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Atlas/Monoclonal antibodies/First dose

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

From the FDA and EMA reviews of all 117 approved monoclonal antibodies. Each answer links to the regulator's own sentence.

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Short answer
Rarely public: 6 of 117 reviews say how the first human dose was set.
Stated1/117
Partly stated5/117
Not stated publicly111/117
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 monoclonal antibodies, each step quoted from the guidance:

NOAEL to human equivalent dose (HED) with a safety factor

Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.

Read the sourced method →
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 →
Oncology start dose under ICH S9 (1/10 STD10, 1/6 HNSTD)

In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.

Read the sourced method →

Precedent by precedent

117 approved monoclonal antibodies, with the reviewers' own words.

Sarclisa

isatuximab · CD38
First-in-human starting dose
MABEL and in vitro receptor occupancy: 0.0001 mg/kg, about 10% predicted CD38 occupancy in B and T cells
“Based on the overall data, the recommended starting human dose for the first-in-human study was 0.0001 mg/kg, which is approximately 10% of the predicted CD38 receptor occupancy measured in normal human B and T cells.”
✓ VerifiedEMA assessment report, p. 28Source ↗
NOAEL / key findings
Monkey NOAEL 100 mg/kg/week, highest dose; no isatuximab-related findings
“Therefore, under these study conditions, the dose of 100 mg/kg/week was considered to be the no-observed adverse effect level (NOAEL)”
✓ VerifiedFDA multi-discipline review, p. 51Source ↗

Anthim

obiltoxaximab · B. anthracis PA
First-in-human starting dose
Single-dose clinical escalation supported by monkey AUC margin: 10 mg/kg AUC ~50,000 µg·hr/mL vs human AUC 10,000 at 114 mg
“The 10 mg/kg dose to monkeys with an approximate AUC of 50,000 µg·hr/ml provides an appropriate margin of safety based upon the human AUC of 10,000 following a 114 mg dose of Anthim.”
✓ VerifiedFDA pharmacology/toxicology review, p. 53Source ↗
NOAEL / key findings
NOAEL 30 mg/kg (highest dose) in definitive rat study; no test article-related toxicity; MTD not reached
“The NOAEL was the high dose, 30 mg/kg, for both the Lonza and Baxter material”
✓ VerifiedFDA pharmacology/toxicology review, p. 101Source ↗

Cinqair

reslizumab · IL-5
First-in-human starting dose
Phase 1 single-dose escalation in severe asthma at 0.03 to 1.0 mg/kg; derivation of starting dose not described
“This product has been used in Europe in an initial phase 1 single dose, dose escalation trial for treatment of 32 subjects with severe asthma (I96-350). Doses ranged from 0.03 mg/kg to 1.0 mg/kg.”
✓ VerifiedFDA pharmacology/toxicology review, p. 125Source ↗
NOAEL / key findings
NOAEL 25 mg/kg (highest dose) in mice and monkeys; no target organs; about 3-fold exposure margin
“The NOAELs of 25 mg/kg provided a safety margin of approximately 3-fold compared to the recommended clinical dose based on systemic exposure comparisons.”
✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Danyelza

naxitamab · GD2
First-in-human starting dose
Initial trials based on prior clinical data with the murine parent antibody, not on toxicology data with naxitamab
“The initial clinical trials investigating the activity and dosing of naxitamab were conducted on the basis of previous clinical data with the murine parent antibody rather than supported by toxicology data with the clinical candidate.”
✓ VerifiedFDA multi-discipline review, p. 41Source ↗
NOAEL / key findings
13-week NOAEL 10 mg/kg/day (30 mg/kg per cycle) in male nude rats; adverse glandular stomach findings
“In the 13-week study, adverse findings in histopathology evaluations of the stomach resulted in the NOAEL to be established at 10 mg/kg/day (30 mg/kg per cycle) in male rats only”
✓ VerifiedFDA multi-discipline review, p. 62Source ↗

Imaavy

nipocalimab · FcRn
First-in-human starting dose
First-in-human SAD in healthy volunteers started at 0.3 mg/kg IV, escalating to 60 mg/kg; derivation not stated
“In the SAD portion of the study, six groups received a single IV infusion of placebo (N=10) or escalating doses of nipocalimab at 0.3 mg/kg (N=3), 3 mg/kg (N=3), 10 mg/kg (N=6), 30 mg/kg (N=6), or 60 mg/kg (N=6).”
✓ VerifiedFDA integrated review, p. 157Source ↗
NOAEL / key findings
26-week NOAEL 100 mg/kg, as systemic lymphoproliferation in a euthanised high-dose monkey could not be excluded as drug-related
“As nipocalimab cannot be ruled out as involved in the mechanism of systemic lymphoproliferation in the euthanised monkey in the 26-week study, the NOAEL should be lowered to 100 mg/kg providing safety margins of 10.8 and 6.7 based on AUC0-last and Cmax, respectively.”
✓ VerifiedEMA assessment report, p. 48Source ↗

Rituxan

rituximab · CD20
First-in-human starting dose
Based on monkey pilot study relating multiple-dose rituximab exposure to B-cell depletion
“A repeated pilot pharmacology/toxicology experiment in Cynomolgus monkeys (using 16.8 mg/kg doses) demonstrated the relationship between exposure of multiple injections of rituximab to the degree of B–cell depletion in the peripheral blood and bone marrow, as well as within the lymphatic tissues. This experiment formed the basis for the initial dose escalating study in humans.”
✓ VerifiedEMA assessment report, p. 6Source ↗
NOAEL / key findings
No toxicity beyond expected B-cell depletion in blood and lymphoid tissues; no NOAEL stated
“No effect other than the expected pharmacological depletion of B–cells in peripheral blood as well as in lymphatic tissues was observed in toxicity studies.”
✓ VerifiedEMA assessment report, p. 5Source ↗

Actemra

tocilizumab · IL-6R
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No major clinical pathology or histopathology findings; exposure 8- to 10-fold above maximum human exposure
“No major abnormal findings were observed in either the clinical pathology investigations or in the histopathological evaluation of tissues. The systemic steady state exposure to tocilizumab in these monkey studies was 8-to10-fold above the maximum human exposure”
✓ VerifiedEMA assessment report, p. 16Source ↗

Adakveo

crizanlizumab · P-selectin
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Well tolerated up to 25 mg/kg for 26 weeks; vascular inflammation in several tissues in two animals at 50 mg/kg
“Toxicity data suggests that crizanlizumab is well tolerated up to 25 mg/kg once per week intravenous administration up to 26 weeks. An inflammatory reaction in the blood vessels of several tissues was observed in two animals of the high dose of 50 mg/kg group.”
✓ VerifiedEMA assessment report, p. 42Source ↗

