Obexelimab lowers IgG4-RD activity, glucocorticoid need: Trial data
Application seeking approval of treatment recently submitted to US regulators
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The investigational antibody therapy obexelimab lowered disease activity and reduced the need for glucocorticoid rescue therapy among people with immunoglobulin G4-related disease (IgG4-RD), according to final published data from a global clinical trial.
The Phase 3 study, called INDIGO (NCT05662241), is the largest ever conducted in IgG4-RD, according to Zenas BioPharma, the developer of obexelimab.
The data were recently presented at the European Alliance of Associations for Rheumatology 2026 Congress and simultaneously published in the New England Journal of Medicine in a study, titled “Obexelimab for the Treatment of IgG4-Related Disease.”
“The findings … mark a significant milestone for both the rheumatology community and patients living with this devastating disease,” Lonnie Moulder, founder and CEO of Zenas, said in a company press release. “We believe obexelimab has the opportunity to become an important first-line therapy for the long-term management of IgG4-RD.”
Rheumatology comprises the field of autoimmune and inflammatory conditions affecting the joints, muscles, bones, and connective tissues, such as IgG4-RD.
Zenas submitted an application to U.S. regulators last week seeking approval of obexelimab for the treatment of IgG4-RD. The company has plans to submit a similar application to European regulators later this year.
“We are excited about the possibility of making this important therapy available to patients,” Moulder said.
Obexelimab works by suppressing pair of proteins
In IgG4-RD, abnormal clumps of immune cells, mainly B-cells producing the IgG4 antibody, infiltrate tissues. This leads to inflammation and scarring, which cause organ damage.
The standard first-line treatment for IgG4-RD is glucocorticoids, also known as steroids, which have strong anti-inflammatory and immunosuppressive effects. However, these medications can cause toxicity and serious side effects with prolonged use.
Designed to be self-administered via weekly under-the-skin (subcutaneous) injections, obexelimab works by suppressing two proteins important for B-cell function — CD19 and FCGR2B. In doing so, it aims to reduce the activation of these cells, thereby lowering IgG4-RD activity and easing symptoms.
Unlike other B-cell-targeted therapies, obexelimab is intended to suppress B-cell activity rather than entirely eliminate the cells. This could potentially reduce the risk of certain complications associated with prolonged B-cell loss, such as infections or impaired vaccine responses.
In INDIGO, the experimental therapy was tested against a placebo in nearly 200 adults with active IgG4-RD who required glucocorticoid treatment. For all participants, the glucocorticoid dose was gradually tapered over the first two months and used only to manage disease flare-ups thereafter.
Data showed that the trial met its primary goal and all of its key secondary goals.
Obexelimab associated with much longer time to first IgG4-RD flare
As previously reported, obexelimab was associated with a significantly longer time to the first IgG4-RD flare requiring rescue treatment, as determined by the trial investigator and an independent committee, lowering the risk by 56% overall and attaining the main goal.
The findings were similar when flare risk was assessed only by the trial investigator, meeting a key secondary goal.
The experimental therapy was associated with a 52% significantly lower annual rate of relapses needing rescue therapy, relative to the placebo, meeting another key secondary goal.
Most people on obexelimab (73.2%) remained free of disease flares through one year, compared with fewer than half (45.5%) on the placebo. After a year, 37.1% of obexelimab-treated participants had achieved complete remission — a state of no disease activity — compared with 19.6% of those in the placebo group.
The mean cumulative use of glucocorticoid rescue therapy over the one-year study period was significantly reduced (65%) with obexelimab compared with the placebo. Correspondingly, fewer patients on obexelimab experienced a clinically meaningful worsening of toxicity from glucocorticoid use.
The … data indicate obexelimab could offer a novel, highly active, self-administered therapy for people living with IgG4-RD, one that has the potential to avoid the safety concerns associated with chronic steroid use and long-term B-cell depletion.
Although B-cell counts declined somewhat with obexelimab, they generally remained within normal limits. Blood levels of IgG4 showed an initial decline in both groups. These lower levels were sustained only in the obexelimab group, whereas they increased in the placebo group.
Consistent with earlier reports, obexelimab’s safety profile was favorable. Adverse events more commonly reported in the obexelimab group than the placebo group included joint pain (19.6% vs. 11.3%), the common cold (18.6% vs. 14.4%), allergic reactions (16.5% vs. 11.3%), diarrhea (11.3% vs. 6.2%), fever (7.2% vs. 3.1%), and hives (6.2% vs. 1%).
“Physicians currently have very few treatment options for patients living with this chronic, progressive and debilitating disease,” said Emanuel Della Torre, MD, PhD, of Vita-Salute San Raffaele University in Milan, Italy. “The … data indicate obexelimab could offer a novel, highly active, self-administered therapy for people living with IgG4-RD, one that has the potential to avoid the safety concerns associated with chronic steroid use and long-term B cell depletion.”
After completing the placebo-controlled part of the trial, participants could enter its open-label extension, during which all will receive obexelimab for up to three years. That extension period will offer “additional efficacy and safety data,” and “allow for observation of B-cell recovery after treatment cessation,” the researchers wrote.
Zenas is also testing obexelimab for the treatment of the autoimmune disorder systemic lupus erythematosus.
