Amondys 45
casimersen · DMD exon 45 (PMO)Dose-related complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
Defitelio: which risks did reviewers probe?
defibrotide · Fragmented DNA oligonucleotides
Immune & cytokine safety
Mouse 4-week immune function assays (NK activity, anti-SRBC response, macrophage cytotoxicity, lymphocyte proliferation): no clear effect
“Mice were treated orally or i.p. daily (5 days a week) for 4 weeks and a number of functional assays were performed (NK cell activity, anti-SRBC antibody response, macrophage cytotoxicity, lymphocyte proliferation). No clear effect on immune functions was observed.”
Biodistribution & persistence
Radiolabel distributed to kidneys, liver, bone marrow, spleen and small intestine; low levels in brain and fat
“Radio-labelled defibrotide showed preferential distribution into highly perfused tissues: kidneys, liver, bone marrow, spleen and small intestine with lower levels in rat testes and low levels to the brain and to fat.”
Modality-specific risk
Direct effects on coagulation (dose-dependent PT and APTT prolongation)
“Defibrotide may have direct effects on coagulation based on the dose-dependent effects of the drug on PT and APTT.”
Anti-drug antibodies: animals
Anti-drug antibodies assessed in rat and dog 13-week studies; results not reported
“The antigenicity and the potential of defibrotide to elicit anti-drug antibodies was assessed by testing rat and dog plasma samples generated in the repeat dose 13-week toxicity studies.”
Anti-drug antibodies: patients
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.
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
Cyfendus
anthrax vaccine adsorbed, adjuvanted · TLR9 (CpG 7909 adjuvant)Transient neutrophil, monocyte, basophil and inflammatory-marker increases; spleen weight increase and lymphoid hyperplasia
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
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
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · TLR9 (CpG 1018 adjuvant)Serum IL-12p40 rose only 2-fold at ~20x the human CpG 1018 dose; no IL-12p40 or IFN-gamma increase at the 1x human dose
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
Onpattro
patisiran · TTR (siRNA)Transient complement activation (C3a, Bb) in monkeys, siRNA-independent; ADA to PEG lipid in rats reduced exposure
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