Litifilimab superior to placebo in reducing tender, swollen joints in lupus
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Litifilimab is superior to placebo in reducing tender and swollen joints among patients with systemic lupus erythematosus, according to phase 2 trial data published in the New England Journal of Medicine.
“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,” Richard A. Furie, MD, chief of rheumatology at Northwell Health in New York, and co-authors wrote. “In a phase 1 trial that included 12 participants with SLE and cutaneous lupus erythematosus, biologic activity of litifilimab was shown by a dampened interferon signature in blood and modulated type I interferon–induced proteins in skin.
“Here, we report the findings from part A [of the phase 2 trial], which involved participants with SLE who had both active arthritis and rash,” they added. “Part B, which focused on cutaneous lupus erythematosus with or without systemic manifestations, has been reported previously.”
To investigate the safety and efficacy of litifilimab (BIIB059, Biogen) in patients with SLE, Furie and colleagues conducted the LILAC trial, a phase 2, two-part, multicenter, double-blind, randomized, controlled study. The trial included patients between the ages of 18 and 75 years who had SLE according to the 1997 American College of Rheumatology classification criteria. Patients were required to have the diagnosis in writing 24 weeks before agreeing to participate in the trial.
Included patients were also required to demonstrate antinuclear antibody (ANA) titers of 1:80 or greater, anti-double-stranded DNA antibody levels of 30 IU per mL, or both. In addition, patients were allowed to enroll while receiving prednisone in doses of less than 20 mg per day.
The trial included two distinct protocols for enrollment. The first protocol allowed patients with active skin disease at the time of screening and randomization. Protocol two, meanwhile, included patients with one or more active skin lesions, as well as active arthritis. Under the first protocol, patients were randomized 1:1:1:1, but the trial was reconfigured before unblinding took place in part to slow recruitment, the authors wrote.
In protocol two, patients were randomized 1:1 following a 28-day screening process. Patients in this protocol received litifilimab 450 mg or placebo at weeks 0, 2, 4, 8, 12, 16 and 20. Following the 24-week dosing period, patients were followed for a 12-week safety observation period.
Following the protocol change, the primary endpoint was the change from baseline in the total number of active joints at week 24. Secondary endpoints included a decrease of 50% or more from baseline in skin-related disease activity. Overall changes in SLE disease activity were included as an additional secondary endpoint. The researchers monitored adverse events, serious adverse events and changes in laboratory numbers.
In total, the study included 132 patients, of whom 64 were treated with litifilimab 450 mg, six received litifilimab 150 mg, six received litifilimab 50 mg and 56 received placebo. The analysis, however, only included the patients who received litifilimab 450 mg or placebo, the authors wrote.
According to the researchers, the least-squares mean change from baseline to week 24, as measured by the total number of active joints, was –15.0±1.2 with litifilimab and –11.6±1.3 in the placebo group (mean difference = –3.4; 95% CI, –6.7 to –0.2). Regarding safety, litifilimab was associated more commonly with adverse events, including two cases of herpes zoster and one case of herpes keratitis, the authors wrote.
“In this phase 2, randomized, placebo-controlled trial that involved participants with SLE, arthritis, and active skin disease, litifilimab at a dose of 450 mg was superior to placebo in the change from baseline in the total number of active joints at week 24,” Furie and colleagues wrote. “Larger and longer trials are necessary to determine the effect and safety of litifilimab in patients with SLE.”
References:
Furie R, et al. J Clin Invest. 2019;doi:10.1172/JCI124466.
Perspective
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We see in this report more fruit borne of a tree that was first a sprig some five decades ago, an approach suggested in a 1979 paper in this same journal and frequently cited by the first author above, the recognition of the key role of interferons in systemic lupus and autoimmune disorders.
Extensive study into the manipulation of interferon alpha and beta and their main source, the plasmacytoid dendritic cell, led to the development and approval recently of anifrolumab (Saphnelo, AstraZeneca) and now litifilimab (BIIB059, Biogen), an antibody to BDCA2, a plasmacytoid dendritic cell surface receptor. The drug’s binding to this antigen, which is specific to those cells, downregulates interferon alpha production, enabling its therapeutic effect.
The current study is only one part of a two-pronged trial. The other arm, part B, was limited to cutaneous lupus and published previously, also an encouragingly positive study. Meanwhile, part A, herein described, represents amended protocol encompassing both skin and overall SLE disease activity, featuring joint activity, the latter becoming the primary endpoint.
For part B, 110 patients were enrolled and randomized to litifilimab 450 mg and standard of care (SOC), or placebo and SOC. The study drug was administered via loading dose every two weeks for the first month, then monthly for the next 4 months to week 20. Assessments were performed at 24 weeks, with safety followed for another 12 weeks.
The primary endpoint evaluated percent change in the sum of swollen and tender joints at 6 months, and, in fact, statistically significant reductions (P = .04) in this variable were confirmed. Total tender and swollen active joints reduced from 15 (+/- 1.2) on active treatment compared with 11.6 (+/- 1.3) in the placebo group. Multiple secondary endpoints, which included CLASI skin score, SRI4, SLEDAI-2K changes, BILAG2004 and PGA, were not met — the trial was not powered for this.
The monoclonal antibody was not found to alter the immunologic parameters we use to serologically assess lupus activity and, as emphasized by Daniel J. Wallace, MD, in an accompanying editorial, it should not be expected to reduce the protective effect of other cytokines’ efforts combatting viral and other pathogens.
Observations on the of safety of the new drug found mild-to-moderate adverse effects, diarrhea, upper respiratory infection, urinary tract infection, headache, influenza and zoster infections as could be expected, the last of which we can in practice mitigate with the available recombinant zoster vaccine.
We can venture a few criticisms of this study, for its short duration and small denominator, lack of diverse representation among entrants, and ultimately a somewhat unimpressive movement of the needle in its efficacy. For the practicing rheumatologist, this non-renal study population with SLEDAI scores averaging 10 may be a bit more ill than we typically treat, but the agent should fit nicely alongside the other old and new lupus biologics in our armamentarium. One looks forward to forthcoming litifilimab data, as well as further fruit from the pDC and interferon alpha pathogenesis tree.
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Furie RA, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2118025.
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