2nd generation CD40L blocker safely reduces new lesions in Phase 2 trial

Frexalimab may control immune activity without side effects of its predecessors

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Frexalimab, an experimental anti-CD40L antibody therapy from Sanofi, significantly reduced the number of new brain lesions with active inflammation in people with relapsing forms of multiple sclerosis (MS), according to new Phase 2 clinical trial data.

Sanofi believes its second-generation CD40L blocker will effectively control immune activity in MS without the concerning side effects that stopped development of its anti-CD40L predecessors.

Frexalimab may also prevent the depletion of immune cells needed to fight infections (lymphocytes) that comes as a consequence of some other MS therapies.

The company is now planning to launch pivotal trials of frexalimab for MS early next year. If positive, data from those trials could potentially support applications for the treatment’s regulatory approval.

The findings were presented in a poster, titled “Frexalimab, a CD40L Inhibitor, in Relapsing Multiple Sclerosis: Results from a Randomized Controlled Phase 2 Trial,” at the Consortium of Multiple Sclerosis Centers’ annual meeting, being held May 31-June 3, in Aurora, Colorado.

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“We are thrilled with the results achieved with frexalimab in just 3 months, which shows that CD40L inhibition rapidly controls MS disease activity without lymphocyte depletion,” Gavin Giovannoni, MD, PhD, chair of neurology at Barts and the London School of Medicine and Dentistry at Queen Mary University of London, said in a company press release.

CD40L is a protein that’s important for the function of a signaling pathway called the CD40/CD40L costimulatory pathway, which promotes activation of the innate and adaptive immune systems.

Innate immune cells work as the body’s non-specific, first line of defense against harmful invaders, whereas adaptive immune cells are specialized cells that recognize particular pathogens.

Activation of the CD40/CD40L pathway has been implicated in the inflammation that characterizes MS, as well as certain other autoimmune diseases.

More than 20 years ago, companies started working on the development of experimental antibodies that could block CD40L as a way to treat autoimmune diseases.

However, development of these treatment candidates was stopped during Phase 2 clinical testing, when patients began to experience serious blood clots in their veins, also known as thromboembolic events.

Frexalimab is a second-generation anti-CD40L antibody that Sanofi believes will have the same promising efficacy as its predecessors, but without the same side effects.

Originally developed by ImmuNext, the experimental treatment was licensed to Sanofi in 2017, which is now developing it for various autoimmune conditions, including MS, lupus, and Sjögren’s syndrome.

We are thrilled with the results achieved with frexalimab in just 3 months, which shows that CD40L inhibition rapidly controls MS disease activity without lymphocyte depletion.

Trial tested safety and efficacy of frexalimab in 129 adults with relapsing MS

The Phase 2 trial (NCT04879628) was designed to evaluate the treatment’s safety and efficacy against a placebo in 129 adults, ages 18-55, with relapsing forms of MS, including relapsing-remitting MS and active secondary progressive MS.

In its first part, participants were randomly assigned to receive one of two doses of frexalimab or a placebo for 12 weeks (about three months). After completing that part, participants on the placebo switched to the experimental treatment, and all are continuing to receive frexalimab in the study’s open-label part.

The study’s main goal was to assess reductions in new active brain lesions — those with signs of active inflammation — after 12 weeks of treatment.

That goal was met, with both doses of frexalimab being associated with a significant reduction in such lesions compared with a placebo — an 89% reduction for the high-dose group and a 79% reduction for those given the low dose.

Both treatment groups also exhibited reductions in the total number of lesions relative to a placebo — by 92% in the high-dose group and 86% in the low-dose group. Also, the total number of inflammatory lesions was reduced by at least 80% in both groups.

At week 24, or after about six months, 96% of patients in the high-dose arm and 80% of those given the low dose were free of new inflammatory lesions.

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Frexalimab found to be well-tolerated by trial participants

Significant improvements were also observed in the physical component of quality of life, and patients given frexalimab experienced significant reductions in neurofilament light chain levels, a marker of nerve damage.

Frexalimab was well-tolerated, with 97% of patients completing the first part of the trial and continuing into the extension phase. The most common side effects among frexalimab-treated patients were mild-to-moderate COVID-19 infection and headache.

Sanofi, which markets approved MS therapies Aubagio (teriflunomide) and Lemtrada (alemtuzumab), is also leading the Phase 3 development of tolebrutinib, an investigational oral therapy for MS.

“Building on our 20 years of research and development in multiple sclerosis, we are committed to growing our robust pipeline of MS therapies by exploring multiple treatment approaches with unique [mechanisms] that have the potential to slow or halt disability, which remains one of the greatest unmet medical needs in multiple sclerosis today,” said Erik Wallström, MD, PhD, global head of neurology development at Sanofi.