Adbry

tralokinumab · IL-13
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 90 mg/kg/week (13-week SC) and 100 mg/kg/week (26-week IV); no adverse effects or target organs
“The no observed adverse effect level (NOAEL) for tralokinumab in cynomolgus monkeys was 90 mg/kg/week in the 13-week SC toxicology study and 100 mg/kg/week in the 26-week IV toxicology study.”
✓ VerifiedFDA integrated review, p. 131Source ↗

Aduhelm

aducanumab · Aggregated amyloid-β
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 monoclonal antibodies outside oncology →
NOAEL / key findings
13-week transgenic mouse ch12F6A NOAEL 10 mg/kg/week; brain meningeal vascular inflammation and hemorrhage at 70 mg/kg/week
“Based on the meningeal vascular inflammation and acute hemorrhage in brain at the MD of 70 mg/kg/week, the NOAEL was the LD of 10 mg/kg/week IV ch12F6A.”
✓ VerifiedFDA pharmacology/toxicology review, p. 48Source ↗

Aimovig

erenumab · CGRP receptor
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAELs: 150 mg/kg twice weekly (3- and 6-month study) and 50 mg/kg Q2W (ePPND); AUC margins >100 and ~17 times human
“The highest subcutaneous doses tested in the combined 3- and 6-month toxicity (150 mg/kg twice weekly) and the ePPND (50 mg/kg Q2W) studies (both NOAELs) provided serum exposure (AUC) margins >100 and ~17 times”
✓ VerifiedFDA pharmacology/toxicology review, p. 5Source ↗

Ajovy

fremanezumab · CGRP
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Chronic monkey study, weekly SC up to 300 mg/kg: no adverse effects except injection-site inflammation
“Monkeys were dosed weekly via SC injection at dose levels of up to 300 mg/kg for 25 weeks, followed by a 16-week recovery period. No adverse effects except injection site inflammation were observed at any dose.”
✓ VerifiedFDA pharmacology/toxicology review, p. 71Source ↗

Alhemo

concizumab · TFPI
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 monoclonal antibodies outside oncology →
NOAEL / key findings
52-week NOAEL 0.5 mg/kg/day SC (~70x clinical exposure), based on thrombus formation
“The NOAEL for this study was 0.5 mg/kg/day based on thrombus formation. The exposure at the NOAEL was approximately 70-times that of the intended clinical exposure.”
✓ VerifiedEMA assessment report, p. 37Source ↗

Andembry

garadacimab · Factor XIIa
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 monoclonal antibodies outside oncology →
NOAEL / key findings
26-week monkey NOAEL 30 mg/kg/week IV and 60 mg/kg/week SC, based on deaths at 100 mg/kg IV and 200 mg/kg SC
“NOAELs were identified as the mid doses (MDs) of 30 mg/kg/week (IV) and 60 mg/kg/week (SC) based upon deaths observed at 100 mg/kg/week (IV) and 200 mg/kg/week (SC).”
✓ VerifiedFDA integrated review, p. 118Source ↗

Arzerra

ofatumumab · CD20
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Haemolytic anaemia (possibly ADA/immune-complex mediated) with unscheduled deaths; lymphoid germinal centre atrophy; infections
“In repeat-dose toxicity studies, haemolytic anaemia developed in cynomolgus monkeys, leading to unscheduled deaths.”
✓ VerifiedEMA assessment report, p. 20Source ↗

Avastin

bevacizumab · VEGF-A
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
No NOAEL stated; physeal dysplasia from about 2 mg/kg (males) and 10 mg/kg (females) in monkeys
“Physeal dysplasia occurred in males at about 2 mg/kg and in females at 10 mg/kg.”
✓ VerifiedEMA assessment report, p. 21Source ↗

Bavencio

avelumab · PD-L1
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 monoclonal antibodies →
NOAEL / key findings
No NOAEL in 13-week monkey study: perivascular mononuclear infiltrates in brain and spinal cord at all doses; LOAEL 1.5-fold human exposure
“Due to the finding of perivascular mononuclear cell infiltrates in the brain and spinal cord at all dose levels in the 13-week monkey study, there was no NOAEL in this study and accordingly only a LOAEL, which was 1.5-fold above the human therapeutic exposure.”
✓ VerifiedEMA assessment report, p. 29Source ↗

Benlysta

belimumab · BLyS (BAFF)
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Few noteworthy findings beyond pharmacological B-cell effects; low potential for toxicity
“Aside from effects associated with the pharmacological activity of belimumab, there were few noteworthy findings in the toxicology studies indicating a low potential for toxicity.”
✓ VerifiedEMA assessment report, p. 19Source ↗

Beovu

brolucizumab · VEGF-A
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 6 mg/eye (highest dose tested); well tolerated, no systemic toxicity
“Overall, results of the different studies revealed that brolucizumab was well tolerated with a NOAEL value of 6 mg/eye corresponding to the highest tested dose and no systemic toxicity was observed.”
✓ VerifiedEMA assessment report, p. 29Source ↗

Beyfortus

nirsevimab · RSV F protein
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 300 mg/kg IV or IM (highest dose); minor nonadverse APTT, globulin, total protein increases and splenic macrophage hypertrophy
“No adverse, drug-related findings were observed in the GLP 4-week toxicology study in cynomolgus monkeys up to the highest doses tested (no observed adverse effect level (NOAEL) =300 mg/kg IM or IV).”
✓ VerifiedFDA integrated review, p. 121Source ↗

Bimzelx

bimekizumab · IL-17A/IL-17F
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL was highest dose in 8-week studies (200 and 20 mg/kg/week); none in 26-week study (skin findings, GI infection deaths)
“The no-observed adverse effect level (NOAEL) was the highest dose tested in the 8-week studies (200mg/kg/week and 20mg/kg/week, respectively, for Study NCD2260 and Study NCD2384). Due to the severity of skin findings in some high-dose animals and mortalities in the low dose group consecutive to GI infection, no NOAEL could be determined in the 26-week study.”
✓ VerifiedEMA assessment report, p. 25Source ↗

Briumvi

ublituximab · CD20
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No NOAEL identified in the 26-week study, as only one dose level was tested
“Since only one dose level of ublituximab was administered, no NOAEL was identified.”
✓ VerifiedFDA pharmacology/toxicology review, p. 51Source ↗

