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Atlas/Bispecific antibodies/Bizengri/Risks

Bizengri: which risks did reviewers probe?

zenocutuzumab · HER2 x HER3
Check my plan vs. these
Immune & cytokine safety
Low whole-blood cytokine release; cytokine release (IFN-g, IL-6, IL-8, TNF-a) when target and effector cells co-cultured; ADA in ~1/3 of monkeys
“In vitro cytokine release studies using whole human blood from healthy donors showed only slight increases in cytokine levels.”
✓ VerifiedFDA multi-discipline review, p. 58Source ↗
Biodistribution & persistence
No distribution studies (ICH S6(R1)); limited distribution outside vascular compartment
“No distribution studies were performed.”
✓ VerifiedFDA multi-discipline review, p. 72Source ↗
Modality-specific risk
Embryo-fetal toxicity (HER2/HER3 class effect; boxed warning); diarrhea/GI, skin, infusion reaction
“FDA recommends including a box warning for embryo-fetal toxicity and advising females of reproductive potential to use effective contraception”
✓ VerifiedFDA multi-discipline review, p. 86Source ↗

Same question, other bispecifics

Blincyto

blinatumomab · CD19 x CD3
IL-2, IL-6, IFN-gamma release in chimpanzees, consistent with clinical CRS; ADA to surrogate in mice

Columvi

glofitamab · CD20 x CD3
Marked dose-dependent cytokine release (IL-6 >581-fold); step-up dosing/obinutuzumab mitigated; high ADA incidence limited exposure

Elrexfio

elranatamab · BCMA x CD3
Transient cytokine increases mainly after first dose; B-cell/plasma cell depletion; ADA incidence up to 67% at low dose

Epkinly

epcoritamab · CD20 x CD3
Dose-dependent first-dose cytokine release (lower with SC); strong neutralizing ADA at ≤0.1 mg/kg IV

Hemlibra

emicizumab · FIXa x FX
Low cytokine release risk in vitro; ADA in 9/40 monkeys (4 NAb); one Arthus-type injection-site reaction

Imdelltra

tarlatamab · DLL3 x CD3
Inflammatory markers (CRP, MCP-1, IFNg) in 10-day study; dose-related ADAs, one ADA immune-complex vascular injury case

Kimmtrak

tebentafusp · CD3 x gp100 (TCR fusion)
Whole-blood assays: no cytokine increase <1 nM; IL-6, TNFa, IFNg at 10-100 nM; no alloreactivity or platelet activation

Korjuny

catumaxomab · EpCAM x CD3
In vitro TNF-α/IL-6/IL-2 release with EpCAM+ cells; transient lymphopenia (BiLu); neutralising HAMA/HARA

Lunsumio

mosunetuzumab · CD20 x CD3
Dose-dependent cytokine release 2-6 h post-dose; step-up dosing mitigated CRS; high ADA in monkeys; B-cell depletion infections

Lynozyfic

linvoseltamab · BCMA x CD3
Transient emesis with CRP/cytokine increase; sustained CRP, IL-2, IL-6, MCP-1 inflammation; ADA in 36-47% of monkeys reduced exposure

Ordspono

odronextamab · CD20 x CD3
Transient T-cell activation and plasma cytokine rise after first dose only; limited translatability of in vitro cytokine data to CRS

Removab

catumaxomab · EpCAM x CD3
In vitro TNF-α, IL-6, IL-2 release (needs EpCAM+ cells); no cytokine change in monkey; anti-mouse/rat ADA

Rybrevant

amivantamab · EGFR x MET
Low CRS risk in human blood cytokine release assay; ADA in 17/67 monkeys; no immunotoxicity

Talvey

talquetamab · GPRC5D x CD3
In vitro dose-dependent cytokine release (IL-6, IFN-g, TNF-a etc.); ADAs in 10/12 monkeys reduced exposure

Tecvayli

teclistamab · BCMA x CD3
ADA in 21/30 monkeys (7 with reduced exposure); in vitro whole-blood cytokine release of IL-8, IFN-γ, TNF-α

Vabysmo

faricimab · VEGF-A x Ang-2
ADA-driven immune-complex ocular inflammation in monkey; minimal in vitro cytokine release or complement activation

Ziihera

zanidatamab · HER2 x HER2 (biparatopic)
Low immunogenic potential (PBMC assay); no immunotoxicity in 13-week study; ADA assay drug interference

Summary across all 18 bispecifics →