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).”
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”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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.”