Cablivi

caplacizumab · von Willebrand factor (A1 domain)
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 monoclonal antibodies outside oncology →
NOAEL / key findings
26-week monkey NOAEL 4 mg/kg/day, based on high-dose (40 mg/kg/day) male sacrificed with persistent anaemia
“In this study, the NOAEL was set to 4 mg/kg/day based on a premature sacrifice of one male in the high dose-group administered 13.5 mg/kg 3 times/day (40 mg/kg/day) on day 85 due to persistent signs of anaemia”
✓ VerifiedEMA assessment report, p. 28Source ↗

Campath

alemtuzumab · CD52
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
No NOAEL defined; dose-limiting infections or hypersensitivity causing deaths; reduced CD52 affinity in monkey limits model
“dose-limiting toxicity (increased susceptibility to infections or hypersensitivity leading to lethality/early sacrifice) and limitation of the animal model (decreased affinity of alemtuzumab for CD52 in the cynomolgus monkey).”
✓ VerifiedEMA assessment report, p. 26Source ↗

Cimzia

certolizumab pegol · TNF-α
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Cellular vacuolation, mainly in macrophages, in multiple organs including choroid plexus of the brain
“In rats and monkeys histopathology revealed cellular vacuolation, present mainly in macrophages, in a number of organs (lymph nodes; injection sites, spleen; adrenal; uterine, cervix; choroid plexus of the brain, and in the epithelial cells of the choroid plexus).”
✓ VerifiedEMA assessment report, p. 14Source ↗

Cosentyx

secukinumab · IL-17A
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 50 mg/kg/week in monkey repeat-dose studies, based on clinical chemistry effects and immunotoxicity (lymphocyte, B- and T-cell decreases) at high dose
“Due to clinical chemistry effects and immunotoxicity (decreases in total lymphocytes, B cells and T cells) observed at the high dose, the NOAEL appears to be 50 mg/kg/week.”
✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Crysvita

burosumab · FGF23
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Adult monkey NOAEL 0.3 mg/kg (0.9x adult human AUC) in both repeat-dose studies
“The NOAEL was 0.3 mg/kg (0.9x adult human AUC) in both”
✓ VerifiedFDA multi-discipline review, p. 45Source ↗

Cyramza

ramucirumab · VEGFR2
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Target organs: kidney (glomerulonephritis), epiphyseal growth plate (thickening, abnormal ossification), ovaries and uterus (decreased weight)
“The target organs identified in repeated dose Cynomolgus monkey toxicity studies were kidney (glomerulonephritis), bone (thickening and abnormal endochondral ossification of the epiphyseal growth plate) and female reproductive organs (decreased weight of ovaries and uterus)”
✓ VerifiedEMA assessment report, p. 27Source ↗

Darzalex

daratumumab · CD38
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Chimpanzee: infusion-related reactions, thrombocytopenia, anemia, leukopenia and elevated AST
“The primary toxicities identified in chimpanzees were infusion related reactions, thrombocytopenia, anemia, leukopenia, in addition to elevated AST values.”
✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Dupixent

dupilumab · IL-4Ra
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No adverse effects in repeat-dose studies; NOAEL was the highest dose in all studies
“In summary, no adverse effects were observed in the repeat-dose studies. In all studies, the NOAEL was the highest dose administered”
✓ VerifiedEMA assessment report, p. 20Source ↗

Ebanga

ansuvimab · Zaire ebolavirus glycoprotein
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 500 mg/kg/dose (highest dose); no adverse drug-related toxicity; 7.6-fold AUC margin
“NOAEL =500 mg/kg/dose (AUClast =222664 µg.day/mL at Day 22, gender-averaged) Exposure multiple =7.6”
✓ VerifiedFDA integrated review, p. 85Source ↗

Ebglyss

lebrikizumab · IL-13
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL = highest dose: 22.7 mg/kg/week (6-week IV), 25 mg/kg/week (9-month IV and 13-week SC)
“The NOAEL for lebrikizumab in cynomolgus monkeys was the highest dose tested in all three studies, i.e., 22.7 mg/kg/week in the 6-week intravenous toxicology study and 25 mg/kg/week in the 9-month intravenous toxicology study and 13-week subcutaneous toxicology study.”
✓ VerifiedFDA multi-discipline review, p. 50Source ↗

Emgality

galcanezumab · CGRP
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Rat 6-month NOAEL low dose (2 high-dose male deaths, drug relation not ruled out); monkey 6-month NOAEL high dose (injection-site irritation non-adverse)
“The NOAEL in the 6-month rat study was the LD, because a drug-related cause of death could not be ruled out in the 2 HDM. In the 6-month monkey study, the NOAEL was the HD, because the injection site irritation was not considered adverse.”
✓ VerifiedFDA pharmacology/toxicology review, p. 60Source ↗

Empliciti

elotuzumab · SLAMF7
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Single IV doses of 30 or 100 mg/kg well tolerated in rhesus monkeys
“Single IV administration of elotuzumab at dose levels of 30 or 100 mg/kg (≤ AUC[INF] range of 335 to 447 mg•h/mL) were well tolerated.”
✓ VerifiedEMA assessment report, p. 20Source ↗

Enflonsia

clesrovimab · RSV F protein (site IV)
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No adverse findings; NOAEL 300 mg/kg IV and 25 mg/kg IM (highest doses tested)
“No adverse, product-related findings were observed in the GLP 2-week toxicology study in Wistar Han rats up to the highest doses tested (no-observed-adverse-effect level [NOAEL] =300 mg/kg [IV] and 25 mg/kg [IM]).”
✓ VerifiedFDA integrated review, p. 119Source ↗

Enjaymo

sutimlimab · Complement C1s
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 180 mg/kg/week (highest dose) in repeat-dose monkey study; no adverse findings despite near-complete classical complement inhibition
“The no observed adverse effect level (NOAEL) in the repeat-dose toxicity study was 180 mg/kg weekly in male and female monkeys.”
✓ VerifiedFDA pharmacology/toxicology review, p. 40Source ↗

Enspryng

satralizumab · IL-6R
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 50 mg/kg/week (high dose) in 26-week SC monkey study; no notable toxicity
“The NOAEL was the high dose of 50 mg/kg/week.”
✓ VerifiedFDA pharmacology/toxicology review, p. 32Source ↗

Entyvio

vedolizumab · α4β7-integrin
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 100 mg/kg in monkeys, about 18 times the human AUC at 300 mg
“The exposure (AUC) at the NOAEL dose of 100 mg/kg in monkeys is approximately 18 times higher than the mean AUC at the recommended human dose of 300 mg.”
✓ VerifiedFDA pharmacology/toxicology review, p. 158Source ↗

