Phase 0 and Phase 1: first studies in healthy volunteers

Before rentosertib was given to anyone with idiopathic pulmonary fibrosis (IPF), it was given to 134 healthy volunteers in three studies: a microdose study in Australia, a full Phase 1 study in New Zealand, and a second Phase 1 study in China. These studies were designed to find side effects and to measure how the body handles the drug, not to show whether it works.

Australia: the 100 microgram microdose study

The first time rentosertib entered a human being was in Adelaide in November 2021, at the CMAX clinical trial unit. Eight healthy volunteers each received a single dose of 100 micrograms, given directly into a vein. That is one ten-thousandth of a gram, and far below any dose expected to have a biological effect.

The study is registered in Australia as ACTRN12621001541897. Its purpose was to measure how quickly the drug appeared in and disappeared from the blood. Insilico Medicine reported that it was well tolerated. The detailed numbers appear only in the supplementary material of the 2024 Nature Biotechnology paper, and have not been published as a standalone report.

New Zealand: the main Phase 1 study

The larger study ran in Christchurch, New Zealand, from 21 February to 30 September 2022, registered as NCT05154240. It had two parts.

In the single-dose part, volunteers took one capsule at 10, 30, 60, 90 or 120 mg. A separate group took 90 mg with and without food, to see whether a meal changed absorption. In the multiple-dose part, volunteers took 30, 60 or 120 mg once daily for seven days.

Insilico reported the results in January 2023. There were no deaths and no serious adverse events. All side effects judged to be related to treatment were mild. One volunteer withdrew with a flu-like illness, which the investigators judged unrelated to the drug.

China: the second Phase 1 study

A parallel Phase 1 study began at Zhejiang Xiaoshan Hospital in Hangzhou on 28 July 2022, registered in China as CTR20221542. It enrolled 48 healthy volunteers, according to Insilico’s press release; the Chinese registry entry cannot be opened to confirm this independently.

Single doses were 30, 60 or 120 mg. The repeated-dose part used 30, 60 or 90 mg twice daily for seven days, which is different from the New Zealand study and is where the twice-daily arm later tested in the Phase 2a trial comes from. Insilico reported that drug levels were comparable to those seen in New Zealand.

What the studies showed about drug levels

In plain terms: rentosertib is absorbed quickly, peaks in the blood about an hour after a capsule is swallowed, and is roughly half cleared from the body between 7 and 12 hours later. Taking it with food delays and lowers the peak but does not greatly change the total amount absorbed. Taking it every day for a week did not cause it to build up in the body.

Detail for clinicians

In the China study, exposure rose slightly more than proportionally between 60 and 120 mg. Metabolism is thought to involve the liver enzymes CYP3A4 and CYP1A2, inferred from the later trial protocols, which banned grapefruit.

What was never published

No maximum tolerated dose has ever been published for rentosertib. Dose escalation stopped at 120 mg in both Phase 1 studies, but neither Insilico nor the authors have stated whether that was the highest dose the studies planned to give or the highest dose volunteers could tolerate.

The per-group side effect tables from the Phase 1 studies also exist only in supplementary material, so it is not possible to see which side effects occurred at which dose. This matters because the liver problems seen later in the Phase 2a trial in people with IPF were not reported in healthy volunteers.