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

Q: How was the first-in-human dose set for approved small molecules?

Rarely public: 5 of 211 reviews of approved small molecules say even partly how the first human dose was set. Standard methods inside. Each product's answer is quoted from its FDA or EMA review on https://theatlas.bio/m/small/first-dose.

From the FDA and EMA reviews of all 211 approved small molecules. Each answer links to the regulator's own sentence.

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Short answer

Rarely public: 5 of 211 reviews say even partly how the first human dose was set.

Partly stated5/211

Not stated publicly206/211

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 small molecules, 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 →

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

211 approved small molecules, with the reviewers' own words.

Lumakras

sotorasib · KRAS G12C

First-in-human starting dose

Derivation not stated; clinical exposures at 180-960 mg were below those at the rat STD10 but above those at the dog HNSTD

“The mean observed sotorasib clinical exposures from 180, 360, 720, and 960 mg once daily (QD) dosing in subjects (Study 20170543) were lower than the exposures observed at the STD10 of 180 mg/kg in rats in the 3-month GLP repeat-dose toxicology study (Study 150432), but higher than the exposures observed at the HNSTD of 1000 mg/kg/day in dogs”

✓ VerifiedEMA assessment report, p. 35Source ↗

NOAEL / key findings

Rat kidney tubular degeneration/necrosis with renal injury biomarkers at ≥0.5x clinical AUC

“In rats, renal toxicity including minimal to marked histologic tubular degeneration/necrosis and increased kidney weight, urea nitrogen, creatinine, and urinary biomarkers of renal tubular injury were present at doses resulting in exposures approximately ≥ 0.5 times the human AUC at the clinical dose of 960 mg.”

✓ VerifiedUS prescribing informationSource ↗

Nulibry

fosdenopterin · cPMP replacement (MoCD type A)

First-in-human starting dose

FIH single IV doses 0.075, 0.25 and 0.68 mg/kg in healthy subjects; starting-dose derivation not described

“A total of 24 subjects was randomized into three sequential cohorts (6 active: 2 placebo) and received a single IV infusion of fosdenopterin at doses of 0.075, 0.25, and 0.68 mg/kg.”

✓ VerifiedFDA integrated review, p. 93Source ↗

NOAEL / key findings

No adverse findings; minor dog changes non-adverse; NOAELs 5 mg/kg/day (rat) and 10 mg/kg/day (dog), highest doses tested

“These findings were without histopathological correlates and were considered non-adverse. NOAELs for fosdenopterin were 5 mg/kg/day (rats) and 10 mg/kg/day (dogs), the highest dose levels evaluated.”

✓ VerifiedEMA assessment report, p. 24Source ↗

Scemblix

asciminib · BCR-ABL1 (STAMP, myristoyl pocket)

First-in-human starting dose

10 mg BID, based on 4-week GLP rat and dog toxicology studies

“The starting dose of asciminib for patients with CML-CP/-AP selected for the dose escalation part of this study was set at 10 mg orally administered BID under fasted conditions. The selection of the starting dose of asciminib was based on 4-week GLP toxicology studies conducted in rats and dogs.”

✓ VerifiedFDA multi-discipline review, p. 165Source ↗

NOAEL / key findings

Target organs: hematopoietic system, liver, kidney, adrenal gland, GI tract, and pancreas (dog only)

“The general toxicology studies identified toxicities in the hematopoietic system, liver, kidney, adrenal gland, gastro-intestinal (GI) tract, and pancreas (dog only).”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

Vanrafia

atrasentan · Endothelin A receptor

First-in-human starting dose

First-in-human single-dose study started at 139.5 mg; derivation not described

“Initially, the study was designed as a single dose, dose-escalating study with the starting dose of 139.5 mg.”

✓ VerifiedFDA integrated review, p. 140Source ↗

NOAEL / key findings

No NOAEL in rat or dog; male rat LOAEL 5 mg/kg/day for testicular degeneration

“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established. In male rats, the lowest dose tested, i.e., 5 mg/kg/day, was considered to be the lowest-observed-adverse-effect level (LOAEL) because of modest testicular degeneration”

✓ VerifiedFDA integrated review, p. 117Source ↗

Xpovio

selinexor · XPO1

First-in-human starting dose

3 mg/m2 starting dose in Phase 1 3+3 dose escalation

“Study treatment on Arm 1 during the dose escalation phase followed a standard 3+3 design with a starting dose of selinexor 3 mg/m2.”

✓ VerifiedFDA multi-discipline review, p. 81Source ↗

NOAEL / key findings

Rat: hematopoietic/lymphoid hypoplasia, reproductive organ toxicity; monkey: GI effects, lymphoid/hematologic depletion

“Rats exhibited toxicological sequalae due to hematopoietic/lymphoid hypoplasia and male/female reproductive organ effects. Female rats also exhibited higher liver weights and/or centrilobular hepatocellular hypertrophy and/or increased mitotic figures. Monkeys exhibited gastrointestinal effects and lymphoid/hematologic depletion.”

✓ VerifiedFDA multi-discipline review, p. 30Source ↗

Accrufer

ferric maltol · Iron replacement

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 small molecules outside oncology →

NOAEL / key findings

Dog: reduced food intake; raised platelets, ALP and bilirubin; increased liver, kidney, adrenal and thyroid weights; iron in liver and kidney cells

“Test article-related toxicities included reduced food intake, increased platelet counts, alkaline phosphatase activity, and bilirubin concentrations. Liver, kidney, adrenals, and thyroid weights increased. Liver and kidney cells stained for the presence of iron.”

✓ VerifiedFDA multi-discipline review, p. 29Source ↗

Adquey

difamilast · PDE4 (topical)

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 small molecules outside oncology →

NOAEL / key findings

No significant systemic or dermal toxicity; only decreased body weight gain in 26-week dermal rat study

“There were no significant systemic or dermal toxicities noted in these studies, except a decrease in body weight gain observed in a 26-week dermal toxicity study in rats.”

✓ VerifiedFDA multi-discipline review, p. 49Source ↗

Agamree

vamorolone · Glucocorticoid receptor (dissociative)

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 small molecules outside oncology →

NOAEL / key findings

Targets: liver, adrenals, lymphoid tissues, reproductive tissues, skeletal muscle; NOELs at or below clinical exposure

“In the general toxicology studies, the target tissues of vamorolone were liver, adrenal glands, lymphocytes and lymphoid tissues, male and female reproductive tissues, and skeletal muscle; plasma exposures at the no effect level for the findings in these tissues were similar to or less than that in humans at the proposed clinical dose of 6 mg/kg (Table 44).”

✓ VerifiedFDA integrated review, p. 120Source ↗

Alyftrek

vanzacaftor, tezacaftor and deutivacaftor · CFTR

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 small molecules outside oncology →

NOAEL / key findings

Vanzacaftor rat target organs: stomach (erosion/ulcers) and liver at >20x (male) and >60x (female) MRHD exposure

“In the general toxicology program for VNZ in rats, the major target organs of toxicity were the stomach (erosion/ulcers) and liver (hepatocellular vacuolar degeneration, multifocal hepatocellular necrosis) at exposures greater than 20 times (males) and 60 times (females) the exposure at the maximum recommended human dose (MRHD) of 20 mg VNZ.”

✓ VerifiedFDA integrated review, p. 97Source ↗

Anzupgo

delgocitinib · Pan-JAK (topical)

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 small molecules outside oncology →

NOAEL / key findings

9-month dermal minipig NOAEL 5% (20 mg/kg/day, max feasible); 9-month oral dog NOAEL 0.6 mg/kg/day, skin lesions at 3.0 mg/kg/day

“The no-observed-adverse-effect level (NOAEL) was 5% (20 mg/kg/day) delgocitinib ointment, the maximum feasible dose. Skin lesions were observed in a 9-month oral toxicity study in dogs at 3.0 mg/kg/day and the dose was lowered to 1.5 mg/kg/day from Week 24. The NOAEL was 0.6 mg/kg/day.”

✓ VerifiedFDA integrated review, p. 77Source ↗

Aqneursa

levacetylleucine · Neuronal metabolism (proposed)

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 small molecules outside oncology →

NOAEL / key findings

NOAEL exposure margins 2-3-fold in rats and 6-9-fold in dogs vs human AUC at MRHD

“Safety margins achieved at the no-observed-adverse-effect levels were 2- to 3-fold in rats and 6- to 9-fold in dogs compared to the steady-state AUCs in humans at the maximum recommended human dose (MRHD).”

✓ VerifiedFDA integrated review, p. 88Source ↗

Artesunate

artesunate · Plasmodium (antimalarial)

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 small molecules outside oncology →

NOAEL / key findings

Rat NOAEL 3 mg/kg/day (~0.2x clinical dose by BSA); hematologic and histopathologic changes reversible after recovery

“Histopathologic and hematologic changes were comparable to controls at the end of recovery, indicating reversibility of effects. The NOAEL was 3 mg/kg/day, a dose equivalent to 0.2 that of the clinical dose based on body surface area comparisons.”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

Attruby

acoramidis · Transthyretin (stabiliser)

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 small molecules outside oncology →

NOAEL / key findings

Rat 26-week NOAEL 50 mg/kg/day (males, body weight loss) and 600 mg/kg/day (females)

“The no observed adverse effect level (NOAEL) was determined to be 50 mg/kg/day in male rats based on significant body weight reductions (>10%), and 600 mg/kg/day in female rats”

✓ VerifiedFDA integrated review, p. 131Source ↗

Augtyro

repotrectinib · ROS1/TRK

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs: skin and CNS (rat), bone marrow (rat and monkey), GI tract (monkey); mostly reversible

“In the pivotal GLP-compliant RD-toxicity studies, the major target organs across species were the skin (rat), CNS (rat), bone marrow (rat and monkey), and GI (monkey). These findings were generally dose-dependent and were reversible or showed a trend towards reversibility.”

✓ VerifiedEMA assessment report, p. 30Source ↗

Avmapki Fakzynja Co-pack

avutometinib and defactinib · RAF/MEK clamp; FAK

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 small molecules (ICH S9) →

NOAEL / key findings

Avutometinib: skin and lymphoid organs; also eye, kidney, heart, liver (rat) and GI tract, ovary (monkey)

“The major target organs of toxicity in rats and monkeys included the skin and lymphoid organs. Additional organs in rats included the eye, kidney, heart, and liver, and in monkeys, gastrointestinal organs, and ovary.”

✓ VerifiedFDA multi-discipline review, p. 35Source ↗

Ayvakit

avapritinib · KIT/PDGFRA

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 small molecules (ICH S9) →

NOAEL / key findings

Dogs: brain hemorrhage and choroid plexus edema at >=0.4x human exposure; rat convulsions at >=8x

“Repeat dose studies in dogs indicated haemorrhage and choroid plexus oedema in the brain at ≥ 0.4 times the human exposure at the clinical dose of 300 mg once daily. Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily.”

✓ VerifiedEMA assessment report, p. 50Source ↗

Azstarys

serdexmethylphenidate and dexmethylphenidate · Dopamine/norepinephrine reuptake

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 small molecules outside oncology →

NOAEL / key findings

Dose-limiting stimulant clinical signs and body weight effects; rat NOAEL 25 mg/kg; dog NOAEL below lowest dose

“For rats, the exposures at the no adverse effect level (NOAEL) for stimulant-related findings (25 mg/kg) was less than the human exposure at the MRHD. For dogs, the NOAEL for stimulant-related findings was not established because the NOAEL is less than the lowest dose tested.”

✓ VerifiedFDA multi-discipline review, p. 45Source ↗

Balversa

erdafitinib · FGFR1-4

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 oncology small molecules (ICH S9) →

NOAEL / key findings

Aorta/heart mineralisation, chondroid dysplasia of bone, epithelial atrophy of tongue, oral mucosa, salivary and lacrimal glands, eye, teeth

“The predominant target organs were aorta (vascular/degeneration), heart (mineralisation/degeneration), bone femur and sternum (chondroid dysplasia), skin (increased hair follicles) and epithelial atrophy in the tongue, oral mucosa, parotid salivary glands, eye, teeth and lacrimal glands.”

✓ VerifiedEMA assessment report, p. 33Source ↗

Barhemsys

amisulpride · Dopamine D2/D3 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 small molecules outside oncology →

NOAEL / key findings

Rat: mammary feminization (males) and acinar proliferation/secretory activity (females) at all doses, reversed after 14-day recovery

“Microscopic examinations showed changes in the mammary area (feminization in surviving males and acinar proliferation/secretory activity in surviving females) in all dose groups. These findings were reversed following 14-day treatment free period.”

✓ VerifiedFDA multi-discipline review, p. 66Source ↗

Baxfendy

baxdrostat · Aldosterone synthase (CYP11B2)

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 small molecules outside oncology →

NOAEL / key findings

Dehydration; adrenal zona glomerulosa hypertrophy and renal juxtaglomerular hyperplasia in monkeys, pharmacology-related

“Frequently observed findings were primarily related to the primary pharmacology of baxdrostat, including dehydration (rats and monkeys) and microscopic findings in adrenal glands (zona glomerulosa hypertrophy) and kidneys (juxtaglomerular cell hyperplasia) in monkeys.”

✓ VerifiedFDA pharmacology/toxicology review, p. 20Source ↗

Beqalzi

sonrotoclax · BCL-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 small molecules (ICH S9) →

NOAEL / key findings

Dog targets: liver, gallbladder, male reproductive tract, skin, lymphatic system; male reproductive and skin findings not reversible

“Pathology observations identified the liver, gallbladder, male reproductive tract, skin, and lymphatic system as targets of sonrotoclax.”

