Roche's Fenebrutinib Shows Brain Penetration and Lesion Reduction in Multiple Sclerosis Patients: Late-breaking Data

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• New data from Phase II FENopta study in relapsing multiple sclerosis (RMS) show fenebrutinib crosses the blood-brain barrier with the potential to act directly on the chronic inflammation related to multiple sclerosis (MS)
• More than 90% relative reduction in new/enlarging T2 lesions and new T1 gadolinium-enhancing (Gd+) lesions with fenebrutinib beginning at 8 weeks
• The safety profile of fenebrutinib was consistent with previous and ongoing clinical trials across more than 2,500 people to date

“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., Roche’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 in patients.

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% for fenebrutinib and 33% for 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). Roche is committed to advancing innovative clinical research programmes to broaden the scientific understanding of MS, further reduce disability worsening in RMS and PPMS and improve the treatment experiences for those living with the disease.