Amondys 45
casimersen · DMD exon 45 (PMO)Dose-related complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
Onpattro: which risks did reviewers probe?
patisiran · TTR (siRNA)
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.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)No ADA in rats; non-dose-related ADA in 8/32 monkeys without impact; no cytokine stimulation in vitro or in monkeys
Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)No cytokine/chemokine or C3 effects; minimal transient complement Bb increase at 30 mg/kg/week; ADAs 12.5-62.5% in monkey without impact
Defitelio
defibrotide · Fragmented DNA oligonucleotidesMouse 4-week immune function assays (NK activity, anti-SRBC response, macrophage cytotoxicity, lymphocyte proliferation): no clear effect
Exondys 51
eteplirsen · DMD exon 51 (PMO)No effects on TDAR or immunophenotyping in juvenile rat; lymphoid necrosis in spleen/thymus at high dose in mouse
Givlaari
givosiran · ALAS1 (siRNA)Low ADA incidence: rat negative, one monkey ADA-positive; no dedicated antigenicity studies
Hibsago
bepirovirsen · HBV RNA (ASO)Sequence-specific, hTLR8-dependent innate immune activity; no activity at other pattern recognition receptors
Izervay
avacincaptad pegol · C5 (aptamer)Main pharmacology-related risk is increased susceptibility to infections (C5 inhibition); no complement activation by the aptamer in monkeys; panuveitis with Lucentis combination
Kynamro
mipomersen · APOB (ASO)Class proinflammatory effects (MCP-1, IL-1b, CRP); alternative complement activation, C3 depletion in monkeys; no clear ADA
Leqvio
inclisiran · PCSK9 (siRNA)Delayed/suppressed TDAR (KLH IgM/IgG) in 40-week monkey study, reversible; sporadic low-titre ADA without PD impact
Macugen
pegaptanib · VEGF-165 (aptamer)No local/systemic immune response or antibody induction; antibody assay of unclear accuracy
Oxlumo
lumasiran · HAO1 (siRNA)Low-titre ADA in 3/36 monkeys, no impact on exposure or tox; no ADA in rats; not immunostimulatory
Qalsody
tofersen · SOD1 (ASO)CSF inflammation at 35 mg in monkey; ADA not assessed in animal studies (58.4% of patients ADA-positive)
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)No ADA in monkeys (0.1-1 mg/kg/week); injection-site hypersensitivity-type skin reactions in rats and monkeys at all doses
Redemplo
plozasiran · APOC3 (siRNA)Proinflammatory cytokines induced in human whole blood in vitro at high concentrations; none in rat/monkey studies
Rivfloza
nedosiran · LDHA (siRNA)No cytokine or complement activation in 39-week monkey study; nonclinical ADA not assessed
Rytelo
imetelstat · Telomerase (oligo)Alternative complement activation (Bb, C5a); no immunotoxicity; no ADA assessment in animals
Spinraza
nusinersen · SMN2 (ASO)No complement activation or systemic inflammation in IT monkey studies; proinflammatory effects in mice
Tegsedi
inotersen · TTR (ASO)Monkey perivascular inflammation with ADA, CRP, IL-6, TNFa, IgG/IgM rises; complement Bb activation; ADA in some monkeys
Tryngolza
olezarsen · APOC3 (ASO)Complement activation (Bb up, C3 down) in monkeys; MCP-1/CRP/IFN-gamma increases; ADAs in 25-62.5% of monkeys
Viltepso
viltolarsen · DMD exon 53 (PMO)No cytokine or immunophenotype effects; transient ~2-fold C3 rise at high dose in mouse; no anti-drug antibodies
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)Ocular inflammation in monkeys: acute anterior uveitis and cyclitis with inflammatory cells, flare and iris neovascularization
Vyondys 53
golodirsen · DMD exon 53 (PMO)Transient complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
Wainua
eplontersen · TTR (ASO)Transient complement Bb increases; non-neutralising ADAs in chronic monkey study; minimal cytokine changes
Waylivra
volanesorsen · APOC3 (ASO)Complement activation in monkeys (class effect, species-specific); cytokine/chemokine increases (MCP-1, MIP-1b); anti-volanesorsen antibodies in 50-72% of monkeys
Zanvastro
zilganersen · GFAP (ASO)Low-severity proinflammatory findings (liver mononuclear infiltrates, vacuolated macrophages) in 26-week SC mouse study