ACTRIMS 2026 | Primary results from the Phase III FENtrepid study of fenebrutinib versus ocrelizumab in PPMS

FENtrepid was the study of the efficacy and safety of fenebrutinib head-to-head against the anti-CD20 ocrelizumab in individuals with primary progressive multiple sclerosis. Fenebrutinib is one of the BTK inhibitors being studied in MS. It is unique in that it is both CNS penetrant but also a non-covalent reversible BTK inhibitor that underwent a great deal of PK-PD profiling to end up with a dose that has been used in patients. The objective of FENtrepid was to evaluate again its efficacy and safety in this pivotal Phase III trial in primary progressive MS. It was a large multi-center randomized trial that recruited individuals between the ages of 18 and 65 with primary progressive MS, an EDSS of at least three and up to 6.5, and then randomized them one-to-one to either fenebrutinib, 200 milligrams by mouth twice a day, or the ocrelizumab standard of care dosing. Individuals were followed with an event-driven planned analysis, but also with a requirement that each individual be followed for at least 120 weeks, which provided an important both efficacy and safety data set. The primary outcome measure was the composite confirmed disability progression at 12 weeks, the CCDP12, as it’s called. And this is made of three different elements. You could meet the primary endpoint of disability progression either by having an EDSS change based on the standard criteria or having at least a 20% increase in the time 25-foot walk or at least a 20% increase in the nine-hole PEG-10. And the study was designed as a non-inferiority trial, meaning the primary outcome was to see whether fenebrutinib was at least as good at limiting progression of disability as ocrelizumab, which of course is currently the only approved therapy for primary progressive MS.

Baseline characteristics were quite well balanced between the groups, an age of approximately 50, typical for a PPMS population, approximately nine years in both groups from symptom onset and five years or so since the diagnosis. About a quarter of individuals had some primary DMT use. This included ocrelizumab, but not limited to. The baseline proportion of individuals with GAD lesions was only 10 to 11% in both groups, which is low compared to prior trials of primary progressive MS and makes the point that these individuals who needed to progress prior to the trial likely had their progression driven mostly by non-relapsing progressive MS. And then the three elements of the CCDP12 were also very nicely balanced at baseline.

The primary endpoint of non-inferiority of fenebrutinib versus ocrelizumab was indeed achieved. There appeared to be a separation of the curves on the Kaplan-Meier curve starting at week 24. And in fact, although not designed as a superiority trial, there was nominally a separation with fenebrutinib performing a little better than ocrelizumab throughout the course, and the curves remain separated, and that would amount nominally to a 12% risk reduction in the risk of disability progression, but certainly meeting non-inferiority relative to ocrelizumab. It’s interesting to note that if you ask about what the different contributors were to the treatment effect of fenebrutinib versus ocrelizumab with respect to the CCDP, that the time 25 foot walk was the main reason that in 63% of people resulted in them meeting their endpoint. Once you meet your endpoint on one of the parameters, you’re no longer considered for the others. Unfortunately, the 25-time foot walk was the least informative, probably because of some aspects of the population, the extent to which the 25-time foot walk was sensitive to change in this group. Most of the effect of non-inferiority was actually driven by the nine-hole PEG test and subsequently the EDSS, which contributed to only about 35-40% of the effect. And had we used only two elements of the CCDP without the 25-foot walk, in fact, one would have achieved superiority with a 22% risk reduction of fenebrutinib versus ocrelizumab. This, of course, is a post hoc analysis, but it’s interesting to note that it is what was used in the ORATORIO-HAND trial of primary progressive MS looking at ocrelizumab versus placebo. That was a trial that also met its endpoint and did so without including the 25-time foot walk. So we’re also learning about what outcome measures may be better used in different populations where there’s progression.

Another point on efficacy is the subgroup analysis, where in essence, the non-inferiority was established across multiple different subgroups, be it older, younger age, male, female, sex, as well as importantly, the GAD lesions, where in fact, the greatest effect was on those individuals who did not have GAD lesions at baseline, again, reinforcing the view that this drug is working on limiting progression of disability, not simply by limiting focal inflammatory contribution to worsening over time, but actually to non-relapsing progressive disease.

From the standpoint of adverse events, overall adverse events were balanced between fenebrutinib and ocrelizumab. Serious AEs were also balanced at approximately 20% in both groups. There was an imbalance of fatal AEs with seven individuals in the fenebrutinib arm and one in the ocrelizumab arm, and a greater discontinuation rate in fenebrutinib, most of which were based on protocol-defined or mandated discontinuation due to liver enzyme elevations. With respect to the fatalities, of course, one looks to see whether there’s any particular theme or pattern, and there was no obvious pattern. Deaths on the fenebrutinib arm included COVID-19 death, unfortunately, in an individual who was not vaccinated, a diabetic ketoacidosis in someone whose insulin pump failed, a myocardial infarction in an individual with no prior risk factors, and then one with a pre-existing cardiac arrhythmia and a sudden death. There was a completed suicide, but this happened 15 days into the trial, and another suspected suicide in someone with known anxiety and insomnia, and a pulmonary embolus in someone with cardiac failure and hypertension as a history. In the ocrelizumab arm, there was a single death of a lung cancer metastasis in someone with tobacco use. So those are the deaths where there was an imbalance, but again, no obvious pattern. And for what it’s worth, the investigators considered all of these deaths in the fenebrutinib arm as not related to the study drug.

The liver enzyme elevations were almost all milder, although there were some in the higher range. There were no actual confirmed Hy’s law cases. There were two biochemical Hy’s law in the fenebrutinib group and one biochemical Hy’s law in the ocrelizumab group. This is when you have greater than three times upper limit normal of the liver enzyme, as well as at least twofold increase in bilirubin, but have alternate explanations, such as was the case here with pancreatitis and adenocarcinoma as alternate explanations, hence not actually being a confirmed Hy’s law case. And all of these elevations occurred within the first 20 weeks of treatment and all of them resolved with treatment discontinuation. There were no unusual, unexpected issues with fenebrutinib in the context of BTKi-related adverse events, a slight increased risk of bruising, but no serious bleeding and no imbalance in malignant type of neoplasm.

So overall, fenebrutinib achieved non-inferiority to ocrelizumab, reducing disability progression on this composite confirmed disability progression at week 12, with favorable outcomes starting at week 24 and throughout, including in those individuals who did not have GAD lesions at baseline and with the strongest treatment effect observed on the nine-hole PEG test. AEs and SAEs were overall comparable, including infection, although there was the anticipated higher risk of liver enzyme elevations with full reversibility and an imbalance in fatal AEs in the fenebrutinib versus ocrelizumab arm. We’re looking to see further data that will emerge from the FENHANCE trial in relapsing MS, but hoping that this will indeed emerge as the first oral and second ever therapy to demonstrate efficacy in primary progressive MS, providing hopefully a unique CNS penetrant treatment option, and hopefully with further results on the relapsing side, perhaps confirming the utility of fenebrutinib, both for relapsing and primary progressive MS.

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