Ojemda (tovorafenib): what was done before first-in-human, and what came after?

Precedia/Small molecules/Ojemda/Tox package

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

tovorafenib · RAF (type II pan-RAF)

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 Ojemda 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.”

✓ VerifiedICH 2009: ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, p. 13Source ↗

This product's starting point

NOAEL / key findings: No exposure margin at NOAELs in pivotal studies (rat 0.39-fold, monkey 0.41-fold adult exposure) (EMA assessment report, p. 41)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

3-month rat and 3-month monkey (oral); rat 3-month study with 2-week recovery

“In males, the 3-month study highlighted decreased testes and epididymal weights with associated microscopic findings of seminiferous tubules degeneration/atrophy and reduced epididymal luminal sperm at all doses (≥ 50 mg/kg Q2D, 0.3-fold human exposure); lower testes weight persisted after 2 weeks of recovery.”

✓ VerifiedEMA assessment report, p. 42Source ↗

Pivotal GLP studies

Up to 3-month oral rat and cynomolgus monkey studies, dosed every other day (Q2D)

“Repeat-dose toxicity studies of up to 3 months in rats and monkeys with QD, Q2D, every 3 days (Q3D), and/or once weekly (QW) PO dosing were performed. Since dose range-finding pilot studies with daily dosing showed intolerability in both species, the Q2D regimen showed improved tolerability.”

✓ VerifiedEMA assessment report, p. 40Source ↗

DART package

Species: DART

Rat only (fertility and preliminary EFD)

“In consistency with reproductive toxicity findings in the FEED study, in the preliminary EFD study, administration of tovorafenib caused 100% early resorptions and total litter loss in all treated pregnant rats at doses of 37.5, 75, or 150 mg/kg/day.”

✓ VerifiedEMA assessment report, p. 50Source ↗

Reproductive & developmental

Rat EFD: early resorptions and total litter loss at all doses (37.5–150 mg/kg)

“In an embryo-fetal development study, once daily oral administration of tovorafenib to pregnant rats during the period of organogenesis from gestation days 7 through 17 at doses of 37.5, 75, and 150 mg/kg resulted in early resorptions and total litter loss at all doses.”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

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

Species: carcinogenicity

Tg rasH2 mouse (26-week)

“The study report of 26-week Tg Ras mouse carcinogenicity study was submitted. In this study Tg Ras mice were dosed at 10, 30, and 100 mg/kg/day by oral gavage for 26 weeks.”

✓ VerifiedEMA assessment report, p. 41Source ↗

Carcinogenicity model

26-week Tg rasH2 mouse up to 100 mg/kg/day: no effect on carcinogenicity

“In this study Tg Ras mice were dosed at 10, 30, and 100 mg/kg/day by oral gavage for 26 weeks. It was concluded that tovorafenib was well tolerated at all doses with no effects on carcinogenicity, survival rate, or adverse findings.”

✓ VerifiedEMA assessment report, p. 41Source ↗

Carcinogenicity timing

26-week Tg rasH2 mouse completed before the marketing application; 2-year rat ongoing at approval

“The 2-year rat carcinogenicity study is ongoing. The carcinogenicity evaluation is considered adequate considering the ongoing 2-year study.”

✓ VerifiedEMA assessment report, p. 41Source ↗

Summary across all 211 small molecules →

Ojemda: 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