✓ VerifiedFDA multi-discipline review, p. 27Source ↗

Blujepa

gepotidacin · Bacterial topoisomerases (gyrase/topo 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 small molecules outside oncology →

NOAEL / key findings

Kidney: tubular basophilia and dilation in 4-week rat at ≥450 mg/kg/day, about the clinical exposure

“In a 4-week repeat dose study of gepotidacin in rats, tubular basophilia and dilation of proximal and distal tubules in the kidney were observed at doses at and above 450 mg/kg/day (about equal to the clinical exposure based on AUC)”

✓ VerifiedFDA integrated review, p. 67Source ↗

Brenzavvy

bexagliflozin · SGLT2

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 small molecules outside oncology →

NOAEL / key findings

NOAEL was the highest dose tested in monkeys and rats (78x and 89x clinical AUC)

“In both monkeys and rats, the no observed adverse effect level (NOAEL) was the highest dose tested, which corresponded to 78 and 89 times the clinical dose of 20 mg, respectively, based on AUC.”

✓ VerifiedFDA integrated review, p. 87Source ↗

Brexafemme

ibrexafungerp · Fungal glucan synthase

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 small molecules outside oncology →

NOAEL / key findings

Rat: skeletal muscle and stomach glandular mucosa degeneration, hepatocyte single-cell necrosis (1-month)

“Several ibrexafungerp-related toxicities with potential clinical relevance occurred in a dose-dependent manner in the 1-month toxicology study in rats including degeneration of skeletal muscle cells and stomach glandular mucosa and single-cell necrosis of hepatocytes.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Brinsupri

brensocatib · DPP1 (cathepsin C)

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 small molecules outside oncology →

NOAEL / key findings

26-week dog: adverse findings at 8 and 50 mg/kg/day in testis/epididymis, lungs, lymphoid tissues, spleen, kidney and teeth

“drug-related adverse findings were evident in the 8 and 50 mg/kg dosing groups in epididymis and testis (male), lungs, lymphoid tissues, spleen, kidney, and teeth.”

✓ VerifiedFDA integrated review, p. 134Source ↗

Brukinsa

zanubrutinib · BTK

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 small molecules (ICH S9) →

NOAEL / key findings

Increased WBCs, multi-organ inflammation, GI necrosis, hemorrhage, lymphoid depletion; pancreatic lesions in rats

“Drug-related findings included increased white blood cells (WBCs) and differentials, multi-organ inflammation, GI tract necrosis, multi-organ hemorrhage, and lymphoid depletion. The findings were more prominent in the rat, particularly those in the pancreas (e.g. fibrin deposit and hemorrhage).”

✓ VerifiedFDA multi-discipline review, p. 26Source ↗

Byfavo

remimazolam · GABA-A receptor (benzodiazepine site)

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 small molecules outside oncology →

NOAEL / key findings

Local injection-site toxicity: thickened intima and partially recoverable endothelial fibrosis in monkey

“Local toxicities included thickened intima and partially recoverable endothelial fibrosis of blood vessels at 2.5 mg/mL in monkey.”

✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Bylvay

odevixibat · IBAT

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 small molecules outside oncology →

NOAEL / key findings

NOAELs were the high doses: 300 mg/kg/day in the 26-week rat and 150 mg/kg/day in the 39-week dog study

“The NOAEL (no observed adverse effect level) in the 26-week oral toxicity study in rats and the 39-week oral toxicity study in dogs was the high dose (300 mg/kg/day and 150 mg/kg/day, respectively).”

✓ VerifiedFDA integrated review, p. 78Source ↗

Cabenuva

cabotegravir and rilpivirine · HIV-1 integrase; NNRTI

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 small molecules outside oncology →

NOAEL / key findings

Monkey: no adverse findings up to 500 mg/kg/dose in 4- and 39-week studies

“In monkeys, no adverse findings were observed up to the highest doses tested (500 mg/kg/dose) in the 4- and 39-week studies.”

✓ VerifiedFDA integrated review, p. 126Source ↗

Camzyos

mavacamten · Cardiac myosin

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 small molecules outside oncology →

NOAEL / key findings

NOAEL 0.3 mg/kg/day (rat) and 0.06 mg/kg/day (dog), based on cardiac echo, ECG and histology endpoints

“A no-observed-adverse-effect-level (NOAEL) was determined to be 0.3 mg/kg/day and 0.06 mg/kg/day, respectively for the rat and dog, based on echocardiographic, electrocardiographic, or histological endpoints in the heart in the chronic toxicity studies.”

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

Caplyta

lumateperone · 5-HT2A / D2 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 small molecules outside oncology →

NOAEL / key findings

Dog CNS adverse effects at 4x MRHD; NOAEL 2x MRHD (mg/m2 basis)

“Adverse effects in the central nervous system of dogs occurred at doses of lumateperone that are 4 times the MRHD of 42 mg on a mg/m2 basis. The dose of lumateperone that corresponds to the NOAEL was 2 times the MRHD of 42 mg on a mg/m2 basis.”

✓ VerifiedFDA multi-discipline review, p. 41Source ↗

Cardamyst

etripamil · L-type calcium channel

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 small molecules outside oncology →

NOAEL / key findings

No significant systemic toxicity up to highest doses in 6-month monkey and 14-day rat; local nasal toxicity at all doses

“In the 6-month monkey and 14-day rat studies, there were no significant systemic toxicities observed up to the highest doses tested. However, local nasal toxicity at the site of administration was noted at all doses in both species.”

✓ VerifiedFDA integrated review, p. 80Source ↗

Cibinqo

abrocitinib · JAK1

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 small molecules outside oncology →

NOAEL / key findings

Rat NOAEL 30 mg/kg/day; reversible, dose-related urinary crystals at ≥45 mg/kg/day

“Abrocitinib produced reversible, dose-related urinary crystals at doses ≥45 mg/kg/day. The NOAEL was 30 mg/kg/day, which corresponds to Day 182 AUC24 and Cmax of 58500 ng·hr/mL and 9110 ng/mL, respectively.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

Cobenfy

xanomeline and trospium · Muscarinic M1/M4 agonist; peripheral antagonist

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 small molecules outside oncology →

NOAEL / key findings

Target organs: hepatobiliary, cardiovascular, CNS and GI

“The target organs include the hepatobiliary, cardiovascular, CNS, and gastrointestinal (GI) systems.”

✓ VerifiedFDA integrated review, p. 72Source ↗

Cosela

trilaciclib · CDK4/6

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 small molecules outside oncology →

NOAEL / key findings

Rat: non-adverse hematology changes at 10 mg/kg/d; adverse marked neutrophil (↓60%) and lymphocyte (↓77%) reductions at 25 mg/kg/d

“Drug-related effects in the low dose were limited to slight hematology changes and hematology changes in the 10 mg/kg/d were considered of insufficient magnitude to be adverse to the animals. Marked reductions in neutrophils (↓ 60%, mean count <600/μL) and lymphocytes ((↓ 77%, mean count <60/μL) at 25 mg/kg/d were considered adverse.”

✓ VerifiedFDA pharmacology/toxicology review, p. 50Source ↗

Crenessity

crinecerfont · CRF1 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 small molecules outside oncology →

NOAEL / key findings

Target organs: liver, thyroid, GI tract (mouse, rat) and coagulation effects

“The target organs for crinecerfont were liver (mouse, rat, and dog), thyroid gland (rat and dog), gastrointestinal (GI) tract (mouse and rat), and coagulation-associated effects.”

✓ VerifiedFDA integrated review, p. 95Source ↗

Cypsedo

cipepofol · GABA-A 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 small molecules outside oncology →

NOAEL / key findings

Target organs: CNS and cardiovascular system

“Target organs of toxicity identified after cipepofol administration were the central nervous system and cardiovascular system.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

Daybue

trofinetide · IGF-1 tripeptide analogue

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 small molecules outside oncology →

NOAEL / key findings

Few findings; NOAELs 2000 mg/kg/day juvenile rat, 1000 (male) and 300 (female) mg/kg/day dog (uterine weight, estrus)

“These data resulted in NOAELs of 2000 mg/kg/day (1000 mg/kg BID) in juvenile rats, 1000 mg/kg/day (500 mg/kg BID) in M dogs, and 300 mg/kg/day (150 mg/kg BID) in F dogs.”

✓ VerifiedFDA pharmacology/toxicology review, p. 9Source ↗

Dayvigo

lemborexant · Orexin OX1/OX2 receptors

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 small molecules outside oncology →

NOAEL / key findings

NOAEL rat 100 (male) and 30 (female) mg/kg/day, 41x and 12x MRHD AUC

“The NOAEL in male and female rats is 100 and 30 mg/kg/day which are 41 times and 12 times the MRHD based on AUC, respectively.”

✓ VerifiedFDA multi-discipline review, p. 48Source ↗

Defencath

taurolidine and heparin · Antimicrobial catheter lock

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 small molecules outside oncology →

NOAEL / key findings

No toxicity in rats given diluted product IV daily for 14 days

“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”

✓ VerifiedFDA multi-discipline review, p. 44Source ↗

Dojolvi

triheptanoin · Anaplerotic energy substrate

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 small molecules outside oncology →

NOAEL / key findings

Minipig NOAEL 50% DCI, the highest dose tested; no target organs

“The NOAEL for systemic toxicity was the highest administered dose of 50% DCI in minipigs.”

✓ VerifiedFDA integrated review, p. 82Source ↗

Duvyzat

givinostat · Histone deacetylase (class I/II)

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 small molecules outside oncology →

NOAEL / key findings

Transient CNS signs (rat, monkey); decreased WBC and bone marrow myeloid series (rat); bile duct hyperplasia and thymic atrophy (monkey)

“Primary toxicities included transient CNS signs in rat and monkey, decreases in WBC counts and bone myeloid series in rats, and bile duct hyperplasia and thymic atrophy in monkeys.”

✓ VerifiedFDA integrated review, p. 133Source ↗

Egaten

triclabendazole · Fasciola (tubulin)

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 small molecules outside oncology →

NOAEL / key findings

NOAEL 0.7-0.8 mg/kg/day in rats and 0.35 mg/kg/day in dogs (10 ppm diet)

“The no observed adverse effect level (NOAEL) was 0.7 to 0.8 mg/kg/day dose in rats (10 ppm) and 0.35 mg/kg/day dose in dogs (10 ppm).”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

Ekterly

sebetralstat · 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 small molecules outside oncology →

NOAEL / key findings

26-week rat NOAEL 300 mg/kg/day (highest dose); all findings non-adverse

“Therefore, all findings in the 26-week study were considered non-adverse. Thus, the NOAEL was 300 mg/kg/day, the highest dose tested”

✓ VerifiedEMA assessment report, p. 27Source ↗

Ensacove

ensartinib · ALK

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 small molecules (ICH S9) →

NOAEL / key findings

Dog target organs: skin, liver and thymus; severe ear skin lesions at 20 mg/kg forced a dose holiday and reduction to 15 mg/kg

“Dogs exhibited severe skin lesions particularly on the ear at 20 mg/kg, which led to dose holiday on Days 12-17 and reduced dosing at 15 mg/kg on Day 18. • The target organs of toxicity were skin, liver, and thymus.”

✓ VerifiedFDA integrated review, p. 121Source ↗

Evrysdi

risdiplam · SMN2 splicing

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 small molecules outside oncology →

NOAEL / key findings

39-week monkey NOAEL 1.5 mg/kg/day (AUC 1870/2060 ng·h/mL, males/females)

“The NOAEL (1.5 mg/kg/day) was associated with RIS exposures of 414 / 396 ng/mL (Cmax) and 1870 / 2060 ng·hr/mL (AUC0-24 h) during Week 39 of the dosing phase for males / females.”

✓ VerifiedFDA pharmacology/toxicology review, p. 8Source ↗

Exblifep

cefepime and enmetazobactam · PBPs; beta-lactamase (enmetazobactam)

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 small molecules outside oncology →

NOAEL / key findings

Liver target: enzyme increases with single-hepatocyte necrosis (28-day dog) and hepatocellular inclusions (combination study)

“In the 28-day study in dogs, the increased liver enzymes correlated with microscopic evidence of single-hepatocyte necrosis, and in the combination toxicology study, liver enzyme increases correlated with granular hepatocellular inclusions.”

✓ VerifiedFDA integrated review, p. 42Source ↗

Exkivity

mobocertinib · EGFR exon 20 insertion

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs consistent with clinical findings: pancreas (increased amylase), liver (ALT/AST elevations) and skin

“Findings in one or both species consistent with clinical experience included effects on the pancreas (increased amylase), liver (elevated alanine aminotransferase [ALT], aspartate transaminase [AST]), skin”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Exxua

gepirone · 5-HT1A 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 small molecules outside oncology →

NOAEL / key findings

Rat: pulmonary histiocytosis, distended bladders, prostate/ovary/uterus weight changes; dose-limiting body weight loss

“Toxicities were limited to slightly increased incidence of histiocytosis in lungs at the high dose, distended bladders seen at necropsy in high dose males, and some changes in organ weights (increased weights of prostate and ovaries, decreased weights of uteruses) that might indicate “endocrine effects,” a not unexpected effect of serotonergic compounds in rats.”

