Late-breaking data for BTK inhibitor fenebrutinib show brain penetration and significant reduction in lesions in patients with relapsing multiple sclerosis.- Genentech/Roche

The late-breaking data were featured in an oral presentation at the 9th Joint ECTRIMS-ACTRIMS Meeting (European and Americas Committees for Treatment and Research in Multiple Sclerosis).

“These interesting results raise the possibility that fenebrutinib slows MS disease progression in part by acting directly within the brain,” said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. “These data, which we are currently confirming in pivotal trials of both relapsing and progressive MS, suggest that fenebrutinib may have the potential to counteract acute and chronic inflammation within the brain to reduce disease activity in people with MS.”

Brain penetrance was measured by the level of fenebrutinib in the cerebrospinal fluid (CSF) of a subgroup of 11 patients with RMS. After 12 weeks of continuous treatment, the mean fenebrutinib concentration was 43.1 ng/mL. Similar fenebrutinib concentrations can produce near-maximal inhibition (IC90) in preclinical studies. Thus, the level of fenebrutinib in the brain and central nervous system may conceivably become high enough to reduce MS disease activity and progression.

Fenebrutinib significantly reduced the total number of new T1 gadolinium-enhancing (T1 Gd+) brain lesions, which are markers of active inflammation, and the total number of new or enlarging T2-weighted (T2) brain lesions, which represent the amount of disease burden or chronic lesion load. A rapid onset of lesion reduction was observed by 4 weeks, with relative reductions of 92% and 90% in T1 Gd+ lesions and relative reductions of 90% and 95% in T2 lesions observed at 8 and 12 weeks, respectively.

Furthermore, patients treated with fenebrutinib were four times more likely to be free from any new T1 Gd+ brain lesions and new or enlarging T2 brain lesions at weeks 4, 8 and 12 combined, compared to patients who received placebo (odds ratio 4.005, p=0.0117).

The safety profile of fenebrutinib was consistent with previous and ongoing fenebrutinib clinical trials across more than 2,500 people to date. There were no new safety concerns identified in the FENopta study.Overall rates of adverse events were 38% with fenebrutinib and 33% with placebo. The most common adverse events that were higher with fenebrutinib than placebo were abnormal liver enzyme levels (5.5% fenebrutinib, 0% placebo), headache (4.1% fenebrutinib, 2.8% placebo), nasopharyngitis (2.7% fenebrutinib, 0% placebo) and upper abdominal pain (2.7% fenebrutinib, 0% placebo).

Fenebrutinib is the only non-covalent and reversible BTK inhibitor in Phase III trials for MS and was designed to be highly selective, which may be important in reducing off-target effects of a molecule and potentially contribute to long-term safety outcomes. An open-label extension of FENopta is ongoing, with Phase III studies FENhance 1 and 2 currently enrolling patients with RMS and FENtrepid fully enrolled for patients with primary progressive MS (PPMS).

About the FENopta study. ; The FENopta study is a global Phase II, randomized, double-blind, placebo-controlled 12-week study to investigate the efficacy, safety and pharmacokinetics of fenebrutinib in 109 adults aged 18-55 years with RMS. The primary endpoint is the total number of new T1 Gd+ lesions as measured by MRI scans of the brain at 4, 8 and 12 weeks. Secondary endpoints include the number of new or enlarging T2 lesions as measured by MRI scans of the brain at 4, 8 and 12 weeks, and the proportion of patients free from any new T1 Gd+ lesions and new or enlarging T2 lesions as measured by MRI scans of the brain at 4, 8 and 12 weeks. The goal of the FENopta study is to characterize the effect of fenebrutinib on MRI and soluble biomarkers of disease activity and progression, and it includes an optional substudy to measure cerebrospinal fluid biomarkers of neuronal injury. Patients who complete the double-blind period are eligible for an open-label extension study.