Erbitux

cetuximab · EGFR
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Skin primary target organ with dose-dependent effects at all doses; severe skin reactions and 5 deaths at high dose
“Clinical and necropsy findings indicated that the skin was the primary target organ, with dose-dependent effects observed at all dose levels. Severe skin reactions and 5 intercurrent deaths were observed in the high dose group.”
✓ VerifiedEMA assessment report, p. 11Source ↗

Evenity

romosozumab · Sclerostin
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No adverse effects at up to 100 mg/kg weekly SC for 26 weeks in rats and monkeys (37x and 90x human exposure); findings pharmacologic (bone)
“No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 37 and 90 times, respectively, the systemic exposure observed in humans”
✓ VerifiedUS prescribing informationSource ↗

Evkeeza

evinacumab · ANGPTL3
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 100 mg/kg/week IV in rats and monkeys (chronic studies)
“The NOAELs for chronic administration of evinacumab in rats and monkeys were 100 mg/kg/week IV for both species”
✓ VerifiedFDA pharmacology/toxicology review, p. 8Source ↗

Exdensur

depemokimab · IL-5
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg) or 100 mg/kg (applicant); reduced eosinophils; vasculitis in single-dose study
“The NOAEL in the 26week repeat dose toxicity was considered by the Rapporteur to be 10 mg/kg instead of 100 mg/kg due to the increase in QTc at 100 mg/kg in 4/6 animals at 100 mg/kg, which is considered to be an adverse effect.”
✓ VerifiedEMA assessment report, p. 55Source ↗

Fasenra

benralizumab · IL-5Rα
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 10 mg/kg IV and 30 mg/kg SC; post-dose reaction (bruising, low platelets, abnormal erythrocytes) in one 25 mg/kg IV female
“NOAELs of 10 mg/kg IV and 30 mg/kg SC were identified. The primary finding at a dose of 25 mg/kg IV was a post-dose reaction in one high-dose female that included bruising in the areas of the eyes, face, chest and lower abdomen, a decrease in platelet counts, and abnormal erythrocytes after the fourth dose.”
✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Gamifant

emapalumab · IFN-γ
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Tolerated up to 30 mg/kg/week (highest dose) in the follow-up monkey study
“NI-0501 was tolerated in monkeys up to 30 mg/kg/week, the highest dose tested.”
✓ VerifiedFDA multi-discipline review, p. 39Source ↗

Gazyva

obinutuzumab · CD20
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Hypersensitivity at all doses (≥5 mg/kg) in 26-week study: immune-complex glomerulonephritis, arteritis, deaths; expected B-cell depletion; no off-target toxicity
“Hypersensitivity reactions were noted at all doses (≥5 mg/kg) in the 26-week study and were attributed to cross-species reactivity to a foreign protein.”
✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Herceptin

trastuzumab · HER2
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Minimal toxicity in all repeat-dose studies; only injection-site trauma in rhesus monkey
“In all three studies there was a minimal toxic response, with the only noteworthy observations concerning injection-site trauma in the rhesus monkey.”
✓ VerifiedEMA assessment report, p. 8Source ↗

Humira

adalimumab · TNF-α
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 monoclonal antibodies outside oncology →
NOAEL / key findings
39-week monkey NOAEL 32 mg/kg; thymus and spleen immune effects, mostly reversible over 20-week recovery
“In the 39 weeks study, most of these changes were reversible within the 20-week recovery period. In this study, the NOAEL was 32 mg/kg, with an AUC of 304 800 µg*h/ml.”
✓ VerifiedEMA assessment report, p. 7Source ↗

Hympavzi

marstacimab · TFPI
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAELs at top weekly IV doses: 1000 mg/kg rat, 500 mg/kg monkey (~200x MRHD AUC)
“Thus, the top weekly intravenous dose of 1000 mg/kg/dose in rats and 500 mg/kg/dose in monkeys were regarded as the no observed adverse effect level (NOAEL) doses, with AUC exposures approximately 200-times greater than clinical exposure at the maximum recommended human dose”
✓ VerifiedFDA integrated review, p. 122Source ↗

Ilaris

canakinumab · IL-1β
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOEL/NOAEL at highest dose (100 mg/kg IV or 150 mg/kg SC); no general or reproductive toxicity signals
“In all the studies, NOEL or NOAEL was the highest dose administered (100 mg/kg/dose IV or 150 mg/kg/dose SC). No signals were identified for general toxicity and for reproductive toxicity.”
✓ VerifiedEMA assessment report, p. 15Source ↗

Ilumya

tildrakizumab · IL-23 p19
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 140 mg/kg Q2W IV/SC (3-month) and 100 mg/kg SC Q2W (9-month), highest doses; no adverse effects
“In the 3-months study, the NOAEL was 140 mg/kg following either IV or SC administration every 2 weeks; in the 9-months study, the NOAEL was 100 mg/kg SC Q2W.”
✓ VerifiedEMA assessment report, p. 24Source ↗

Imfinzi

durvalumab · PD-L1
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 monoclonal antibodies →
NOAEL / key findings
NOAEL at the high dose (200/100 mg/kg) in the pivotal toxicity studies
“The selection of the high dose in all three studies is therefore also accepted as NOAEL (200/100 mg/kg) in the pivotal toxicity studies.”
✓ VerifiedEMA assessment report, p. 31Source ↗

Imjudo

tremelimumab · CTLA-4
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 monoclonal antibodies →
NOAEL / key findings
NOAEL 5 mg/kg in 1-month study; no NOAEL in 6-month study, 15 mg/kg considered the maximum tolerated dose
“A dose of 5 mg/kg was considered to be the no‐observed effect level (NOAEL) following 1‐month of dosing and following 6‐months of dosing a NOAEL was not established but 15 mg/kg was considered to be the maximum tolerated dose.”
✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Jemperli

dostarlimab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal
“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg).”
✓ VerifiedEMA assessment report, p. 43Source ↗

Kevzara

sarilumab · IL-6R
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 50 mg/kg/week (high dose) in pivotal monkey study; no target organs of toxicity; >80-fold exposure margin
“The NOAEL was identified at the high dose of 50 mg/kg/week based upon no findings of dose-limiting toxicity or target organs of toxicity. Exposure at the NOAEL provided a safety margin >80 times the exposures at proposed clinical doses.”
✓ VerifiedFDA pharmacology/toxicology review, p. 47Source ↗

Keytruda

pembrolizumab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
Well tolerated; NOAEL was the highest dose tested in both studies
“Overall, pembrolizumab was well tolerated and the NOAEL in both studies was the highest dose tested.”
✓ VerifiedEMA assessment report, p. 30Source ↗

