#MSVirtual2020 – Roche Launches Phase 3 Clinical Program to Test Fenebrutinib

Roche has launched a Phase 3 clinical trial program to evaluate fenebrutinib, its investigational oral BTK inhibitor, in people with relapsing forms of multiple sclerosis (MS) and primary progressive MS (PPMS).

Data on fenebrutinib’s potency and selectivity, as well as the design of the clinical program will be presented at MSVirtual2020, the 8th joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The annual meeting, set for Sept. 11–13, is being held online.

“We remain committed to advancing the science in MS by investigating potential new medicines such as fenebrutinib, with the ultimate goal of halting progression of this disease,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of global product development, said in a press release.

Fenebrutinib (GDC-0853, RG7845), developed by Roche’s subsidiary Genentech, is an orally administered small molecule that can cross the blood-brain barrier. This barrier tightly regulates what substances from the bloodstream can access the brain, and crossing it is often a challenge for brain-targeting therapies.

The therapy works by blocking the activity of Bruton’s tyrosine kinase (BTK), an enzyme important for the activation of B-cells and microglia — immune cells that drive the inflammation that damages the nervous system in MS.

By blocking BTK, fenebrutinib is expected to prevent the activation of these cells, targeting both acute and chronic inflammatory aspects of MS and potentially slowing disease progression.

Other BTK inhibitors, such as Sanofi’s tolebrutinib (previously known as SAR442168) and EMD Serono’s evobrutinib, are currently being evaluated as potential therapies for relapsing forms of MS, with promising Phase 2 results. EMD Serono is known as Merck KGaA outside North America.

Notably, fenebrutinib binds to BTK in a new way that is believed to increase its effectiveness. Safety data from more than 1,200 people with several inflammatory diseases treated with fenebrutinib suggest that its high selectivity may limit off-target effects — those on molecules other than BTK — and subsequently, the occurrence of adverse events.

These findings suggest that the therapy has a potentially favorable benefit-risk ratio.

In a poster titled “Fenebrutinib, a noncovalent, highly selective, long residence time investigational Btk inhibitor for the treatment of MS” (abstract #P0338), the researchers will present data on fenebrutinib’s potency, selectivity, and mechanism of action.

Preclinical results showed that the therapy potently blocks the activation of target immune cells and acts as a reversible (non-covalent) agent with a very slow release rate from its target, remaining bound to BTK for 18.3 hours.

Fenebrutinib’s long residence time — the length of time a compound stays bound to its target — suggests that it may mimic the durable blocking effects of a covalent inhibitor, which never dissociates from its target, “but without the safety risks of covalent BTK inhibitors,” the researchers wrote in the abstract.

In terms of potency, fenebrutinib was found to be comparable to tolebrutinib and more potent than evobrutinib. In addition, fenebrutinib had fewer off-targets and was 130 times more selective against all 218 kinase enzymes tested than the other two BTK inhibitors.

“The high selectivity and potency of [fenebrutinib] has the potential to be associated with fewer off-target adverse events and an improved MS therapeutic index compared with less selective BTK inhibitors,” the researchers wrote.

The design of the new Phase 3 clinical program of fenebrutinib will be shared through a poster titled “Examination of fenebrutinib, a highly selective BTKi, on disease progression of multiple sclerosis” (abstract #P0211).

The program includes two identical trials, called FENhance 1 and FENhance 2, each involving up to 734 relapsing MS patients. It also involves a trial called FENtrepid, which will enroll up to 946 people with PPMS.

In the relapsing MS trials, the participants will be randomly assigned to receive either fenebrutinib or Aubagio (teriflunomide), an approved oral MS therapy marketed by Sanofi. The participants in the PPMS trial will be randomly assigned to receive either fenebrutinib or Ocrevus (ocrelizumab), a therapy also developed by Genentech and approved for PPMS treatment.

The main goal of all three trials will be to assess changes in patients’ disability progression using the 12-week composite confirmed disability progression (cCDP12). The cCDP12 measures disability progression based on at least one of three disability measures: the expanded disability status scale (EDSS), the 9-hole peg test, and the timed 25-foot walk.

“The use of the cCDP12 as a primary [goal] may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone,” the researchers wrote in the abstract.

FENhance 1 and FENhance 2 also will evaluate changes in annualized relapse rates, which is the number of relapses per year, as a co-main goal. FENtrepid is the first trial to have an active comparator (Ocrevus) rather than a placebo in people with PPMS.

According to Roche, fenebrutinib is the only reversible BTK inhibitor currently in Phase 3 trials in people with MS.

Roche/Genentech will present other data from their MS product portfolio, including Ocrevus, at MSVirtual2020.