Safety and side effects seen so far

Rentosertib is an investigational medicine. Everything known about its side effects comes from a small number of short trials, and nobody has yet taken it for longer than 12 weeks in a published study.

Where the safety information comes from

Two groups of people have taken rentosertib in published trials.

The first group is healthy volunteers. About 130 took part across three early studies: 8 people in Adelaide, Australia, 78 in Christchurch, New Zealand, and 48 in Hangzhou, China. Sources differ on the New Zealand number, which is reported as 78 in one place and 64 in another.

The second group is 71 people with idiopathic pulmonary fibrosis (IPF) in the GENESIS-IPF phase 2a trial in China. They took rentosertib or a dummy medicine (placebo) for 12 weeks, on top of their usual treatment.

That is the whole published safety record. No one has published data from more than 12 weeks of treatment.

Healthy volunteers

Insilico Medicine reported no deaths and no serious adverse events in the healthy-volunteer studies. The company says all treatment-related side effects were mild. Per-person tables for these studies were published only as supplementary material, so the detail cannot be checked independently.

What happened in the phase 2a trial

The 71 people were split into four groups: 18 took 30 mg once daily, 18 took 30 mg twice daily, 18 took 60 mg once daily, and 17 took placebo. The trial’s main purpose was to measure side effects, not to test whether the medicine works.

An adverse event is any medical problem that happens during a trial, whether or not the medicine caused it.

The pattern the authors report is that side effects judged related to treatment rose steadily with dose, from about 3 in 10 people on placebo to nearly 8 in 10 people on 60 mg once daily.

The most common problems, in the same order of groups (placebo, 30 mg once daily, 30 mg twice daily, 60 mg once daily), were:

• Low potassium in the blood (hypokalaemia): 2, 3, 5 and 4 people.
• Diarrhoea: 0, 2, 3 and 5 people. The authors describe this as dose-related.
• Raised ALT, a liver enzyme measured in a blood test: 1, 1, 1 and 6 people.
• Raised bilirubin, another liver blood test: 2, 0, 1 and 4 people.
• Chest and throat infections: 1, 1, 4 and 1 people.

“Abnormal liver function” was also recorded as a separate event term. Counts by group for that term are not given in the published sources.

The liver signal

This is the clearest safety concern in the data.

Twelve people stopped the trial because of an adverse event. Seven of those 12 stopped because of liver injury or liver dysfunction. None of them were in the 30 mg once daily group. Four of 18 were in the 30 mg twice daily group (22.2%) and 3 of 18 were in the 60 mg once daily group (16.7%).

Four of those 7 people were also taking nintedanib, one of the two antifibrotic medicines used in IPF today. None were taking pirfenidone. The trial authors say this needs proper drug-interaction studies before the two are combined again. No such study has been registered.

Insilico says the liver problems resolved after the medicine was stopped.

Acute exacerbations of IPF

An acute exacerbation is a sudden, severe worsening of IPF. It is dangerous and often fatal.

There were 3 in the 60 mg once daily group (3 of 18, 16.7%) and 1 in the placebo group (1 of 17, 5.9%). All four people were admitted to hospital, for an average of 23.3 days. The same group also recorded two cases of pneumonia, one of interstitial lung disease and one of respiratory failure.

The authors suggest a possible explanation: that the medicine may dampen the immune response and make infection more likely. They describe this as a hypothesis. With so few people, chance is also a plausible explanation. It remains an open question.

Deaths and people leaving the trial

One person died, in the 30 mg twice daily group, from heart failure. An independent adjudication judged the death unrelated to the medicine.

In total, 16 of the 71 people (22.5%) left the trial early: 2 on placebo, 2 on 30 mg once daily, 6 on 30 mg twice daily and 6 on 60 mg once daily. Twelve of the 16 left because of an adverse event.

What is not yet known

• Long-term safety. The longest published exposure is 12 weeks. The phase 3 trial runs for 52 weeks and will not report before about 2028.
• Interactions with other medicines. The authors called for drug-interaction studies. None has been registered.
• Effects in people who are not Chinese. Everyone in the phase 2a trial was recruited in China and recorded as Asian.
• Effects alongside nintedanib. Four of the seven liver discontinuations were in people also taking nintedanib, which is not enough to say what is going on.
• The maximum tolerated dose. This has never been published for rentosertib.

How side-effect reporting works in the UK

In the UK, side effects of licensed medicines are reported through the Yellow Card scheme, run by the Medicines and Healthcare products Regulatory Agency (MHRA). Anyone can submit a report: patients, carers, pharmacists and doctors. The MHRA uses the reports to spot safety problems after a medicine reaches the market.

Yellow Card does not apply to rentosertib, because rentosertib has no UK marketing authorisation and is not supplied in the UK.

If you take pirfenidone or nintedanib and have a side effect, tell your ILD centre team. You can also report it yourself at yellowcard.mhra.gov.uk. Both medicines need regular blood tests to check the liver, and your team will tell you how often.