Kisunla

donanemab · Amyloid-β (N3pG)
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No drug-related adverse effects: monkey at 100 mg/kg/week IV for 6 weeks; PDAPP mice (mE8c) at 100 mg/kg/week SC for 5 months
“In summary, there were no drug-related adverse effects in aged PDAPP mice administered mE8c at 100 mg/kg/week SC for 5 months, or in cynomolgus monkeys administered donanemab for 6 weeks at 100 mg/kg/week IV.”
✓ VerifiedFDA pharmacology/toxicology review, p. 20Source ↗

Lartruvo

olaratumab · PDGFRα
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
NOAEL 75 mg/kg (highest dose) in 39-week monkey study; non-adverse ALT rise and liver infiltrates; potential targets skin, liver, lung, pancreas
“In this study, monkey serum Cmin was 1164 μg/mL at the no observed adverse effect level (NOAEL) of 75 mg/kg”
✓ VerifiedEMA assessment report, p. 35Source ↗

Leqembi

lecanemab · Amyloid-β protofibrils
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 100 mg/kg once weekly in the 39-week study
“In the 39-week intermittent intravenous dose toxicity study with 13-week recovery period, NOAEL (be 100 mg/kg, once a week) corresponded to mean AUC(0-384h) for males and females of”
✓ VerifiedEMA assessment report, p. 31Source ↗

Libtayo

cemiplimab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
NOAEL 50 mg/kg/week (highest dose), excluding immunogenicity-related effects; two deaths in 26-week study from immune complex deposition
“The NOAEL was considered to be 50 mg/kg/week in all repeat-dose toxicity studies in monkeys, the highest dose administered. However, while setting this dose as the NOAEL any adverse reactions as a consequence of high immunogenicity was excluded. Given that in 26-week toxicity study in monkeys two animals died (one in 10 and 50 mg/kg dose groups in each) due to immune complex deposition and associated tissue damage.”
✓ VerifiedEMA assessment report, p. 33Source ↗

Loqtorzi

toripalimab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
NOAEL 100 mg/kg (highest dose) in 26-week study; no toripalimab-related adverse effects
“Therefore, the NOAEL was considered 100 mg/kg for this study.”
✓ VerifiedFDA multi-discipline review, p. 91Source ↗

Lucentis

ranibizumab · VEGF-A
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No NOAEL: all doses (0.25-2 mg) caused dose-related ocular inflammation; also perivascular sheathing, retinal haemorrhages, cataracts
“The NOEL or NOAEL were not identified in any of the studies, since all doses tested (0.25-2 mg) resulted in an ocular inflammation.”
✓ VerifiedEMA assessment report, p. 11Source ↗

Margenza

margetuximab · HER2
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
NOAEL 150 mg/kg/dose (highest dose) after 6 weekly IV doses in monkeys
“or 6 weekly doses of 0, 15, 50 or 150 mg/kg/dose (Report UOK00019). These data support a no-observed-adverse-effect level (NOAEL) of 150 mg/kg/dose.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗

Monjuvi

tafasitamab · CD19
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
NOAEL 100 mg/kg/week (13-week); reversible B-cell depletion, reduced germinal center cellularity; tremors and body temperature changes at high dose
“In general, tafasitamab was well tolerated in single-dose studies up to 10 mg/kg and in repeat-dose studies up to 100 mg/kg, supporting the NOAEL of 100 mg/kg determined based on the 13-week”
✓ VerifiedEMA assessment report, p. 40Source ↗

Nemluvio

nemolizumab · IL-31RA
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 25 mg/kg every two weeks (high dose) in 26-week monkey study; no significant toxicity
“No significant toxicity was noted in this study. The NOAEL was identified as the high dose, 25 mg/kg once every two weeks.”
✓ VerifiedFDA integrated review, p. 105Source ↗

Niktimvo

axatilimab · CSF-1R
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Adverse findings at all doses: basophilic material accumulation in numerous organs and femoral growth plate thickening/degeneration
“Axatilimab-related microscopic findings included dose-dependent accumulation of basophilic material within numerous organs/tissues and alterations in femoral bone thickening of the growth plate and metaphysis and degeneration of the growth plate at all dose levels.”
✓ VerifiedFDA multi-discipline review, p. 43Source ↗

Nucala

mepolizumab · IL-5
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Monkey NOAEL 100 mg/kg IV or 10 mg/kg SC q4 weeks; ~70-fold exposure margin
“The NOAEL was the high IV dose of 100 mg/kg q4 weeks or the SC dose of 10 mg/kg q4 weeks; the NOAEL for IV dosing provided a safety margin of approximately 70-fold compared to the maximum recommended clinical dose based on systemic exposure comparisons.”
✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Ocrevus

ocrelizumab · CD20
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 100 mg/kg; B-cell repopulation at all dose levels
“Repopulation of B cells was demonstrated at all dose levels. NOAEL is100 mg/kg.”
✓ VerifiedFDA pharmacology/toxicology review, p. 95Source ↗

Omvoh

mirikizumab · IL-23 p19
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 100 mg/kg/dose (twice-weekly IV monkey study); decreased RBC indices in one female at 300 mg/kg/dose
“The NOAEL was 100 mg/kg/dose • Findings were limited to changes in hematology parameters which included mildly to moderately decreased red blood cell indices for one female monkey at 300 mg/kg/dose on day 180.”
✓ VerifiedFDA multi-discipline review, p. 72Source ↗

Opdivo

nivolumab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
Well tolerated up to 50 mg/kg in 4- and 13-week monkey studies
“Nivolumab was evaluated in 4- and 13-week repeat dose studies in the cynomolgus monkey and was well-tolerated at doses of up to 50 mg/kg.”
✓ VerifiedFDA pharmacology/toxicology review, p. 13Source ↗

Pasatru

garetosmab · Activin A
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Cynomolgus monkey NOAEL 50 mg/kg for both sexes (highest dose; about five-times clinical AUC)
“A no observed adverse effect level was established at 50 mg/kg (the highest dose tested, approximately five-times the maximum clinical exposure by AUC) for both sexes.”
✓ VerifiedFDA integrated review, p. 59Source ↗

Penpulimab

penpulimab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
13-week monkey NOAEL 60 mg/kg; lymph node increased cellularity and erythrophagocytosis
“Histological findings included increased cellularity and erythrophagocytosis in the inguinal, mandibular, and mesenteric lymph nodes. • The NOAEL was 60 mg/kg.”
✓ VerifiedFDA multi-discipline review, p. 53Source ↗

