Experimental MS Drug Nearly Eliminates Disease Activity
'At week 96, there was almost complete suppression of new gadolinium-enhancing lesions with very similar pattern seen with new or enhancing T2 lesions,' said study investigator Stephen Krieger, MD, professor of neurology, Icahn School of Medicine at Mount Sinai, New York City.
Two phase 3 international studies with this drug are already enrolling.
'Part of the interest in frexalimab and anti-CD40 therapies is the idea that one can modulate both B- and T-cell activity without cell depletion,' explained Krieger, who presented the long-term open-label data on May 29 at the Consortium of Multiple Sclerosis Centers (CMSC) 2025 Annual Meeting.
Near Complete Disease Suppression
The latest data suggest frexalimab is fulfilling its promise. Over follow-up to date, there has been nearly complete suppression of gadolinium-enhancing (Gd+) lesions on MRI among those taking the dose now being tested in the phase 3 trials. At 2 years, with an annualized relapse rate of 0.08%, 92% of patients were relapse-free.
The randomized portion of this phase 2 trial attracted attention when it was published a year ago in The New England Journal of Medicine , but the 2-year results showed that the efficacy and safety observed at 12 weeks persist.
In the controlled trial, 129 patients with relapsing MS were randomized to 300-mg, 400-mg, 600-mg, or 1200-mg frexalimab or matching placebos. Suppression of Gd+ lesions was the primary endpoint.
At 12 weeks, the adjusted mean of new Gd+ lesions was 1.4 in the combined placebo groups but 0.3 in the 300-mg frexalimab group and 0.2 in the 1200-mg group.
Of those who participated in the randomized portion of the phase 2 trial, 97% continued into the long-term OLE. The OLE consisted of two arms: 1200-mg frexalimab administered intravenously every 4 weeks or 300-mg frexalimab administered subcutaneously every 2 weeks.
At the end of 2 years, when 82% of those enrolled in the OLE were still on medication, the adjusted mean for new T1-weighted Gd+ lesions ranged from 0.1 to 0.3 across study arms whether on continuous frexalimab or switched from placebo to frexalimab.
For those who were initiated on the 1200-mg dose in the controlled portion of the trial and remained on this dose for the OLE, the mean was 0.1.
For the secondary endpoint of new or enlarging T2 lesions, the suppression at 2 years was almost the same. Again, the adjusted mean for new lesions across all arms ranged from 0.1 to 0.3. For those receiving the 1200-mg dose, the mean was 0.2.
Mean T2 lesion volume increased in the placebo arm but not in the treatment arms during the randomized phase. After entering the OLE, T2 lesion volume fell in placebo patients now on active therapy.
In the 1200-mg arm, the fall in lesion volume during the randomized phase continued into the first 24 weeks of the OLE. After 24 weeks, the lesion volume remained suppressed with no return toward baseline. Those initiated on placebo never caught up after switching to frexalimab.
Relapse Rare — 2% at 96 Weeks
On the 1200-mg dose of frexalimab, only 8% had any relapse recorded over the extended follow-up. In half, there was a single relapse. Only 2% had three or more relapses.
While the Expanded Disability Status Scale score declined slightly among placebo patients once started on active therapy, there was no change from baseline through 96 weeks in patients started on any active therapy.
As postulated by earlier preclinical and clinical studies, frexalimab had no effect on lymphocyte counts over time. Over the 96-week follow-up, levels of immunoglobulins remained unchanged, according to Krieger who showed graphs with straight lines for these values over the course of the OLE.
Due to the potential of suppressing activation of both T and B cells over time, anti-CD40 therapies have long been considered a promising mechanism for control of MS. However, clinical development of first-generation drugs was abandoned because of an association with thromboembolism.
'Frexalimab has been engineered to avoid these events through a change in the Fc receptors with reduces downstream inflammatory events,' said Krieger.
The long-term data support this premise. Over 2 years, there was one pulmonary embolism, but this exception was observed in a patient with a viral illness and a genetic predisposition for an inflammatory response, according to Krieger.
When surveying other adverse events, 'nothing jumps out' in the OLE relative to the randomized phase. One potential exception is a rise in liver function tests observed in two (4%) patients on the 1200-mg dose. Only one of these patients discontinued therapy, and the levels returned to normal over time in both.
The effects of the anti-CD40 mechanism on both the adaptive and innate immune systems suggest frexalimab might offer efficacy for both progressive and relapsing MS. In the ongoing phase 3 program, one of the trials (FREXALT) is enrolling patients with relapsing MS. The other (FREVIVA) is enrolling patients with progressive disease.
Fulfilling its Promise
Commenting on the results, Amit Bar-Or, MD, Chief of the Multiple Sclerosis Division, the Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, described frexalimab as 'a very interesting drug.'
He agreed that the CD40 ligand is a promising target in MS but cautioned that these phase 2 data cannot answer the most interesting questions.
This includes the more robust evidence of safety and efficacy from phase 3 trials, but it remains unclear whether the benefits extend beyond controlling relapsing disease.
'I think there is particular interest in whether it will also show extended benefit in progressive MS, and this will be a major focus of interest from the next set of studies,' Bar-Or said.
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