Onpattro
patisiran
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey pharmacologically active; rat off-target/LNP)
“As a consequence, general toxicology studies have been performed in cynomolgus monkeys (pharmacologically active) and rats (off-target).”
Why that species
siRNA sequence cross-reacts with cynomolgus TTR but not rat, mouse or rabbit
“Patisiran is a siRNA directed against human TTR mRNA and has cross-reactivity in the cynomolgus monkeys, but not in rat mouse or rabbit.”
Surrogate molecule
Yes: rodent-specific surrogate siRNA-LNP (AF-011-18534) in rat DART; luciferase-siRNA LNP control in general tox
“To evaluate on-target reproductive and developmental toxicities related to siRNA- mediated reduction in serum TTR concentrations (TTR reduction and associated reductions in vitamin A and thyroxine) the rodent reproductive and developmental toxicity studies included a rodent surrogate siRNA (AD-18534).”
Species: general tox
Rat and cynomolgus monkey
“As a consequence, general toxicology studies have been performed in cynomolgus monkeys (pharmacologically active) and rats (off-target).”
Species: DART
Rat (with rodent-specific surrogate) and rabbit
“In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”
Species: carcinogenicity
TgRasH2 mouse (26-week); no 2-year rat study
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Surrogate used in
Yes: rodent surrogate siRNA (AD-18534) in rat reproductive and developmental toxicity studies
“To evaluate on-target reproductive and developmental toxicities related to siRNA- mediated reduction in serum TTR concentrations (TTR reduction and associated reductions in vitamin A and thyroxine) the rodent reproductive and developmental toxicity studies included a rodent surrogate siRNA (AD-18534).”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count.”
Pivotal GLP studies
Monkey 6-week (q2w) and 39-week (q3w) IV; rat 6-week and 26-week IV; plus luciferase-LNP control arms
“It is noted that no single cell necrosis or adverse findings are found in the 26-week rat study.”
Route in tox
IV infusion, q2w-q3w, matching clinical route
“IV infusion was used in the repeat-dose toxicology studies with in general a once every two- or three-week dosing interval to support the clinical route and timing of dose administration.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, human lymphocyte chromosome aberration, mouse micronucleus; all negative
“It can be concluded that patisiran-LNP was not genotoxic in either the in vitro or in vivo assays.”
Carcinogenicity
26-week TgRasH2 mouse study (not carcinogenic); 2-year rat not done due to IV/ADA issues
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study.”
Reproductive & developmental
Full DART: rat fertility/EFD and PPND (with rodent surrogate), rabbit EFD; no adverse effects in rat
“No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”
Safety pharmacology
Single-dose monkey CV/CNS study (NOAEL 1 mg/kg; fever, tachycardia at >=3 mg/kg); hERG with LNP only
“Increased body temperature and heart rate were seen in cynomolgus monkeys after a single IV 60min infusion dose at ≥3mg/kg (max dose at 6mg/kg), giving a NOEL and NOAEL for patisiran-LNP at 1mg/kg and a LOAEL of 3mg/kg”
Genotox: Ames
Bacterial reverse mutation assay: negative
“Patisiran-LNP (10 mg/mL) was neither mutagenic in the bacterial reverse mutation assay, nor clastogenic or aneugenic in the mammalian chromosome aberration assay in human blood peripheral lymphocytes.”
Genotox: in vitro mammalian
Chromosome aberration assay in human peripheral blood lymphocytes: negative
“Patisiran-LNP (10 mg/mL) was neither mutagenic in the bacterial reverse mutation assay, nor clastogenic or aneugenic in the mammalian chromosome aberration assay in human blood peripheral lymphocytes.”
Genotox: in vivo
Mouse bone marrow micronucleus (single IV doses up to 30 mg/kg): negative
“Single IV doses of patisiran-LNP at ≤ 30 mg/kg (MTD) did not induce micronucleus formation in the bone marrow of male and female CD-1 mice.”
Carcinogenicity model
26-week TgRasH2 mouse; 2-year rat not conducted (long-term IV challenges, ADA in rats)
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Carcinogenicity timing
26-week TgRasH2 mouse completed before the marketing application; 2-year rat not conducted
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
hERG / QT
No hERG inhibition by the LNP (tested with control luciferase siRNA); patisiran siRNA itself not tested
“In-vitro hERG testing was not conducted for the ds-siRNA but only for the possible impact from the LNP (with patisiran exchanged for an insect luciferase siRNA with no target in the human genome). There was no indication that the LNP in itself can inhibit the hERG channel (see Discussion on non-clinical aspects).”
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 Onpattro 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: Liver (single-cell necrosis, vacuolation) drove NOAELs in all species; also spleen, bone marrow, lymph nodes, adrenal (EMA assessment report, p. 40)
NOAEL / key findings
Liver (single-cell necrosis, vacuolation) drove NOAELs in all species; also spleen, bone marrow, lymph nodes, adrenal
“The liver is the primary site of patisiran-LNP uptake and accumulation, and hepatotoxicity determined the NOAELS in all non-clinical species.”
Risksopen answer page →
Immune & cytokine safety
Transient complement activation (C3a, Bb) in monkeys, siRNA-independent; ADA to PEG lipid in rats reduced exposure
“Data from the 6-week study indicate that administration of patisiran-LNP or AF-011-1955 resulted in transient complement activation after 15 minutes, 6h and 24 h after dosing.”