Perjeta

pertuzumab · HER2
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
No NOAEL in 26-week study: severe diarrhoea and increased urea nitrogen at all dose levels
“Due to the severe diarrhoea and increased urea nitrogen values at all dose levels, a No Observed Adverse Effect Level (NOAEL) could not be determined.”
✓ VerifiedEMA assessment report, p. 38Source ↗

Piasky

crovalimab · Complement C5
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 10 mg/kg/week SC in 6-month study; arteritis/periarteritis in multiple organs at higher doses
“The no observed adverse effect level (NOAEL) for crovalimab in cynomolgus monkeys after 6 months of SC intermittent dosing is defined at the low dose of 10 mg/kg/week based on the occurrence of arteritis/periarteritis in multiple organs at higher doses tested”
✓ VerifiedFDA integrated review, p. 178Source ↗

Portrazza

necitumumab · EGFR
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
No NOAEL in 26-week monkey study: adverse skin effects (hyperplastic dermatitis) at all doses
“A no-observed-adverse-effect level (NOAEL) was not established in the 26-week toxicity study due to adverse skin effects at all dose levels.”
✓ VerifiedEMA assessment report, p. 31Source ↗

Poteligeo

mogamulizumab · CCR4
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Monkey NOAEL ≥40 mg/kg (highest dose); no toxicologically significant changes
“The NOAEL of mogamulizumab was judged to be 40 mg/kg or greater since no toxicologically significant changes were observed in any examination.”
✓ VerifiedEMA assessment report, p. 47Source ↗

Praluent

alirocumab · PCSK9
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL at highest doses in 6-month studies (rat 50, monkey 75 mg/kg/week SC); no dose-limiting toxicity
“Alirocumab was subcutaneously administered for 6 months to rats at up to 50 mg/kg/week and to monkeys at up to 75 mg/kg/week; no evidence of dose-limiting test item-related toxicity was observed”
✓ VerifiedFDA pharmacology/toxicology review, p. 144Source ↗

Praxbind

idarucizumab · Dabigatran
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Rhesus NOAEL 500 mg/kg/day with or without dabigatran (2 days or 2 weeks); margins 5-7x Cmax, 3-6x AUC
“In summary, the NOAEL in rhesus monkeys treated with idarucizumab in the absence or presence of dabigatran for 2 days or 2 weeks was 500 mg/kg/day. The resulting exposure multiples, taking into account different human populations (healthy, elderly, with renal impairment) were approx. 5-7x based on Cmax and 3-6x based on AUC0-24.”
✓ VerifiedEMA assessment report, p. 24Source ↗

Prolia

denosumab · RANKL
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No target organ toxicity at doses up to 50 mg/kg in 6/12-month monkey study
“In 6/12-Month Repeated-dose Study in Monkeys (102090) denosumab was administrated at doses of 0, 1, 10, and 50 mg/kg. Overall, no effects on organ weights or macroscopic or microscopic evidence of target organ toxicity were noted.”
✓ VerifiedEMA assessment report, p. 16Source ↗

Raxibacumab

raxibacumab · B. anthracis protective antigen
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Greater CNS lesion severity (bacteria, inflammation, hemorrhage) in anthrax-infected non-survivors given 40 mg/kg
“Anthrax infected rabbits and monkeys administered an intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia reproducibly showed greater severity of CNS lesions (bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals compared to dead placebo control animals”
✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Remicade

infliximab · TNF-α
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No toxicity in mouse surrogate study except dose-related bilateral lens capsule crystalline deposits in males
“However, ophthalmic examinations revealed a dose-related increase of bilateral crystalline deposits in the lens capsule of treated male mice. The relevance of this finding for humans is not known.”
✓ VerifiedEMA assessment report, p. 8Source ↗

Repatha

evolocumab · PCSK9
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Monkey 26-week study: NOAEL 300 mg/kg/week, the highest dose tested
“Evolocumab was administered to monkeys (6/sex/dose) at 0, 3, 30 and 300 mg/kg/week for 26 weeks via subcutaneous injection. Two monkeys/sex/group were allowed a 25-week treatment-free recovery period. The NOAEL is considered to be 300 mg/kg/week, the highest dose tested.”
✓ VerifiedFDA pharmacology/toxicology review, p. 59Source ↗

Rystiggo

rozanolixizumab · FcRn
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No adverse effects up to 150 mg/kg SC every 3 days for 4, 13 and 26 weeks; reduced IgG, total protein and albumin (pharmacology)
“No adverse effects were seen in male and female cynomolgus monkeys administered subcutaneous (SC) doses of up to 150 mg/kg UCB7665 every 3 days for 4, 13, and 26 weeks.”
✓ VerifiedFDA integrated review, p. 91Source ↗

Saphnelo

anifrolumab · IFNAR1
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 monoclonal antibodies outside oncology →
NOAEL / key findings
39-week males: NOAEL below 5 mg/kg IV and 15 mg/kg SC due to arteritis; at least 50 IV/60 SC if arteritis excluded
“Based on the arterial inflammation observed, the NOAEL for males is less than 5 mg/kg IV and 15 mg/kg SC. If the observed arteritis is not factored into the NOAEL determination, the NOAEL of anifrolumab for males is at least 50 mg/kg IV and 60 mg/kg SC, the highest doses tested.”
✓ VerifiedEMA assessment report, p. 33Source ↗

Siliq

brodalumab · IL-17RA
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 monoclonal antibodies outside oncology →
NOAEL / key findings
6-month monkey NOAEL 90 mg/kg/dose; findings at least partially reversible during six-month recovery
“These changes were at least partially reversible during the six month recovery period. The NOAEL for this study was determined to be 90 mg/kg/dose.”
✓ VerifiedFDA pharmacology/toxicology review, p. 21Source ↗

Simponi

golimumab · TNF-α
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Monkey NOAEL 50 mg/kg despite lymphocyte increases; margin ~600 (Cmax) and 50 (AUC)
“Despite the increase in total lymphocytes, it is agreed by the assessor that a NOAEL can be set to 50 mg/kg, which gives a margin to maximum human exposure of approximately 600 (mean for male/female animals), based on Cmax values and 50 based on AUC values.”
✓ VerifiedEMA assessment report, p. 14Source ↗

Simulect

basiliximab · IL-2Rα (CD25)
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No toxic effects up to the maximum dose of 5 mg/kg in rhesus monkeys; no target organs identified
“the results of several repeated dose toxicity studies in Rhesus monkeys indicated no toxic effects up to the maximum dose of 5mg/kg.”
✓ VerifiedEMA assessment report, p. 6Source ↗

