Upadacitinib Alone and With Elsubrutinib Continue to Yield SLE Responses in Long-Term Data

Upadacitinib monotherapy and upadacitinib/elsubrutinib combined continued to be well-tolerated and improve disease activity, glucocorticoid dose and flares in people with systemic lupus erythematosus (SLE) through 104 weeks in a long-term extension (LTE) study.1

“SLE, a chronic autoimmune disease, affects approximately 3.4 million people worldwide, about 90% of whom are women.2 Although a few advanced therapeutic options are available, SLE remains challenging to treat. Responses to any individual treatment are known to vary between patients, and the response of an individual patient may change over time. Remission or low disease activity is the accepted goal of treatment, but there are formidable barriers to achieving long-term remission, which include the heterogeneity and fluctuating nature of the immune disorder, limited therapeutic options and the lack of validated predictive or prognostic biomarkers,” study investigator Joan T Merrill, MD, Professor, Arthritis & Clinical Immunology Research Program, University of Oklahoma Health Sciences Center, and Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA, and colleagues wrote.1

The 1-year LTE study (NCT04451772) followed the 48-week phase 2 SLEek study (NCT03978520) that evaluated the JAK1 inhibitor upadacitinib alone or combined with the BTK inhibitor elsubrutinib in adults with moderately to severely active SLE. The primary study previously found that the primary endpoint of Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and glucocorticoid dose ≤10 mg QD at week 24 was achieved by 54.8% (P =.028) of patients in the upadacitinib monotherapy group and 48.5% (P = .081) of patients in the upadacitinib/elsubrutinib HD combination group, compared with 37.3% of patients in the placebo group. The LTE evaluated an additional 56 weeks of safety and efficacy.

The LTE included patients randomized to upadacitinib 30 mg 1 time per day (QD) or upadacitinib 30 mg/elsubrutinib 60 mg QD (upadacitinib/elsubrutinib) from the SLEek study that continued their assigned treatment during the LTE. Patients originally receiving placebo switched to upadacitinib/elsubrutinib in the LTE for a total of 127 patients included in the analysis. Investigators assessed SRI-4, British Isles Lupus Assessment Group-based Combined Lupus Assessment (BICLA), Lupus Low Disease Activity State (LLDAS), change from baseline in glucocorticoid dose, flare events and adverse events (AEs) through week 104.

Merrill and colleagues found that efficacy responses for the groups receiving upadacitinib, upadacitinib/elsubrutinib and placebo to upadacitinib/elsubrutinib were maintained or increased from weeks 48 to 104 (week 104: SRI-4: 82.1%, 85.4% and 61.3%; BICLA: 69.2%, 78.0% and 54.8%; LLDAS: 60.0%, 78.0% and 34.4%).

Notably, daily glucocorticoid dose decreased from week 0 to week 104 in all treatment groups. In the upadacitinib 30 mg, upadacitinib/elsubrutinib and placebo to upadacitinib/elsubrutinib groups, baseline mean daily glucocorticoid dose was 5.9 mg, 6.1 mg and 8.3 mg, and decreased to 0.4 mg, 0.3 mg and 0.6 mg at week 104, respectively.

Furthermore, the incidence of overall flares from weeks 0 to 48 compared with weeks 48 through 104 was maintained in the upadacitinib 30 mg group (1.38 vs 1.45 flares/PY) and reduced in the upadacitinib/elsubrutinib (1.18 vs 0.62 flares/PY) and placebo to upadacitinib/elsubrutinib groups (2.54 vs 1.56 flares/PY).

In terms of safety, findings were similar to those seen in the primary SLEek study, although there was 1 AE of an abscessed limb was deemed by the investigator as having a reasonable possibility of being related to study drug.

“The long-term extension of the phase 2, multicenter, double-blind, SLEek study demonstrated sustained or improved efficacy in multiple endpoints and no new safety findings for up to 104 weeks of continuous treatment with upadacitinib 30 mg monotherapy or upadacitinib/elsubrutinib HD combination therapy. Patients who switched from placebo to upadacitinib/elsubrutinib HD when entering the 56-week LTE study had improvements in SLE disease activity at week 104,” “The daily glucocorticoid dose was reduced in all treatment groups, with patients achieving a low mean glucocorticoid dose in the upadacitinib monotherapy and upadacitinib/elsubrutinib HD groups at week 104. Corticosteroid dosing in those crossing over from placebo was reduced to the same level as those who began the LTE on the active treatments.”

References

1. Merrill JT, Saxena A, Aringer M, et al. Efficacy and safety of upadacitinib as monotherapy or combined with elsubrutinib for the treatment of systemic lupus erythematosus: results through 104 weeks in a long-term extension study. RMD Open. 2025;11(3):e005742. Published 2025 Aug 18. doi:10.1136/rmdopen-2025-005742

2. Dörner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet. 2019;393(10188):2344-2358. doi:10.1016/S0140-6736(19)30546-X