Roche has claimed the latest phase 2 readout for its multiple sclerosis (MS) drug backs up the BTK inhibitor’s “best in disease” potential by achieving the “holy grail” in biopharma: crossing the blood-brain barrier.
The Swiss company unveiled the results of the phase 2 FENopta study in 109 adults with relapsing MS at the ECTRIMS-ACTRIMS meeting in Milan on Friday. The BTK inhibitor fenebrutinib resulted in a relative reduction of 90% in new or enlarging gadolinium-enhancing T1 lesions as measured by MRI scan at 12 weeks, hitting the trial’s primary endpoint.
Similar success was reported against the secondary endpoint of T2 lesions, which saw a relative reduction of 95% in the same period. In fact, patients treated with fenebrutinib were four times more likely to be free from any new T1 Gd+ brain lesions or T2 brain lesions at weeks 4, 8 and 12 than patients who received placebo, the company noted.
As well as these key endpoints, Roche was keen to point out an apparent ability of fenebrutinib to achieve that rarest of feats, crossing the blood-brain barrier. The Big Pharma measured the level of the drug in the cerebrospinal fluid of a subgroup of 11 patients in the trial, which showed a mean fenebrutinib concentration of 43.1 ng/mL.
“Thus, the level of fenebrutinib in the brain and central nervous system may conceivably become high enough to reduce MS disease activity and progression in patients,” the company concluded in its Oct. 13 release.
Alexandra Goodyear, M.D., Roche’s global development lead for fenebrutinib, told Fierce Biotech in an interview that brain penetration remains a “holy grail, especially within the BTK inhibitor space.”
“We’ve seen with the anti-CD20s and Ocrevus specifically that acting on the cells in the periphery can have a profound effect on MS disease activity,” Goodyear said. “What we’re hoping for is that with this dual mechanism of action—hitting B cells and myeloid cells—if you can get into the brain, then you could perhaps act on resident B cells within the central nervous system, and on microglia.”
BTK inhibitor trials have often been marred by serious adverse events, with Merck KGaA’s evobrutinib placed on partial hold by the FDA earlier this year. The rate of adverse events in Roche’s latest trial was 38% for patients taking fenebrutinib compared to 33% for those on placebo, which the company said was a consistent safety profile with other studies of the drug. Of the adverse events that were not seen in the placebo cohort, the most common was abnormal liver enzyme levels, which was reported among 5.5% of patients who received fenebrutinib.
Unlike rival candidates, fenebrutinib is a non-covalent BTK molecule, and Goodyear said the drug was “designed on purpose” to try to offer “good long-term safety” for patients. However, she was clear that it will only be in the ongoing phase 3 trials that Roche will finally know “how significantly those structural differences translate into safety.”
The safety profile isn’t the only thing riding on those late-stage trials. As well as two phase 3 studies in relapsing MS, Roche has also launched a late-stage study in primary progressive MS where the drug is going head-to-head with the Big Pharma’s own MS blockbuster Ocrevus.
When asked whether any of those studies are likely to read out initial data before the end of the year, Goodyear suggested that the trials are “going to be a little bit longer than that.”