ABBV-599, a novel combination of upadacitinib, improves lupus, expands pathology coverage

A new combination of elsubrutinib and upadacitinib, called ABBV-599, significantly improved systemic lupus erythematosus disease activity and outbreaks within 48 weeks, according to data presented at ACR Convergence 2023. This is one of the first early-stage trials in lupus to test two treatments simultaneously, finding out which theoretically promising treatments seem best suited for further development.

ABBV-599 combines the novel selective BTK inhibitor elsubrutinib (AbbVie) with the JAK inhibitor upadatinib (Rinvoq, AbbVie) to target non-overlapping signaling pathways associated with systemic lupus erythematosus (SLE). To analyze the efficacy and safety of this combination compared with upapatinib or elsubrutinib monotherapy in adults with moderately to severely active systemic lupus erythematosus, the SLEek trial was a phase 2 randomized placebo-controlled parallel-group multicenter study.

The investigators recruited 341 patients who were randomized in a 1:1:1:1:1 ratio to receive a high-dose combination of elsubrutinib 60 mg and upatinib 30 mg, a low-dose combination of elsubrutinib 60 mg and upadacitinib 15 mg, elsubrutinib 60 mg monotherapy, elsubrutinib 30 mg monotherapy, or placebo. All treatments were performed daily. The primary endpoint was the proportion of patients achieving a systemic lupus erythematosus remission index-4 (SRI-4) and using less than 10 mg of daily steroids at week 24. After a planned interim analysis, when half the cohort reached 24 weeks, elsubrutinib 60 mg monotherapy and low-dose combination therapy were discontinued due to lack of efficacy. According to the researchers, these discontinuations did not involve safety concerns. The remaining cohort included 68 patients who received the high-dose combination, 62 patients who received upadatinib monotherapy, and 75 patients who received placebo.

According to the researchers, 48.5% (95% confidence interval, 36.7-6.4) of patients in the high-dose combination group and 43.5% (95% confidence interval, 3'1.2-55.9) of patients in the upapatinib monotherapy group met the primary endpoint at 24 weeks. Both treatment arms additionally met "key secondary endpoints" including SRI-4 treatment alone and British Isles Lupus Assessment Group-based composite lupus assessment (BICLA) response. Study results at week 48 also showed that the high-dose combination andpatinibBoth monotherapy reduced overall seizures and time to first seizure. In addition, both treatments were associated with a decrease in anti-double-stranded DNA antibodies.

At the same time, safety data showed that treatment-emergent adverse events were 42.6% in the high-dose combination group, 32.3% in the upatinib monotherapy group, and 33.3% in the placebo group. There were no malignancies or venous thromboembolism. Three nonfatal cardiovascular events were reported, one in each of the three treatment groups, but none were related to the study drug. No new safety signals were observed for any of the compounds.

Based on these results, upadatinib will enter a Phase 3 trial as a single treatment for lupus. It is also possible that further analyzes comparing and contrasting the baseline immune patterns of patients who responded or did not respond to each treatment could help understand the results and whether there are smaller subpopulations where the combination of JAK1 and BTK inhibitors may be uniquely helpful. There is currently an approved drug to treat lupus that inhibits the IFNAR receptor. Upatinib also inhibits signaling through the IFNAR receptor, but also acts on several other key receptors that regulate other pathways related to lupus.

The original drug Upatinib has been launched in China, and has subsequently entered the scope of Class B medical insurance. Only eligible patients can be reimbursed. Specifications The price of each box of 15mg*28 tablets may be around RMB 3,000. The European version of the original drug sold overseas is priced at more than 20,000 yuan for 15mg*30 tablets (the price may fluctuate due to exchange rates), which is expensive. Cheaper upadatinib generic drugs are also sold overseas, and their pharmaceutical ingredients are basically the same as those of the original drugs sold domestically and abroad. For example, the price of 15mg*30 tablets produced by Bangladesh pharmaceutical factory is around 900 yuan (the price may fluctuate due to the exchange rate).