✓ VerifiedFDA pharmacology/toxicology review, p. 132Source ↗

Fabhalta

iptacopan · Complement factor 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 small molecules outside oncology →

NOAEL / key findings

39-week dog targets: thyroid, male reproductive system, lymphoid tissues, liver, bone marrow

“Target organs of toxicity included thyroid, male reproductive system, lymphoid tissues, liver and bone marrow.”

✓ VerifiedFDA integrated review, p. 196Source ↗

Fetroja

cefiderocol · Penicillin-binding proteins

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 small molecules outside oncology →

NOAEL / key findings

3-month monkey NOAEL 100 mg/kg/day, only 3-fold (Cmax) and 0.3-fold (AUC) human exposure; red blood cell decreases above it

“It should however be noted that the margins to clinical exposure from NOAEL (100mg/kg/day in the 3- month monkey study) is only 3-fold and 0.3-fold of the Cmax and AUC-values in humans respectively.”

✓ VerifiedEMA assessment report, p. 27Source ↗

Fexinidazole

fexinidazole · Trypanosoma brucei

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 small molecules outside oncology →

NOAEL / key findings

Target organs liver and thymus in 28-day rat and dog studies (50-800 mg/kg/day)

“The liver and thymus were identified as the target organs of toxicity in repeat-dose toxicity studies in rats and dogs at doses of 50, 200, and 800 mg/kg/day for 28 days.”

✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Filspari

sparsentan · Endothelin A / angiotensin II receptors

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 small molecules outside oncology →

NOAEL / key findings

9-month monkey NOAEL 50 mg/kg/day; changes reversible or reversing after 1–2-month recovery

“All sparsentan-related changes were reversible or reversing at the end of the 1-or 2-month recovery periods. The NOAEL in the monkeys in the 9-month study was 50 mg/kg/d.”

✓ VerifiedEMA assessment report, p. 24Source ↗

Fotivda

tivozanib · VEGFR1-3

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 small molecules (ICH S9) →

NOAEL / key findings

Rat and monkey targets: adrenal, GI (stomach, duodenum, pancreas), kidney, bone, liver, brain, pituitary, heart, incisors, ovaries/uterus

“The predominant toxicities in both species were associated with the following systems/organs: adrenal gland, gastrointestinal system (stomach, duodenum, and pancreas), kidney, bone (femur and tibia), liver, brain, pituitary gland, heart, incisors and reproductive system (ovaries and uterus).”

✓ VerifiedFDA multi-discipline review, p. 29Source ↗

Foundayo

orforglipron · GLP-1 receptor (non-peptide)

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 small molecules outside oncology →

NOAEL / key findings

No target organ toxicity or adverse histopathology in rats or monkeys up to the highest doses tested

“No target organ toxicity or adverse histopathologic effects were noted in monkeys or rats up to the highest doses tested for each species.”

✓ VerifiedFDA multi-discipline review, p. 58Source ↗

Fruzaqla

fruquintinib · VEGFR1-3

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs: liver, kidney, adrenal gland, thymus, spleen, bone marrow and femur

“The identified target organs of fruquintinib toxicity were liver, kidney, adrenal gland, thymus, spleen, bone marrow (sternum), and femur.”

✓ VerifiedEMA assessment report, p. 40Source ↗

Gavreto

pralsetinib · RET

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 small molecules (ICH S9) →

NOAEL / key findings

Targets in rat and monkey: bone marrow (decreased RBCs, WBCs), kidney (tubular basophilia/mineralization) and lung (macrophage aggregation)

“Target organs in both species included the bone marrow, with findings of decreased cellularity histopathologically consistent with decreases in red blood cells (RBCs) and mild decreases in white blood cells (WBCs), kidney (decreased weight and tubular basophilia/mineralization), and lung (macrophage aggregation).”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Gemtesa

vibegron · β3-adrenergic 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 small molecules outside oncology →

NOAEL / key findings

Rat NOAEL 30 mg/kg/day (~21.3-fold AUC); monkey NOEL 25 mg/kg/day based on ECG findings

“In rats, the NOAEL was determined to be 30 mg/kg/day (~ 21.3-fold AUC at the clinical dose of 75 mg) and in monkeys, a NOEL (due to ECG findings) was determined to be 25 mg/kg/day (6.4-fold Cmax at the clinical dose of 75 mg, 2.1-fold AUC).”

✓ VerifiedFDA pharmacology/toxicology review, p. 4Source ↗

Gomekli

mirdametinib · MEK1/2

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 small molecules outside oncology →

NOAEL / key findings

Rat NOAEL 0.1 mg/kg/day (males) and 0.3 mg/kg/day (females), at exposures below clinical exposure

“The determined NOAEL was 0.1 mg/kg/day in male rats and 0.3 mg/kg/day in female rats. Exposures at these doses are below the clinical predicted exposure at the intended posology.”

✓ VerifiedEMA assessment report, p. 32Source ↗

Grafapex

treosulfan · DNA alkylation

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 small molecules (ICH S9) →

NOAEL / key findings

Rat 4-week: bone marrow suppression, lymphoid and thymic atrophy, GI hyperplasia, muscle necrosis, multi-organ inflammation

“Drug-related adverse findings included bone marrow suppression, lymphoid atrophy in spleen, thymic hemorrhage and atrophy, GI tract hyperplasia, muscle necrosis, multi-organ inflammation, and injection site reactions.”

✓ VerifiedFDA multi-discipline review, p. 145Source ↗

Hernexeos

zongertinib · HER2 (mutant)

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs in rats and/or dogs: GI tract, adrenal gland and oral mucosa

“The major target organs of zongertinib in rats and/or dogs included the gastrointestinal (GI) tract, adrenal gland, and oral mucosa.”

✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Hyrnuo

sevabertinib · HER2 (mutant)

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 small molecules (ICH S9) →

NOAEL / key findings

Skin erosion/ulcer, liver fat accumulation and pancreatic acinar atrophy in rats and monkeys

“Additional target organs in both species included the skin (wounds and scab formation; histological findings of up to moderate erosion/ulcer, atrophy, crust, hyperplasia, and inflammation), liver (up to marked fat accumulation), and pancreas (acinar cell atrophy).”

✓ VerifiedFDA multi-discipline review, p. 43Source ↗

Ibsrela

tenapanor · NHE3

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 small molecules outside oncology →

NOAEL / key findings

Rat NOAEL 3 mg/kg/day (males) and 10 mg/kg/day (females); adverse GI effects are expected pharmacology

“These adverse gastrointestinal effects in rats are expected pharmacological effects of tenapanor. The NOAEL was determined to be 3 mg/kg/day for males and 10 mg/kg/day for females.”

✓ VerifiedFDA multi-discipline review, p. 35Source ↗

Ibtrozi

taletrectinib · ROS1

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs in rats and monkeys: lung, lymph nodes, kidney, GI tract and pituitary

“Drug-related target organs in both species included lung, lymph nodes, kidney, GI tract, and pituitary.”

✓ VerifiedFDA multi-discipline review, p. 45Source ↗

Idvynso

doravirine and islatravir · NNRTI; NRTTI

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 small molecules outside oncology →

NOAEL / key findings

Islatravir NOAEL 3 mg/kg/day in rats (119x) and 20 mg/kg Q3D in monkeys (539x)

“The no-observed-adverse-effect levels (NOAELs) are 3 mg/kg/day in rats and 20 mg/kg every three days (Q3D) in monkeys, at exposures (based on AUC0-24h) 119 and 539 times higher than human exposure at the RHD, respectively.”

✓ VerifiedFDA multi-discipline review, p. 193Source ↗

Inluriyo

imlunestrant · Estrogen receptor (SERD)

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 small molecules (ICH S9) →

NOAEL / key findings

Ovarian follicular cysts and vagina, cervix and uterus atrophy at ≥10 mg/kg/day in rats and ≥15 mg/kg/day in monkeys

“Daily oral administration of imlunestrant resulted in follicular cysts in the ovary and atrophy in the vagina, cervix, and uterus at doses ≥ 10 mg/kg/day in female rats (≥ 4 times the human AUC at the recommended dose) and ≥ 15 mg/kg/day in female cynomolgus monkeys”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Inpefa

sotagliflozin · SGLT1/SGLT2

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 small molecules outside oncology →

NOAEL / key findings

26-week rat NOAEL 30 mg/kg/day (females; males LOAEL 30); 39-week dog NOAEL 20 mg/kg/day

“the low-observed-adverse level (LOAEL) for male rats and No-observed adverse level (NOAEL) for female rats in 26-week oral sotagliflozin were 30 and 30 mg/kg/day, respectively; the NOAEL in 39-week oral sotagliflozin for male and female beagle dogs was 20 mg/kg/day”

✓ VerifiedFDA integrated review, p. 260Source ↗

Inqovi

decitabine and cedazuridine · DNMT (decitabine); cytidine deaminase (cedazuridine)

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 small molecules (ICH S9) →

NOAEL / key findings

Reversible myelosuppression; reversible reproductive tract effects from cedazuridine

“In summary, the main repeat-dose toxicity findings from studies conducted in mice, rats, and monkeys were characterized by reversible myelosuppression (leukopenia, neutropenia, lymphopenia, and/or decreased platelet counts) due to decitabine, or both (ASTX727), reversible reproductive tract effects due to cedazuridine”

✓ VerifiedFDA multi-discipline review, p. 61Source ↗

Inrebic

fedratinib · JAK2

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 small molecules (ICH S9) →

NOAEL / key findings

Rat targets: bone marrow and liver; also lymphoid tissues, lungs and heart

“In rats, the main target organs of toxicity included the bone marrow and liver. Effects were also observed in the lymphoid tissues, lungs and heart.”

✓ VerifiedEMA assessment report, p. 34Source ↗

Iqirvo

elafibranor · PPARα/δ

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 small molecules outside oncology →

NOAEL / key findings

Monkey 52-week: minimal liver hypertrophy, degeneration/necrosis and single-cell necrosis at ≥10 mg/kg/day (0.5× human AUC)

“Microscopic changes in liver included hepatocytic hypertrophy (minimal), hepatocellular degeneration/necrosis (minimal), single cell necrosis/apoptosis (minimal to slight), and granulocytic foci (minimal) at ≥ 10 mg/kg/day (0.5 times the recommended dose based on combined AUC for elafibranor and GFT1007).”

✓ VerifiedFDA integrated review, p. 88Source ↗

Isturisa

osilodrostat · 11β-hydroxylase (CYP11B1)

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 small molecules outside oncology →

NOAEL / key findings

Targets: adrenal gland, liver and female reproductive tissues; mostly reversible

“The primary target organs were the adrenal gland, liver, and female reproductive tissues. Adverse effects increased in severity with dosage and study duration, with most demonstrating recovery upon treatment cessation.”

✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Itovebi

inavolisib · PI3Kα (mutant-selective)

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs: lymphoid tissues and bone marrow, eye, pancreas, male and female reproductive organs

“Overall, the major target organs of toxicity in rats or dogs were the lymphoid tissues (thymus, gut-associated lymphoid tissue/Peyer’s patch, mesenteric and mandibular lymph nodes, spleen, bone marrow), eye, pancreas, and male and female reproductive organs.”

✓ VerifiedFDA multi-discipline review, p. 41Source ↗

Jascayd

nerandomilast · PDE4B

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 small molecules outside oncology →

NOAEL / key findings

Vasculopathy (inflammation, haemorrhage, necrosis of blood vessels) in rats and minipigs was the primary adverse finding

“In repeat-dose general toxicity studies, vasculopathy (inflammation, haemorrhage, and necrosis of in and around blood vessels) was the primary nerandomilast-related adverse finding observed in rats and minipigs.”

✓ VerifiedEMA assessment report, p. 34Source ↗

Jaypirca

pirtobrutinib · BTK (non-covalent)

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 small molecules (ICH S9) →

NOAEL / key findings

Dog: minimal to mild corneal lesions at high dose; NOAEL 2.5 mg/kg BID, limited by adverse eye effects at 5 mg/kg BID

“Minimal to mild corneal lesions were observed in two high dose dogs at systemic exposure below human exposure at 200 mg QD. In addition, pirtobrutinib caused a decrease in B lymphocytes and a decrease in the TDAR following KLH immunisation. The NOAEL was 2.5 mg/kg BID, due to adverse eye effects at 5 mg/kg BID.”

✓ VerifiedEMA assessment report, p. 33Source ↗

Jesduvroq

daprodustat · HIF prolyl hydroxylase

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 small molecules outside oncology →

NOAEL / key findings

39-week monkey NOAEL 3 mg/kg/day; choroid plexus, kidney and stomach findings at ≥10 mg/kg/day

“The NOAEL is determined at 3 mg/kg/day based on the microscopic findings in choroid plexus, kidney, and stomach at ≥10 mg/kg/day.”

✓ VerifiedFDA integrated review, p. 257Source ↗

Jideytro

zidesamtinib · ROS1

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs: pancreas and liver (rat), CNS (dog), GI tract and lymphoid organs (both species)

“The major target organs of zidesamtinib in the 13-week studies included the pancreas and liver (rats), CNS (dogs), and gastrointestinal (GI) tract and lymphoid organs (both species).”

✓ VerifiedFDA multi-discipline review, p. 37Source ↗

Joenja

leniolisib · PI3Kδ

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 small molecules outside oncology →

NOAEL / key findings

Immune suppression and skin lesions (rats, monkeys), germ cell depletion (rats), GI inflammation and QTc prolongation (monkeys)

“Leniolisib-related toxicities included immune suppression (rats & monkeys), skin lesions (rats & monkeys), germ cell depletion (rats), GI tract inflammation (monkeys), and QTc prolongation (monkeys).”

