Baricitinib shows potential as SLE therapy in phase 2 study

A higher proportion of patients with systemic lupus erythematosus (SLE) experienced improvements in joint and skin symptoms with baricitinib 4 mg once daily vs placebo in a phase II randomized, double-blind, global study.

Baricitinib is a selective JAK1/2 inhibitor approved for use in rheumatoid arthritis in over 40 countries in Europe, Japan, and recently in the US. Available biologic treatments for SLE target the B cell survival factor BAFF/BlyS, also responsible for plasma cells considered as autoantibody producing cells and characteristic of the disease. Baricitinib blocks a number of cytokines, including the interferon type I and II pathways and other potentially relevant cytokines including interleukins 6, 12, and 23, hence it may have therapeutic value in SLE.

In the current study, 67 percent of patients treated with baricitinib 4 mg once daily met the primary endpoint of diminished arthritis or rash as measured by the SLE Disease Activity Index-2K (SLEDAI-2K) at week 24 vs 53 percent in those administered a matching placebo (p<0.05). [EULAR 2018, abstract OP0019]

The findings were “very promising for the 4-mg dose,” said Dr Thomas Dörner of the Charité University Hospital in Berlin, Germany and chairman of the abstract selection committee of EULAR, during the press briefing. Those receiving baricitinib 2 mg once daily also showed improvement, with SLEDAI-2K resolution of rash or arthritis in 58.1 percent of patients. However, this did not meet statistical significance.

The study enrolled 314 patients with active SLE who were positive for antinuclear antibodies or anti-double stranded DNA antibodies, with SLEDAI scores of 8-9 at baseline, and receiving a standard background therapy that included corticosteroids, NSAIDs, antimalarials, and immunosuppressants. Ninety-nine percent of the patients were female with a disease duration of nearly 10 years and had an average of eight tender and six swollen joints. Mean age was 44 years. Around two-thirds of the patients were Caucasians; 19 percent were of Asian descent.

Greater responses with 4 mg dose

Patients treated with baricitinib 4 mg once daily had significantly greater responses vs those given placebo on multiple secondary endpoints, said study investigator Dr Daniel Wallace, Professor of Medicine at Cedars-Sinai Medical Center, Los Angeles, US, who presented the results at EULAR 2018.

 

At 24 weeks, more patients on the baricitinib 4 mg arm achieved the SLE Responder Index (SRI-4) response, defined as a 4-point improvement in the SLEDAI and no new worsening in major organ function or physician global assessment (64.4 percent vs 47.6 percent for the placebo arm; p<0.05).

Achievement of lupus low disease activity state (LLDAS) was achieved in 38 percent (n = 27) of patients treated with baricitinib 4 mg, 33 percent of those treated with baricitinib 2 mg, and 26 percent of those given placebo (p<0.05 for baricitinib 4 mg vs placebo). There were also numerically fewer SLE flares, including fewer severe flares.

For tender joint counts, there was a change of -6.86 percent in the baricitinib 4-mg group vs -5.59 percent in the placebo group (p<0.05). For swollen joint counts, the changes were -4.76 with baricitinib and -4.60 with placebo. The changes in worst pain scores were -1.31 and -0.56, respectively (p<0.05).

In terms of fatigue, improvements were modest. There was little change in cutaneous disease scores.

No new safety and tolerability signals

“In general, I think the rate of adverse events in lupus population is usually two to threefold higher than in other autoimmune diseases like RA, that is for infections and severe infectious events,” said Dörner. “Surprisingly enough, there were not so many adverse events reported in this trial.”

Treatment-emergent adverse events were seen in about 71–73 percent of patients given baricitinib vs 65 percent of those given placebo but were mostly mild or moderate in nature. Serious adverse events occurred in 9.6 percent of patients on baricitinib 4 mg and in 4.8 percent of those on placebo. Serious infections were reported in the 2- and 4-mg baricitinib arm (1.9 percent and 5.8 percent) vs placebo (1 percent). “But this is what we expect for lupus patients,” Dörner said.

Of note was the rate of thromboembolic events in the trial. “Several studies of SLE have shown a five to 13-fold increased venous thromboembolism [VTE] rate in SLE compared to a two-and-a-half-fold increase in RA,” he said. “In this study, there was only one deep vein thrombosis [DVT] in the 4-mg group and this was in a high-risk patient with co-existing antiphospholipid syndrome. Notably, in the other treated active SLE patients, we have not seen DVT or pulmonary embolism while about 22 percent of the studied patients were positive for antiphospholipid antibodies.”

There was one case each of herpes zoster infection – which is known to be frequently reactivated in lupus – with placebo and baricitinib, both of which were mild. No multidermal herpes zoster was observed.

There were modest dose-related changes in haemoglobin and neutrophil levels, as well as in platelets and lipids. “The safety and tolerability profile was similar to what has been seen in tens of thousands of patients in more than 40 countries who have received the drug,” said Wallace.

With no new safety or tolerability issues, these findings suggest that baricitinib could be of benefit to SLE patients, he added.

A phase III trial of baricitinib in SLE population is expected.