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.”
Species: general tox
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.”
Species: DART
Not conducted (reproductive effects assumed from cytotoxic and genotoxic properties)
“A potential for an influence on reproductive performance and intrauterine development in humans can be assumed based on the cytotoxic and genotoxic properties of treosulfan. Therefore, no dedicated reproductive and developmental toxicity studies for treosulfan according to current regulatory guidance were conducted.”
Species: carcinogenicity
Not conducted (classified human carcinogen)
“Treosulfan is classified as a human carcinogen. Therefore, no carcinogenicity studies in animals have been performed.”
Surrogate used in
No surrogate used; treosulfan tested directly
“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).”
Genotox: Ames
Positive (mutagenic in Ames test)
“Treosulfan was mutagenic in the in vitro bacterial mutagenicity assay (Ames test) and clastogenic in the in vitro micronucleus assay in human lymphocytes.”
Genotox: in vitro mammalian
In vitro micronucleus in human lymphocytes: positive (clastogenic)
“Treosulfan was mutagenic in the in vitro bacterial mutagenicity assay (Ames test) and clastogenic in the in vitro micronucleus assay in human lymphocytes.”
Genotox: in vivo
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Carcinogenicity model
Not conducted (classified human carcinogen)
“Treosulfan is classified as a human carcinogen. Therefore, no carcinogenicity studies in animals have been performed.”
Carcinogenicity timing
Not needed: treosulfan is an IARC Group 1 human carcinogen
“Due to sufficient evidence in humans, treosulfan was considered by International Agency for Research on Cancer (IARC) Working Groups as “carcinogenic to humans (Group 1)”. (IARC, 2012) Therefore, carcinogenicity studies in animals were deemed not necessary.”
hERG / QT
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
Boxed warning: Myelosuppression
- Myelosuppression
- Seizures
- Skin Disorders
- Injection Site Reactions and Tissue Necrosis
- Secondary Malignancies
- Increased Early Morbidity and Mortality at Dosages Higher than Recommended
- Embryo-Fetal Toxicity
CytopeniasNeurotoxicitySkin reactionsHypersensitivity & infusion reactionsSecondary malignancyEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
7-month Wistar rat chronic study, recovery not stated; longest GLP study is 4-week rat
“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).”
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”
DART package
Species: DART
Not conducted (reproductive effects assumed from cytotoxic and genotoxic properties)
“A potential for an influence on reproductive performance and intrauterine development in humans can be assumed based on the cytotoxic and genotoxic properties of treosulfan. Therefore, no dedicated reproductive and developmental toxicity studies for treosulfan according to current regulatory guidance were conducted.”
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).”
PPND / ePPND: when
No dedicated DART studies; reproductive effects assumed from cytotoxic and genotoxic properties
“A potential for an influence on reproductive performance and intrauterine development in humans can be assumed based on the cytotoxic and genotoxic properties of treosulfan. Therefore, no dedicated reproductive and developmental toxicity studies for treosulfan according to current regulatory guidance were conducted.”
Carcinogenicity
Species: carcinogenicity
Not conducted (classified human carcinogen)
“Treosulfan is classified as a human carcinogen. Therefore, no carcinogenicity studies in animals have been performed.”
Carcinogenicity model
Not conducted (classified human carcinogen)
“Treosulfan is classified as a human carcinogen. Therefore, no carcinogenicity studies in animals have been performed.”
Carcinogenicity timing
Not needed: treosulfan is an IARC Group 1 human carcinogen
“Due to sufficient evidence in humans, treosulfan was considered by International Agency for Research on Cancer (IARC) Working Groups as “carcinogenic to humans (Group 1)”. (IARC, 2012) Therefore, carcinogenicity studies in animals were deemed not necessary.”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews; no NOAEL in adult repeat-dose studies (adverse effects at lowest dose)
“In the other repeat-dose studies, adverse effects were observed at the lowest dose tested.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Murine allogeneic bone marrow transplant model (myeloablation, immunosuppression)
“Treosulfan showed in vivo myeloablative and immunosuppressive activity in a murine allogeneic bone marrow transplant model.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: data did not convincingly show DNA alkylation/breaks as MOA
“During the review of the NDA, it was determined that the nonclinical data for treosulfan submitted to the NDA in studies or literature for which the Applicant has the right to reference did not provide convincing evidence of DNA alkylation and breaks as the mechanism of action (MOA) of treosulfan.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No dedicated reproductive and developmental toxicity studies
Why: Reproductive toxicity assumed from cytotoxic and genotoxic properties; decades of clinical use and alkylating-agent experience · Weight of evidence · Human data · Class precedent
“A potential for an influence on reproductive performance and intrauterine development in humans can be assumed based on the cytotoxic and genotoxic properties of treosulfan. Therefore, no dedicated reproductive and developmental toxicity studies for treosulfan according to current regulatory guidance were conducted.”
“In view of the fact that treosulfan is mutagenic, cytotoxic, carcinogenic and toxic to reproduction, and in view of its established clinical use for decades as well as the extensive experience with other alkylating agents, further non-clinical studies are not warranted.”
GLPAcceptedBeyond the letter
Package largely published literature and brief summaries of 1970s-1980s studies; only recent studies GLP
Why: Known mutagenic, cytotoxic, carcinogenic, reprotoxic profile; decades of clinical use; experience with other alkylating agents · Human data · Class precedent
“Most of the study results are derived from the published literature whilst other studies are presented as brief summaries of studies conducted in the 1970s and 1980s.”
“In view of the fact that treosulfan is mutagenic, cytotoxic, carcinogenic and toxic to reproduction, and in view of its established clinical use for decades as well as the extensive experience with other alkylating agents, further non-clinical studies are not warranted.”
GenotoxicityAcceptedBeyond the letter
Original submission lacked convincing evidence of DNA alkylation or genotoxicity; new Ames and chromosomal aberration studies required
“During the review of the NDA, it was determined that the nonclinical data for treosulfan submitted to the NDA in studies or literature for which the Applicant has the right to reference did not provide convincing evidence of DNA alkylation and breaks as the mechanism of action (MOA) of treosulfan or to address genotoxicity potential of the drug.”
“To address this issue, the Applicant conducted genetic toxicology studies, and submitted the results to demonstrate the genotoxicity of treosulfan.”
Safety marginVerdict not stated
No NOAEL in most repeat-dose studies; adverse effects at the lowest dose tested
“In the other repeat-dose studies, adverse effects were observed at the lowest dose tested.”
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