✓ VerifiedFDA multi-discipline review, p. 36Source ↗

Journavx

suzetrigine · NaV1.8

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 small molecules outside oncology →

NOAEL / key findings

91-day rat (females): ovarian cysts, fewer corpora lutea, pituitary and mammary hyperplasia

“In the 91-day rat study, oral administration of SUZ to female rats for 91 days resulted in ovarian cyst formation, decreased number of corpora lutea, pituitary gland hyperplasia, and mammary hyperplasia/dilatation.”

✓ VerifiedFDA integrated review, p. 66Source ↗

Kerendia

finerenone · Mineralocorticoid 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 small molecules outside oncology →

NOAEL / key findings

Exaggerated pharmacology: adrenals (rat, dog) and reduced prostate size (dog)

“Target organs of exaggerated pharmacology after chronic treatment were the adrenals in both the rat and dog and also the prostate in the dog (decrease in prostate size and weight not accompanied by histopathological changes).”

✓ VerifiedFDA integrated review, p. 58Source ↗

Klisyri

tirbanibulin · Tubulin / Src

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 small molecules outside oncology →

NOAEL / key findings

Rat 4-week oral: thymus, testes, epididymis and bone marrow lesions, tending to reverse

“included findings in the thymus (lymphocyte deletion), testes (germ cell degeneration and depletion, sperm granuloma), epididymis (cellular debris, oligospermia), and bone marrow (hypocellularity). These effects tended to reverse during the recovery period.”

✓ VerifiedFDA multi-discipline review, p. 34Source ↗

Komzifti

ziftomenib · Menin-KMT2A

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 small molecules (ICH S9) →

NOAEL / key findings

Liver primary target (cholestasis, biliary hyperplasia); also lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenals

“The liver was the primary organ of toxicity, where elevated liver enzyme levels in the blood were observed along with discoloring and microscopic findings of cholestasis and biliary hyperplasia. Other organs of toxicity included the lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenal glands”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

Koselugo

selumetinib · MEK1/2

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 small molecules (ICH S9) →

NOAEL / key findings

Major target organs: GI tract, plus skin and lower urinary tract in rodents

“In addition to the GI tract, the other major target organs in the rodent toxicology studies were the skin and lower urinary tract.”

✓ VerifiedFDA multi-discipline review, p. 43Source ↗

Krazati

adagrasib · KRAS G12C

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs in rats and dogs: heart, lungs, adrenal gland, kidney and liver

“In both rats and dogs, the target organs were heart, lungs, adrenal gland, kidney, and liver.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Kygevvi

doxecitine and doxribtimine · Pyrimidine nucleoside replacement (TK2 deficiency)

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 small molecules outside oncology →

NOAEL / key findings

No target organ toxicity; NOAELs at highest doses: 400 (mouse), 2000 (rat), 100 (dog) mg/kg/day

“In repeat-dose toxicity studies conducted in mice, rats, and dogs, no target organ toxicity or other toxicologically significant findings were identified. The no observed adverse effect level (NOAEL) corresponded to the highest dose level evaluated in each species: 400 mg/kg/day in mice, 2000 mg/kg/day in rats, and 100 mg/kg/day in dogs.”

✓ VerifiedFDA integrated review, p. 81Source ↗

Lampit

nifurtimox · Trypanosoma cruzi

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 small molecules outside oncology →

NOAEL / key findings

NOAEL 25 mg/kg/day (13-week rat) and 30 mg/kg/day (1-year dog)

“The NOAEL values for nifurtimox in rats and dogs in the 13-week and 1-year toxicology studies were considered to be 25 and 30 mg/kg/day, respectively.”

✓ VerifiedFDA multi-discipline review, p. 44Source ↗

Lazcluze

lazertinib · EGFR (mutant-selective)

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 small molecules (ICH S9) →

NOAEL / key findings

Skin, eye, GI, liver, kidney, heart, esophagus, lung, reproductive organs and bone marrow

“Consistent with its mechanism of action as an EGFR inhibitor, lazertinib induced skin/eyelid, ocular, and gastrointestinal (GI) toxicity in rats and/or dogs. Additional target organs in animals included the liver, kidney, heart, esophagus, lung, reproductive organs, and bone marrow.”

✓ VerifiedFDA multi-discipline review, p. 41Source ↗

Leqselvi

deuruxolitinib · JAK1/JAK2

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 small molecules outside oncology →

NOAEL / key findings

NOAELs 37.5 mg/kg/day (26-week rat) and 3 mg/kg/day (52-week dog), ~0.8x and 1.4x human AUC

“26-week rat study Oral 37.5 1640 0.8 52-week dog study Oral 3 2850 1.4”

✓ VerifiedFDA multi-discipline review, p. 217Source ↗

Lifyorli

relacorilant · Glucocorticoid receptor (antagonist)

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 small molecules (ICH S9) →

NOAEL / key findings

39-week monkey NOAEL 30 mg/kg/day; observed changes considered non-adverse

“None of these changes were considered adverse. Therefore, the NOAEL was considered to be 30 mg/kg/day. The NOAEL was associated with a Week 39 relacorilant AUC0-24 of 22510.9 ng.h/mL and 22847.1 ng.h /mL respectively, in female and male monkeys.”

✓ VerifiedFDA multi-discipline review, p. 59Source ↗

Litfulo

ritlecitinib · JAK3/TEC kinases

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 small molecules outside oncology →

NOAEL / key findings

NOAEL 5 mg/kg/day: brainstem findings at ≥20 mg/kg/day; immunosuppression and hearing effects at high dose

“The NOAEL was 5 mg/kg/day based on microscopic findings in the brainstem at doses ≥20 mg/kg/day and adverse immunosuppressive effects and effects on hearing at the HD.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

Livdelzi

seladelpar · PPARδ

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 small molecules outside oncology →

NOAEL / key findings

Main target organs: liver, skeletal and cardiac muscle, stomach and kidney

“The main target organs of toxicity were liver, skeletal and cardiac muscle, stomach, and kidney.”

✓ VerifiedFDA integrated review, p. 93Source ↗

Livmarli

maralixibat · IBAT (ASBT)

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 small molecules outside oncology →

NOAEL / key findings

1-year dog NOAEL 5 mg/kg/day (AUC 57.7 ng•h/mL; 96- to 358-fold human AUC)

“In a 1-year toxicity study in dogs, the no observable adverse effect level in both sexes was 5 mg/kg/day with an area under the concentration-time curve from time 0 to 24 h (AUC0-24h) of 57.7 ng•h/mL on Day 358 (96 to 358-fold the human AUC of 0.6 and 0.161 ng•h/mL at 50 and 20 mg/day, respectively).”

✓ VerifiedFDA integrated review, p. 68Source ↗

Livtencity

maribavir · CMV UL97 protein kinase

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 small molecules outside oncology →

NOAEL / key findings

Regenerative anemia and gastrointestinal effects in the 52-week monkey and 26-week rat studies

“The major findings in the 52-week study in monkeys and 26-week study in rats were regenerative anemia and gastrointestinal effects”

✓ VerifiedFDA integrated review, p. 75Source ↗

Lupkynis

voclosporin · Calcineurin

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 small molecules outside oncology →

NOAEL / key findings

Immunosuppression plus class effects: renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity

“The adverse findings observed were either expected due to drug-related immunosuppression (e.g., thymic medullary atrophy, absence of germinal centers, lymphomas, decreased lymphocyte counts) or to the known drug class specific adverse effects (e.g., renal toxicity, neurotoxicity, gingival hyperplasia, liver toxicity).”

✓ VerifiedFDA multi-discipline review, p. 367Source ↗

Lybalvi

olanzapine and samidorphan · D2/5-HT2A; opioid receptors (samidorphan)

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 small molecules outside oncology →

NOAEL / key findings

Samidorphan dog NOAEL 1 mg/kg/day, approximately equal to clinical exposure at the MRHD

“The NOAEL for SAM in dogs is 1 mg/kg/day, which is approximately equal to the clinical exposure at the MRHD of 10 mg SAM based on AUC.”

✓ VerifiedFDA multi-discipline review, p. 320Source ↗

Lynavoy

linerixibat · IBAT

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 small molecules outside oncology →

NOAEL / key findings

Findings non-adverse; NOAELs were the highest doses: 1000 mg/kg/day (26-week rat), 500 mg/kg/day (39-week dog)

“The findings in these studies were not considered adverse and the no observed adverse effect level (NOAEL) in the 26-week rat and 39-week dog studies were the highest doses administered (1000 and 500 mg/kg/day, respectively).”

✓ VerifiedFDA integrated review, p. 96Source ↗

Lynkuet

elinzanetant · NK1/NK3 receptors

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 small molecules outside oncology →

NOAEL / key findings

PD-related reproductive findings: none adverse up to 25 mg/kg (rat) and 30 mg/kg (monkey), margins 10 and 0.3

“No adverse PD related reproductive findings were observed in rats up to 25 mg/kg and in monkeys up to 30 mg/kg, corresponding to a safety margin of 10 and 0.3, respectively, based on total exposure (AUC0-24).”

✓ VerifiedEMA assessment report, p. 32Source ↗

Lytgobi

futibatinib · FGFR1-4 (covalent)

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 small molecules (ICH S9) →

NOAEL / key findings

Increased plasma phosphorus, ectopic mineralization in multiple tissues and bone lesions at clinically relevant exposures

“Drug‐related findings in both species were consistent with FGFR inhibition including increases in plasma phosphorus, ectopic mineralization in multiple tissues, and lesions in bone at exposure levels that are in range with human exposures at the recommended clinical dose of 20 mg.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Mayzent

siponimod · S1P1/S1P5 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 small molecules outside oncology →

NOAEL / key findings

Lung toxicity NOAELs: <5 mg/kg mouse, 50 (M) and 10 (F) mg/kg rat, 100 mg/kg monkey

“The NOAEL for lung toxicities were <5 mg/kg in mice, 50 and 10 mg/kg in M and F rats, and 100 mg/kg in monkeys.”

✓ VerifiedFDA pharmacology/toxicology review, p. 14Source ↗

Miebo

perfluorohexyloctane · Tear film evaporation barrier

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 small molecules outside oncology →

NOAEL / key findings

No ocular or systemic toxicity; rabbit systemic NOAEL 427.8 mg/day, ocular NOAEL 213.92 mg/eye/day (3.6x ocular MRHD)

“The systemic no-observed-adverse-effect level (NOAEL) was 427.8 mg/animal/day whereas the ocular NOAEL was 213.92 mg/eye/day. At the proposed clinical dosing regimen, the ocular exposure margin is 3.6X for the MRHD (60 mg/eye/day), and the systemic exposure margin is 39X for the MRHD (120 mg/day).”

✓ VerifiedFDA pharmacology/toxicology review, p. 34Source ↗

Miplyffa

arimoclomol · Heat-shock response amplifier

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 small molecules outside oncology →

NOAEL / key findings

NOAEL 200 mg/kg/day in rats and 160 mg/kg/day in dogs

“In the pivotal toxicology studies, the NOAEL for arimoclomol is 200 mg/kg/day in rats, and 160 mg/kg/day in dogs.”

✓ VerifiedFDA integrated review, p. 199Source ↗

Modeyso

dordaviprone · DRD2 antagonist / ClpP agonist

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 small molecules (ICH S9) →

NOAEL / key findings

Rat NOAEL 125 mg/kg weekly; dog LOAEL 60 mg/kg weekly (reversible clinical signs); Cmax 1.9- and 3.9-fold human

“The Cmax plasma concentrations measured in rats (NOAEL; 125 mg/kg once weekly as the highest dose administered) and dogs (LOAEL; 60 mg/kg once weekly exhibiting adverse but reversible clinical signs) exceeded plasma concentrations observed in humans administered 625 mg dordaviprone by 1.9 and 3.9-fold, respectively.”

✓ VerifiedFDA multi-discipline review, p. 58Source ↗

Myqorzo

aficamten · Cardiac myosin

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 small molecules outside oncology →

NOAEL / key findings

Heart primary target in rats and dogs; dose- and duration-dependent cardiac toxicity up to heart failure from exaggerated pharmacology

“The heart was identified as the primary organ of toxicity in both species with repeated aficamten administrations. Cardiac toxicities culminating in heart failure resulting from exaggerated pharmacology of the drug were observed in both rats and dogs in a dose- and duration-dependent fashion.”

✓ VerifiedFDA integrated review, p. 111Source ↗

Nereus

tradipitant · NK1 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 small molecules outside oncology →

NOAEL / key findings

Target organs liver and thyroid

“Repeat-dose oral toxicity studies with tradipitant have been conducted in mice (13 weeks), rats (up to 6 months), and dogs (up to 3 months). Target organs were identified as liver and thyroid.”

✓ VerifiedFDA integrated review, p. 107Source ↗

Nexletol

bempedoic acid · ATP citrate lyase

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 small molecules outside oncology →

NOAEL / key findings

NOAEL exposures <1x (26-week rat) and 13x (52-week monkey) human AUC at 180 mg/day

“safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid and correspond to at least <1 and 13 times the clinical exposure at the human dose of 180 mg, respectively, based on AUC exposures at the nonclinical no observed adverse effect levels (NOAELs).”

