Remibrutinib demonstrates ‘apparent efficacy’ in Sjogren’s syndrome
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PHILADELPHIA — Results of a phase 2 proof-of-concept study showed that an oral Bruton’s tyrosine kinase inhibitor demonstrates trends toward efficacy in Sjögren's syndrome, according to data presented at ACR Convergence 2022.
“The inhibition of BTK has emerged as a potential therapeutic option for a number of autoimmune diseases,” Thomas Dorner, MD, of the department of rheumatology and clinical immunology at Charité Universitätsmedizin Berlin, told attendees.
In the current presentation, Dorner reported on 24-week efficacy and safety results for a phase 2 proof-of-concept study of remibrutinib (Novartis), an oral, covalent and highly specific inhibitor of BTK in patients with Sjögren's syndrome, he said.
The double-blind, randomized, placebo-controlled study included 73 patients randomly assigned remibrutinib 100 mg twice daily (n = 24), 100 mg daily (n = 25) or placebo (n = 24).
The study was conducted between August 2019 and May 2021.
Ultimately, 17 patients in the two treatment groups and 21 patients in the placebo arm completed study.
“There was not a particular reason for discontinuation,” Dorner said.
All but two patients were women. The mean patient age was just younger than 52 years. “This is a very representative Sjögren's population,” Dorner said.
The primary endpoint was EULAR Sjögren's syndrome disease activity index (ESSDAI) score at 24 weeks in the treatment arms compared with the placebo group.
According to Dorner, treatment with remibrutinib resulted in significant improvement in ESSDAI score compared with placebo (delta = –2.86; P = .003).
“At week 24, this was positive for the primary endpoint,” he said.
Dorner added that the curves begin to separate “between weeks 2 and 4.” In addition, both remibrutinib dosing levels yielded comparable outcomes.
Dorner also reported on key secondary outcomes.
“There was a trend toward improvement in salivary flow rate,” he said.
Further data showed that total serum immunoglobulin G (IgG) and IgM declined from baseline after treatment with remibrutinib. However, the same result was not seen in IgA.
Anti-SS-A and anti-SS-B autoantibodies followed the trend of total IgG, according to the findings.
“This confirms the impact of the BTK inhibitor on the autoantibodies,” Dorner said.
Dorner added that patient-reported measures such as EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) were positive in the active therapy arms.
“The study shows that the primary endpoint has been achieved,” he said. “Remibrutinib over 24 weeks has apparent efficacy.”
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David A. McLain, MD, MACR, FACP, FRCP
Thomas Dorner, MD, of the Charité Universitätsmedizin, in Berlin, presented phase 2 results of a potent oral Bruton tyrosine kinase (BTK) inhibitor, remibrutinib (Novartis), in moderate-to-severe Sjögren’s syndrome.
BTK is not a familiar disease target for most rheumatologists. In Lahita's Systemic Lupus Erythematosus (Sixth Edition, 2021), there is a chapter on “Pipeline Therapies and Future Drug Development” for lupus, and BTK inhibitors are discussed. Mutations in the gene for BTK are the etiology of Bruton’s X-linked agammaglobulinemia, and in 92% of patients the cause is a single nucleotide variant. BTK, a cytoplasmic nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays a role in the maturation of pro-B cells to pre-B cells and is present in many immune cells, but not T cells.
BTK was initially discovered as a critical mediator of B-cell receptor signaling in the development and functioning of adaptive immunity. Growing evidence also suggests multiple roles for BTK in mononuclear cells of the innate immune system, especially in dendritic cells and macrophages. As an example of this, the BTK inhibitor ibrutinib (Imbruvica; Pharmacyclics, Janssen) being used in lymphoma, Waldenström macroglobulinemia and graft-versus-host disease, has had some patients develop invasive aspergillosis during treatment.
BTK has also been identified as a direct regulator of the innate inflammatory NLRP3 inflammasome, which leads to release of IL-1β. A BTK inhibitor has even been experimentally used in severe COVID-19 due to its effect on the innate immune system, macrophage activation syndrome and cytokine storm.
With remibrutinib, in the present study, there was significant improvement in the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) in the treated groups. Salivary flow increased, though this was not statistically significant. In addition, total serum IgG and IgM decreased from baseline but remained in the normal range in those receiving remibrutinib. Infection was the most common adverse event with similar events in the treatment and placebo groups. It is encouraging that Sjögren’s syndrome is now on the radar of investigators and new therapies are being developed.
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Dorner T. Abstract 1113. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
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