UPDATED June 12, 2023 // Editor's note: This story has been updated with additional comments from Dr Ahmed Obeidat from the Medical College of Wisconsin.
Frexalimab, a novel, second-generation anti-CD40L antibody, shows "strikingly positive" effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.
"We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity," study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts and the London School of Medicine and Dentistry, in London, U nited K ingdom , told Medscape Medical News.
"It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission," he said.
The late-breaking study was presented this month at the Consortium of Multiple Sclerosis Centers (CMSC) 2023 Annual Meeting.
Significant Lesion Reduction
With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway.
Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.
To investigate the drug’s efficacy and safety, Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups — high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose ), for the 12-week placebo-controlled period, followed by an open label extension period that is currently ongoing.
Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint.
After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.
The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% vs the pooled placebo group (P = .0021).
Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.
In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.
In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants.
No serious adverse events were reported.
Looking ahead at safety, Giovannoni noted that "a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L."
That said, "we didn't see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections," he added.
In his newsletter, Giovannoni characterized the study's results as "strikingly positive," adding that they "are the most exciting to emerge in MS in the last 12-24 months."
Overall, "these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy," the investigators note.
"Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated," they add.
Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the Department of Neurology at Washington University in St. Louis, Missouri, said that frexalimab represents an intriguing mechanistic approach to MS.
"In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before," Chahin told Medscape Medical News.
"Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development," he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.
Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues.
"Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments," Chahin said.
"But phase 3 trial data are much needed to clarify the immunosuppressive risk."
Also commenting for Medscape Medical News, Ahmed Obeidat, MD, PhD, said the frexalimab study results are important in understanding the potential benefits of its novel mechanistic approach.
"The findings from the phase 2 clinical trial of frexalimab provide the foundation for future studies to target the co-stimulation between T cells and other immune cells without depleting the immune cells, and testing in larger phase 3 clinical trials is exciting and timely," said Obeidat, of the Department of Neurology, Medical College of Wisconsin in Milwaukee.
However, Obeidat said he was "skeptical, although intrigued and excited, to see if primarily targeting the cross-talk between the T cells and other elements of the immune system has comparable effectiveness or not in relapsing MS, but more importantly whether it does modulate disease progression."
"Moreover, I think that future studies of CD40L antibodies may prove that there is more to the story than the B cells," Obeidat said.
He added that he is cautiously optimistic about the results of future phase 3 studies of the drug. "While the initial efficacy of the MRI outcomes looks promising, clinical outcomes, including relapses and disease progression measures, are very important in larger phase 3 studies.
"Also, while the initial safety frexalimab looks good, it might be an underestimation of what we could see in a larger clinical trial, where inclusion/exclusion criteria allow for a population that is more representative of the clinical population to be enrolled, he said
Obeidat added that earlier studies of first-generation monoclonal antibodies have been stopped for safety and therefore, "Safety along with efficacy outcomes are key to watch for in future studies."
The study received funding from Sanofi. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Chahin reports no relevant financial relationships. Obeidat reports receiving fees for speaking or consulting received from Alexion, Banner Life Sciences, Biogen, Biologix, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, GW Pharma, Horizon Therapeutics, Jazz Pharma, Novartis, Sanofi/Genzyme, Sandoz Pharmaceuticals, TG therapeutics, VielaBio. Honoraria from Medscape and MJH Life Sciences.
Consortium of Multiple Sclerosis Centers (CMSC) 2023 Annual Meeting. Abstract #LB02. Presented June 2, 2023.
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