Fenebrutinib

Roche will seek approval of its multiple sclerosis pill after the asset succeeded in a third Phase 3 trial. But the study also found liver side effects, including one case of the worrying liver damage signal known as Hy’s Law, and there was an unexplained imbalance in the death rate. These findings could imperil the drug’s chances of gaining approval, and even if it does, its market uptake could be limited. The Swiss company said Monday that, in the FENhance 1 study in the relapsing form of MS, fenebrutinib reduced relapses by 51% compared with Sanofi’s marketed oral drug Aubagio. It also unveiled the figure from its earlier Phase 3 trial in relapsing MS, FENhance 2, which was disclosed as a success in November . In this study, fenebrutinib, a BTK inhibitor, cut the annualized relapse rate by 59% versus Aubagio. Roche said the difference over Aubagio in both studies was clinically meaningful and statistically significant. Patients in both trials took the pills for at least 96 weeks. As for safety, FENhance 1 saw a case of Hy’s Law — a benchmark that suggests a patient is at risk of serious liver damage — in the fenebrutinib arm and another in the Aubagio arm. Both cases were asymptomatic, Roche said, and resolved after the patients stopped taking the drugs. And some patients in both arms of both FENhance trials had increased levels of liver enzymes called transaminases, which can also point to liver injury. “We are not concerned about the liver enzyme elevations we have seen,” Roche’s deputy chief medical officer Stefan Frings told Endpoints News . To monitor the risk of Hy’s Law, the company has implemented managing criteria, he said. “We are testing liver function every two weeks for 20 weeks. So from our perspective, it is under control.” Analysts from Jefferies, however, wrote that there is a clear liver signal and that “approvability will depend on how the regulator puts this risk into perspective.” Another BTK inhibitor, Sanofi’s tolebrutinib, was rejected by the FDA in late December, with the complete response letter stating that there was “a serious risk of severe drug-induced liver injury” with that drug. Eight of the patients taking fenebrutinib in the FENhance 1 and 2 died, versus just one patient given Aubagio. The deaths in the fenebrutinib arms had various causes and happened at different points in treatment, Roche said, and it is analyzing the data “to better understand these findings.” There was also an imbalance in deaths in a pivotal study called FENtrepid that investigated the drug in the primary progressive form of MS (PPMS). Seven fenebrutinib patients died, but only one in the comparator arm with Roche’s own Ocrevus. All the fenebrutinib deaths were determined to be unrelated to the drug. “Whilst this remains unexplained, there seems to be a consistent imbalance,” the Jefferies analysts wrote, adding that they are not sure whether fenebrutinib “clears the bar” for an approval risk-benefit profile. “We have an independent Drug Monitoring Committee which always observes the trial,” Frings said. “They have informed us that they see a positive benefit-risk for fenebrutinib in RMS and PPMS, and we agree with those findings.” Roche said it would present full data from both FENhance 1 and 2 at the American Academy of Neurology’s annual meeting in Chicago in late April. The drugmaker also plans to submit data from both relapsing MS trials to regulators “as soon as we get this dossier completed,” Frings said. The submission will also include the results of the PPMS trial. Data revealed in February showed that fenebrutinib cut the risk of disability progression by 12% compared with Ocrevus. Frings explained that the FENhance trials used Aubagio, rather than Ocrevus, as the comparator because both drugs are oral. Ocrevus is administered via injection or infusion. But Roche needs fenebrutinib to succeed in the market as Ocrevus, which had sales of just over 7 billion Swiss francs ($8.8 billion) last year, will start to shed its patent protection in 2029. And the choice of Aubagio as comparator in the FENhance studies could make it hard for Roche to show that fenebrutinib is as good a drug as Ocrevus. Frings said based on data from their respective trials, fenebrutinib “is far more effective” compared with Aubagio and “at least as good” as Ocrevus.

Roche announced Monday that a third Phase III study of fenebrutinib met its primary endpoint, with the investigational brain-penetrant oral BTK inhibitor demonstrating clinically meaningful and statistically significant results in relapsing multiple sclerosis (RMS). However, a number of deaths in patients given fenebrutinib is being analysed in more detail by the company."These pivotal results, together with the earlier data, provide convincing evidence that fenebrutinib can become the first high-efficacy oral treatment for RMS and [primary progressive MS]," said Levi Garraway, Roche's head of global product development.The drugmaker reported positive results last November from the FENhance 2 study — in RMS — and the FENtrepid trial — in primary progressive MS (PPMS). In the first study, fenebrutinib significantly lowered the annualised relapse rate compared with Sanofi’s Aubagio (teriflunomide), while in the second trial, the therapy was non-inferior to Roche's Ocrevus (ocrelizumab) in delaying composite confirmed disability progression.In the latest study, dubbed FENhance 1, fenebrutinib reduced the annualised relapse rate (ARR) by 51% compared to Aubagio over a period of at least 96 weeks of treatment, consistent with FENhance 2 results showing a 59% reduction in ARR. Roche added that secondary endpoints in both RMS studies show statistically significant and clinically meaningful reductions in brain lesions, with all progression endpoints showing favourable trends for fenebrutinib.Safety at the foreThe BTK inhibitor class has long been troubled by liver toxicity problems, leading the FDA to previously place clinical holds not only on fenebrutinib, but also on Sanofi's tolebrutinib, Merck KGaA's evobrutinib and InnoCare's orelabrutinib.Roche said Monday that across the FENhance studies, liver transaminase elevations were comparable with Aubagio. In the FENhance 1 trial, there was one Hy's Law case in the fenebrutinib arm and one in the Aubagio arm, with both being asymptomatic and resolving after study drug discontinuation. Meanwhile, the company added that across the 1497 patients in the FENhance studies, there was one death in the Aubagio arm, compared to eight deaths in those on fenebrutinib. Roche noted that the fatalities were due to "various causes and at different points in treatment," with further analyses ongoing to better understand these findings.Commenting on the news, Morgan Stanley analysts suggested that the latest safety "data heightens risks on the approval pathway and even if approved, commercial potential."Roche indicated that the "totality of data" from all three Phase III fenebrutinib studies will be submitted to regulatory authorities, with full data scheduled to be presented at American Academy of Neurology (AAN) annual meeting.Following detailed results from FENtrepid released last month, physicians polled by FirstWord expressed cautious optimism about the potential of fenebrutinib, although concerns still remain among respondents regarding its liver safety profile and additional monitoring requirements.