Iberdomide confers dermatologic benefit for SLE
A high dose of the high-affinity cereblon ligand iberdomide delivered beneficial effects on the cutaneous manifestations of systemic lupus erythematosus (SLE), according to a phase II study presented at EULAR 2021.
“[The effect] is more pronounced in patients with subacute cutaneous lupus erythematosus (SCLE) or chronic CLE (CCLE) subtypes treated with the highest dose of iberdomide relative to placebo,” said Dr Victoria Werth from the University of Pennsylvania and the Michael J Crescenz VA Medical Center, Philadelphia, Pennsylvania, US, during her virtual presentation.
A total of 280 participants (mean age 44.6 years, 97 percent female) were randomized 2:2:2:1 to receive either placebo or QD iberdomide 0.45, 0.30, or 0.15 mg for 24 weeks. Following which, the three iberdomide regimens were continued up to the blinded active treatment and long-term extension phases (weeks 52 and 104, respectively), while those on placebo were rerandomized to either the 0.45- or the 0.30-mg iberdomide dose. [EULAR 2021, abstract OP0132]
Participants had SLE for a mean 9.3 years, with a mean SLE Disease Activity Index 2K global score of 9.6 and a mean Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity (CLASI-A) score of 6.95. About 20 percent of participants had CLASI-A scores ≥8, 27 percent were Aiolos-high, while about 45 percent were type 1 interferon-high. Most of the participants had acute CLE (~60 percent), while the rest either had SCLE or CCLE.
In the overall cohort at week 24, similar CLASI-50 response rates were seen with all iberdomide doses relative to placebo (stratified differences, 0.4; p=0.96 [0.15 mg], 5.3; p=0.49 [0.30 mg], and 10.9; p=0.16 [0.45 mg]). There were also no significant differences across all patient subgroups evaluated (ie, CLASI-A ≥8, ACLE, SCLE, and CCLE). Werth attributed the lack of statistical significance to the increase in placebo response at this timepoint.
However, the highest dose of iberdomide led to significant improvements in CLASI-50 response rates among participants with SCLE (stratified difference, 38.7; p=0.035) and CCLE (stratified difference, 34.1; p=0.029) compared with placebo. “[The] treatment differences were observed as early as week 4, with continuous improvements over time to week 24,” noted Werth.
Among participants with baseline CLASI-A score ≥8, mean improvement from baseline CLASI-A scores were similar across all iberdomide doses, dropping from week 4 through 24.
When stratified by CLE subtype, a significant improvement from baseline CLASI-A score was observed with the highest dose of iberdomide compared with placebo among patients with SCLE (p=0.024). A trend towards improvement was also seen with the two higher iberdomide doses among those CCLE.
Iberdomide stimulates proteasomal degradation of Ikaros and Aiolos – two cereblon substrates tied to the genetic risk for SLE. [J Med Chem 2018;61:535-542] The findings align with the pharmacodynamic effects of iberdomide, which has been shown to decrease B-cell and type 1 interferon pathway activity. [Ann Rheum Dis 2018;77:1516-1523; Arthritis Rheumatol 2020;72(suppl 10);abstract 0851]
“Iberdomide was also well-tolerated in the overall trial [and has an] acceptable safety profile, with dose-dependent neutropenia, infections, and rash,” said Werth.