Frexalimab Shows Promise in​ Multiple Sclerosis Treatment

⁣ Updated June 07, 2025

Phoenix—The investigational drug frexalimab‌ is showing promise as a treatment ‍for⁣ multiple sclerosis⁣ (MS), with new data ‍indicating it can provide extended control of‍ the disease. ⁣Results from a phase 2 trial’s⁤ open-label extension (OLE) reveal that frexalimab, ‍a ‌second-generation anti-CD40 ligand monoclonal antibody, effectively manages MS, as measured⁤ by both relapse rates and brain imaging results‍ over ⁢a two-year period.

Dr. Stephen Krieger, professor of neurology at the Icahn School of Medicine at⁢ Mount Sinai, presented the findings at the Consortium of Multiple Sclerosis Centers (CMSC) 2025 Annual ​Meeting. ​He noted that by‌ week 96 of the study, the drug nearly ​eliminated new ⁣gadolinium-enhancing ​lesions, with ‌similar results seen in new or‌ enlarging T2 lesions.

Frexalimab’s mechanism of action, modulating both ‌B-‌ and‌ T-cell activity without depleting cells, is a key area of interest, Krieger explained. Two international phase 3 studies are currently enrolling participants to further investigate‌ the potential of⁣ frexalimab for multiple sclerosis treatment.

The latest data suggest frexalimab‌ is fulfilling⁣ its⁤ promise in multiple sclerosis treatment. The study showed nearly complete suppression of gadolinium-enhancing lesions on MRI scans among patients taking the dose being tested in⁤ phase 3 trials. After​ two years, 92% of patients⁢ where ⁤relapse-free, ⁣with an annualized relapse rate of just 0.08%.

The initial phase 2 ⁢trial garnered attention ⁢when its results were ‍published in The​ New ⁤England Journal of​ Medicine. ⁣The two-year follow-up confirms ‍the drug’s sustained efficacy and safety profile initially⁤ observed ⁤at 12 weeks.

In the controlled phase‌ 2 trial, ​patients with relapsing MS were randomly assigned⁣ to receive varying doses of frexalimab (300 mg, 400⁣ mg, 600 mg, or ‍1200 mg) or ‌a⁣ placebo.⁤ The‍ primary⁣ goal was to ⁤assess ⁣the suppression of gadolinium-enhancing lesions.

At 12 weeks, ‍the ‍adjusted mean of new gadolinium-enhancing lesions ⁤was significantly lower in the frexalimab groups (0.3 in the 300-mg group and 0.2‌ in the 1200-mg group) compared to the combined placebo groups (1.4).

Of ​those who completed the randomized phase 2 trial, 97% continued into the long-term OLE, receiving either 1200 mg of frexalimab intravenously‌ every⁢ four weeks ‌or ⁤300 mg subcutaneously every two⁤ weeks.

After two years, with‌ 82% of OLE participants still on medication, ⁣the adjusted⁢ mean for ⁣new T1-weighted gadolinium-enhancing lesions ranged from 0.1 to 0.3 across all ‌study ⁢arms, regardless of whether‍ patients were on continuous frexalimab⁣ or​ switched from placebo.

Patients who started⁢ on ‍the ​1200-mg ⁤dose in the controlled⁢ trial and‌ continued on it during‍ the OLE had a mean of 0.1 for ​new T1-weighted gadolinium-enhancing⁤ lesions.

Suppression of new or enlarging T2 lesions, ⁣a secondary ‍endpoint, was nearly as significant. The adjusted mean for new lesions across all arms ‌ranged 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 not in the treatment arms.⁢ After ⁣placebo patients switched to active therapy in the OLE, their ‍T2 lesion ⁣volume decreased.

In the 1200-mg arm, the decrease in lesion volume observed during the randomized phase continued into the first 24 weeks of the OLE, remaining suppressed thereafter. Patients initially ⁤on placebo did not ‍catch up⁢ after‍ switching to frexalimab.

“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.

Only 8% of ‌patients on the 1200-mg dose of ⁤frexalimab experienced any relapse during the extended follow-up. Half of those ​patients ‌had only one relapse, ‌and ⁣only 2% had three or more relapses.

While Expanded Disability Status Scale scores slightly improved among placebo patients after starting active therapy, there was no change from baseline ⁢through 96 weeks in patients who started on active ‌therapy.

Frexalimab did not affect lymphocyte counts or‌ immunoglobulin levels over the 96-week follow-up,consistent with ‌earlier⁣ studies,according to ⁤Krieger.

Anti-CD40 therapies have long been considered a⁤ promising approach for managing MS due to their potential to suppress both T and B cell activation.‍ However, first-generation drugs were abandoned⁣ due to thromboembolism risks.

Krieger‍ said that frexalimab has been engineered to avoid these ‌events through a change⁤ in the fc receptors, which reduces ‍downstream‍ inflammatory events. The long-term data support this premise. Over ⁢two years, there was one pulmonary embolism⁣ in⁢ a​ patient ⁤with ‌a viral​ illness and a genetic ‌predisposition for an⁢ inflammatory response.

Reviewing other​ adverse events, Krieger noted that nothing​ stood ⁣out in the OLE compared to the randomized phase, except for⁣ a rise in⁤ liver function tests in two patients (4%) on the 1200-mg ⁤dose. One patient discontinued therapy, but levels returned to normal in⁣ both patients over time.

The effects of ​the anti-CD40 mechanism on both adaptive and innate immune ⁣systems suggest frexalimab might be effective ‌for both⁣ progressive and relapsing MS. The ongoing ‌phase 3 program includes trials ⁢enrolling‍ patients with relapsing MS (FREXALT) and progressive disease (FREVIVA).

What’s next

Dr. Amit Bar-Or, ​chief of⁤ the multiple​ Sclerosis⁢ Division‌ at the University of Pennsylvania Perelman School of medicine,‍ called​ frexalimab “a‌ very engaging drug.” While agreeing that the CD40 ligand is a promising target ‌in MS, Bar-Or cautioned‍ that phase 2⁤ data cannot answer the most critical questions, including whether the benefits extend beyond controlling relapsing disease and whether it will show extended benefit ‌in progressive MS. Phase 3​ trials should provide more robust‍ evidence of safety and efficacy.