Biodistribution & persistence
>90% of LNP to liver in rat QWBA; also spleen, kidney, lymph nodes, adrenals; minimal CNS
“Based on male adult rat autoradiography (QWBA) studies with 0.3mg/kg single dose IV patisiran-LNP with radiolabelled 14C-DLin-MC3-DMA, most of the radioactivity (>90%) is rapidly distributed to the liver”
Modality-specific risk
LNP-driven hepatotoxicity, infusion reactions/complement; novel lipid excipients; vitamin A reduction
“Overall, the toxicities seen are not primarily related to the pharmacology of the TTR-targeting siRNA but are more likely derived from the LNP.”
Anti-drug antibodies: animals
ADA to PEG2000-C-DMG in ~50% of rats in 26-week study; siRNA exposure undetectable, study not fully informative
“It is noted that no single cell necrosis or adverse findings are found in the 26-week rat study. However, as noted in the toxicokinetics section, systemic exposure to ALN-18328 was not detected at the end of the dosing period in any dose group and around 50% of the animals had detectable ADA directed against PEG2000-C-DMG.”
Anti-drug antibodies: patients
Treatment-emergent ADA (anti-PEG2000-C-DMG) in 7/194 (3.6%) patients
“In the placebo-controlled and open-label clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with ONPATTRO.”
Label warnings
- Infusion-Related Reactions
- Reduced Serum Vitamin A Levels and Recommended Supplementation
Hypersensitivity & infusion reactionsMetabolic & endocrine
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 Onpattro 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: Liver (single-cell necrosis, vacuolation) drove NOAELs in all species; also spleen, bone marrow, lymph nodes, adrenal (EMA assessment report, p. 40)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week monkey IV study (every 3 weeks); recovery phase not stated
“Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count.”
Pivotal GLP studies
Monkey 6-week (q2w) and 39-week (q3w) IV; rat 6-week and 26-week IV; plus luciferase-LNP control arms
“It is noted that no single cell necrosis or adverse findings are found in the 26-week rat study.”
DART package
Species: DART
Rat (with rodent-specific surrogate) and rabbit
“In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”
Reproductive & developmental
Full DART: rat fertility/EFD and PPND (with rodent surrogate), rabbit EFD; no adverse effects in rat
“No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”
PPND / ePPND: when
PPND with patisiran-LNP and rodent surrogate AF-011-18534 completed before the marketing application; NOAEL 1.5 mg/kg
“Prenatal and postnatal development, including maternal function: The NOAEL for maternal toxicity and for viability and growth in the offspring for patisiran-LNP and AF-011-18534 were 1.5 mg/kg, the highest dose tested for patisiran-LNP”
Carcinogenicity
Species: carcinogenicity
TgRasH2 mouse (26-week); no 2-year rat study
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Carcinogenicity model
26-week TgRasH2 mouse; 2-year rat not conducted (long-term IV challenges, ADA in rats)
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Carcinogenicity timing
26-week TgRasH2 mouse completed before the marketing application; 2-year rat not conducted
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
Liver (single-cell necrosis, vacuolation) drove NOAELs in all species; also spleen, bone marrow, lymph nodes, adrenal
“The liver is the primary site of patisiran-LNP uptake and accumulation, and hepatotoxicity determined the NOAELS in all non-clinical species.”
Efficacy evidenceopen answer page →
Efficacy evidence
V30M/Hsf-1 KO mouse disease model (ALN-TTR01, same siRNA): 97-100% tissue TTR protein suppression
“In a mouse disease model (the V30M/Hsf-1 KO mouse model), the tissue TTR protein suppression is 97-100% after 6 doses of ALN-TTR01 (LNP with same siRNA as patisiran-LNP) at 3mg/kg (bi-weekly; only one dose was tested).”
Why that model
siRNA targets human TTR mRNA; cross-reacts with cynomolgus monkey but not rat, mouse or rabbit
“Patisiran is a siRNA directed against human TTR mRNA and has cross-reactivity in the cynomolgus monkeys, but not in rat mouse or rabbit.”
Reviewer's view of the efficacy data
EMA: unclear whether inhibition is equal for all TTR variants, but in vitro IC50 similar (~16-36 pM) across five common mutations
“While it is not clear if the patisiran inhibition effect is the same for all possible TTR polymorphisms, the in-vitro inhibition range for the five more common human transthyretin disease-linked polymorphisms (V30M, T60A, S77Y, S77F, and V122I) is relatively similar at an IC50 between ~16pM and 36pM.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
No 2-year rat carcinogenicity study; 26-week TgRasH2 mouse study only
Why: Technical challenges of long-term IV administration and ADA development in the 26-week rat study · Other reason
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study.”
Safety pharmacologyVerdict not stated
In vitro hERG testing done only for the lipid nanoparticle with a control siRNA, not for the patisiran siRNA
“In-vitro hERG testing was not conducted for the ds-siRNA but only for the possible impact from the LNP (with patisiran exchanged for an insect luciferase siRNA with no target in the human genome).”
DARTVerdict not stated
Rat reproductive and developmental studies used a rodent-specific surrogate siRNA formulation alongside patisiran-LNP
Why: Patisiran not pharmacologically active in rats or rabbits · No relevant species
“Since ALN-18328 is not pharmacologically active in rats or rabbits, the rat-specific surrogate formulation AF-011-18534 was used in the reproductive and developmental toxicity studies in rats to assess potential on-target pharmacological effects of patisiran-LNP on reproduction and development”
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