Grafapex
treosulfan
Species
MonkeyRatDog
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat, dog and monkey
“Following repeated administration of treosulfan to rats, dogs or monkeys, the targets of toxicity were the haematopoietic and the lymphatic systems.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats received treosulfan at doses of 10, 50, or 150 mg/kg via i.v. once per day x 28 days, followed by a 2-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
4 (4-week rat GLP study)
“To assess the safety of treosulfan, the Applicant conducted a GLP-compliant toxicology study up to 4 weeks in adult Sprague-Dawley rats.”
Pivotal GLP studies
4-week intravenous bolus rat study
“Study title/ number: 4-Week Subchronic Toxicity Study of Treosulfan by Repeated Intravenous Bolus Injection to CD® Rats/ Study # 37259”
Route in tox
Intravenous bolus
“Route of administration: IV bolus”
Skipped studiesopen answer page →
Genotoxicity
Mutagenic in Ames test and clastogenic in in vitro human lymphocyte micronucleus assay
“Treosulfan was mutagenic in the in vitro bacterial mutagenicity assay (Ames test) and clastogenic in the in vitro micronucleus assay in human lymphocytes.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Dedicated carcinogenicity or fertility studies were not conducted with treosulfan, as they are not needed to support the use of a drug intended to treat patients with advanced cancer.”
Reproductive & developmental
No dedicated studies; 7-month rat study: dose-dependent male and female fertility impairment
“A 7-month chronic-dose study conducted in Wistar rats revealed dose-dependent fertility impairment in males and females (i.e. arrested spermatogenesis and absent corpora lutea and follicles).”
Safety pharmacology
No effect on hERG tail current (IC50 >5000 µM)
“Treosulfan had no effect on hERG tail current (IC50 > 5000 μM).”
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 Grafapex 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: Rat 4-week: bone marrow suppression, lymphoid and thymic atrophy, GI hyperplasia, muscle necrosis, multi-organ inflammation (FDA multi-discipline review, p. 145)
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.”
Risksopen answer page →
Immune & cytokine safety
Myeloablative and immunosuppressive in a murine allogeneic bone marrow transplant model
“Treosulfan showed in vivo myeloablative and immunosuppressive activity in a murine allogeneic bone marrow transplant model.”
Biodistribution & persistence
Rat: highest levels in kidney, lowest in brain
“Highest concentrations of treosulfan were observed in kidneys, and lowest quantifiable levels of treosulfan and EBDM were observed in the brain tissue.”
Modality-specific risk
Genotoxicity and risk of secondary malignancy
“Treosulfan is genotoxic. Due to the genotoxic properties, there is a risk of secondary malignancies after treatment with treosulfan.”