Mixed Results for Novel Lupus Drug in Mid-Stage Trial

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09/08/2022

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medpagetoday.com

An investigational biologic agent with an entirely new mechanism of action appeared effective for limiting joint involvement in systemic lupus erythematosus (SLE), results from a phase II randomized trial indicated.

Lupus patients receiving the drug, called litifilimab (previously BIIB059), had an average of 15.0 fewer active joints relative to baseline after 24 weeks, compared with a decrease of 11.6 active joints in a placebo group (difference 3.4, 95% CI 0.2-6.7, P=0.04), reported Richard Furie, MD, of Northwell Health in Great Neck, New York, Nathalie Franchimont, MD, PhD, of Biogen in Cambridge, Massachusetts, and colleagues.

However, most secondary endpoints did not show significant benefit, and joint involvement was not the trial's original primary outcome, they reported in noting these issues in the New England Journal of Medicine.

The investigators were suitably cautious about the drug's potential. "Larger and longer trials are necessary to determine the effect and safety of litifilimab in patients with SLE," Furie and colleagues wrote. They noted that these are already underway, as developer Biogen is now conducting two phase III trials with a wider range of endpoints.

In an accompanying editorial, Daniel J. Wallace, MD, of Cedars-Sinai Medical Center in Los Angeles, was actually more enthusiastic about litifilimab, calling the results "provocative for phase II trials" and highlighted the importance of its novel target.

Litifilimab binds to a target called blood dendritic cell antigen 2 (BDCA2), which serves to downregulate interferon production by plasmacytoid dendritic cells. Wallace wrote that the phase II results "encourage further exploration of interventions that affect upstream lupus inflammatory pathways in the innate immune system in lupus."

Wallace also saw the effort as overdue: "Lupus has lagged behind its rheumatic disease cousins, such as vasculitis and rheumatoid arthritis, in drug development." He noted that BDCA2 isn't the only new target to attract pharma interest, citing other projects targeting complement, cell-surface receptors, so-called tolerogens, and varied immune cell species.

As initially designed, the LILAC trial was intended to examine litifilimab's effects on cutaneous lupus manifestations via Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI-A) scores. But after 22 patients had been enrolled and started treatment (though before results were unblinded), the investigators decided instead that, because of "slow recruitment" and an increased desire to evaluate arthritis as well, the primary outcome was changed to the number of active (swollen/tender) joints; skin manifestations became a secondary endpoint. Eligibility criteria were also changed to require that patients have at least four swollen and four tender joints. Another 110 patients were enrolled under this scheme. Results were reported for 120 SLE patients who received their assigned treatment.

Mean patient age was about 40. Despite the randomization, there were some potentially important differences between the treatment arms: 98% of the litifilimab group were women versus 88% of the placebo group. The racial makeup differed somewhat as well (e.g., none of the placebo group were Black, as opposed to 9% for litifilimab), and fewer patients assigned to litifilimab came into the study with skin manifestations (58% vs 68%).

The protocol changes also included altered dosing regimens. Patients treated under the original version received a variety of subcutaneous litifilimab doses, ranging from 50 to 450 mg. Later recruits in the active-drug arm all received 450 mg, but with fewer doses (five in all, versus seven in the original protocol).

Litifilimab was associated with a trend toward greater decrease in skin manifestations, with 64% of patients seeing at least 50% declines from baseline in CLASI-A scores, compared with 42% of the placebo group. However, the least squares mean difference versus placebo was put at 20.0 points with a 95% confidence interval that spanned 0 (-1.3 to 41.3).

Results were similar for mean changes in CLASI-A scores, all trending in litifilimab's favor but missing statistical significance.

Statistically significant advantages for the drug were seen for overall lupus severity as evaluated with the SLE Disease Activity Index-2K. Some 56% of litifilimab patients had declines of 4 or more points on this measure, versus 29% of the placebo group, and the mean absolute declines were 4.4 and 2.6 points, respectively. No differences were observed, though, in rates of lupus progression during the 24-week study or in Physician's Global Assessment scores.

In general, litifilimab was well tolerated, but one noteworthy safety finding was that three patients receiving litifilimab suffered herpes zoster or keratitis attacks (versus two in the placebo group). Wallace said this mainly highlights the need for all lupus patients to receive shingles vaccines before starting immunomodulator therapy.

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