Skyrizi

risankizumab · IL-23 p19
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 50 mg/kg/week (highest dose), about 70-fold exposure margin; no toxicologically significant findings
“The NOAEL was 50 mg/kg/week, the highest dose tested, with exposure levels that were significantly above the recommended clinical dose in psoriasis patients (150 mg SC on Weeks 0 and 4, then every 12 weeks), providing a margin of exposure of approximately 70.”
✓ VerifiedEMA assessment report, p. 24Source ↗

Soliris

eculizumab · Complement C5
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Surrogate 26-week mouse study: no treatment effects on any toxicity parameter at either dose; no target organs
“Treatment did not affect any of the toxicity parameters examined.”
✓ VerifiedEMA assessment report, p. 9Source ↗

Spevigo

spesolimab · IL-36R
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 50 mg/kg/dose (highest dose) in 6-month mouse surrogate study; no mortality, clinical signs, or gross/histopathology findings
“The NOAEL for the 6-month toxicity study was the highest dose 50 mg/kg/dose.”
✓ VerifiedFDA multi-discipline review, p. 37Source ↗

Stelara

ustekinumab · IL-12/23 p40
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Well tolerated at 45 mg/kg twice weekly SC for 6 months in monkeys; no target organs, no delayed toxicity
“ustekinumab was generally well tolerated under a regimen of twice weekly subcutaneous dosing at 45 mg/kg for 6 months in cynomolgus monkeys and adequate margins of exposure over the human clinical exposure were demonstrated. No target organs were identified and there was no delayed toxicity after dosing had stopped.”
✓ VerifiedEMA assessment report, p. 18Source ↗

Sylvant

siltuximab · IL-6
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No significant toxicities in 3- or 6-month monkey studies; pharmacology-related lower globulin, reduced TDAR, smaller splenic germinal centers, skin erythema
“No significant toxicities were observed in the 3- or 6-month toxicology studies with siltuximab and the toxicokinetic (TK) results indicated that anti-siltuximab antibodies did not interfere with exposure or study results.”
✓ VerifiedFDA pharmacology/toxicology review, p. 16Source ↗

Synagis

palivizumab · RSV F protein
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No toxicity after single IV doses in rats and monkeys; no injection-site effects in rabbit local tolerance study
“gave no indication of toxicity or statistically significant deviations from normal caused by the test article for the described parameters.”
✓ VerifiedEMA assessment report, p. 5Source ↗

Takhzyro

lanadelumab · Plasma kallikrein
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Monkey NOAEL 50 mg/kg; target organ SC injection site, monitorable clinically
“The target organs of toxicity were SC injection sites, although these findings were considered monitorable in a clinical setting. The mean AUClast at the no observed adverse effect level (NOAEL) of 50 mg/kg was 110,500 µg*hr/ml.”
✓ VerifiedFDA multi-discipline review, p. 26Source ↗

Taltz

ixekizumab · IL-17A
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 monoclonal antibodies outside oncology →
NOAEL / key findings
9-month SC NOAEL 5 mg/kg/week, limited by injection site reactions requiring dose suspension at the high dose
“Based on the injection site reactions requiring dose suspension, the NOAEL for this 9-month study was 5 mg/kg/week.”
✓ VerifiedFDA pharmacology/toxicology review, p. 6Source ↗

Tecentriq

atezolizumab · PD-L1
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 monoclonal antibodies →
NOAEL / key findings
Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response
“Atezolizumab-related findings in the repeated dose toxicity studies were sciatic neuropathy in C57BL/6 mice and arteritis/periarteritis in Cynomolgus monkeys. Both findings may be due to enhancement of an autoreactive immune-response in pre-disposed animals.”
✓ VerifiedEMA assessment report, p. 36Source ↗

Tepezza

teprotumumab · IGF-1R
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No NOAEL (LOAEL 3 mg/kg/week): halted weight gain, decreased ALP, thymic atrophy; juveniles also reduced bone growth and density
“For adults, the low-dose (3 mg/kg/week IV) is the lowest adverse effect level (LOAEL), and a no observed adverse effect level (NOAEL) was not identified.”
✓ VerifiedFDA pharmacology/toxicology review, p. 21Source ↗

Tevimbra

tislelizumab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
NOAEL 30 mg/kg Q2W, 4.3-6.6x human exposure at 200 mg; no treatment-related toxicity or histopathology
“no apparent treatment-related toxicity or histopathological changes were observed at doses up to 30 mg/kg every 2 weeks, corresponding to 4.3 to 6.6 times the exposure in humans with the clinical dose of 200 mg.”
✓ VerifiedEMA assessment report, p. 30Source ↗

Tezspire

tezepelumab · TSLP
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL was the highest dose tested in each study; minimal to mild serum cholesterol decrease at 300 mg/kg
“The NOAEL was the highest dose tested for each route of administration in each repeat-dose study. Serum cholesterol was minimally to mildly decreased at the 300 mg/kg dose level in most repeat-dose studies.”
✓ VerifiedEMA assessment report, p. 30Source ↗

Tremfya

guselkumab · IL-23 p19
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 50 mg/kg/week for 5-week IV and 24-week SC dosing in monkeys
“The no observed adverse effect level (NOAEL) was 50 mg/kg/week for 5-week IV administration and for 24-week SC administration in cynomolgus monkeys”
✓ VerifiedFDA multi-discipline review, p. 58Source ↗

Trogarzo

ibalizumab · CD4
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Cynomolgus monkey: glomerulopathy and reduced albumin only in animals with strong anti-drug antibody responses
“Multifocal glomerulopathy was observed together with reduced albumin levels, which can be an indication for protein loss through the kidney. As these effects were observed only in animals with a strong antibody response against ibalizumab, its relevance for humans is limited.”
✓ VerifiedEMA assessment report, p. 29Source ↗

Tysabri

natalizumab · α4-integrin
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL not stated; dose-related WBC increases persisting through recovery, elevated reticulocytes, marked spleen weight increases in monkeys
“Common and reproducible effects of natalizumab in cynomolgus monkeys were: • dose related, significantly increased counts of WBC even at the end of recovery periods • elevated reticulocyte counts • severe increases in spleen weights”
✓ VerifiedEMA assessment report, p. 10Source ↗

Tzield

teplizumab · 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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL <0.3 mg/kg in intermittent-dose mouse surrogate study due to severe hypersensitivity; T-cell depletion and thymic medulla hypocellularity
“The NOAEL was <0.3 mg/kg based on severe hypersensitivity reactions.”
✓ VerifiedFDA pharmacology/toxicology review, p. 8Source ↗

