FDA slaps clinical hold on Merck’s MS drug evobrutinib

Germany’s Merck KGaA said this morning that the FDA has placed a partial clinical hold on its multiple sclerosis drug candidate evobrutinib, vying to become a new oral therapy for the disease.

The hold – which comes after two cases of liver injury that seem to have been caused by the drug – means that new patients cannot be dosed with the drug, while those who have been taking it for less than 70 days should discontinue treatment, said the drugmaker.

It stressed, however, that its phase 3 EVOLUTION study of evobrutinib in relapsing MS won’t be affected by the move, as all patients have passed that time threshold, and a readout is still on track for the fourth quarter of this year.

Evobrutinib is one of a clutch of BTK inhibitors being developed for MS, and isn’t the first to come under scrutiny over the potential to cause liver toxicity.

Last year, the FDA placed similar partial clinical holds on Sanofi’s late-stage candidate tolebrutinib – holding up a programme that was a key part of the drugmaker’s $3.7 billion buyout of Principia Biopharma – as well as Biogen and InnoCare’s orelabrutinib, which is in phase 2.

That leaves Roche/Genentech’s phase 3 candidate fenebrutinib as the remaining late-stage BTK inhibitor that hasn’t been subjected to restrictions by the US regulator.

In its statement, Merck said that both of the patients showing drug-induced liver injury were asymptomatic, did not require any treatment or hospitalisation, and saw enzyme biomarkers used to measure liver damage return to normal after evobrutinib treatment was discontinued.

“Merck is working closely with the FDA to establish the best path forward for the benefit of patients in current and future trials with evobrutinib,” said the company, which is now investigating whether the patients had some characteristics that could predispose them to liver injury.

There are high expectations for BTK inhibitors in MS, with some neurologists now talking about the possibility that the drugs could not only slow down progression of the disabling disease, but even potentially offer a functional cure.

The disease has been linked to abnormal over-stimulation of B-cells thought to cause the body to attack the myelin sheaths surrounding nerve cells, which leads to the damage to the nervous system that causes the symptoms of MS. BTK inhibitors are thought to restrict that over-stimulation.

Evobrutinib was the first BTK inhibitor to show proof-of-concept in relapsing MS in a phase 2 trial reported in 2019, reducing the cumulative number of brain lesions over time compared to placebo.