postmarketing (TgRasH2 and 2-year studies)
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Reproductive & developmental
Mouse FEED/EFD/PPND clean; rabbit EFD: fetal loss and malformations at >=0.7-2x MRHD (unexplained, off-target)
“Higher postimplantation loss and lower numbers of live fetuses were observed at doses of ≥6 mg/kg/dose (0.7x the MRHD, based on body surface area), and fetal cardiovascular and skeletal malformations were observed at a dose of 20 mg/kg/dose (2x the MRHD).”
Safety pharmacology
Stand-alone in vitro hERG plus CNS/respiratory/CV studies in conscious monkeys; no significant effects
“Nedosiran had no significant adverse effect on central nervous system, respiratory, or cardiovascular function of cynomolgus monkeys at doses up to 300 mg/kg.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Nedosiran was non-mutagenic in an in vitro bacterial reverse mutation assay.”
Genotox: in vitro mammalian
In vitro micronucleus (human peripheral blood lymphocytes): negative
“Nedosiran was not genotoxic in the in vitro bacterial mutagenicity, in vitro micronucleus assays (human peripheral blood lymphocytes) and in vivo bone marrow micronucleus assay in mice.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Nedosiran was not genotoxic in the in vitro bacterial mutagenicity, in vitro micronucleus assays (human peripheral blood lymphocytes) and in vivo bone marrow micronucleus assay in mice.”
Carcinogenicity model
Not conducted pre-approval; TgRasH2 mouse and 2-year rodent studies to follow
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Carcinogenicity timing
Not assessed at approval; transgenic mouse and long-term rodent carcinogenicity studies to be conducted postmarketing
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
hERG / QT
No hERG inhibition up to 48 µg/mL; no CV effects in monkeys
“Nedosiran did not inhibit human ether-a-go-go related gene channel current up to a concentration of 48 μg/mL.”
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 Rivfloza 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: Juvenile monkey NOAEL 100 mg/kg (29x AUC); Kupffer/macrophage basophilic hypertrophy in liver, lymph nodes, testes, injection sites (FDA integrated review, p. 51)
NOAEL / key findings
Juvenile monkey NOAEL 100 mg/kg (29x AUC); Kupffer/macrophage basophilic hypertrophy in liver, lymph nodes, testes, injection sites
“The NOAEL for nedosiran in the most sensitive and relevant species, the juvenile monkey, is 100 mg/kg, with a corresponding AUC0-48h 400 µg·h/mL, which is approximately 29-fold higher”
Risksopen answer page →
Immune & cytokine safety
No cytokine or complement activation in 39-week monkey study; nonclinical ADA not assessed
“No test article-related effect on cytokine activation was evident at any time point evaluated.”
Biodistribution & persistence
Mainly liver, less kidney; other tissues <2% of liver; long liver half-life (12-23 days)
“Nedosiran is distributed primarily to the liver, and to a lesser extent to the kidney.”
Modality-specific risk
Oligonucleotide accumulation in Kupffer cells/macrophages (class effect); GalNAc-siRNA hepatic, renal, injection-site risks
“The hypertrophic changes in the Kupffer cell/macrophage in the liver may be due to accumulation of the test article and are considered a class effect of oligonucleotides.”
Anti-drug antibodies: animals
Not measured; PK/PD and absence of immune complex deposition suggest no neutralizing ADA in mice and monkeys
“ADA analysis has not been conducted with samples from the nonclinical studies; however, PK and pharmacodynamics (PD) data from the nonclinical studies suggest that neutralizing ADAs against nedosiran were not formed.”
Anti-drug antibodies: patients
No treatment-emergent ADA among 79 patients tested
“Among 79 patients tested with the ADA assay, none developed treatment-emergent ADA.”
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 Rivfloza 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: Juvenile monkey NOAEL 100 mg/kg (29x AUC); Kupffer/macrophage basophilic hypertrophy in liver, lymph nodes, testes, injection sites (FDA integrated review, p. 51)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (SC, every 4 weeks; juvenile and young adult) with 8-week recovery
“At the injection sites, minimal to mild macrophage basophilic hypertrophy was observed in the subcutaneous tissues in the juvenile mice and monkeys, which resolved following an 8-week recovery period, indicating hybridization-independent effects. Findings in Young Adult Monkeys In the young adult cynomolgus monkey study, nedosiran was tested at one dose level of 300 mg/kg once every 4 weeks for 9 months.”
Pivotal GLP studies
26-week juvenile mouse and 39-week juvenile/young adult cynomolgus monkey, SC once every 4 weeks
“Repeat dose toxicology studies were conducted in mice for up to 26 weeks and monkeys for up to 39 weeks.”
DART package
Species: DART
Mouse (fertility, EFD, PPND; plus mouse-active analog) and rabbit (EFD)
“In an embryo-fetal development study in mice, no maternal or developmental toxicities were observed with nedosiran at doses up to 2000 mg/kg/dose (58x the maximum recommended human dose (MRHD) or with the mouse active analog DCR-m355.”