Ultomiris

ravulizumab · Complement C5
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Surrogate mouse 26-week study: NOAEL 60 mg/kg/week, the highest dose tested
“The No Observed Adverse Effect Level (NOAEL) for BB5.1 mAb administered to CD‐1 mice via IV injection twice weekly for 26 weeks was determined to be 60 mg/kg/week, the highest dose tested.”
✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Unituxin

dinutuximab · GD2
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Rat NOAEL below 5 mg/kg/day; liver changes, decreased erythrocyte parameters, increased hematopoiesis
“(NOAEL) for males and females was lower than 5 mg/kg/day based on the liver-related changes, the slight decrease in erythrocyte parameters, and changes related to hematopoiesis”
✓ VerifiedEMA assessment report, p. 33Source ↗

Unloxcyt

cosibelimab · PD-L1
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 monoclonal antibodies →
NOAEL / key findings
NOAEL 100 mg/kg once weekly (highest dose) in 13-week monkey study
“No-Observed-Adverse-Effect-Level: 100 mg/kg, once per week”
✓ VerifiedFDA multi-discipline review, p. 55Source ↗

Uplizna

inebilizumab · CD19
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 monoclonal antibodies outside oncology →
NOAEL / key findings
IV NOAEL 30 mg/kg/week in huCD19 Tg mice; HED safety margin 6.9-fold and exposure margin 55-fold
“A HED-based safety margin of 6.9-fold and an exposure-based safety margin of 55-fold was calculated by comparing doses and exposures at the NOAEL of 30 mg/kg/week over a 6-month treatment period in huCD19 Tg mice in the 09-2153 study and human patients.”
✓ VerifiedEMA assessment report, p. 34Source ↗

Vectibix

panitumumab · EGFR
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
Skin toxicity and diarrhoea were the primary toxicities, severe enough to cause unscheduled deaths
“Toxicity to skin and diarrhoea was the primary toxicity of panitumumab in monkeys. These effects were severe enough to cause a significant number of unscheduled deaths.”
✓ VerifiedEMA assessment report, p. 9Source ↗

Veopoz

pozelimab · Complement C5
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 100 mg/kg/week (highest dose) in 13- and 26-week monkey studies; no adverse findings; clinical margins 12-15
“No adverse effects of pozelimab were observed in repeat-dose toxicity studies at doses up to 100 mg/kg/week SC (13 weeks) or IV (26 weeks). Clinical safety margins are 12-15 relative to the predicted drug exposure”
✓ VerifiedFDA multi-discipline review, p. 36Source ↗

Voyxact

sibeprenlimab · APRIL
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 100 mg/kg every 2 weeks IV (high dose) in IV monkey study
“The no-observed-adverse-effect level (NOAEL) was established at the high dose of 100 mg/kg/2-week”
✓ VerifiedFDA integrated review, p. 101Source ↗

Vyepti

eptinezumab · CGRP
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 monoclonal antibodies outside oncology →
NOAEL / key findings
No adverse effects; NOAEL 100 mg/kg/week (rat 4-week) and 150 mg/kg every 2 weeks (monkey 6-month)
“No adverse effects of IV eptinezumab were observed in either the rat 4-week or monkey 6-month general toxicology studies; the NOAELs were determined to be 100 mg/kg/week and 150 mg/kg every 2 weeks, respectively.”
✓ VerifiedFDA pharmacology/toxicology review, p. 8Source ↗

Vyloy

zolbetuximab · Claudin 18.2
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 oncology monoclonal antibodies (ICH S9) →
NOAEL / key findings
No adverse findings in mice; isolated vomiting in one male each at 10 and 30 mg/kg on Day 8 in the 4-week monkey study
“No adverse findings were observed in mice. In the 4-week monkey study, vomiting was observed in one male each from the 10 mg/kg and 30 mg/kg dose groups on Day 8 (second administration).”
✓ VerifiedFDA multi-discipline review, p. 52Source ↗

Xolair

omalizumab · IgE
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Well tolerated except dose-related, age-dependent platelet decreases (greater in juveniles); injection-site haemorrhage
“Chronic administration of omalizumab was well tolerated in non-human primates, with the exception of a dose-related and age-dependent decrease in blood platelets, with a greater sensitivity in juvenile animals.”
✓ VerifiedEMA assessment report, p. 33Source ↗

Yartemlea

narsoplimab · MASP-2
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 monoclonal antibodies outside oncology →
NOAEL / key findings
Monkey 26-week NOAEL 300 mg/kg/week SC (38-fold MRHD); IV NOAEL not set due to irreversible protein/albumin decreases at 150 mg/kg
“The no observed adverse effect level (NOAEL) identified in the 26-week monkey study was 300 mg/kg/week by the SC route (38-fold the maximum recommended human dose (MRHD)), while the NOAEL for the IV route was not established due to irreversible changes in protein and albumin levels at 150 mg/kg”
✓ VerifiedFDA integrated review, p. 180Source ↗

Yervoy

ipilimumab · CTLA-4
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 monoclonal antibodies →
NOAEL / key findings
Fatal colitis and persistent dermatitis/rash in two monkeys, considered immune-related adverse events of CTLA-4 blockade
“Fatal colitis and persistent dermatitis/rash observed in two animals along the toxicology programme were considered by the Applicant as immune-related adverse event (irAEs) linked with the intended pharmacologic basis of CTLA-4 blockade.”
✓ VerifiedEMA assessment report, p. 21Source ↗

Zinbryta

daclizumab · IL-2Rα (CD25)
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL 10 mg/kg biweekly for CNS microglial aggregates in 39-week and 9-month studies
“In the 39-week and 9-month studies, the NOAEL for microglial aggregates was 10 mg/kg administered biweekly”
✓ VerifiedFDA pharmacology/toxicology review, p. 22Source ↗

Zinplava

bezlotoxumab · C. difficile toxin B
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 monoclonal antibodies outside oncology →
NOAEL / key findings
NOAEL >=125 mg/kg/dose alone or with actoxumab (up to 5-fold clinical exposure); no findings of toxicological significance
“The no-observed-adverse-effect-level (NOAEL) for bezlotoxumab alone or in combination with actoxumab was ≥125 mg/kg/dose. This is up to 5 fold over the exposure in humans at the clinically recommended dose (10mg/Kg).”
✓ VerifiedEMA assessment report, p. 19Source ↗

Zynyz

retifanlimab · PD-1
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 monoclonal antibodies →
NOAEL / key findings
13-week monkey NOAEL 100 mg/kg per dose, the highest dose evaluated
“Following administration for 13 weeks, the NOAEL was considered to be 100 mg/kg per dose, the highest dose evaluated (sex combined mean Cmax of 4.88 mg/mL and AUC of 237 h•mg/mL).”
✓ VerifiedEMA assessment report, p. 47Source ↗