Beqalzi
sonrotoclax
Sources:FDA multi-discipline review ↗
Species
MouseDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and dog
“The GLP-compliant repeat-dose toxicology studies of up to 13 weeks of dosing were conducted in mice and dogs with animals dosed daily via oral gavage.”
Why that species
Pharmacologically relevant: high BCL2 sequence homology, comparable in vitro metabolism, adequate bioavailability
“Mice and dogs were pharmacologically relevant species for toxicity evaluation, based on their high BCL2 sequence homology with humans, comparable metabolism profiles with humans in in vitro studies, and adequate bioavailability.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 13-week dog study, sonrotoclax was administered at doses of 10, 30, or 100 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The GLP-compliant repeat-dose toxicology studies of up to 13 weeks of dosing were conducted in mice and dogs with animals dosed daily via oral gavage.”
Pivotal GLP studies
28-day and 13-week GLP oral gavage studies in mice and dogs
“The nonclinical toxicity and toxicokinetic profiles of sonrotoclax were characterized in single-dose (GLP), 14-day (non-GLP, dose-range finding), 28-day (GLP), and 13-week (GLP)”
Route in tox
Oral gavage
“The GLP-compliant repeat-dose toxicology studies of up to 13 weeks of dosing were conducted in mice and dogs with animals dosed daily via oral gavage.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and mouse bone marrow micronucleus assays
“No genotoxic potential was identified in the standard battery of genotoxic toxicology, including in vitro Ames and chromosomal aberration assays, and in vivo bone marrow micronucleus assay in mice (Module 4.2.3.3).”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“No carcinogenicity studies were conducted. These studies were not required for an oncology drug intended for treatment of patients with severe or life-threatening malignancies per ICH S9 guidance.”
Reproductive & developmental
Mouse and rabbit EFD: malformations in rabbits at high dose; post-implantation loss and lower fetal weight in mice
“Abnormalities included external, visceral, and skeletal malformations observed in the high dose group.”
Safety pharmacology
No hERG effect; no cardiovascular effects in dogs up to 100 mg/kg; no CNS effects in mice up to 300 mg/kg
“Based on findings from non-GLP and GLP assays, sonrotoclax had no effect on the human Ether-a-go-go-Related Gene (hERG) channel in Chinese Hamster Ovary cells. Sonrotoclax had no effect on cardiovascular parameters in dogs after single or repeated doses of up to 100 mg/kg or on central nervous system parameters in mice after repeated doses of up to 300 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Beqalzi don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
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.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Dog targets: liver, gallbladder, male reproductive tract, skin, lymphatic system; male reproductive and skin findings not reversible (FDA multi-discipline review, p. 27)
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.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion; one mouse death from opportunistic infection secondary to lymphoid depletion
“Mortality was only noted in 1 male at 100 mg/kg/day and was most likely caused by an opportunistic infection secondary to lymphoid depletion.”
Biodistribution & persistence
Mouse distribution to intestine, kidney, spleen, liver, muscle, bone marrow and uterus
“Sonrotoclax distribution in the mouse included the small intestine, large intestine, kidney, spleen, liver, muscle, bone marrow, and uterus.”
Modality-specific risk
Embryofetal toxicity (labeled Warning and Precaution)
“Based on data from the embryo-fetal development studies, a Warning and Precaution for embryo-fetal toxicity is included in the labeling for this product.”