Evobrutinib

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.

The negative reaction to the impending departure of Sanofi CEO Paul Hudson, and Merck KGaA leader Belén Garijo as his replacement, is perhaps surprising given the French company’s muted performance under Hudson’s leadership. Sanofi’s shares fell about 3% in Paris and 4% in New York, a cold shoulder that may simply reflect the scale of the challenge that Garijo faces when she takes the reins in late April. She’ll have less than five years before the company’s immunological juggernaut Dupixent goes generic. Investors are concerned Garijo doesn’t have a track record of delivering R&D productivity at Merck KGaA, Jefferies managing director Michael Leuchten told Endpoints News in an interview. He considers that criticism “a little unfair” because the German conglomerate focused its capital allocation on areas other than pharma. “We thought the negative reaction on share price was harsh and kind of misses some of the nuances of what may be going on here,” Leuchten said. The company’s shares have lost about a quarter of their value in the past year. Garijo and her team will have to find pragmatic ways to extend Dupixent’s exclusivity, which could be possible through patent settlements and building on its joint venture with Regeneron, because there isn’t time to “rebuild an R&D organization from scratch” before Dupixent’s patent expires, Leuchten said. “One scenario that I think is possible is for Sanofi to go and acquire some assets that they fully fund and put those assets into the joint venture,” Leuchten said. Sanofi’s strategic priorities will remain unchanged under Garijo, a company spokesperson told Endpoints in an email. At Merck KGaA, Garijo’s history of dealmaking wasn’t scintillating. The biggest deal the company closed under her leadership was the $3.9 billion SpringWorks acquisition , and the rare cancer drugs Merck KGaA obtained haven’t been particularly lucrative so far. Another aspect driving some of the skepticism is that Garijo has had trouble delivering on promises in the past. In a letter in early 2022, she set out a goal for Merck KGaA known as “25 by 25” — achieving €25 billion ($27 billion) in total sales by 2025. The group won’t report its 2025 earnings until next month, but last October it guided to 2025 net sales between €20.8 billion and €21.4 billion. This missed goal is undeniably partly due to pipeline misfires. The failure of Merck KGaA’s evobrutinib in multiple sclerosis in late 2023 was followed by the cancellation of the pivotal trial of the head and neck cancer drug xevinapant in June 2024, after an interim analysis concluded the study was headed for failure. But Sanofi’s efforts to improve its drug development under Hudson didn’t always go as planned either. In 2019, at the beginning of his tenure as CEO, Hudson highlighted six programs as priorities. Two made it to market, Qfitlia (for hemophilia) and Beyfortus (for respiratory syncytial virus), but the others have either disappointed or failed entirely. Hudson also stopped developing a GLP-1 program for diabetes called efpeglenatide, just as other drugmakers were stepping up development efforts of this mechanism in obesity. There is no guarantee that asset would have gone on to do well, but the decision looks poor in retrospect. Sanofi’s current strategy involves going big on vaccines and investing in deals with a budget of up to €15 billion to spend across four key therapeutic areas: immunology, vaccines, neurology and rare diseases. This seems unlikely to compensate for Dupixent’s loss of exclusivity, since the drug accounted for 36% of Sanofi’s 2025 revenues. It was perhaps Sanofi’s eagerness on immunology that led things to go wrong at the French drugmaker under Hudson in the first place, Leuchten said. Sanofi assumed that immunology can be approached rationally and with acceptable risk, but time has shown that the space is “a lot more complicated than we thought,” Leuchten said. “The placebo response rates are all over the shop, you get intratrial variability, so the rational approach doesn’t work as well as anybody thought.” Sanofi’s change at the top seems to have happened fast; CEO transitions can be planned around a year in advance in the normal run of things. But Sanofi has ousted leaders with unceremonious haste before. In 2014 it sacked then-CEO Chris Viehbacher after a boardroom clash over Viehbacher’s management style.