New data from an open-label extension (OLE) of a phase 2 trial indicates that frexalimab, a second-generation anti-CD40 ligand monoclonal antibody, maintains strong control of multiple sclerosis (MS) over a two-year period. The control was evident in both relapse rates and brain imaging results.

according to study investigator Stephen krieger, MD, professor of neurology, Icahn School of medicine at Mount Sinai, New York City, “At week 96, ther was almost complete suppression of new gadolinium-enhancing lesions with very similar pattern seen with new or enhancing T2 lesions.”

Currently, two phase 3 international studies are underway to further investigate the drug’s efficacy.

“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 suppression of MS Disease Activity

The latest findings suggest that frexalimab is effectively reducing disease activity in MS patients. The data showed near-complete suppression of gadolinium-enhancing (Gd+) lesions on MRI scans among participants receiving the dosage currently being evaluated in phase 3 trials. After two years, 92% of patients were relapse-free, with an annualized relapse rate of just 0.08%.

The initial randomized phase 2 trial garnered notable attention when its results were published a year ago in The New England journal of Medicine. the two-year follow-up data confirms that the positive efficacy and safety outcomes observed at 12 weeks were sustained over a longer period.

In the original controlled trial, 129 patients with relapsing MS were randomly assigned to receive either 300-mg, 400-mg, 600-mg, or 1200-mg doses of frexalimab or a placebo. The primary goal of the study was to assess the suppression of Gd+ lesions.

After 12 weeks, the adjusted mean number of new Gd+ lesions was 1.4 in the combined placebo groups, compared to 0.3 in the 300-mg frexalimab group and 0.2 in the 1200-mg group.

Notably, 97% of those who completed the randomized phase 2 trial continued into the long-term OLE. This extension study included two arms: one receiving 1200-mg of frexalimab intravenously every four weeks,and the other receiving 300-mg of frexalimab subcutaneously every two weeks.

At the two-year mark, with 82% of OLE participants still on the medication, the adjusted mean for new T1-weighted Gd+ lesions ranged from 0.1 to 0.3 across all study arms, regardless of whether patients were on continuous frexalimab or had switched from placebo to the active drug.

For those who started on the 1200-mg dose in the controlled trial and continued on it during the OLE, the mean number of new lesions was 0.1.

The results for the secondary endpoint of new or enlarging T2 lesions were similar, with the adjusted mean for new lesions across all arms ranging from 0.1 to 0.3. Patients receiving the 1200-mg dose had a mean of 0.2.

During the randomized phase, the mean T2 lesion volume increased in the placebo arm but remained stable in the treatment arms. Following the switch to active therapy in the OLE, T2 lesion volume decreased in the former placebo patients.

In the 1200-mg arm, the reduction in lesion volume observed during the randomized phase continued for the first 24 weeks of the OLE, after which the lesion volume remained suppressed without returning to baseline. Patients initially on placebo did not catch up after being switched to frexalimab.

Relapse Rare – Only 2% at 96 Weeks

Among patients receiving the 1200-mg dose of frexalimab, only 8% experienced any relapses during the extended follow-up period. Half of these patients had only one relapse,and only 2% had three or more relapses.

The Expanded Disability Status Scale (EDSS) score showed a slight decline among placebo patients after starting active therapy, but there was no change from baseline through 96 weeks in patients who started on active therapy from the outset.

Consistent with earlier preclinical and clinical findings, frexalimab did not affect lymphocyte counts over time. According to Krieger,levels of immunoglobulins also remained stable throughout the 96-week follow-up,as demonstrated by consistent values over the course of the OLE.

The potential of anti-CD40 therapies to suppress the activation of both T and B cells has long been considered a promising approach for managing MS. however, the development of first-generation drugs was halted due to 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 appear to support this, with only one pulmonary embolism reported over two years. This event occurred in a patient with a viral illness and a genetic predisposition for an inflammatory response, according to Krieger.

Regarding other adverse events, “nothing jumps out” in the OLE compared to the randomized phase. One possible exception was 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 in both over time.

The effects of the anti-CD40 mechanism on both the adaptive and innate immune systems suggest that frexalimab may be effective for both progressive and relapsing MS. The ongoing phase 3 program includes two trials: FREXALT, which is enrolling patients with relapsing MS, and FREVIVA, which 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 concurred that the CD40 ligand is a promising target in MS but cautioned that these phase 2 data cannot definitively answer all the key questions.

This includes the need for more robust evidence of safety and efficacy from phase 3 trials, as well as 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.

“At week 96, there was almost complete suppression of new gadolinium-enhancing lesions with very similar pattern seen with new or enhancing T2 lesions.”