NeuroVoices: Diana Gallagher, MD, on New Phase 2 FUSION Study of BTK Inhibitor BIIB091


The head of Biogen’s MS and Immunology Department Unit provided an overview of FUSION, a currently recruiting study assessing the efficacy and safety of BIIB091 as a monotherapy and in combination with diroximel fumarate.

Diana Gallagher, MD, head of Biogen’s MS and Immunology Department Unit

Diana Gallagher, MD

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system. Despite the expansion of treatment options for relapsing forms of the disease, these therapies have shown to be less effective at slowing disability accumulation, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability.

Bruton tyrosine kinase (BTK) is considered an important signaling molecule involved in regulating the maturation, proliferation, survival, and activation of B cells and myeloid cells. There are several different agents in the clinical pipeline that inhibit BTK, including BIIB091, Biogen’s highly selective, reversible, non-covalent therapy. At MSMilan 2023, the joint ECTRIMS-ACTRIMS meeting, held October 11-13, in Milan, Italy, investigators presented the outline design of FUSION, a phase 2 trial assessing the efficacy and safety of BIIB091 in patients with relapsing forms of MS.

The 2-part study will assess whether BIIB091 can be more effective as a monotherapy or in combination with diroximel fumarate (Vumerity; Biogen), a previously approved disease-modifying therapy. As part of a new iteration of NeuroVoices, Diana Gallagher, MD, head of Biogen’s MS and Immunology Department Unit, gave an overview of the study, which is currently recruiting, and how it will add to the growing literature of BTK inhibitors. She spoke specifically about BIIB091, how it differs from other agents in the pipeline, and the reasons for testing it as both a monotherapy and in combination.

NeurologyLive®: Can you provide an overview of the Phase 2 FUSION study?

FUSION is our study with BIIB091, which is our BTK molecule. It's a two-part multicenter, randomized, blinded, but also with an active control phase 2. We are studying patients with relapsing MS. The two different parts are both 48-week active control treatment periods with a primary analysis at week 16. In part 1, we look at high dose versus a lower dose. We compared that to the standard dose DRF (diroximel fumarate). Then we'll look at week 16 and assess the impact on gadolinium-enhanced lesions. We'll also go out to week 48 and look at additional endpoints. It does have this early look at what we think is a clinically meaningful endpoint, those gadolinium-enhancing lesions. Depending on what we see, we may continue to part two, where we'll pick a dose of BIIB091 selected, one of the two doses that we took in part one, into this part two. Then we'll compare it to the standard dose, primary versus a lower dose of diroximel fumarate, to see if combining two different mechanisms of action may impact patients with RMS. As I mentioned, the primary endpoint is really at that week 16, the cumulative number of new gad-enhancing lesions that we'll look at. Of course, we're going to collect additional efficacy and endpoints on imaging, clinical PRL, etc.

With BTK inhibitors, do trial designs change in comparison to other traditional disease-modifying agents?

I think it's pretty typical for a relapsing MS trial. Of course, we have learned as a field that there are some safety signals in other BTK trials that we need to look out for. Like all BTKs, we will be implementing maybe more stringent criteria with respect to specifically excluding patients with pre-existing liver disease. We will also monitor patients for any liver function abnormalities throughout the trial. Otherwise, I would say it's pretty standard.

Why does BIIB091 stand above other BTK inhibitors?

In many ways, people dichotomize the BTK inhibitors into covalent or non-covalent. BIIB091 is a selective non-covalent, reversible, peripherally restricted small molecule inhibitor of BTK with some really nice potency. It's our expectation that it will strongly suppress B cells and myeloid cell activation. Based on some of our early SAD and MAD studies, we're trying to target a dose selection that will get us 90% suppression on B cell activation. We hope that this will demonstrate really nice high efficacy in relapsing MS with a good safety and tolerability profile.

Was there a reason you chose diroximel fumarate? Could this type of combination approach work in other areas of MS?

I think there are probably multiple agents one could think about. I don't think MS, compared to other therapeutic areas, is typically amenable to combination work but rather switching and sequential approaches. However, it's probably worth thinking about whether for certain patients, two discrete mechanisms of action may be able to push through and achieve higher efficacy. We happen to have a lot of experience with diroximel fumarate. That's why we felt that the combination of BTK plus diroximel fumarate might create a synergistic approach to suppressing circulating inflammatory cells and restoring immune function. That was our rationale. You could certainly imagine it being combined with other MS agents. We just like our fumarates. Yeah, absolutely.

How significant would a successful study be?

BTK is a really exciting mechanism in MS. We have a lot of great drugs, but there's still a serious unmet need. Patients are still progressing, even despite highly efficacious therapy. So, we see this as something that can hopefully provide as good, if not superior, efficacy compared to what's currently available. Whether we can achieve that with monotherapy using just a BTK is possible, but we'll see in part one. If not, the idea of a combination and manipulating proinflammatory T cells and myeloid cells by adding diroximel fumarate could really be the trick to achieving greater efficacy, especially early on cumulative disability and other ways. Maybe it's really the combination that will unlock additional benefits for patients. It's a hypothesis that needs to be tested in a trial. I think that would be a paradigm shift and quite exciting.

What sorts of questions do we still need to answer about BTK inhibitors?

Clinically, it's a field with many players in it. Why keep pushing it? It's because we really think the mechanism is fascinating and could offer differentiated efficacy. However, the unknowns remain, particularly the magnitude of impact, not just on gad lesions. I think there's still enough evidence across the field, liver function issues notwithstanding, to suggest that it is mostly engaging the target. When you do that, you can manipulate biology. We believe BTKs are working in MS, but it's really about understanding the magnitude of clinical relapse activity over time, not just a snapshot after four months of dosing. It's also about addressing progressive biology because, as I mentioned earlier, even between relapses, patients are likely continuing to progress in ways we're still trying to understand. Additionally, the long-term safety profile in MS patients remains to be seen, and that will require testing over many weeks and months with enough patients.

Transcript edited by artificial intelligence.

1. Kramer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol. 2023;19(5):289-304. doi:10.1038/s41582-023-00800-7
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