The evidence that drug-induced liver injury is a classwide problem for BTK inhibitors is mounting up. In the wake of its partial clinical holds on studies involving Biogen and Sanofi, the FDA has clamped down on trials of Merck KGaA’s contender in response to evidence of damage to the liver of two patients.
A who’s who of leading autoimmune drug developers have identified BTK inhibitors as a way to improve outcomes in diseases including multiple sclerosis (MS). However, the progression of the drug candidates into larger clinical trials has triggered a spate of partial clinical holds in relation to reports of liver injury, with Sanofi, Biogen and now Merck all being held back by the FDA over the past 10 months.
Merck disclosed the imposition of a partial hold on its candidate, evobrutinib, early on Wednesday. The FDA action prohibits the German drugmaker from starting new patients on evobrutinib and from giving the BTK inhibitor to patients with less than 70 days exposure to the molecule in the U.S.
The terms of the partial clinical hold will limit its impact. Merck has already fully enrolled its EVOLUTION phase 3 clinical trial program in relapsing multiple sclerosis and treated the participants for more than 70 days, meaning the studies can continue. The program is still on track to deliver data in the fourth quarter.
Even so, the regulatory action is potentially a hit to Merck’s hopes for evobrutinib. The FDA imposed the hold on the program after assessing two recent “cases of laboratory values suggestive of drug-induced liver injury,” Merck said. Both patients were asymptomatic and their liver enzymes normalized, without medical intervention or hospitalization, after they stopped taking evobrutinib.
The reports and resulting clinical hold echo what happened to Sanofi and Biogen. Last summer, Sanofi, which joined the BTK race through its $3.7 billion takeover of Principia Biopharma, reported that the FDA had issued a partial clinical hold in response to “a limited number of cases of drug-induced liver injury.” Months later, InnoCare Pharma received (PDF) a similar notice, after which its partner Biogen bailed.
Sanofi’s experience suggests it may take Merck many months to resolve the situation. In August, around five weeks after being hit with the partial hold, Sanofi was aiming to resolve the situation by the fourth quarter. But in February, Sanofi told investors that work, requested by the FDA, to gain a mechanistic understanding of the liver injuries was “ongoing.”
Merck is “assessing the potential contributory role of predisposing factors” to its two liver injury cases and working “with the FDA to establish the best path forward for the benefit of patients in current and future trials with evobrutinib.” The German drug developer is yet to share a target timeline for getting out from under the partial hold.
Another uncertainty is whether all BTK inhibitors will ultimately be linked to cases of liver injury. People close to Novartis’ candidate have been bullish on its prospects, with Warner Carr, M.D., CEO of Allergy and Asthma Associates of Southern California, recently saying “we repeatedly have not seen [issues with liver function tests] with this particular product, so, that’s probably not going to be a class effect” while presenting clinical data on the Swiss drugmaker’s remibrutinib.
Novartis is alert to the liver toxicity risk, though, and started a phase 1 study of remibrutinib in people with hepatic impairment late last year. The phase 3 program for remibrutinib has, so far, stayed out of the FDA’s crosshairs, but the lack of a clinical hold may simply reflect the fact it has treated too few patients to see liver injuries. Novartis began its phase 3 trial program late in 2021, putting it more than one year behind Sanofi and Merck.
Talking to investors in February, John Reed, M.D., Ph.D., then Sanofi’s head of global R&D, said: “We certainly have exposed far more patients than any of the other companies. And so, I’ll leave you to speculate whether it’s a matter of time and simply testing enough patients to adjudicate this issue.”