✓ VerifiedFDA integrated review, p. 72Source ↗

Nextstellis

drospirenone and estetrol · Estrogen / progestin receptors

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 small molecules outside oncology →

NOAEL / key findings

Exaggerated estrogenic effects: mammary/uterine epithelial proliferation, estrous inhibition, depressed erythropoiesis, cholestasis

“E4 demonstrated an ability to stimulate mammary and uterine epithelium proliferation, inhibit estrous cyclicity, depress erythropoiesis, and cause cholestasis in both rats and monkeys.”

✓ VerifiedFDA multi-discipline review, p. 36Source ↗

Nourianz

istradefylline · Adenosine A2A 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 small molecules outside oncology →

NOAEL / key findings

Target organs in rat and dog: adrenal (hypertrophy/hyperplasia) and lung (pneumonitis with septal thickening)

“The target organs for istradefylline in rats and dogs are consistent and are the adrenal gland (hypertrophy/hyperplasia) and lung (pneumonitis with septal thickening).”

✓ VerifiedFDA pharmacology/toxicology review, p. 29Source ↗

Nubeqa

darolutamide · Androgen 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 oncology small molecules (ICH S9) →

NOAEL / key findings

Male reproductive organ atrophy at ≥100 mg/kg/day rat and ≥50 mg/kg/day dog (~0.6–1x human AUC); GI, mammary, adrenal, thyroid

“Toxicities in male reproductive organs occurred at doses ≥ 100 mg/kg/day in male rats (0.6 times the human exposure based on AUC) and ≥ 50 mg/kg/day in dogs (1 times the human exposure based on AUC).”

✓ VerifiedFDA multi-discipline review, p. 29Source ↗

Nurtec ODT

rimegepant · 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 small molecules outside oncology →

NOAEL / key findings

Rat: liver vacuolation at all doses, no NOAEL; monkey 9-month NOAEL 15 mg/kg (weight gain decreases)

“based on liver vacuolation at all doses (0, 5, 20, or 45 mg/kg) in the 6-month study, a NOAEL was not established in rats. The primary toxicity in monkeys consisted of decreases in weight gain; based on this finding, the NOAEL for daily administration of BHV-3000 for 9 months was 15 mg/kg.”

✓ VerifiedFDA pharmacology/toxicology review, p. 9Source ↗

Nuzolvence

zoliflodacin · Bacterial topoisomerase II

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 small molecules outside oncology →

NOAEL / key findings

Dog NOAEL 100 mg/kg/day; reduced RBC parameters, increased bilirubin and testicular degeneration at 200 mg/kg/day

“The NOAEL in this study was the low dose of 100 mg/kg/day, based on the reduced RBC parameters, increased bilirubin, and testicular degeneration seen in the mid dose group (200 mg/kg/day).”

✓ VerifiedFDA integrated review, p. 131Source ↗

Ogsiveo

nirogacestat · Gamma secretase

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 small molecules (ICH S9) →

NOAEL / key findings

No NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day)

“Due to oocyte mineralization at the lowest dose in the 3-month dog study, a NOAEL was not identified. The lowest dose in the dog was 2 mg/kg/day (human equivalent dose of 70 mg/day).”

✓ VerifiedEMA assessment report, p. 35Source ↗

Ohtuvayre

ensifentrine · PDE3/PDE4

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 small molecules outside oncology →

NOAEL / key findings

Rat: salivary gland acinar hypertrophy, testis atrophy, epididymal germ cell debris; dog: coronary artery vasculopathy

“Target organs of toxicity were identified as mandibular and parotid salivary glands (acinar cell hypertrophy), testis (tubular degeneration/atrophy), and epididymis (intraluminal germ cell debris) in rats, and heart (coronary artery vasculopathy) in dogs.”

✓ VerifiedFDA integrated review, p. 79Source ↗

Ojemda

tovorafenib · RAF (type II pan-RAF)

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 small molecules (ICH S9) →

NOAEL / key findings

No exposure margin at NOAELs in pivotal studies (rat 0.39-fold, monkey 0.41-fold adult exposure)

“However, exposure multiples compared to the NOAEL of the clinical exposure demonstrated no margins of exposure within the pivotal long-term repeat-dose toxicology studies (rats: 0.39 (M) for adults and 0.22 (M) for paediatric patients; monkeys: 0.41 (M) for adults and 0.23 (M) for paediatric patients).”

✓ VerifiedEMA assessment report, p. 41Source ↗

Ojjaara

momelotinib · JAK1/JAK2/ACVR1

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 small molecules (ICH S9) →

NOAEL / key findings

Rat NOAEL 5 mg/kg/day (renal tubular degeneration at ≥15); 5-10x MRHD

“Based on adverse renal tubular degeneration at ≥15 mg/kg/day, the low dose of 5 mg/kg/day was considered the no observed adverse effect level (NOAEL) in rats (5x to 10x the maximum recommended human dose (MRHD) based on combined clinical momelotinib and M21 AUC).”

✓ VerifiedFDA integrated review, p. 104Source ↗

Olinvyk

oliceridine · μ-opioid receptor (G-protein biased)

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 small molecules outside oncology →

NOAEL / key findings

Dose-dependent infusion-site inflammation in 28-day rat study; NOAEL 0.5 mg/kg/h

“dose-dependent increases in inflammation were observed at infusion sites in the 28-day rat general toxicity study with a no observed adverse effect level (NOAEL) of 0.5 mg/kg/h at a concentration of 0.5 mg/mL”

✓ VerifiedFDA multi-discipline review, p. 164Source ↗

Omlonti

omidenepag isopropyl · EP2 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 small molecules outside oncology →

NOAEL / key findings

Monkey 13-week: no NOAEL; LOAEL 0.9 µg/eye/day based on nasal cavity findings

“No NOAEL. The low dose, 0.9 µg/eye/day is the LOAEL, based on two findings in the nasal cavity:”

✓ VerifiedFDA pharmacology/toxicology review, p. 190Source ↗

Ongentys

opicapone · COMT

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 small molecules outside oncology →

NOAEL / key findings

6-month rat NOAEL 500 mg/kg/day; increased bilirubin without histologic change at 1000 mg/kg/day

“In the 6-month study in rat, the MD (500 mg/kg/day) was the NOAEL due to increased bilirubin levels (in the absence of histologic changes) at the HD of 1000 mg/kg/day.”

✓ VerifiedFDA pharmacology/toxicology review, p. 88Source ↗

Orgovyx

relugolix · GnRH 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 oncology small molecules (ICH S9) →

NOAEL / key findings

Liver toxicity in monkeys at ≥50 mg/kg/day (~53x clinical AUC), with some reversibility

“Relugolix caused liver toxicity (increased liver enzymes with or without histopathology correlates of up to severe yellow/brown pigment deposition and up to moderate bile plug) in monkeys at ≥ 50 mg/kg/day (approximately 53x the clinical exposure based on AUC). This effect exhibited some reversibility.”

✓ VerifiedFDA multi-discipline review, p. 33Source ↗

Orladeyo

berotralstat · 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 small molecules outside oncology →

NOAEL / key findings

Monkey target organs: kidney, liver, intestine, lung, spleen, lymph nodes and bone marrow

“The target organs of toxicity of berotralstat in monkeys were the kidney, liver, intestine, lung, spleen, lymph nodes, and bone marrow.”

✓ VerifiedFDA multi-discipline review, p. 36Source ↗

Orlynvah

sulopenem etzadroxil and probenecid · Penicillin-binding proteins

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 small molecules outside oncology →

NOAEL / key findings

Monkey ≥400 mg/kg: positive Coombs test, decreased red blood cell parameters and GI effects

“PF-03709270 administered by oral gavage to Cynomolgus monkeys at ≥400 mg/kg caused positive Coombs’ test, decreased red blood cell parameters, and GI side effects.”

✓ VerifiedFDA integrated review, p. 281Source ↗

Orserdu

elacestrant · Estrogen receptor (SERD)

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 small molecules (ICH S9) →

NOAEL / key findings

Anti-estrogenic atrophy of uterus, vagina, cervix and mammary gland, ovarian follicular cysts, pituitary atrophy (rats)

“Female rats and monkeys displayed decreased weight and atrophy of the uterus, vagina, cervix, and mammary gland, increased weight of the ovaries correlating with the presence of follicular cysts, and atrophy of the pituitary gland (only in rats).”

✓ VerifiedEMA assessment report, p. 61Source ↗

Orzeyful

oveporexton · Orexin OX2 receptor agonist

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 small molecules outside oncology →

NOAEL / key findings

26-week rat NOAEL 100 mg/kg in both sexes

“• NOAEL: 100 mg/kg for both sexes, associated with a mean Cmax of 7860 and 11,800 ng/mL, and a mean AUC24h of 115,000 and 168,000 h*ng/mL in males and females, respectively, in Week 26 of dosing.”

✓ VerifiedFDA multi-discipline review, p. 68Source ↗

Oxbryta

voxelotor · HbS polymerisation

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 small molecules outside oncology →

NOAEL / key findings

Erythrocytosis, marrow hypercellularity and splenic haematopoiesis (exaggerated pharmacology)

“Hematologic changes included increased RBCs, reticulocytes, and haematocrit, with increased cellularity of bone marrow and extramedullary haematopoiesis in spleen consistent with exaggerated pharmacology of voxelotor in normal animals.”

✓ VerifiedEMA assessment report, p. 50Source ↗

Palsonify

paltusotine · Somatostatin receptor 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 small molecules outside oncology →

NOAEL / key findings

Dog NOAEL 10 mg/kg/day (3x MRHD) for nervous system effects; tremors only at 75 mg/kg/day (~23x MRHD)

“The no-observed-adverse-effect level (NOAEL) (10 mg/kg/day) for nervous system effects in dogs was three-fold the clinical exposures at the MRHD based on area under the concentration-time curve (AUC) and the tremors were observed only at 75 mg/kg/day at approximately 23-fold the MRHD based on AUC.”

✓ VerifiedFDA integrated review, p. 87Source ↗

Paxlovid

nirmatrelvir and ritonavir · SARS-CoV-2 Mpro (3CL protease)

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 small molecules outside oncology →

NOAEL / key findings

NOAELs were the highest doses tested (rat 1000, monkey 600 mg/kg/day); all findings non-adverse

“Pivotal repeat-dose toxicology studies were conducted in rats (2-week and 1-month durations) up to 1000 mg/kg/day and in monkeys (15-day and 1-month durations) up to 600 mg/kg/day. All the findings discussed below are considered drug-related but non-adverse.”

✓ VerifiedFDA integrated review, p. 125Source ↗

Pemazyre

pemigatinib · FGFR1-3

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 small molecules (ICH S9) →

NOAEL / key findings

Hyperphosphatemia with multi-organ soft tissue and vascular mineralization in rats at >=0.27 mg/kg (~0.4x human AUC)

“Treatment with ≥0.27 mg/kg pemigatinib (approximately 0.4 times the exposure based on AUC at the human dose of 13.5 mg) induced hyperphosphatemia in rats, which correlated with firm/white areas in the aorta and vena cava and multi-organ histologic soft tissue and vascular mineralization.”

✓ VerifiedFDA multi-discipline review, p. 35Source ↗

Piqray

alpelisib · PI3Kα

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 small molecules (ICH S9) →

NOAEL / key findings

Targets: GI tract, hemolymphoid system, skin, metabolic (glucose/insulin) and reproductive system

“Administration of alpelisib to rats and dogs resulted in adverse effects in the GI tract, hemolymphoid system, skin, metabolic, and reproductive system.”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

Pizensy

lactitol · Osmotic laxative

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 small molecules outside oncology →

NOAEL / key findings

No target organs identified; NOAEL 2000 mg/kg/day (highest dose) in mice and rats

“Target organs could not be identified in the absence of significant treatment-related histopathological changes in any organ or tissue in either species. The No Observed Adverse Effect Level (NOAEL) was 2000 mg/kg/day for both mice and rats.”

✓ VerifiedFDA multi-discipline review, p. 30Source ↗

Ponvory

ponesimod · S1P1 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 small molecules outside oncology →

NOAEL / key findings

Lung toxicity NOAELs: 90/30 mg/kg (male/female mouse), 4 mg/kg (rat), 3 mg/kg (dog)

“The NOAELs for lung toxicity were 90 and 30 mg/kg in M and F mice, respectively, 4 mg/kg in rats, and 3 mg/kg in dogs.”

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Pretomanid

pretomanid · Mycobacterial cell wall / respiration

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 small molecules outside oncology →

NOAEL / key findings

26-week rat: irreversible late-onset cataracts at 100 mg/kg/day; testicular atrophy/degeneration at ≥30 mg/kg/day

“Pretomanid caused irreversible, late onset, cataracts at 100 mg/kg/day and testicular atrophy/degeneration at doses of 30 mg/kg/day and higher.”

✓ VerifiedEMA assessment report, p. 23Source ↗

Pyrukynd

mitapivat · Pyruvate kinase (activator)

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 small molecules outside oncology →

NOAEL / key findings

NOAEL 25 (M) / 50 (F) mg/kg BID (1.2x / 2.2x MRHD AUC), based on subcapsular inflammation/necrosis at higher doses

“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”

✓ VerifiedFDA integrated review, p. 153Source ↗

Qelbree

viloxazine · Norepinephrine reuptake

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 small molecules outside oncology →

NOAEL / key findings

Dose-dependent hepatocellular hypertrophy and/or vacuolation in rat, mouse and dog

“In all three species (rat, mouse, and dog), repeat administration of viloxazine caused dose-dependent hepatocellular hypertrophy and/or vacuolation in the liver.”

