Amondys 45
casimersen · DMD exon 45 (PMO)Dose-related complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
Wainua: which risks did reviewers probe?
eplontersen · TTR (ASO)
Immune & cytokine safety
Transient complement Bb increases; non-neutralising ADAs in chronic monkey study; minimal cytokine changes
“Thus, these ADAs represent binding antibodies without neutralising capacity.”
Biodistribution & persistence
Distributes mainly to liver and kidney; undetectable in brain and spinal cord (rat)
“In SD rats administered [3H]ASO-eplontersen, radioactivity levels peaked in plasma at 0.5 h postdose, then distributed into tissues, primarily liver and kidney, with the highest levels observed in the liver at 8 h and kidney at 2 days; radioactivity was undetectable in brain and spinal cord.”
Modality-specific risk
ASO class risks: thrombocytopenia, glomerulonephritis, renal/liver effects (from inotersen); vitamin A deficiency from MoA
“Potential safety concerns for eplontersen based on the route of administration and therapeutic class (including information from the previously approved hATTR drug inotersen) were thrombocytopenia, glomerulonephritis, renal impairment, abnormal liver function, injection site reactions, flu-like symptoms, central nervous system disorders, hemorrhages, and coagulation abnormalities.”
Anti-drug antibodies: animals
ADAs in chronic monkey study: binding, non-neutralising; increased trough concentrations; no impact on efficacy or toxicity
“ADAs were confirmed in the chronic toxicity study in monkeys that were identified as binding antibodies without neutralising capacity. These ADAs increased median plasma trough concentrations of eplontersen”
Anti-drug antibodies: patients
37% (53/144) treatment-emergent ADAs; no effect on Cmax/AUC, increased Ctrough
“53 out of 144 (37%) patients developed treatment-emergent ADAs during treatment with WAINUA. The presence of ADAs did not affect eplontersen plasma C max or AUC, but increased C trough .”
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
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
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