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Atlas/Antibody-drug conjugates/Zynlonta/Safety margin

Zynlonta: what safety margin did regulators accept?

loncastuximab tesirine · CD19
Check my plan vs. these
Safety margin at NOAEL
Monkey 0.3 mg/kg ~3x human AUC at MRHD 0.15 mg/kg
“The dose of 0.3 mg/kg in animals results in an exposure (AUC) that is approximately 3 times the exposure at the maximum recommended human recommended dose [MRHD] of 0.15 mg/kg.”
✓ VerifiedFDA multi-discipline review, p. 39Source ↗
NOAEL / key findings
No NOAEL stated; 13-week monkey kidney and testis findings at all doses (≥0.075 mg/kg); skin hyperpigmentation dose-limiting; bone marrow, lung
“Also, adverse findings in male reproductive organs were present at 0.6 mg/kg only in the 4‐week study and at all doses (≥ 0.075 mg/kg) in the 13‐week study.”
✓ VerifiedFDA multi-discipline review, p. 51Source ↗

Same question, other ADCs

Adcetris

brentuximab vedotin · CD30
Monkey NOAEL serum exposure ~2 to 3x human exposure at the clinical dose

Besponsa

inotuzumab ozogamicin · CD22
No NOAEL for rat male reproductive effects, seen at ~0.3x human AUC

Datroway

datopotamab deruxtecan · Trop-2
Monkey NOAEL 10 mg/kg (lung, cornea, skin, liver, thymus): margin of exposure 0.25 (below human exposure)

Decnupaz

pivekimab sunirine · CD123
No NOAEL in 13-week monkey study: thymic atrophy at the lowest dose (0.01 mg/kg)

Elahere

mirvetuximab soravtansine · FRα
Monkey NOAEL 4 mg/kg: AUC margin 0.09 (AUC0-24 vs AUCtau) to 0.57 (AUC0-∞)

Enhertu

fam-trastuzumab deruxtecan · HER2
Monkey 30 mg/kg (3-month study) ≥7x human AUC at 5.4 mg/kg

Kadcyla

ado-trastuzumab emtansine · HER2
Monkey HNSTD 10 mg/kg (2040 µg DM1/m2) approximately equivalent to the clinical dose

Padcev

enfortumab vedotin · Nectin-4
Monkey ~3-fold and rat (MTD) ~2-fold human systemic exposure at recommended dose

Tivdak

tisotumab vedotin · Tissue factor
Monkey HNSTD 3 mg/kg ~1.35-2.56x human exposure (Cmax and AUC)

Trodelvy

sacituzumab govitecan · Trop-2
Monkey NOAEL/HNSTD 50 mg/kg: 6.4x (total antibody), 4.6x (total SN-38), 3.1x (free SN-38) human exposure at 10 mg/kg

Emrelis

telisotuzumab vedotin · c-Met
Not stated in public reviews

Mylotarg

gemtuzumab ozogamicin · CD33
Not stated in public reviews

Polivy

polatuzumab vedotin · CD79b
Not stated in public reviews

Summary across all 14 ADCs →