✓ VerifiedFDA integrated review, p. 68Source ↗

Qinlock

ripretinib · KIT/PDGFRA

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 small molecules (ICH S9) →

NOAEL / key findings

Skin was the major target in both species; teeth, lung and male reproductive tract also in rats

“The major target organ of toxicity in both species was the skin; in the rat, the teeth, lung, and male reproductive tract were additional target organs.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

Qulipta

atogepant · 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 small molecules outside oncology →

NOAEL / key findings

6-month rat NOAEL 100 mg/kg/day (~33-fold margin over clinical AUC at 60 mg QD)

“The applicant considers that the NOAEL for atogepant in rats was 100 mg/kg/day in the 6-month study with an AUC0-24hr of 192.5 µM•hr, which represents an approximately 33-fold margin over the clinical exposure of about 5.75 µM•hr following 60 mg QD dosing.”

✓ VerifiedEMA assessment report, p. 23Source ↗

Quviviq

daridorexant · Orexin OX1/OX2 receptors

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 small molecules outside oncology →

NOAEL / key findings

39-week dog NOAEL 10 mg/kg/day, based on cataplexy-like signs and increased liver enzymes

“Based on the cataplexy-like clinical signs and increased liver enzyme levels, the NOAEL is considered to be 10 mg/kg/day in both males and females in the 39-week dog study.”

✓ VerifiedFDA integrated review, p. 179Source ↗

Rapiblyk

landiolol · β1-adrenergic 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 small molecules outside oncology →

NOAEL / key findings

4-week continuous i.v. infusion study NOAEL 1 mg/kg/min (~136-fold MRHD AUC)

“Steady state was reached within 1 hr and constant changes occurred over time until 4-weeks. The NOAEL was 1 mg/kg/min, with the average AUC0-96h of 281.2 µg.h/mL providing ~136-fold margin to the MRHD based on AUC.”

✓ VerifiedFDA pharmacology/toxicology review, p. 22Source ↗

Rasonque

daraxonrasib · RAS(ON) multi-selective

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 small molecules (ICH S9) →

NOAEL / key findings

Mouse 4-week STD10 50/30 mg/kg/day, 13-week NOAEL 25 mg/kg/day; monkey 4-week HNSTD 3 mg/kg/day

“The Severely Toxic Dose in 10% of animals (STD10) in the 4-week study in mice was 50/30 mg/kg/day, and the No Observed Adverse Effect Level (NOAEL) in the 13-week study in mice was 25 mg/kg/day. After 4-weeks of dosing in cynomolgus monkeys, the Highest Non-Severely Toxic Dose (HNSTD) was 3 mg/kg/day.”

✓ VerifiedFDA multi-discipline review, p. 49Source ↗

Recarbrio

imipenem, cilastatin and relebactam · Beta-lactamase (relebactam)

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 small molecules outside oncology →

NOAEL / key findings

CNS signs in rats at 450 mg/kg/day (~7x clinical exposure); rat NOAELs ~2-fold clinical exposure

“In the rat studies, the 450 mg/kg/day relebactam dose associated with neurological clinical signs produced plasma relebactam exposures approximately 7 times higher than the expected clinical exposures, but NOAEL doses in the rat studies were about 2-fold higher than the expected clinical exposures.”

✓ VerifiedFDA multi-discipline review, p. 41Source ↗

Relyvrio

sodium phenylbutyrate and taurursodiol · ER stress / mitochondrial (proposed)

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 small molecules outside oncology →

NOAEL / key findings

No notable toxicity in rat (26-week) or minipig (9-month) studies

“There was no notable toxicity in either species; however, it was unclear why the high dose in the 6- and 9-month studies was reduced to 845 mg/kg.”

✓ VerifiedFDA pharmacology/toxicology review, p. 46Source ↗

Retevmo

selpercatinib · RET

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 small molecules (ICH S9) →

NOAEL / key findings

Minipig most sensitive species; major findings at lethal doses with exposures below human therapeutic exposure

“Minipigs were exquisitely sensitive to selpercatinib and was the most sensitive species. Major toxicological findings that occurred in the minipig were at doses that induced moribundity/lethality with exposures below therapeutic exposures in human.”

✓ VerifiedFDA multi-discipline review, p. 80Source ↗

Revtorpyk

gedatolisib · PI3K/mTOR

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 small molecules (ICH S9) →

NOAEL / key findings

Rat NOAEL 5 mg/kg (8-dose) and 1 mg/kg (4-cycle); mortality, body weight loss, skin ulceration, testicular degeneration at higher doses

“The no-observed-adverse-effect level (NOAEL) was considered to be 5 mg/kg in the 8-dose study (based on mortality, adverse body weight changes, focal skin ulcerations, and testicular tubular degeneration), and 1 mg/kg in the 4-cycle study (based on histopathologic evidence).”

✓ VerifiedFDA multi-discipline review, p. 61Source ↗

Revuforj

revumenib · Menin-KMT2A

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs in rats and dogs: liver, bone marrow, lymphoid tissues, reproductive system; reproductive effects partly irreversible

“Toxicity target organs common to rats and dogs were the liver, bone marrow, lymphoid tissues, and reproductive system, with the majority of the findings partially or fully recovered following the 4- or 13-week recovery period, except for some effects in the male and female reproductive system.”

✓ VerifiedFDA multi-discipline review, p. 55Source ↗

Reyvow

lasmiditan · 5-HT1F 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 small molecules outside oncology →

NOAEL / key findings

39-week dog: tremors and hypoactivity; NOAEL 30 mg/kg (8-fold AUC margin)

“In the 39-week toxicology study in dog, there were lasmiditan-related tremors and hypoactivity. The safety margin was 8-fold compared to the maximum human dose based on AUC at the NOAEL of 30 mg/kg.”

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Rezdiffra

resmetirom · Thyroid hormone receptor 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 small molecules outside oncology →

NOAEL / key findings

Liver mononuclear infiltrates and hepatocellular alteration at ≥30 mg/kg/day; fibrosis at 200 mg/kg/day (57x MRHD AUC)

“Resmetirom at ≥ 30 mg/kg/day produced an increased incidence of mononuclear cell infiltrates in liver, nonspecific hepatocellular cytoplasmic alteration, and subcapsular/interlobular fibrosis (200 mg/kg/day only; 57 times the maximum recommended dose based on AUC).”

✓ VerifiedFDA integrated review, p. 110Source ↗

Rezlidhia

olutasidenib · IDH1 (mutant)

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 small molecules (ICH S9) →

NOAEL / key findings

Target organs: GI tract, liver, cardiovascular system, kidneys, hematopoietic system; altered glucose and lipid metabolism, inflammation, electrolyte imbalance

“Overall, adverse findings included altered glucose and lipid metabolism, inflammation, electrolyte imbalance, and toxicities in the GI tract, liver, cardiovascular system, kidneys, and hematopoietic system.”

✓ VerifiedFDA multi-discipline review, p. 33Source ↗

Rezurock

belumosudil · ROCK2

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 small molecules outside oncology →

NOAEL / key findings

NOAEL margins below clinical exposure: 0.2-0.4x (9-month dog), 0.08x (rabbit EFD)

“In the rabbit embryo-foetal toxicity study, the NOAEL resulted in safety margin of 0.08, and dog 9-month repeat dose toxicity study NOAELs resulted in safety margins of 0.2 and 0.4, when compared to the expected clinical exposure.”

✓ VerifiedEMA assessment report, p. 62Source ↗

Rezzayo

rezafungin · Fungal glucan synthase

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 small molecules outside oncology →

NOAEL / key findings

Rat 26-week: nerve fiber/axonal degeneration at 25 and 45 mg/kg, persisting through 26-week recovery

“In a 26-week study of weekly rezafungin in rats, nerve fiber/axonal degeneration increased in incidence and severity at 25 and 45 mg/kg and persisted at the end of the 26-week recovery period.”

✓ VerifiedFDA integrated review, p. 74Source ↗

Rhapsido

remibrutinib · BTK

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 small molecules outside oncology →

NOAEL / key findings

Targets: lymph nodes, thyroid, liver, pancreas (islet fibrosis) and blood (prolonged bleeding, inhibited platelet aggregation)

“Target organs of toxicity were identified as the lymph nodes (underdeveloped germinal centers, sinusoidal red blood cells), thyroid gland (follicular hypertrophy), liver (hepatocellular hypertrophy, multinucleated hepatocytes, pigment), pancreas (islet fibrosis, pigment), and blood (prolongation of bleeding, inhibition of platelet aggregation).”

✓ VerifiedFDA integrated review, p. 121Source ↗

Rinvoq

upadacitinib · JAK1

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 small molecules outside oncology →

NOAEL / key findings

Rat 26-week NOAEL 20 mg/kg/day, based on kidney histopathology at 50 mg/kg/day

“A No Observed Adverse Effect Level (NOAEL) of 20 mg/kg/day was established for this study based upon observed histopathological findings in the kidneys at 50 mg/kg/day.”

✓ VerifiedFDA pharmacology/toxicology review, p. 36Source ↗

Romvimza

vimseltinib · CSF1R

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 small molecules (ICH S9) →

NOAEL / key findings

Inflammation, hematologic, hepatic, renal, bone and GI toxicities consistent with CSF1R inhibition

“The vimseltinib toxicity profile is characterized by inflammation, hematologic, hepatic, renal, bone, and gastrointestinal toxicities, and is generally consistent with CSF1R inhibition.”

✓ VerifiedFDA multi-discipline review, p. 38Source ↗

Rozlytrek

entrectinib · TRK/ROS1/ALK

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 small molecules (ICH S9) →

NOAEL / key findings

Targets: CNS (convulsions, abnormal gait, tremors), skin (scabs/sores), decreased RBC parameters, at sub-clinical exposures

“Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats were observed in the CNS (convulsions, abnormal gait, tremors) at ≥0.2 times the human exposures by Cmax at the recommended dose, skin (scabs/sores) and decreased RBC parameters at ≥0.1 times the human exposure by AUC at the recommended dose.”

✓ VerifiedEMA assessment report, p. 66Source ↗

Rukobia

fostemsavir · HIV-1 gp120 (attachment)

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 small molecules outside oncology →

NOAEL / key findings

Target organs: testes, kidney and adrenal in rats; liver in dogs

“In repeated-dose toxicity studies, the target organs of toxicity were testes, kidneys, and adrenal gland in rats and liver in dogs.”

✓ VerifiedEMA assessment report, p. 23Source ↗

Sephience

sepiapterin · Tetrahydrobiopterin precursor

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 small molecules outside oncology →

NOAEL / key findings

26-week rat NOAEL 30 mg/kg/day (1.5-fold human exposure); adverse kidney findings at 100 and 200 mg/kg/day

“Based on the adverse kidney findings noted at 100 and 200 mg/kg/day in both sexes, the no observed adverse effect level (NOAEL) was determined to be 30 mg/kg/day (1.5-fold the human exposure at the maximum recommended human dose)”

✓ VerifiedFDA integrated review, p. 101Source ↗

Simtriyo

centanafadine · Triple monoamine reuptake

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 small molecules outside oncology →

NOAEL / key findings

Dose-limiting but monitorable body weight reductions; no unmonitorable toxicities below body-weight-effect doses

“The reductions in body weight were dose-limiting in animals and would be monitorable in humans. There were no unmonitorable toxicities observed at doses below those with adverse effects on body weight.”

✓ VerifiedFDA multi-discipline review, p. 35Source ↗

Skyclarys

omaveloxolone · Nrf2 activator

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 small molecules outside oncology →

NOAEL / key findings

Liver bile duct hyperplasia and kidney tubular degeneration at all doses; no NOAEL in 26-week rat

“Based on the liver (bile duct hyperplasia) and kidney (tubular degeneration/regeneration) findings at all doses (0, 0.3, 1, or 3 mg/kg) in the 26-week study, a NOAEL was not established in rats.”

✓ VerifiedFDA pharmacology/toxicology review, p. 4Source ↗

Sofdra

sofpironium · Muscarinic receptors (topical)

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 small molecules outside oncology →

NOAEL / key findings

Mainly administration-site findings; anticholinergic effects in rats at ≥1.5 mg/kg/day sc

“The major treatment-related effects observed in repeat-dose studies were findings at the test article administration sites. Pharmacologic anticholinergic effects were observed in rats with subchronic or chronic subcutaneous administration at doses of ≥1.5 mg/kg/day.”

✓ VerifiedFDA multi-discipline review, p. 34Source ↗

Sohonos

palovarotene · RARγ

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 small molecules outside oncology →

NOAEL / key findings

No NOAEL in 26-week rat: skin, growth plate (knee, sternum) and forestomach findings at all doses

“The target organs were the skin, growth plate of stifle or knee joints and sternum, and nonglandular forestomach during the interim and terminal sacrifices at all doses.”

✓ VerifiedFDA integrated review, p. 281Source ↗

Sotyktu

deucravacitinib · TYK2

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 small molecules outside oncology →

NOAEL / key findings

Rat 6-month NOAEL 5 mg/kg/day, based on sustained body weight reduction at 15 and 50 mg/kg/day

“The NOAEL for the 6-month oral toxicity study in rats was 5 mg/kg/day due to the sustained body weight reduction at 15 and 50 mg/kg/day.”

