Phase II data shows treatment potential of litifilimab for CLE

In part B* of the two-part 16-week LILAC study, the anti-BDCA2** antibody litifilimab reduced skin disease activity in individuals with cutaneous lupus erythematosus (CLE).

“CLE causes irreversible damage and disfigurement, impairs patients’ quality of life, and is associated with depression, anxiety, and fatigue,” said the researchers. Topical glucocorticoids and antimalarial drugs are considered first-line treatment options for CLE. However, there is insufficient evidence corroborating the benefit of glucocorticoids; with antimalarials, the responses have been inconsistent. [J Eur Acad Dermatol Venereol 2017;31:389-404; Br J Dermatol 2017;177:188-196; Cochrane Database Syst Rev 2021;3:CD007478]

“This phase II trial involving participants with active, histologically confirmed CLE with or without manifestations [of systemic lupus erythematosus (SLE)] showed a significant dose-response relationship for the primary endpoint of CLASI-A*** score, a measure of skin disease activity, over a period of 16 weeks,” said the researchers.

Part B of LILAC comprised 132 participants with moderate-to-severe subacute^# or chronic^## CLE (or both). They were randomized to receive SC litifilimab 50, 150, or 450 mg (n=26, 25, and 48, respectively) or placebo (n=33) at weeks 0, 2, 4, 8, and 12. Eligible participants had also received previous treatment with topical or antimalarial agents (or both) which have failed or rendered intolerable side effects. [N Engl J Med 2022;387:321-331]

Mean baseline CLASI-A scores were 15.2, 18.4, 16.5, and 16.5 for the respective litifilimab 50, 150, and 450 mg, and placebo arms.

At week 16, the baseline CLASI-A scores dropped across all arms, more so with litifilimab (least squares mean [LSM] changes, –38.8, –47.9, and –42.5 percent with the 50-, 150-, and 450-mg doses, respectively) than with placebo (LSM change, –14.5 percent). “[The] negative values indicate improvement from baseline,” the researchers noted. Using the best-fit dose-response model, these were deemed significant.

Between litifilimab and placebo, LSM differences in CLASI-A score changes from baseline to week 16 were –24.3, –33.4, and –28.0 percentage points for the respective 50-, 150-, and 450-mg doses. However, the summary dose-response analysis did not compare the three doses against each other.

Three cases of hypersensitivity were reported with litifilimab, leading to treatment cessation. Viral infections were also reported with litifilimab use (systemic [though unspecified]; influenza, oral herpes, herpes zoster, upper respiratory tract infection, rash).

Seven litifilimab recipients had serious adverse events, two had SLE flares (with litifilimab 150 mg), and one had a serious case of herpes zoster meningitis (with litifilimab 50 mg) about 4 months after receiving the last dose.

“The high rate of herpes zoster among participants emphasizes the importance of administering zoster vaccine to patients before starting these drugs,” said Dr Daniel Wallace from Cedars-Sinai Medical Center, Los Angeles, California, US, in an accompanying editorial. [N Engl J Med 2022;387:939-940]

Altering upstream lupus inflammatory pathways

“[The findings] and the subsequent FDA approval of anifrolumab, a monoclonal antibody that binds to and internalizes type I interferon receptor, for the treatment of SLE, suggest the possibilities of altering the upstream pathways of the innate immune system,” Wallace noted.

The CLASI-A score improvements with litifilimab reported in LILAC outdid those seen in previous reports. However, direct comparisons between studies cannot be made as they had different patient populations, Wallace pointed out.

“The findings are nevertheless all provocative for phase II trials … Lupus has lagged behind its rheumatic disease cousins, such as vasculitis and rheumatoid arthritis, in drug development,” Wallace noted. “The results … encourage further exploration of interventions that affect upstream lupus inflammatory pathways in the innate immune system in lupus.”

Larger and longer trials are warranted to validate the efficacy and safety of litifilimab for the treatment of a lifelong disorder.