Oral drug shows promise in trial as standalone treatment for IgG4-RD
Proof-of-concept study shows therapy may bypass need for steroids
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In a proof-of-concept clinical trial, the oral treatment candidate zanubrutinib was shown to reduce disease activity for 10 people with hard-to-treat immunoglobulin G4-related disease (IgG4-RD) affecting the tear and salivary glands.
Importantly, according to the researchers, zanubrutinib showed disease-controlling potential as a standalone therapy, bypassing the need for glucocorticoids — a class of steroids that serves as the standard first-line treatment for IgG4-RD but carries significant risks with long-term use.
Although the investigator-initiated Phase 2 clinical trial (NCT04602598) — funded by zanubrutinib’s developer Beone Medicines (formerly Beigene) — was small and further validation is needed, the scientists say its results support advancing zanubrutinib as a potential treatment for IgG4-RD.
Trial findings were detailed in a study titled “Zanubrutinib monotherapy for IgG4-related head and neck disease,” which was published in the journal Annals of the Rheumatic Diseases.
IgG4-RD is a rare disorder in which immune cells, including B-cells, form abnormal clumps in the body’s tissues, driving inflammation, scarring, and organ damage. These B-cells characteristically produce high levels of a type of antibody called immunoglobulin 4, or IgG4.
The disease can involve virtually any tissue in the body, but the glands that produce tears and saliva are among its most common targets.
Drug approved in US for treating certain blood cancers
Zanubrutinib, tested as oral capsules, works by blocking the activity of Bruton’s tyrosine kinase (BTK), an enzyme that plays a key role in B-cell activation and survival. The therapy is already approved in the U.S. under the name Brukinsa for certain blood cancers characterized by the uncontrolled growth of B-cells.
This Phase 2 or midstage trial tested zanubrutinib, at a dose of 80 mg twice daily, in people ages 18 to 85 with active IgG4-RD affecting the tear glands and major salivary glands. All participants were recruited at a single U.S. site, and each had previously experienced a poor response to glucocorticoids or was unable to tolerate them.
No IgG-RD treatment other than zanubrutinib was permitted during the study. Its main goal was to evaluate how the treatment candidate affected the size of the tear and salivary glands, as determined via imaging scans, after six months of treatment.
“To our knowledge, this represents the first clinical trial evaluating BTK [suppressor] [on its own] in IgG4-related disease,” the scientists wrote.
The trial’s design was distinctly different from what’s typically used in IgG4-RD, the researchers noted. Usually, participants are first treated with glucocorticoids as an induction treatment, aiming to drive their disease into remission. Patients are then given an experimental therapy with the goal of seeing how well the treatment prevents future disease flares.
As such, this study’s design has two major advantages: First, it allowed researchers to directly evaluate the effects of zanubrutinib without potential effects from glucocorticoid treatment. And second, by relying on imaging scans, the researchers could objectively track disease activity over a set period of time, rather than waiting for patients to experience a flare.
“By directly quantifying changes in tissue volume and metabolic activity at prespecified timepoints, [imaging] enables objective assessment of inflammatory burden without reliance on glucocorticoid induction and subsequent flare,” the researchers wrote.
Size of tear, saliva glands cut with IgG4-RD treatment
Among participants who could be evaluated after six months, the size of the tear and salivary glands decreased significantly, the data showed. Tear glands were reduced by a mean of 46.7% while saliva glands were cut by 29.9%. Imaging data also showed a reduction in metabolic activity, which reflect inflammatory lesions.
Zanubrutinib treatment was also associated with a reduction in blood levels of IgG4 antibodies, disease-related immune cells, and measures of overall disease severity. Patient-reported outcomes showed a trend toward reduced eye and mouth dryness after treatment. Fatigue was unchanged.
The consistent … improvements [seen] without glucocorticoid induction support the robustness of the treatment effects. … [Use of zanubrutinib and similar drugs may be] a promising [glucocorticoid-sparing] therapeutic strategy for active glandular IgG4-RD.
Most adverse events were mild to moderate in severity, and commonly involved upper respiratory tract infections, lower counts of certain immune cells, and COVID-19. A serious case of COVID-19 developed months after zanubrutinib treatment was stopped.
Two patients discontinued zanubrutinib in the first weeks of the trial due to adverse events: One developed an autoimmune skin condition called bullous pemphigoid; the other had blood in the urine. A third participant stopped treatment after three months due to worsened eye discomfort, which the patient interpreted as evidence that zanubrutinib was not effectively controlling the condition.
Overall, however, “the consistent imaging, clinical, and [biomarker] improvements without glucocorticoid induction support the robustness of the treatment effects,” the researchers wrote.
The team stressed that more research is needed, but said the data suggest zanubrutinib and other BTK-suppressing therapies may be “a promising [glucocorticoid-sparing] therapeutic strategy for active glandular IgG4-RD.”
The promising results also lend credence to imaging-based assessments as a useful [outcome] in IgG4-RD trials, according to the team.
“These findings suggest that imaging-based endpoints [outcomes] can capture treatment-associated changes that are biologically meaningful and reflect modulation of IgG4-associated disease activity,” the researchers wrote. “In future IgG4-RD trials, imaging-defined endpoints may complement conventional clinical outcomes.”
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