✓ VerifiedFDA multi-discipline review, p. 55Source ↗

Sunlenca

lenacapavir · HIV-1 capsid

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 small molecules outside oncology →

NOAEL / key findings

Injection site in both species; liver, gall bladder, kidneys and stomach in 9-month dog studies

“However, repeat-dose studies up to 9 months in dogs identified the liver, gall bladder, kidneys, and stomach as targeted organs of toxicity.”

✓ VerifiedFDA integrated review, p. 270Source ↗

Sunosi

solriamfetol · Dopamine/norepinephrine reuptake

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 small molecules outside oncology →

NOAEL / key findings

Lung target organ in rats and dogs: alveolar macrophages and phospholipidosis-like inclusions without functional adversity

“In both rats and dogs, the target organ of the drug is the lung with elevated macrophages and phospholipidosis-like inclusion bodies (without functional adversity in the lung).”

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Tabrecta

capmatinib · 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 oncology small molecules (ICH S9) →

NOAEL / key findings

13-week NOAELs: rat 40 (male) and 20 (female) mg/kg/day; monkey 30 mg/kg/day

“The applicant established the NOAEL values (40 mg/kg/day for males and 20 mg/kg/day for females in the case of rat, and 30 mg/Kg/day for monkey species), based on the findings observed in the 13-”

✓ VerifiedEMA assessment report, p. 23Source ↗

Tavneos

avacopan · C5a receptor (C5aR1)

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 small molecules outside oncology →

NOAEL / key findings

No dose-limiting toxicity or target organs identified; NOAEL was the high dose

“No dose-limiting toxicity or target organs of toxicity were identified. The NOAEL was considered as the high dose.”

✓ VerifiedFDA multi-discipline review, p. 383Source ↗

Tazverik

tazemetostat · EZH2

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 small molecules (ICH S9) →

NOAEL / key findings

13-week rat: thymic lymphoblastic lymphoma at 300 and 600 mg/kg (40% females, 15% males at 300 mg/kg)

“In total, lymphoblastic lymphoma originating from the thymus occurred in 40% of the females and 15% of the males treated at 300 mg/kg and 5% of the males treated at 600 mg/kg.”

✓ VerifiedFDA multi-discipline review, p. 32Source ↗

Tepmetko

tepotinib · 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 oncology small molecules (ICH S9) →

NOAEL / key findings

Liver toxicity in rats and dogs: elevated enzymes, histopathology, liver enlargement

“Both species experienced liver toxicity following tepotinib exposure, with dose-dependent elevated liver enzymes (AST, ALT, and/or ALP), histopathologic changes, liver enlargement”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Trikafta

elexacaftor, tezacaftor and ivacaftor · CFTR

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 small molecules outside oncology →

NOAEL / key findings

Deaths with gastric glandular mucosal erosion at high doses; NOAEL 15 mg/kg/day (4-12x human AUC)

“Multiple deaths/euthanasia were noted in those animals with the findings of decreased food intake leading to lower body weight and declining clinical condition with erosion of the glandular mucosa of the stomach. There was no adverse changes identified at 15 mg/kg/day; this dose level was considered as the NOAEL corresponding to AUC values 4 (males) or 12 (females) times the recommended human dose.”

✓ VerifiedFDA multi-discipline review, p. 44Source ↗

Truqap

capivasertib · AKT1-3

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 small molecules (ICH S9) →

NOAEL / key findings

Targets: insulin signaling, cardiovascular system, male reproductive organs, liver, kidney, HPA axis, hematopoietic system

“The major target organs/systems identified in the nonclinical studies comprised insulin signaling, cardiovascular system, male reproductive organs, liver, kidneys, hypothalamic pituitary axis and hematopoietic system.”

✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Truseltiq

infigratinib · FGFR1-3

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 small molecules (ICH S9) →

NOAEL / key findings

Bone (reduced strength and density, growth plate fractures) and liver (centrilobular vacuolation, mild focal necrosis in rat)

“Targets of toxicity included bone (decreases in bone strength, decreases in total bone mineral density, and multifocal growth plate fractures) and liver (centrilobular vacuolation and mild focal necrosis in the rat).”

✓ VerifiedFDA multi-discipline review, p. 43Source ↗

Tryptyr

acoltremon · TRPM8 agonist

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 small molecules outside oncology →

NOAEL / key findings

Reversible, nonadverse conjunctival redness and swelling (rabbit) and ocular discharge (dog)

“Test-article-related, reversible, nonadverse conjunctival redness and swelling (rabbit) and/or ocular discharge (dog) were observed.”

✓ VerifiedFDA integrated review, p. 76Source ↗

Tryvio

aprocitentan · Endothelin A/B receptors

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 small molecules outside oncology →

NOAEL / key findings

NOAEL 50 mg/kg/day in rats and 5 mg/kg/day in dogs (~14- and 11-fold MRHD exposure)

“The NOAEL was thus established at 50 mg/kg/day in rats and 5 mg/kg/day in dogs, which represent approximately 14- and 11-fold, respectively, the exposure at the MRHD based on AUC.”

✓ VerifiedFDA integrated review, p. 65Source ↗

Tukysa

tucatinib · 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 small molecules (ICH S9) →

NOAEL / key findings

Targets: GI tract and liver (rat, monkey); hemolymphoid, skeletal muscle and reproductive system (rat)

“Administration of tucatinib to rats and monkeys resulted in body weight loss, reduced food consumption, and adverse effects in the gastrointestinal (GI) system (rat and monkey), liver (rat and monkey), hemolymphoid system (rat), skeletal muscle (rat), and reproductive system (rat).”

✓ VerifiedFDA multi-discipline review, p. 34Source ↗

Turalio

pexidartinib · CSF1R

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 small molecules (ICH S9) →

NOAEL / key findings

Liver: hemosiderin, necrotizing inflammation and raised AST/ALT at ≥20 mg/kg (~0.6x clinical exposure)

“In the liver, hemosiderin deposition and necrotizing inflammation with increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occurred at doses ≥20 mg/kg (approximately 0.6 times the clinical exposure at 800 mg).”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Ubrelvy

ubrogepant · 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 small molecules outside oncology →

NOAEL / key findings

No adverse findings up to 160 mg/kg (6-month rat) and 175 mg/kg (9-month monkey)

“In the 6-month rat (up to 160 mg/kg) and 9-month monkey (up to 175 mg/kg) studies, there were no adverse findings.”

✓ VerifiedFDA pharmacology/toxicology review, p. 11Source ↗

Ukoniq

umbralisib · PI3Kδ / CK1ε

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 small molecules (ICH S9) →

NOAEL / key findings

Main target organs: liver in mice, gastrointestinal tract in dogs

“The liver was identified as the main target organ in mice and the gastrointestinal tract in dogs.”

✓ VerifiedFDA multi-discipline review, p. 39Source ↗

Utebzi

tebipenem pivoxil · Penicillin-binding proteins

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 small molecules outside oncology →

NOAEL / key findings

Rat NOAEL 1000 mg/kg/day (28-day GLP) and 300 mg/kg/day (90-day); low-grade stomach and heart findings

“Because of the low incidence, low severity and the absence of dose-dependency of findings in the stomach and heart, the NOAELs of the GLP 28-day study and non-GLP 14- and 28-day studies in rats are considered to be the high dose of 1000 mg/kg/day and the NOAEL of the non-GLP 90-day study in rats is considered to be 300 mg/kg/day”

✓ VerifiedFDA integrated review, p. 211Source ↗

Vafseo

vadadustat · HIF prolyl hydroxylase

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 small molecules outside oncology →

NOAEL / key findings

Exaggerated erythropoiesis causing thromboses, tissue necrosis and deaths; NOAEL exposures below clinical exposure at 600 mg

“The predominate toxicity observed in nonclinical studies can be reasonably attributed to the exaggerated pharmacological effects of excessive erythropoiesis; the toxicity was marked by thromboses, tissue necrosis, and mortalities. Exposure in animals at the ‘no observed adverse effect level’ (NOAEL) were all below human exposure at the clinical dose of 600 mg QD”

✓ VerifiedFDA integrated review, p. 270Source ↗

Vanflyta

quizartinib · FLT3

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 small molecules (ICH S9) →

NOAEL / key findings

13-week NOAELs: rat 3, dog 5, monkey 3 mg/kg/day

“NOAELs in the 13-week repeated dose toxicity studies were 3 mg/kg/day in rats, 5 mg/kg/day in dogs, and 3 mg/kg/day in monkeys.”

✓ VerifiedFDA multi-discipline review, p. 58Source ↗

Veklury

remdesivir · SARS-CoV-2 RNA polymerase

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 small molecules outside oncology →

NOAEL / key findings

Kidney injury in rats at ≥3 mg/kg/day; 4-week rat NOAEL 3 mg/kg/day (0.2–0.4x human GS-441524 AUC)

“Also in the 4-week study in rats clinical pathology and microscopic findings indicative of kidney injury and/or dysfunction in animals administered ≥ 3 mg/kg/day, and unscheduled deaths of 2 females and decreased body weight gain and food consumption at 10 mg/kg/day were seen. Based on the nature and severity of the kidney changes the NOAEL was 3 mg/kg/day, which corresponds to 0.4-fold (males) and 0.2-fold (females) the human AUC of GS-441524.”

✓ VerifiedEMA assessment report, p. 39Source ↗

Velsipity

etrasimod · S1P1/S1P4/S1P5 receptors

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 small molecules outside oncology →

NOAEL / key findings

Rat: mortality, decreased weight gain, liver and thymus histopathology at >1000-fold MRHD exposure

“In repeat-dose toxicity studies, mortalities, decreased body weight gain, and histopathological findings in the liver and thymus were observed in rats at exposures > 1000-fold the exposure at the maximum recommended human dose (MRHD) of 2 mg/day (based on AUC comparison).”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Veozah

fezolinetant · Neurokinin-3 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 small molecules outside oncology →

NOAEL / key findings

39-week monkey, high doses: weight loss, lymphocyte hyperplasia (lymph nodes, spleen, lung), kidney perivascular inflammation

“In the 39-week monkey study (Study No 8331280), fezolinetant was administered orally by daily gavage to sexually mature female monkeys at a dose of 0, 10, 25, or 40 mg/kg. High doses of fezolinetant resulted in weight loss and microscopic findings (hyperplasia of lymphocytes in lymph nodes, spleen, and lung, as well as perivascular inflammation in the kidney).”

✓ VerifiedFDA pharmacology/toxicology review, p. 19Source ↗

Veppanu

vepdegestrant · Estrogen receptor (PROTAC degrader)

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 small molecules (ICH S9) →

NOAEL / key findings

Dose-dependent reproductive organ changes in both sexes in rats and dogs, from 1-month studies onward

“Administration of vepdegestrant to rats and dogs resulted in dose-dependent changes in the reproductive systems of both sexes, observed as early as 1-month studies and persisting in longer-duration studies.”

✓ VerifiedFDA multi-discipline review, p. 48Source ↗

Verquvo

vericiguat · Soluble guanylate cyclase

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 small molecules outside oncology →

NOAEL / key findings

Consistent target organs: liver, kidney and adrenals

“Consistent target organs of toxicity were the liver, kidney, and adrenals.”

✓ VerifiedFDA integrated review, p. 146Source ↗

Vivjoa

oteseconazole · Fungal CYP51

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 small molecules outside oncology →

NOAEL / key findings

26-week rat: liver, adrenal, thyroid, kidney and ovary changes; no significant effects at 0.15 mg/kg/day

“Oteseconazole dosing for 26 weeks in rats resulted in changes in the liver, adrenals, thyroid, kidneys, and ovaries with no significant effects at 0.15 mg/kg”

✓ VerifiedFDA integrated review, p. 132Source ↗

Vizz

aceclidine · Muscarinic agonist (miotic)

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 small molecules outside oncology →

NOAEL / key findings

Chronic ocular rabbit study: no adverse ocular or systemic effects

“The chronic ocular toxicity of aceclidine hydrochloride was investigated in rabbits, with no adverse ocular or systemic effects at a dose of”

✓ VerifiedFDA integrated review, p. 77Source ↗

Vonjo

pacritinib · JAK2/FLT3

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 small molecules (ICH S9) →

NOAEL / key findings

39-week dog NOAEL 20 mg/kg/day, based on mortality, weight loss and GI toxicity at the high dose

“The Reviewer agreed with the Applicant’s interpretation that the NOAEL was the MD (20 mg/kg/day) based on the mortality, weight loss and GI toxicity observed at the HD.”

✓ VerifiedFDA integrated review, p. 118Source ↗

Voquezna

vonoprazan · H+/K+-ATPase (potassium-competitive)

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 small molecules outside oncology →

NOAEL / key findings

Rat targets: stomach, liver, thyroid, adrenal glands; dog: mainly stomach

“In repeated dose toxicology studies in rats, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity. In dogs, the stomach was the main target organ of toxicity.”

✓ VerifiedFDA integrated review, p. 140Source ↗

Voranigo

vorasidenib · IDH1/IDH2

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 small molecules (ICH S9) →

NOAEL / key findings

NOAEL 2 mg/kg/day in the 13-week study, safety margin about 2

“A NOAEL was set at 2 mg/kg/day in the 13-week study. The safety margins obtained were around 2.”

