Trikafta
elexacaftor, tezacaftor and ivacaftor
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The rat was the pivotal rodent species in repeat dose toxicity studies with elexacaftor alone or in combination with tezacaftor or ivacaftor. The dog was the pivotal non-rodent species.”
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 compounds were tested
“In the 1-month triple combination study in dogs (VRT-1651445-TX-022), all animals survived until the end of dosing.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog, elexacaftor)
“When VX-445 was administered alone chronically (up to 39-week) in dogs (VX-445-TX-006), test item-related microscopic changes were noted at 14 mg/kg/day including hepatocellular hypertrophy, epithelium vacuolation in gallbladder, and testicular seminiferous tubule atrophy/degeneration.”
Pivotal GLP studies
Rat (up to 6 months) and dog (up to 9 months) studies of elexacaftor alone or with tezacaftor and ivacaftor
“As listed in the following table, general toxicity studies with either VX-445 alone or in combination with tezacaftor (VX-661) and ivacaftor (VX-770) were conducted in rats, mice, and dogs with dosing durations up to 6 months in rodents and 9 months in non-rodents.”
Route in tox
Oral (gavage)
“VX-445: A 26-week Oral (Gavage) Toxicity Study in Sprague Dawley Rats Followed by a 6-week Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Elexacaftor negative in bacterial and mammalian in vitro assays and an in vivo chromosomal damage assay
“Elexacaftor was not genotoxic in a bacterial and a mammalian in vitro assay in the presence or absence of S9 metabolizing mix. Elexacaftor was also not genotoxic in a chromosomal aberration assay in vivo.”
Carcinogenicity
Elexacaftor 6-month Tg.rasH2 mouse and 2-year rat: no tumorigenicity
“A 6-month study in Tg.rasH2 transgenic mice showed no evidence of tumorigenicity at 50 mg/kg/day dose, the highest dose tested. A two-year study was conducted in rats to assess the carcinogenic potential of elexacaftor. No evidence of tumorigenicity was observed in rats at elexacaftor oral doses up to 10 mg/kg/day”
Reproductive & developmental
Elexacaftor rat fertility: lower fertility, copulation and conception indices at high doses (NOAEL 55/25 mg/kg/day M/F)
“In conclusion, the NOAEL for reproductive toxicity was determined to be 55 mg/kg/day in males and 25 mg/kg/day in females based on lower male and female fertility, male copulation, and female conception indices at 75 mg/kg/day (males) and 35 mg/kg/day (females).”
Safety pharmacology
Elexacaftor: no changes in temperature, blood pressure, heart rate or ECG in telemetered dogs (single dose up to 30 mg/kg nominal, 24.78 mg/kg measured)
“Effects of elexacaftor on the cardiovascular system were assessed in telemetered dogs. A single dose of elexacaftor up to a nominal dose of 30 mg/kg (24.78 mg/kg actually measured) did not result in any changes in body temperature, blood pressure, pulse pressure, heart rate, or ECGs.”
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 Trikafta 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 small molecules outside oncology
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.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Deaths with gastric glandular mucosal erosion at high doses; NOAEL 15 mg/kg/day (4-12x human AUC) (FDA multi-discipline review, p. 44)
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.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion in the thymus
“Microscopic correlates consisted of cortical hypertrophy/vacuolation in the adrenal glands, atrophy in the prostate, secretory depletion in the seminal vesicles/coagulating glands, germ cell debris/oligospermia in the epididymides, and lymphoid depletion in the thymus.”
Biodistribution & persistence
Elexacaftor crosses blood-brain barrier (brain ~3-fold below plasma); no preferential melanin binding
“VX-445-related radioactivity crossed the blood-brain barrier, but measured concentrations in the brain were about 3-fold lower relative to plasma. A tissue distribution study in Long-Evans rats showed no significant distribution to melanin-containing tissues (skin, eyes), indicating that VX-445 did not preferentially associate with melanin.”
Modality-specific risk
Major active human metabolite M23 with low nonclinical exposure margins (MIST)
“Levels of M23 formed in nonclinical species were generally lower than in humans, resulting in relatively low exposure margins in some cases.”