FDA puts partial hold on Phase 3 clinical trials of fenebrutinib in MS

2 patients saw increase in liver enzymes suggestive of drug-induced liver injury

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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The U.S. Food and Drug Administration (FDA) has placed a partial hold on Genentech’s ongoing Phase 3 clinical trials testing fenebrutinib for the treatment of relapsing and primary progressive forms of multiple sclerosis (MS).

The decision was based on two cases of patients who experienced elevations in their liver enzymes, suggestive of drug-induced liver injury. The patients did not develop symptoms of liver damage, and their enzyme levels returned to normal after discontinuing the treatment, the company said in a press release.

These two patients were being treated in the FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) trials, which are testing the therapy candidate in people with relapsing forms of MS. In addition, Genentech is running the FENtrepid Phase 3 trial (NCT04544449), involving people with primary progressive MS (PPMS).

The partial hold prevents the company from enrolling and dosing new participants at U.S. sites in all three studies. As enrollment is complete in FENhance 2 and FENtrepid, this applies only to FENhance 1 — although patient recruitment for that trial will continue to progress in other countries.

In addition, patients in the U.S. who have not completed more than 70 days of fenebrutinib dosing — “a small number,” according to the release — will stop treatment across all three trials. Those who have received the drug for more than 70 days will continue treatment as planned.

“Patient safety is Genentech’s highest priority, and we are working closely with the independent data monitoring committee, and investigators around the world,” the company said.

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ECTRIMS 2023: Fenebrutinib lowers new lesions in relapsing MS

2 trials already fully enrolled; 1 will still recruit in other countries

Fenebrutinib is an investigational oral small molecule designed to slow MS progression and reduce disease activity by preventing certain immune cells from driving disease-related inflammation and neuronal damage.

It does so by blocking Bruton’s tyrosine kinase (BTK), an enzyme that’s essential for the activity of immune B-cells and microglia. B-cells are responsible for antibody production, while microglia are the resident immune cells in the brain; both can substantially contribute to the inflammatory attack that drives MS.

According to the company, “this dual inhibition may be able to reduce both MS disease activity and disability progression, thereby potentially addressing the key unmet medical need in people living with MS.”

The therapy previously was tested in the FENopta Phase 2 clinical trial (NCT05119569), which enrolled 109 people with relapsing types of MS. Each was randomly assigned to receive either 200 mg ferebutinib or a placebo.

Findings shared at a conference this fall showed that the treatment reduced the number of new inflammatory lesions visible in MRI scans by 90% after three months. Also, pharmacological data suggested the medication can enter the brain and spinal cord at levels that are sufficient to block the activity of immune cells.

Genentech now is running the Phase 3 trials to potentially support an approval of fenebrutinib in relapsing and progressive forms of MS.

The FENhance studies are collectively testing the medication against an approved treatment, called Aubagio (teriflunomide), in about 1,500 adults with relapsing-remitting MS (RRMS) or active secondary progressive MS (SPMS). The main goal is to determine if fenebrutinib can reduce the annual rate of relapses.

With 985 adults with PPMS enrolled, the FENtrepid study is testing fenebrutinib against Ocrevus (ocrelizumab), the only approved treatment in the U.S. for PPMS. The main goal is to see whether fenebrutinib can slow the progression of disability.

In addition to fenebrutinib, other BTK inhibitors — such as Merck KGaA’s evobrutinib, Sanofi’s tolebrutinib, and Novartis’ remibrutinib — are being tested as potential therapies for people with MS. However, some of their clinical trial programs in the U.S. also have been put on hold by the FDA due to similar cases of elevations in liver enzymes indicative of liver damage.