✓ VerifiedEMA assessment report, p. 29Source ↗

Voydeya

danicopan · Complement factor D

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 small molecules outside oncology →

NOAEL / key findings

Dog: cholestatic liver injury, 150 mg/kg/day not tolerated in 39-week study; bile duct hypertrophy/hyperplasia at ≥75 mg/kg/day

“In the 39-week toxicity study, danicopan at the dose of 150 mg/kg/day was not tolerated due to cholestatic liver injury. Hypertrophy/hyperplasia of the bile duct was observed in males at greater than or equal to 75 mg/kg/day.”

✓ VerifiedEMA assessment report, p. 25Source ↗

Vtama

tapinarof · Aryl hydrocarbon 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 small molecules outside oncology →

NOAEL / key findings

Target organs skin, liver, kidney and thymus, with secondary clinical pathology findings

“The major test article-related findings observed in repeat-dose dermal and subcutaneous studies were related to the skin, liver, kidney, and thymus with associated secondary clinical pathology findings.”

✓ VerifiedFDA multi-discipline review, p. 30Source ↗

Vyndaqel

tafamidis · Transthyretin (stabiliser)

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 small molecules outside oncology →

NOAEL / key findings

26-week rat NOAEL 30 mg/kg/day, the highest dose tested

“In the pivotal 26-week oral toxicity study in rat (with a 13-week interim sacrifice), the NOAEL was determined at high dose of 30 mg/kg/day”

✓ VerifiedFDA pharmacology/toxicology review, p. 13Source ↗

Wakix

pitolisant · Histamine H3 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 small molecules outside oncology →

NOAEL / key findings

Oral NOAELs 75, 30 and 12 mg/kg/day in mice, rats and monkeys

“The NOAEL by oral route were 75, 30 and 12 mg/kg/day in mice, rats and monkeys, respectively”

✓ VerifiedEMA assessment report, p. 19Source ↗

Wayrilz

rilzabrutinib · BTK (reversible covalent)

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 small molecules outside oncology →

NOAEL / key findings

Rat NOAEL 50 mg/kg/day; mortality, meninges/neuropil inflammation and stomach hemorrhage/inflammation at higher doses

“The no observed adverse effect level (NOAEL) was defined at 50 mg/kg/day based on mortality, inflammation of meninges/neuropil and hemorrhage/inflammation of stomach at higher doses”

✓ VerifiedFDA integrated review, p. 121Source ↗

Welireg

belzutifan · HIF-2α

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 small molecules (ICH S9) →

NOAEL / key findings

Reversible decreases in red blood cell parameters at ≥2 mg/kg/day in rats and ≥1 mg/kg/day in dogs, below human exposure

“Belzutifan caused reversible decreases in red blood cell parameters at ≥ 2 mg/kg/day in rats and ≥ 1 mg/kg/day in dogs (approximately ≥ 0.05 times the human exposure at the recommended human dose of 120 mg daily).”

✓ VerifiedFDA multi-discipline review, p. 34Source ↗

Winlevi

clascoterone · Androgen receptor (topical)

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 small molecules outside oncology →

NOAEL / key findings

39-week minipig NOAEL 5% cream; day-272 AUC 269-401 ng·h/mL

“The NOAEL in both sexes was 5% cream, which corresponds to day 272 AUC0-24 and Cmax of 269 ng·hr/mL and 16.8 ng/mL, respectively, in females, and 401 ng·hr/mL and 30.1 ng/mL, respectively, in males.”

✓ VerifiedFDA multi-discipline review, p. 35Source ↗

Xacduro

sulbactam and durlobactam · PBPs; beta-lactamase (durlobactam)

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 small molecules outside oncology →

NOAEL / key findings

Dog IV study: NOAEL not determined (prostate findings at lowest dose); prostate and testes weight changes did not reverse

“A no observed adverse effect level (NOAEL) could not be determined because of prostate findings at the lowest dose, but changes reversed by the end of dosing except for prostate and testes weights.”

✓ VerifiedFDA integrated review, p. 97Source ↗

Xcopri

cenobamate · Sodium channel / GABA-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 small molecules outside oncology →

NOAEL / key findings

26-week rat NOAEL 12 mg/kg/day; male-rat-specific kidney changes and adaptive liver hypertrophy

“Microscopic changes in the kidney (males) and liver (males and females) were attributed to drug, but renal changes were male rat specific, and the liver finding (centrilobular hepatocellular hypertrophy) is considered adaptive. The NOAEL (12 mg/kg/day) was associated with Week 26 Cmax and AUC0-t values of 9.3 ug/mL and 113.9 ug.h/mL in males and 17.6 ug/mL and 213.7 ug.h/mL in females, respectively.”

✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗

Xdemvy

lotilaner · Mite GABA-Cl channel

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 small molecules outside oncology →

NOAEL / key findings

Rat oral: skin/mucosa, ovary, lung, adrenal, pituitary and thymus findings; mortality at ≥40 mg/kg/day (males) and 60 mg/kg/day (females)

“Test-article related microscopic findings were noted in body weight, skin/mucosa, ovary, lung, adrenal, pituitary (males only) and thymus in rats. Mortality due to early sacrifice of moribund animals occurred at 60 mg/kg/day in female rats and at ≥40 mg/kg/day in male rats.”

✓ VerifiedFDA pharmacology/toxicology review, p. 9Source ↗

Xeglyze

abametapir · Lice metalloproteinases

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 small molecules outside oncology →

NOAEL / key findings

Repeat-dose target organs: smooth muscle, kidney and red blood cells

“In both the rodent and nonrodent models target organs of toxicity after repeat dosing were consistently limited to smooth muscle, kidney and red blood cells.”

✓ VerifiedFDA pharmacology/toxicology review, p. 56Source ↗

Xenleta

lefamulin · Bacterial ribosome (50S PTC)

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 small molecules outside oncology →

NOAEL / key findings

Administration-site reactions dose-limiting in rats and monkeys; no systemic target organ up to 13 weeks

“With IV administration, tolerability was limited by local reactions at the administration site in both rats and monkeys. No systemic target organ was identified in studies up to 13 weeks of administration.”

✓ VerifiedEMA assessment report, p. 39Source ↗

Xocova

ensitrelvir · SARS-CoV-2 3CL protease

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 small molecules outside oncology →

NOAEL / key findings

4-week monkey NOAEL 10 mg/kg/day; reduced food intake, weight loss, clinical pathology and multi-organ histopathology at 30 mg/kg

“The NOAEL was 10 mg/kg/day based on adverse findings at 30 mg/kg, including decreased food consumption and body weight loss in females, changes in clinical pathology parameters, along with extensive histopathological changes in several organs.”

✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Xolremdi

mavorixafor · CXCR4

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 small molecules outside oncology →

NOAEL / key findings

39-week dog target organs: liver, gallbladder, testes, epididymides and eyes

“Mavorixafor (free base) target organs of toxicity included the liver, gallbladder, testes, epididymides, and eyes (based on histopathological examination only).”

✓ VerifiedFDA integrated review, p. 126Source ↗

Zavzpret

zavegepant · 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 small molecules outside oncology →

NOAEL / key findings

Reversible nasal olfactory/respiratory epithelium degeneration in 13-week rat; rat intranasal NOAEL 12.5 mg/day

“The primary toxicity following IN administration in rat consisted of olfactory and respiratory epithelium degeneration and regeneration in the 13-week repeat dosing study which resolved over a 4-week recovery period. The NOAEL for IN administration in rat was 12.5 mg/day.”

✓ VerifiedFDA pharmacology/toxicology review, p. 9Source ↗

Zaynich

cefepime and zidebactam · PBPs; beta-lactam enhancer (zidebactam)

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 small molecules outside oncology →

NOAEL / key findings

Minimal kidney proximal tubule necrosis/regeneration in dogs at 500 and 1000 mg/kg/day

“Minimal necrosis and/or regeneration in kidney proximal tubule cells was observed in mid- and high-dose males and female dogs receiving 500 and 1000 mg/kg/day WCK 5107 (zidebactam).”

✓ VerifiedFDA integrated review, p. 257Source ↗

Zegfrovy

sunvozertinib · EGFR exon 20 insertion

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 small molecules (ICH S9) →

NOAEL / key findings

Dose-limiting GI toxicity; main target organs GI tract, eyes, skin, lungs and immune organs

“Dose-limiting toxicity was gastrointestinal (GI) tract effects (including diarrhea, low food consumption and body weight loss), consistent with clinical symptoms in human. The main target organs were GI tract, eyes, skin, lungs, and immune organs, etc.”

✓ VerifiedFDA multi-discipline review, p. 51Source ↗

Zenbexus

iberdomide · Cereblon (CELMoD)

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 small molecules (ICH S9) →

NOAEL / key findings

9-month monkey NOAEL 0.12 mg/kg/day, about 0.95-fold the human steady-state AUC at 1 mg

“In the 9-month monkey study, the NOAEL was 0.12 mg/kg/day with a mean AUC(0-24h) of 77.6 ng•h/mL 0.95-fold of the steady-state AUC(0-24h) of 81.36 ng•h/mL at 1 mg QD.”

✓ VerifiedFDA multi-discipline review, p. 61Source ↗

Zeposia

ozanimod · S1P1/S1P5 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 small molecules outside oncology →

NOAEL / key findings

Lymphopenia and lymphoid depletion; lung weight increase and alveolar histiocytosis set NOAELs of 0.2 (rat) and 0.1 (monkey) mg/kg/day

“In both rats and monkeys, the severity of these lung toxicities did not deteriorate in long-term toxicity studies, but they were incompletely reversible after the 6 weeks recovery period and served to determine the no observed adverse effect level (NOAEL)s (0.2 and 0.1 mg/kg/day in rats and monkeys, respectively) in these investigations.”

✓ VerifiedEMA assessment report, p. 28Source ↗

Zepzelca

lurbinectedin · DNA minor groove (transcription)

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 small molecules (ICH S9) →

NOAEL / key findings

Injection-site lesions and bone marrow suppression (transient leukopenia, mild anemia) in all species

“The major toxicological findings in all three tested species were injection site findings including hemorrhage, edema, inflammation, thrombosis, and necrosis and bone marrow effects leading to transient leukopenia and mild anemia with decreased cellularity in the bone marrow.”

✓ VerifiedFDA multi-discipline review, p. 28Source ↗

Zevtera

ceftobiprole medocaril · Penicillin-binding proteins

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 small molecules outside oncology →

NOAEL / key findings

13-week studies: convulsions and mortality at ≥50 mg/kg (marmoset, 0.2x MRHD) and ≥250 mg/kg (rat, 0.94x MRHD)

“However, in the 13-week studies in the rats and marmosets at similar doses to those used in shorter term studies, convulsions and mortality were observed (≥50 mg/kg in marmosets, 0.2 times the MRHD; ≥250 mg/kg in rats, 0.94 times the MRHD, based on BSA comparisons).”

✓ VerifiedFDA integrated review, p. 125Source ↗

Zokinvy

lonafarnib · Farnesyltransferase

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 small molecules outside oncology →

NOAEL / key findings

6-month rat: renal toxicity (inner medulla necrosis, mineralization) at 30 and 60 mg/kg/day; NOAEL 15 mg/kg/day

“The results of the 6-month oral toxicity study in rats indicated that treatment with lonafarnib (at doses of 30 and 60 mg/kg/day) produced renal toxicity, including necrosis and mineralization in the inner medulla and mononuclear cell infiltrates. The no-observed-adverse-effect level (NOAEL) was 15 mg/kg/day.”

✓ VerifiedFDA integrated review, p. 66Source ↗

Ztalmy

ganaxolone · GABA-A receptor (positive modulator)

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 small molecules outside oncology →

NOAEL / key findings

Dose-related reversible sedation in rats and dogs; little other target-organ or systemic toxicity

“The most common effect observed in the pivotal repeat-dose toxicology studies in adult rats and dogs was dose-related, reversible sedation, an expected pharmacological action of a positive modulator of GABAA receptors. Otherwise, there was little evidence of target organ or systemic toxicity in either species.”

✓ VerifiedFDA pharmacology/toxicology review, p. 112Source ↗

Zulresso

brexanolone · GABA-A receptor (positive modulator)

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 small molecules outside oncology →

NOAEL / key findings

Rat IV infusion NOAEL 60 mg/kg/day (5x human exposure at MRHD)

“NOAEL is 60 mg/kg/day based on the absence of adverse effects at this dose, which is 5- times the human exposure”

✓ VerifiedFDA multi-discipline review, p. 46Source ↗

Zurzuvae

zuranolone · GABA-A receptor (positive modulator)

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 small molecules outside oncology →

NOAEL / key findings

Deaths and sedation; rat NOAEL 10 (M)/1.5 (F) mg/kg, 3x and 2x MRHD exposure

“The safety margin at the NOAEL in males (10 mg/kg) and females (1.5 mg/kg) based on deaths and sedation was 3 and 2 times, respectively, relative to the exposure at the maximum recommended human dose (MRHD) of 50 mg.”

✓ VerifiedFDA integrated review, p. 158Source ↗

Zycubo

copper histidinate · Copper replacement (Menkes disease)

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 small molecules outside oncology →

NOAEL / key findings

Kidney, liver and spleen findings at all doses (from 1 mg/kg/day); NOAEL not determined

“CuHis-related microscopic and clinical pathology in kidneys, liver, and spleen occurred as low as 1 mg/kg/day; thus, the no-observed-adverse-effect level could not be determined.”

✓ VerifiedFDA integrated review, p. 150Source ↗