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Precedia/Multispecific antibodies/First dose

How was the first-in-human dose set for approved multispecifics?

From the FDA and EMA reviews of all 18 approved multispecifics. Each answer links to the regulator's own sentence.

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Short answer
Rarely public: 3 of 18 reviews say how the first human dose was set.
Stated3/18
Not stated publicly15/18
Why most are blank, and what to do instead

Approval reviews rarely explain the first human dose: that rationale is in the IND, which is confidential. These are the methods regulators expect for multispecifics, each step quoted from the guidance:

MABEL and pharmacologically active dose (PAD)

Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.

Read the sourced method →
ADCs and immune-activating products in oncology (ICH S9 and S9 Q&A)

ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.

Read the sourced method →

Precedent by precedent

18 approved multispecifics, with the reviewers' own words.

Columvi

glofitamab · CD20 x CD3
First-in-human starting dose
MABEL: monkey PK/PD IL-6 excursion model plus in vitro human/monkey whole-blood cytokine data; 5 ug flat dose
“A pharmacokinetic-pharmacodynamic (PK/PD) model for cytokine excursions in cynomolgus monkeys, particularly interleukin 6 (IL-6), was built and translated to humans. The human starting dose was selected to keep the predicted IL-6 excursion below a predefined threshold in patients”
✓ VerifiedFDA multi-discipline review, p. 50Source ↗
NOAEL / key findings
HNSTD 30/100 ug/kg step-up (2-week); B-cell depletion, cytokine release, lymphoid hypocellularity; CRS deaths at 100 ug/kg first dose
“Key findings with glofitamab identified in single- and repeat-dose toxicity studies up to 4 weeks in duration in cynomolgus monkeys included B-cell depletion, transient postdose cytokine release, primarily after the first dose,”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Lunsumio

mosunetuzumab · CD20 x CD3
First-in-human starting dose
MABEL-type: EC20 from in vitro human PBMC cytokine release / T-cell activation assay
“The results (EC20 values) were used to inform the starting dose in the first in human study.”
✓ VerifiedFDA multi-discipline review, p. 60Source ↗
NOAEL / key findings
No NOAEL; overall LOAEL 0.01 mg/kg (CRS effects at all doses); CNS perivascular infiltrates, liver, infections, one convulsion
“As CRS related effects were observed at all dose levels, a LOAEL was derived for all studies at the lowest dose levels resulting in an overall LOAEL of 0.01 mg/kg/day in cynomolgus monkeys.”
✓ VerifiedEMA assessment report, p. 35Source ↗

Vabysmo

faricimab · VEGF-A x Ang-2
First-in-human starting dose
Starting dose 0.5 mg/eye IVT supported by monkey tox data (6 mg/eye high dose not initially supported; dose escalation gated)
“The proposed clinical starting dose of 0.5 mg/eye is supported by the nonclinical data but the high dose of 6.0 mg/eye is not.”
✓ VerifiedFDA pharmacology/toxicology review, p. 26Source ↗
NOAEL / key findings
Ocular NOAEL 0.5 mg/eye (ADA-linked ocular inflammation at ≥1.5 mg/eye); systemic NOAEL 1.5 mg/eye; heart squamous cyst/plaque at high dose
“For ocular toxicity, the NOAEL was 0.5 mg/eye (the low dose). The LOAEL was 1.5 mg/eye (the mid-dose), due to ocular inflammation (observed by ophthalmology and confirmed by histopathology).”
✓ VerifiedFDA pharmacology/toxicology review, p. 28Source ↗

Bizengri

zenocutuzumab · HER2 x HER3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
NOAEL 100 mg/kg/wk (1-month) and 101 mg/kg/wk (13-week) per applicant; FDA noted 2 early deaths/moribund, immune-mediated infusion reaction, GI lesions, skin, adrenal
“The Applicant suggests that these findings were unrelated to zenocutuzumab as comparable findings were not observed in animals that showed higher zenocutuzumab exposure compared to the mid-dose animal”
✓ VerifiedFDA multi-discipline review, p. 58Source ↗

Blincyto

blinatumomab · CD19 x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
No NOAEL assigned; lymphoid tissues target organs (lymphocyte depletion, decreased cellularity); chimp hypotension dose-limiting at 0.12 ug/kg
“Following daily administration of the surrogate for 4 or 13 weeks in mice, lymphoid tissues were the target organs of toxicity with decreased spleen weights and decreased cellularity or germinal center development observed in the lymph nodes, Peyer’s patches, and spleen.”
✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Elrexfio

elranatamab · BCMA x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
No NOAEL in 3-month SC study (immunosuppression, infections, moribundity at all doses); NOAEL 0.3 mg/kg/wk in 1-month studies
“Immunosuppression led to secondary infections and moribund euthanasia at all doses; no NOAEL was identified; dose-dependence was evident by incidence and timing”
✓ VerifiedFDA multi-discipline review, p. 58Source ↗

