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

Precedia/Small molecules/Ogsiveo/Tox package

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

nirogacestat · Gamma secretase

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 Ogsiveo 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 NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day) (EMA assessment report, p. 35)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

3-month rat and 3-month dog (oral, GLP), each with 1-month recovery

“Nirogacestat was administered to rats and dogs in repeat dose general toxicology studies up to 3 months in duration followed by a 1‐month recovery.”

✓ VerifiedFDA multi-discipline review, p. 61Source ↗

Pivotal GLP studies

GLP 3-month repeat-dose studies in rats and dogs

“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”

✓ VerifiedFDA multi-discipline review, p. 48Source ↗

DART package

Species: DART

Rat only (two fertility studies and a preliminary EFD study)

“The developmental and reproductive toxicology assessment of nirogacestat consisted of two separate fertility studies in male and female rats and a preliminary embryo-foetal toxicity study in pregnant rats.”

✓ VerifiedEMA assessment report, p. 30Source ↗

Reproductive & developmental

Preliminary rat EFD: decreased fetal weight, post-implantation loss and fetal subcutis edema at ≥20 mg/kg/day

“Daily oral administration of nirogacestat to pregnant rats resulted in decreased fetal body weights, post‐ implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the exposure in patients with desmoid tumors based on AUC at the 150 mg BID dose).”

✓ VerifiedFDA multi-discipline review, p. 49Source ↗

PPND / ePPND: when

Not conducted: rat PPND waived given severe embryo-fetal effects in the rat dose-range finding study

“Based on the severity of the embryo‐fetal development (EFD) effects of nirogacestat observed in the dose‐range finding study in rats (Study 01214026) and the importance of the gamma‐ secretase pathway in embryo implantation and development, SpringWorks requested a waiver for conducting the definitive EFD study in rat, the range finding and definitive EFD studies in rabbits, as well as the pre‐ and post‐natal development (PPND) study in rats.”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Carcinogenicity

Species: carcinogenicity

Tg rasH2 mouse (26-week); no rat study

“The carcinogenicity of nirogacestat was assessed in a 6‐month repeat dose study in transgenic rasH2 mice (20174162).”

✓ VerifiedFDA multi-discipline review, p. 78Source ↗

Carcinogenicity model

26-week Tg rasH2 mouse (negative overall); 2-year rat study not conducted

“A rat 2-year carcinogenicity study was not conducted given that non-melanoma skin cancers have been reported in humans treated with nirogacestat and the fact that human systemic exposures exceed those that can be achieved in animal toxicology studies due to low tolerance in the rat and excess of toxicological findings.”

✓ VerifiedEMA assessment report, p. 37Source ↗

Carcinogenicity timing

26-week Tg rasH2 mouse completed before the marketing application; 2-year rat waived

“In the 6‐month carcinogenicity study (Study 20174162), a significant increase in hemangiosarcomas was noted in both male and female transgenic mice with the incidence above historical control values of the test facility. Therefore, SpringWorks requested a waiver for the 2‐year carcinogenicity study in rats”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Summary across all 211 small molecules →

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

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other small molecules