Silencing Immune Dialogue in Multiple Sclerosis

Multiple sclerosis (MS), a common and debilitating autoimmune disease, has two principal forms. In relapsing MS, patients experience recurrent attacks of neurological symptoms, initially with remissions but over time producing lasting disability. In the other form, progressive MS, continuous worsening leading to a wheelchair or bedbound state is the rule. Progressive MS usually develops after a period of relapsing disease, or less commonly MS is progressive from onset. Relapsing MS is primarily a disorder of the adaptive immune system (B and T lymphocytes) orchestrated by circulating B lymphocytes that traffic into the central nervous system (CNS). Progression, by contrast, is mediated by both the adaptive and innate immune systems – B and T cells, as well as resident microglia and macrophages – located behind an intact blood-brain barrier (BBB) impermeable to most systemically administered drugs.

In this issue of the Journal, Vermersch and colleagues report the results of a phase 2 trial in relapsing MS testing frexalimab, an inhibitor to the CD40 ligand (CD40L), a costimulatory molecule expressed on T lymphocytes that is essential for interactions with antigen presenting cells (APCs).¹ The study was designed to be short – the primary endpoint was new areas of gadolinium enhancement, a magnetic resonance imaging (MRI) marker for focal BBB breakdown, developing between 8 and 12 weeks after beginning treatment. Gadolinium leakage into the brain is a surrogate for focal inflammation and clinical relapses. What can we conclude from this preliminary report? The results appear clear, although the clinical significance is uncertain. Clear because there was an unambiguous benefit on MRI outcomes in patients who received frexalimab compared with placebo controls, and a generally low level of MRI activity sustained during an additional 12 week open-label on-treatment extension phase. A similar decline in MRI activity was also observed in placebo patients crossed over to receive frexalimab in the extension phase. Positive results were further bolstered by the lowering of levels of neurofilament light chains, a biomarker of brain tissue damage measured in peripheral blood, in the active treatment groups. If these benefits are sustained with longer-term use, pivotal studies are likely to show a convincing protective effect of frexalimab on MS relapses. Nonetheless, its ultimate clinical value will await answers to additional questions not yet addressed.

Because of its role as a key costimulatory molecule mediating interactions between T lymphocytes and B cells (as well as other APCs), blockade of the CD40-CD40L pathway has a strong underlying rationale as a therapeutic strategy in MS. It is also supported by genetic evidence. An intronic single nucleotide polymorphism within CD40 modestly increases MS risk. This variant has contrasting functional effects on B cell biology, increasing expression of the CD40 protein, acting as a splice variant altering production of secreted CD40 isoforms that can be stimulatory or inhibitory, and decreasing levels of the regulatory cytokine IL10;² the latter effects could potentially promote deleterious proinflammatory polarization of B cells characteristic of MS.³ In this regard, it is noteworthy that earlier trials of an inhibitor to a different costimulatory molecule (CTLA4) had no effect on relapsing MS,⁴ and an attempt to block B cell activity with atacicept, a decoy receptor for the B cell survivor factors APRIL and BLyS, paradoxically worsened MS.⁵ Thus, the complexities inherent in immunoregulatory networks require cautious translation to the bedside.

Depletion of circulating B cells using anti-CD20 monoclonal antibodies^6,7 has become a standard of care for people with MS. Their rapid onset of benefit indicated that B cell antigen presentation⁸ and cytokine secretion,³ and not antibody production, was likely responsible, leading to a new appreciation of the central role of B cell antigen presentation to T cells, and on B cell cytokines, as mediators of tissue damage. Highly effective therapies against relapsing MS, not only the anti-CD20 agents but also the α4β1 integrin inhibitor natalizumab,⁹ also revealed that an underlying progressive MS, subtle but clinically significant, is present throughout the disease continuum in all patients, even those classified as relapsing MS. In addition to profound effects against relapses, B cell-based therapies also provide partial benefits against progression,¹⁰ suggesting that removal of B cells could reduce microglial activation and neurodegeneration, critical components of progressive MS pathology.

Indeed, the clinical benefits and safety profile of available high-efficacy therapies for relapsing MS are so outstanding that the bar for another new option is quite high. MRI outcomes with frexalimab were impressive, but seemingly less complete than with the anti-CD20 agents, although it is possible that pivotal studies could ultimately show frexalimab to be equally effective. Safety with long-term use is another unknown. To be truly useful, any new drug for relapsing MS will have to best the current champion. The critical need is for more effective therapy against progressive MS, and here may lie frexalimab’s greatest opportunity.

Inhibitors of the CD40 pathway could potentially downregulate innate immunity in the CNS, a major contributor to progressive MS symptoms. Blockade of CD40L signaling on microglia at plaque edges and in normal-appearing white matter, and also on meningeal macrophages, might neutralize their proinflammatory tissue-damaging properties, if adequate tissue concentrations of the drug are reached. MRI surrogates for microglial injury and progressive MS pathology – slowly evolving and paramagnetic rim lesions – were obtained as exploratory endpoints in the study but are not yet reported; these results are awaited with interest. Although the current trial was neither designed nor powered to assess benefits against progression, this is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against MS, will ultimately be defined.