Weekly subcutaneous obexelimab significantly prolongs time to disease flare, increases remission rates and reduces glucocorticoid requirements compared with placebo in patients with active immunoglobulin G4-related disease (IgG4-RD), a new trial has shown.

IgG4-RD is a chronic, systemic fibroinflammatory condition characterised by relapsing disease activity and potential irreversible organ damage. Known as the ‘great mimicker’, the condition often resembles other autoimmune or inflammatory disorders, leading to frequent misdiagnoses – including vasculitis and cancer – and treatment delays.

Once a diagnosis has been reached, there are currently no licensed treatments in the UK, with standard of care relying on moderate-to-high levels of steroids and off-label treatments. While these can help to reduce symptoms for some patients, they do not prevent disease progression or relapse.

The bifunctional monoclonal antibody obexelimab is currently undergoing phase 3 trials in IgG4-RD. It is designed to bind both CD19 and FcγRIIb, which are broadly present across B cell lineage, to inhibit the activity of cells that are implicated in many autoimmune diseases without depleting them.

It is hoped that its unique inhibitory mechanism of action and self-administered, subcutaneous injection regimen may broadly and effectively address the pathogenic role of the B cell lineage in chronic autoimmune disease.

A novel, self-administered treatment option

The results of the double-blind, randomised, placebo-controlled INDIGO phase 3 trial was presented at the recent European Alliance of Associations for Rheumatology (EULAR) 2026 Congress and simultaneously published in The New England Journal of Medicine.

It enrolled 194 adults with active IgG4-RD across 114 sites in 19 countries between January 2023 and November 2024. Patients met the American College of Rheumatology–European League Against Rheumatism classification criteria and had active disease requiring glucocorticoid treatment escalation.

The mean patient age was 59.1 years and 66.5% were male. Recurrent disease was present in 66.5% of participants, while 93.3% had involvement of two or more organs.

The most commonly affected sites were the salivary glands (64.9%), lacrimal glands (53.1%), pancreas (46.9%) and lymph nodes (44.8%).

Participants were randomised 1:1 to receive weekly subcutaneous obexelimab 250mg (n=97) or placebo (n=97) for 52 weeks. All patients received glucocorticoid induction therapy before randomisation, followed by a protocol-directed taper to discontinuation by week 8.

The primary endpoint was time to first disease flare requiring rescue therapy, as confirmed by both investigators and an independent adjudication committee.

Obexelimab efficacy and safety

Obexelimab significantly prolonged time to flare compared with placebo, reducing the risk by 56% (hazard ratio 0.44; 95% CI 0.28–0.71; P<0.001). Disease flares occurred in 26.8% of patients receiving obexelimab compared with 54.6% of those receiving the placebo.

All key secondary endpoints also favoured obexelimab. Complete remission at week 52 was achieved in 37.1% of patients receiving obexelimab versus 19.6% in the placebo group (P=0.005). The adjusted annualised flare rate was 0.34 flares per year with obexelimab compared with 0.70 flares per year with placebo (rate ratio 0.48; P<0.001).

Patients treated with obexelimab also required substantially less glucocorticoid rescue therapy, with a cumulative dose of 329.5mg compared with 929.8mg in the placebo group (P=0.004). Glucocorticoid toxicity scores were also lower with obexelimab at week 52.

Adverse events were common in both groups. Arthralgia, hypersensitivity, diarrhoea, pyrexia and urticaria occurred more frequently with obexelimab, although serious adverse events were less common than with placebo (10.3% vs 18.6%). No deaths occurred in the obexelimab group, whereas one cardiovascular death unrelated to treatment occurred in the placebo group.

Limitations and clinical practice implications

The authors noted several study limitations. The 52-week treatment period did not establish long-term durability of efficacy, nor did it fully characterise long-term safety or assess the economic implications of extended treatment. In addition, imbalances in racial and regional distribution between treatment groups could affect generalisability.

An ongoing open-label extension study with up to three years of follow-up has been designed to provide further data on long-term efficacy, safety and B-cell recovery after treatment cessation.

Commenting on the results, first author Dr Emanuel Della Torre, associate professor of medicine at Vita-Salute San Raffaele University in Milan, Italy, said: ‘Physicians currently have very few treatment options for patients living with this chronic, progressive and debilitating disease.

‘The phase 3 INDIGO 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.’

Reference
Della-Torre E et al. Obexelimab for the Treatment of IgG4-Related Disease. N Engl J Med 2026; Jun 2: doi:10.1056/NEJMoa2601337.