Tazverik
tazemetostat
Species
MonkeyRat
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
Rat and cynomolgus monkey
“To assess the safety of tazemetostat, Epizyme conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and cynomolgus monkeys.”
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
“In the 13-week rat study, animals received tazemetostat once daily by oral gavage at doses of 100, 300, or 600 mg/kg.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“To assess the safety of tazemetostat, Epizyme conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and cynomolgus monkeys.”
Pivotal GLP studies
13-week GLP oral studies in Sprague Dawley rats and cynomolgus monkeys; 13-week juvenile rat study
“Epizyme also conducted a GLP-compliant toxicology study of up to 13-weeks in juvenile Sprague Dawley rats starting from post-natal day (PND) 7 to 98.”
Route in tox
Oral (once-daily gavage in rats; twice-daily in monkeys)
“In the 13-week monkey study, animals received oral tazemetostat at total daily doses of 100, 300, or 600 mg/kg/day (50, 150, 300 mg/kg BID).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus (human lymphocytes) and in vivo rat micronucleus assays
“Tazemetostat did not cause genetic damage in a standard battery of studies including a screening and pivotal bacterial reverse mutation (Ames) assay, an in vitro micronucleus assessment in human peripheral blood lymphocytes, and an in vivo micronucleus assessment in rats after oral administration.”
Carcinogenicity
Not conducted (advanced cancer indication); rodent studies show clear carcinogenic potential
“Dedicated carcinogenicity studies were not conducted with tazemetostat and are not required to support the use of a drug intended to treat patients with advanced cancer; however, findings in the rodent studies demonstrate that the drug has clear carcinogenic potential”
Reproductive & developmental
Rat and rabbit EFD: dose-dependent skeletal developmental abnormalities from ~1.5x human exposure
“Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure”
Safety pharmacology
No changes versus controls in QA, PR, QRS or QT intervals or body temperature
“No changes from control animals occurred in QA interval, body temperature, PR, QRS, and QT intervals in tazemetostat treated animals.”
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 Tazverik 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: 13-week rat: thymic lymphoblastic lymphoma at 300 and 600 mg/kg (40% females, 15% males at 300 mg/kg) (FDA multi-discipline review, p. 32)
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.”
Risksopen answer page →
Immune & cytokine safety
Monkey: lymphoid hyperplasia in mesenteric lymph node of a single male at 600 mg/kg/day
“In addition, lymphoid hyperplasia occurred in the mesenteric lymph node of a single male dosed at 600 mg/kg/day.”
Biodistribution & persistence
CNS tissues below quantifiable levels
“Tissues of the CNS were below quantifiable levels.”
Modality-specific risk
Secondary malignancy (T-cell lymphoblastic lymphoma), mechanistically driven and clinically relevant
“the animal studies appear to be predicting a mechanistically driven and clinically relevant risk of secondary malignancies associated with the drug.”