Novel combination ABBV-599 improves lupus, offers ‘expanded coverage’ of pathology
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SAN DIEGO — A novel combination of elsubrutinib and upadacitinib, called ABBV-599, significantly improves systemic lupus erythematosus disease activity and flares through 48 weeks, according to data presented at ACR Convergence 2023.
Joan Merrill, MD, of the Oklahoma Medical Research Foundation, who presented the findings, said the combination may offer a new paradigm for managing patients with lupus.
“This is one of the first early phase trials in lupus to test two treatments at the same time,” she told Healio. “This is an efficient way to figure out which of the theoretically promising treatments seem most robust for further development, as testing them in the same trial is good resource utilization.”
ABBV-599 combines the novel selective BTK inhibitor elsubrutinib (AbbVie) and the JAK inhibitor upadacitinib (Rinvoq, AbbVie) to target non-overlapping signaling pathways associated with SLE. To analyze the efficacy and safety of this combination, compared with upadacitinib or elsubrutinib monotherapy, among adults with moderately to severely active SLE, Merrill and colleagues conducted the SLEek trial, a phase 2, randomized, placebo-controlled, parallel-group, multicenter study.
The researchers enrolled 341 patients who were randomized 1:1:1:1:1 to receive either a high-dose combination of elsubrutinib 60 mg and upadacitinib 30 mg, a low-dose combination of elsubrutinib 60 mg and upadacitinib 15 mg, elsubrutinib 60 mg monotherapy, upadacitinib 30 mg monotherapy, or placebo. All treatments were administered daily.
The primary endpoint was the proportion of patients reaching SLE Responder Index-4 (SRI-4) and less than 10 mg of daily steroid use at week 24. After a planned interim analysis when half of the cohort reached 24 weeks, the elsubrutinib 60 mg monotherapy and the low-dose combination arms were discontinued due to lack of efficacy. No safety concerns were involved in these discontinuations, according to the researchers. The remaining cohort included 68 patients receiving the high-dose combination, 62 patients receiving upadacitinib monotherapy and 75 patients in the placebo group.
According to the researchers, 48.5% (95% CI, 36.7-60.4) of patients the high-dose combination group, and 43.5% (95% CI, 3`1.2-55.9) of those in the upadacitinib monotherapy arm, achieved the primary endpoint at 24 weeks. The researchers added that both treatment groups additionally achieved “key secondary endpoints,” including SRI-4 alone and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response.
Findings at week 48 also showed that both the high-dose combination and upadacitinib monotherapy reduced overall flares and time to first flare. In addition, both treatments were associated with reductions in anti-double stranded DNA antibodies.
Meanwhile, safety data demonstrated that treatment-emergent adverse events occurred in 42.6% of patients in the high-dose combination group vs. 32.3% in the upadacitinib monotherapy group and 33.3% for placebo. There were no malignancies or venous thromboembolism, according to the researchers. Three non-fatal cardiovascular events were reported, one in each of the three treatment groups, although none were associated with the study drugs. No new safety signals for either compound were observed.
“On the basis of the results, upadacitinib is being taken forward to a phase 3 trial as a single treatment for lupus,” Merrill said. “It is also possible that further analysis comparing and contrasting the baseline immunologic patterns in patients who do or do not respond to each treatment could help to understand the results, and whether there is a smaller subpopulation for which the combination of JAK1 and BTK inhibitors might be uniquely helpful.”
Merrill added that there is currently an approved drug for lupus that inhibits the IFNAR receptor.
“Upadacitinib also inhibits signals through the IFNAR receptor but additionally acts at several other key receptors that modulate other pathways relevant to lupus,” she said. “Although this is a phase 2 study and further trials are needed, the current results suggest the possibility of an alternative treatment with expanded coverage of lupus pathology. We would still need to work on identifying subsets of patients for which each treatment might be optimal.”
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Merrill JT. Abstract 2488. Presented at: ACR Convergence 2023; Nov. 10-15, 2023; San Diego.
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