Litifilimab Shows Promise in Systemic Lupus Erythematosus

Did an anti-BDCA2 antibody agent move one step closer to becoming a new treatment option in systemic lupus erythematosus (SLE)? Possibly, given mixed results from the phase II LILAC trial.

And, in the 102 patients included in the primary analysis, the least-squares mean change from baseline to week 24 in the total number of active joints was –15.0 with litifilimab and –11.6 with placebo, for a –3.4 mean difference (95% CI, –6.7 to –0.2, P=0.04), they stated in The New England Journal of Medicine (NEJM).

But most of the secondary trial endpoints did not support the results of the analysis of the primary endpoint, according to the authors, who explained that "[f]or all but one of the secondary endpoints associated with skin-related disease activity, including the original primary endpoint of change from baseline in CLASI-A [Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity] score [≥8], the 95% confidence intervals for the between-group differences included zero."

They went on to explain that there "was no prespecified plan to adjust the widths of the confidence intervals of the secondary end points for multiple comparisons, so no formal inferences or conclusions can be drawn from the results."

Also, there were more adverse events (AEs) tied to the study agent, including herpes zoster and herpes keratitis, although there were two cases of herpes zoster in the placebo group, and no hypersensitivity or herpes meningitis AEs were seen in this part of the trial. An earlier NEJM study offered details on the agent’s safety profile in the trial.

In an editorial accompanying the current study, Daniel J. Wallace, MD, of Cedars Sinai Medical Center in Los Angeles, pointed out that SLE "has lagged behind its rheumatic disease cousins, such as vasculitis and rheumatoid arthritis, in drug development. The study of monogenic lupus also represents a major advance in the evaluation of patients with enriched lupus serologic profiles."

How meaningful are these LILAC results to the potentially 500,000 U.S. patients who have an SLE diagnosis, or those whom Wallace said "fall on a spectrum that overlaps with that of lupus"? Besides the uncertain results with the secondary endpoints, he noted that the findings may not be generalizable, as <10% of the participants were Black despite the fact that "Black patients make up one third of the U.S. population with lupus."

Other issues were that a small number of patients were taking methotrexate (13% in the study-agent arm), mycophenolate (5%), or azathioprine (16%), the most commonly prescribed immunosuppresants. Finally, Wallace noted that the study patients had relatively mild systemic disease, "as reflected in the fact that only about one third had low complement levels or the presence of anti-dsDNA." The authors reported that eligible patients had to have anti-nuclear antibodies at titers of ≥1:80 anti-double-stranded DNA antibody levels of ≥30 IU/mL.

Ultimately, the LILAC studies "encourage further exploration of interventions that affect upstream lupus inflammatory pathways in the innate immune system in lupus," Wallace concluded.

Franchimont and co-authors explained that litifilimab "is a subcutaneously administered, humanized IgG1 monoclonal antibody that binds BDCA2, resulting in the down-regulation of type I interferon, cytokine, and chemokine production," which is closely associated with the pathogenesis of SLE. The agent led to "a dampened interferon signature in blood and modulated type I interferon-induced proteins in skin" in a phase I trial, they noted.

In an interview with Medicine Matters Rheumatology at the 2020 American College of Rheumatology meeting, LILAC co-investigator Richard A. Furie, MD, of Northwell Health in Great Neck, New York, highlighted that "the strategy [in LILAC] was to try to shut down the synthesis of type 1 interferons… for extrarenal lupus, we have relatively few drugs, especially for cutaneous lupus. So there is a major need for effective and safe drugs for skin disease, but there’s also a major need for just general lupus."

LILAC enrolled patients (age about 40; vast majority female; around 28% White; around 30% no race/ethnicity reported) with SLE, arthritis, and active skin disease who were randomly assigned to either 450-mg litifilimab or placebo. The study endpoint was the change from baseline in the total number of active joints, which was defined as the sum of the swollen joints and the tender joints, at week 24. The authors noted that trial’s original primary endpoint was the percent change from baseline in the CLASI-A score at week 12 but that was changed to an "organ-specific approach to assess the effects of litifilimab on arthritis." Changes in cutaneous and global disease activity were secondary endpoints.

They reported that a secondary endpoint that offers promise was the seven-point decrease from baseline in the CLASI-A score, SLE Responder Index (SRI-4) response, and the change from baseline in the SLE Disease Activity Index-2000 (SLEDAI-2K) score at week 24:

• CLASI-A: 56% in litifilimab participants versus 34% placebo; least-squares mean (LSM) 57.9% versus 36.3%; 21.6 percentage points LSM difference versus placebo (95% CI, 0.1 to 43.1).
• SRI-4: 56% versus 29%; LSM 56.8% versus 30.4%; 26.4 percentage points (95% CI, 9.5 to 43.2).
• SLEDAI-2K: –4.4 versus –2.6 percentage points; –1.7 percentage points (95% CI, –3.0 to –0.5).

Lastly, AEs were reported in 59% in the study-drug arm and 68% in the placebo arm, including diarrhea, urinary tract infections, falls, and headaches, and most were deemed mild to moderate. There were three deaths in the placebo group, none of which were considered related to the trial, and no deaths in the study-agent arm.

Other trial limitations included the lack of imaging to assess arthritis and imbalances in the study arms in terms of participant sex and race. Findings from two TOPAZ trials (both current recruiting with estimated study completion dates in 2025) should offer more clarity on the agent’s safety and efficacy, Franchimont’s group concluded.

LILAC was funded by Biogen. Some co-authors are company employees.

Franchimont reported relationships with OMass Therapeutics.

Furie reported multiple relationships with industry including Biogen.

Co-authors reported multiple relationships with industry including Biogen.

Wallace reported relationships with AstraZeneca, GlaxoSmithKline, EMD Serono, Lilly, and Aurunia.

Furie RA, et al, for the LILAC Trial Investigators "Trial of anti-BDCA2 antibody litifilimab for systemic lupus erythematosus" N Engl J Med 2022; 387: 894-904.

Wallace DJ "Progress toward better treatment of lupus" N Engl J Med 2022; DOI: 10.1056/NEJMe2208772.