Litifilimab Meets Primary Endpoint in Phase 2 Lupus Trial

Christine Kilgore

September 12, 2022

Treatment with the humanized monoclonal antibody litifilimab for patients with systemic lupus erythematosus (SLE) led to greater improvements in joint manifestations than placebo in an international phase 2 trial that reflects keen interest in targeting type 1 interferon and the innate immune system.

Litifilimab was associated with an approximately three-joint reduction in the number of swollen and tender joints, compared with placebo, over 24 weeks in the study, which was published September 8 in The New England Journal of Medicine.

The study was the first part of the LILAC trial, a two-part, phase 2 study. The second part involved cutaneous lupus erythematosus (CLE) with or without systemic manifestations. Treatment led to improvements in skin disease, as measured by Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI-A) scores. It was published July 28 in The New England Journal of Medicine.

Dr Richard Furie

The investigational drug targets blood dendritic cell antigen 2 (BDCA2). The antigen is expressed solely on plasmacytoid dendritic cells (pDCs), which accumulate in skin lesions and organs of patients with SLE. When the antibody binds to BDCA2, "the synthesis of a variety of cytokines is shut down ― type 1 interferons, type 3 interferons, TNF [tumor necrosis factor], and [other cytokines and chemokines] made by the pDCs," said Richard A. Furie, MD, lead author of the article, in an interview.

In a phase 1 trial involving patients with SLE and CLE, the drug's biologic activity was shown by a dampened interferon signature in blood and modulated type 1 interferon-induced proteins in the skin, he and his co-investigators note.

Furie is chief of rheumatology at Northwell Health and professor of medicine at the Feinstein Institutes for Medical Research at Northwell and at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, in Uniondale, New York.

Impact on the Joints

The primary analysis in the SLE trial involved 102 patients who had SLE, arthritis, and active skin disease. The patients received litifilimab 450 mg or placebo, administered subcutaneously, at weeks 0, 2, 4, 8, 12, 16, and 20. The patients were required to have at least four tender joints and at least four swollen joints, and these active joints had to be those classically involved in lupus arthritis.

The mean (± standard deviation) baseline number of active joints was 19 ± 8.4 in the litifilimab group and 21.6 ± 8.5 in placebo group. From baseline to week 24, the least-squares mean (± standard deviation) change in the total number of active joints was -15.0 ± 1.2 with litifilimab and -11.6 ± 1.3 with placebo (mean difference, -3.4; 95% CI, -6.7 to -0.2; P = .04).

Most of the secondary endpoints did not support the results of the primary analysis. However, improvement was seen in the SLE Responder Index (SRI-4) ― a three-component global index that Furie and others developed in 2009 using data from the phase 2 SLE trial of belimumab (Benlysta).

The composite index, used in the phase 3 trial of belimumab, captures improvement in disease activity without a worsening of the condition overall or new significant disease activity in other domains. "It's a dichotomous measure ― either you're a responder or not," Furie said in the interview.

Response on the SRI-4 was defined as a reduction of at least 4 points from baseline in the SLEDAI-2K score (the Systemic Lupus Erythematosus Disease Activity Index), no new disease activity as measured by one score of A (severe) or more than one score of B (moderate) on the BILAG (British Isles Lupus Assessment Group) index, and no increase of 0.3 points or more on the Physician's Global Assessment.

A total of 56% of the patients in the litifilimab group showed responses on the SRI-4 at week 24, compared with 29% in the placebo group (least-squares mean difference, 26.4%; 95% CI, 9.5 – 43.2). This is "a robust response" that is much greater than the effect size seen in the phase 3 trial of belimumab or in research on anifrolumab (Saphnelo). Both of those drugs are approved for SLE, Furie said. "We'll need to see if it's reproduced in phase 3."

There's "little question that litifilimab works for the skin," Furie noted. In the second part of the LILAC study, which focused on CLE, litifilimab demonstrated efficacy, and the SLE trial lends more support. Among several secondary endpoints evaluating skin-related disease activity, a reduction of at least 7 points from baseline in the CLASI-A score (a clinically relevant threshold) occurred in 56% of the litifilimab group and 34% of the placebo group.

The trial was conducted at 55 centers in Asia, Europe, Latin America, and the United States. The SLE part of the study began as a dose-ranging study aimed at evaluating cutaneous lupus activity, but owing to "slow enrollment and to allow an assessment of the effect of litifilimab on arthritis in SLE," the protocol and primary endpoint were amended before the trial data were unblinded to evaluate only the 450-mg dose among participants with active arthritis and skin disease (at least one active skin lesion), the investigators explain.

Background therapy for SLE was allowed if the therapy was initiated at least 12 weeks before randomization and if dose levels were stable through the trial period. Glucocorticoids had to be tapered to ≤10 mg/day according to a specified regimen.

Making Progress for Lupus

Jane E. Salmon, MD, director of the Lupus and APS Center of Excellence and co-director of the Mary Kirkland Center for Lupus Research at the Hospital for Special Surgery in New York, who was not involved in the research, said in an email that she is "cautiously optimistic, because in SLE, successful phase 2 trials too often are followed by unsuccessful phase 3 trials."

Dr Jane Salmon

Blocking the production of type 1 interferon by pDCs implicated in SLE pathogenesis has the theoretical advantage of preserving type 1 interferon critical to protection from viruses, she noted. Herpes infections were reported among patients who received litifilimab, but rates were not increased compared with placebo.

Diversity is an important priority in further research, Salmon also said.

Dr Daniel Wallace

Daniel J. Wallace, MD, of Cedars-Sinai Medical Center, in Los Angeles, similarly pointed out in an editorial that accompanied the SLE phase 2 trial that while Black patients make up one third of the US population with lupus, only about 10% of study participants whose race and ethnicity was reported were Black. (Race was not reported by sites in Europe.)

The results of the LILAC trials "encourage further exploration of interventions that affect upstream lupus inflammatory pathways in the innate immune system in lupus," Wallace wrote. He noted that lupus has "lagged behind its rheumatic cousins," such as rheumatoid arthritis and vasculitis, in drug development.

Developing endpoints and study designs for SLE trials has been challenging, at least partly because it is a multisystem disease, Furie said. "But we're making progress."

Anifrolumab, a type 1 interferon receptor monoclonal antibody that was approved for SLE in July 2021, "may have a broader effect on type 1 interferons," he noted, while litifilimab "may have a broader effect on proinflammatory cytokines, at least those expressed by pDCs."

Biogen, the sponsor of the LILAC trial, is currently enrolling patients in phase 3 studies ― the TOPAZ-1 and TOPAZ-2 studies ― to evaluate litifilimab in SLE over a 52-week period. The company also plans to start a pivotal study of the drug in CLE later this year, according to a company press release.

The study was sponsored by Biogen. Six co-authors are employees of Biogen. Five co-authors, including Furie, reported serving as a consultant to Biogen. One co-author served on a data and safety monitoring board for Biogen. Salmon owns stock in Biogen.

N Engl J Med. Published online September 8, 2022. Abstract, Editorial

Christine Kilgore is a Falls Church, Virginia–based medical journalist whose work has appeared in such publications as Internal Medicine News, Ob.Gyn News, Oncology Times, and The Washington Post.

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