The Promise of Frexalimab in MS Treatment: Part 1

Recently, phase 2 data published in The New England Journal of Medicine indicated that frexalimab, a second-generation investigational anti-CD40L antibody, may be able to benefit patients with multiple sclerosis (MS). Frexalimab contains a unique method of action that has demonstrated promise in having an impact on multiple forms of neuroinflammation while avoiding lymphocyte depletion. Results from the phase 2 clinical trial showed high- and low-treatment groups experienced reductions in new gadolinium enhancing T1 brain lesions at rates of 89% and 79%, respectively, at 12 weeks.

With the potential to dramatically slow disease activity in cases of relapsing MS, Patrick Vermersch, MD, PhD, of the University, Lille, France, joined AJMC^® for an interview to discuss the novel implications of frexalimab for MS treatment. In part 1 of this 3-part interview, Vermersch provides insight into the underlying mechanism and the challenges that accompany developing an intervention such as frexalimab.

This transcript has been lightly edited for clarity and length.

Transcript

AJMC: Can you provide a brief overview of the unique mechanism of action in frexalimab and contextualize the unmet needs in MS treatment it is addressing?

Vermersch: The mechanism of action is unique, because the drug is monoclonal and targets both adaptive immunity and innate immunity. In the field of adaptive immunity, it may target the interactions between dendritic cells and T cells. So it may be very important to shift the profile of the activity of T cells to provoke a more tolerogenic profile of T cells, but also maybe CD40 ligand. To inhibit CD40 ligand is important for the activity of B cells. And also, at the periphery—we don't know about within the CNS [central nervous system]—to decrease the activity of macrophages and microglial cell lineage. So it's very interesting because frexalimab targets both adaptive and innate immunity.

To contextualize the unmet need: We are in a mess. It's very important not only to decrease, or to suppress the inflammation at the periphery, and also the consequences of this focal inflammation to abolish relapses to decrease the MRI activity. The key point is also to target innate immunity into the CNS to decrease the septal neurodegeneration, because neurodegeneration in MS is related more to innate immunity, microglia, macrophages, and so on. The mechanism is unique because we have a dual mechanism of activity: both adaptive and innate immunity. It is fundamental not only to suppress inflammation, but also to limit the neurodegeneration.

AJMC: Were there any notable challenges in the development of this medication to combat varying degrees of neuroinflammation without influencing lymphocyte depletion?

Vermersch: The key point in MS is we have 2 degrees of neuroinflammation: focal inflammation responsible for relapses and the MRI activity, but also the so-called compartmentalized inflammation. This is related to the inflammation in the meninges; the inflammation surrounding lesions into the brain parenchyma, or in the spinal cord; and also the diffuse inflammation we have observed both in white and gray matter in the CNS.

Maybe we need to target both types of inflammation to better control the disease and to limit neurodegeneration. What is important is, probably early in the pathogenesis of MS, we have not only focal inflammation, but very early also this kind of compartmentalized inflammation. So sometimes we have drugs targeting only the focal inflammation, with maybe a limited impact into the CNS and a limited impact to control the progression related to the neurodegenerations. And maybe with frexalimab, possibly we have this dual mechanism of action to combat the 2 degrees of neuroinflammation.

It's very important to have an effect of both types of inflammation to control the disease in the long term. It's very important in the long term, without any depletion of lymphocytes, which could be very safe, in fact, because the key point of the chronic immunosuppression is a risk of infection, for example. And if with frexalimab we have no depletion, it could be a big advantage for the long-term safety.