Epkinly

epcoritamab · CD20 x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
NOAEL 0.1 mg/kg IV, 10 mg/kg SC; cytokine-related clinical signs, one death at 1 mg/kg IV; lymphoid depletion
“In the pivotal 5-week study (503484), the NOAEL in the IV repeat dosing group was 0.1 mg/kg, while the NOAEL in the SC dosing group was 10 mg/kg.”
✓ VerifiedEMA assessment report, p. 36Source ↗

Hemlibra

emicizumab · FIXa x FX
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
NOAEL 30 mg/kg/wk SC (26-week), ~11x clinical AUC; findings limited to injection-site reactions and aPTT shortening
“This is approximately 11-fold above the clinical exposure in a 3 mg/kg QW dosing regimen which is the regimen that is anticipated to yield the highest exposure in patients.”
✓ VerifiedEMA assessment report, p. 35Source ↗

Imdelltra

tarlatamab · DLL3 x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
HNSTD 4500 µg/kg (maximum feasible dose); lymphocyte decreases, transient heart rate increase, pituitary mononuclear infiltrates
“Tarlatamab-related changes are reversible and clinically monitorable, and the highest non-severely toxic dose was determined to be 4500 µg/kg based on the absence of any tarlatamab-related adverse findings.”
✓ VerifiedFDA multi-discipline review, p. 65Source ↗

Kimmtrak

tebentafusp · CD3 x gp100 (TCR fusion)
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
No NOAEL (no animal tox); in vitro reactivity vs melanocytes at 10-100 pM, loss of specificity from 1 nM
“Tebentafusp demonstrated broad loss of specificity for the target pHLA complex from 1 nM (1,000× MABEL), where consistent evidence of T cell activation (IFNγ release) and/or redirected killing (GrB release) was observed across the different normal cells tested.”
✓ VerifiedFDA multi-discipline review, p. 41Source ↗

Korjuny

catumaxomab · EpCAM x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
BiLu NOAEL 0.2-3.0 µg/kg (~clinical dose); liver, mammary, spleen, marrow, lymphocyte findings; catumaxomab tolerated 1.5 mg/kg mouse, 0.5 mg/kg rat
“In this study, the no observed adverse effect level (NOAEL) for BiLu is considered to be the low dose (0.2 to 3.0 μg/kg).”
✓ VerifiedEMA assessment report, p. 38Source ↗

Lynozyfic

linvoseltamab · BCMA x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
5-week: HNSTD 10 mg/kg/wk; 9/14-week: NOAEL not determined (early sacrifice at all doses; multi-organ inflammation, peritonitis/pleuritis, body weight loss)
“In the 9- or 14-week study, a NOAEL could not be determined.”
✓ VerifiedEMA assessment report, p. 36Source ↗

Ordspono

odronextamab · CD20 x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
Up to 1 mg/kg weekly tolerated; no formal NOAEL/HNSTD stated; B-cell depletion, inflammation, presumed opportunistic infections requiring early euthanasia
“In the repeat-dose toxicology studies, once weekly IV infusion of up to 1 mg/kg odronextamab for up to 4 weeks was tolerated.”
✓ VerifiedEMA assessment report, p. 34Source ↗

Removab

catumaxomab · EpCAM x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
No NOAEL for catumaxomab; no acute toxicity at high single doses; surrogate BiLu suggested liver toxicity
“The single-dose toxicity studies with BiLu indicate that catumaxomab may cause liver toxicity.”
✓ VerifiedEMA assessment report, p. 16Source ↗

Rybrevant

amivantamab · EGFR x MET
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
NOAEL 120 mg/kg/wk (highest dose; >=5.3x human AUC); minimal liver, kidney, stomach findings
“The no-observed-adverse-effect level (NOAEL) in the toxicology studies was 120 mg/kg/week (highest tested dose) for the 6-week and 3-month toxicity GLP studies.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Talvey

talquetamab · GPRC5D x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
No adverse effects up to 30 mg/kg weekly (highest dose); transient lymphocyte decrease, increased globulins, fibrinogen, IL-10
“No adverse effects on any toxicology or safety pharmacology parameter evaluated at up to the high dose of 30 mg/kg weekly”
✓ VerifiedFDA multi-discipline review, p. 55Source ↗

Tecvayli

teclistamab · BCMA x CD3
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
NOEL 30 mg/kg/week (highest dose); no PD activity or adverse effects in monkey
“The no-observed-effect level for 5 weekly IV doses of teclistamab-treated monkeys was 30 mg/kg , the highest dose tested”
✓ VerifiedFDA multi-discipline review, p. 44Source ↗

Ziihera

zanidatamab · HER2 x HER2 (biparatopic)
First-in-human starting dose
Not stated in public reviews
Not public: the starting-dose rationale sits in the confidential IND. How it's usually set for multispecifics →
NOAEL / key findings
NOAEL 150 mg/kg QW x13 weeks (highest dose); only non-adverse soft/watery feces, mild BUN increase
“No adverse effects were observed at any dose tested (up to 150 mg/kg QW) for animals in either the 8-week or 13-week dosing cohorts.”
✓ VerifiedFDA multi-discipline review, p. 44Source ↗