Trikafta (elexacaftor, tezacaftor and ivacaftor): what was done before first-in-human, and what came after?

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Trikafta: what was done before first-in-human, and what came after?

elexacaftor, tezacaftor and ivacaftor · CFTR

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 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.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

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)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

39-week dog (elexacaftor, oral) with 6-week recovery

“VX-445: A 39-week Oral (Gavage) Toxicity and Toxicokinetic Study in Beagle Dogs With a 26-week Interim Sacrifice and 6-week Recovery Period”

✓ VerifiedFDA multi-discipline review, p. 43Source ↗

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.”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

DART package

Species: DART

Rat and rabbit (separate studies of each component)

“separate reproductive and developmental studies were conducted with each active component of TRIKAFTA in pregnant rats and rabbits.”

✓ VerifiedUS prescribing informationSource ↗

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).”

✓ VerifiedFDA multi-discipline review, p. 50Source ↗

PPND / ePPND: when

PPND in rat (elexacaftor) completed before the marketing application

“A peri- and postnatal development study with elexacaftor was conducted in rats.”

✓ VerifiedEMA assessment report, p. 45Source ↗

Carcinogenicity

Species: carcinogenicity

Elexacaftor: Tg.rasH2 mouse (6-month) and rat (2-year)

“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.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

Elexacaftor: 6-month Tg.rasH2 mouse (negative at 50 mg/kg/day); 2-year rat

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity timing

Elexacaftor 6-month rasH2 mouse completed; 2-year rat to be completed after approval (postmarketing requirement)

“negative in teratogenicity and carcinogenicity assays (based on the 6-month study in mouse only; the 2-year carcinogenicity study in rat will be completed as a post-marketing requirement)”

✓ VerifiedFDA multi-discipline review, p. 34Source ↗

Summary across all 211 small molecules →

Trikafta: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Email me this as a cited memo

Same question, other small molecules