Amondys 45
casimersen · DMD exon 45 (PMO)Dose-related complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
Leqvio: which risks did reviewers probe?
inclisiran · PCSK9 (siRNA)
Immune & cytokine safety
Delayed/suppressed TDAR (KLH IgM/IgG) in 40-week monkey study, reversible; sporadic low-titre ADA without PD impact
“In a 40-week toxicity study in NHPs, delayed or suppressed IgM (data not shown) and IgG (see Figure 1, below) responses were observed across the dose range at ≥ 2 times the clinical MRHD (BSA) (≥ 30 mg/kg Q4W) in response to keyhole limpet hemocyanin (KLH) sheep antigen”
Biodistribution & persistence
QWBA: highest in injection site, liver, kidney cortex; minimal brain/CNS; slow tissue elimination (t1/2 >100 h)
“In rats, inclisiran-associated radioactivity widely distributed to most tissues with the highest concentrations (based on Cmax) observed at the subcutaneous dose site, and in the liver (target organ), and kidney cortex (site of elimination).”
Modality-specific risk
Tissue accumulation of siRNA (hepatocyte vacuolation, renal basophilic granules), injection-site inflammation, immune (TDAR) effects
“Toxicities with inclisiran were generally non-adverse and largely secondary to tissue accumulation of drug.”
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
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
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
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
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