Reproductive & developmental
Mouse FEED/EFD/PPND clean; rabbit EFD: fetal loss and malformations at >=0.7-2x MRHD (unexplained, off-target)
“Higher postimplantation loss and lower numbers of live fetuses were observed at doses of ≥6 mg/kg/dose (0.7x the MRHD, based on body surface area), and fetal cardiovascular and skeletal malformations were observed at a dose of 20 mg/kg/dose (2x the MRHD).”
PPND / ePPND: when
PPND in mouse (nedosiran and mouse-active analog) completed before the marketing application; no adverse effects on offspring
“In a pre- and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or a mouse-specific (pharmacologically active) analog (10 mg/kg/dose) from implantation to weaning did not have adverse effects on the growth, viability, development, and reproductive performance of the offspring.”
Carcinogenicity
Species: carcinogenicity
Not conducted pre-approval; 2-year study in one rodent species required postmarketing
“Complete a long-term (2-year) GLP carcinogenicity study of nedosiran by subcutaneous injection in one rodent species.”
Carcinogenicity model
Not conducted pre-approval; TgRasH2 mouse and 2-year rodent studies to follow
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Carcinogenicity timing
Not assessed at approval; transgenic mouse and long-term rodent carcinogenicity studies to be conducted postmarketing
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Safety marginopen answer page →
Safety margin at NOAEL
Juvenile monkey NOAEL 100 mg/kg: AUC ~29-fold human exposure
“The NOAEL for nedosiran in the most sensitive and relevant species, the juvenile monkey, is 100 mg/kg, with a corresponding AUC0-48h 400 µg·h/mL, which is approximately 29-fold higher”
NOAEL / key findings
Juvenile monkey NOAEL 100 mg/kg (29x AUC); Kupffer/macrophage basophilic hypertrophy in liver, lymph nodes, testes, injection sites
“The NOAEL for nedosiran in the most sensitive and relevant species, the juvenile monkey, is 100 mg/kg, with a corresponding AUC0-48h 400 µg·h/mL, which is approximately 29-fold higher”
Efficacy evidenceopen answer page →
Efficacy evidence
PH1 (Agxt knockout) and hydroxyproline-induced mouse models with mouse-active analog DCR-m355; LDHA knockdown in monkeys
“In a mouse model of PH1 with knockout of the alanine-glyoxylate aminotransferase gene involved in limiting glyoxylate oxidation to oxalate, administration of the mouse active analog of nedosiran (DCR-m355) at doses of 0.5, 1, and 5 mg/kg caused dose-dependent suppression of hepatic LDH protein”
Why that model
LDHA target sequence conserved in primates but not mice, so nedosiran is inactive in mice
“The target sequence of nedosiran in LDHA mRNA is conserved in humans and nonhuman primates, but not in mice; thus, nedosiran is fully active in cynomolgus monkeys but inactive in mice.”
Reviewer's view of the efficacy data
FDA: nonclinical pharmacology supports proof of concept and the clinical dosing regimen
“The nonclinical pharmacology data support proof of concept, as well as the dosing regimen of nedosiran that was evaluated in the clinical studies based on the following data:”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity assessment before approval; studies deferred to postmarketing
Why: No carcinogenicity concern in available data; serious disease with limited therapeutic options · Serious disease · Rare disease / unmet need
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
“The available data do not raise concern for a risk of carcinogenicity that should delay approval given the serious nature of the disease and limited therapeutic options.”
SpeciesVerdict not stated
Monkey is the only pharmacologically relevant species; mouse toxicity studies assess off-target hybridization only
Why: LDHA mRNA sequence in mouse differs from human · No relevant species
“Nedosiran is inactive in the mouse because the LDHA mRNA sequence is different from humans, and hence, the toxicology of nedosiran was studied in the mouse to assess off-target hybridization effects.”
DARTVerdict not stated
Mouse pre/postnatal (and other DART) studies run with nedosiran, inactive in mouse, plus a mouse-specific active analog
“In a pre- and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or a mouse-specific (pharmacologically active) analog (10 mg/kg/dose) from implantation to weaning did not have adverse effects on the growth, viability, development, and reproductive performance of the offspring.”
Safety marginVerdict not stated
Rabbit embryofetal toxicity below clinical exposure: postimplantation loss at 0.7x and malformations at 2x the MRHD; no-effect dose 0.2x
“Higher postimplantation loss and lower numbers of live fetuses were observed at doses of ≥6 mg/kg/dose (0.7x the MRHD, based on body surface area), and fetal cardiovascular and skeletal malformations were observed at a dose of 20 mg/kg/dose (2x the MRHD). A dose level of 2 mg/kg/dose (0.2x the MRHD) had no effect on maternal toxicity and embryo-fetal development in rabbits.”
OtherVerdict not stated
No antidrug antibody analysis in nonclinical studies; absence of neutralizing ADA inferred from PK and PD data
Why: PK and PD data suggest neutralizing ADAs were not formed · Pharmacology or kinetics
“ADA analysis has not been conducted with samples from the nonclinical studies; however, PK and pharmacodynamics (PD) data from the nonclinical studies suggest that neutralizing ADAs against nedosiran were not formed.”
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