Iberdomide: an upcoming new treatment possibility in lupus erythematosus

In an extension trial after the blinded phase 2 evaluation, iberdomide showed lasting benefits as a therapeutic agent for systemic lupus erythematosus (SLE). Safety assessments up to 1 year were reassuring.

“Iberdomide is a high-affinity cereblon ligand that promotes degradation of 2 transcription factors: Ikaros and Aiolos. These factors are involved in immune-cell development, homeostasis, and genetic variants associated with risk for lupus,” Prof. Joan Merrill (Oklahoma Medical Research Foundation, OK, USA), explained the properties of the study drug [1]. Gene polymorphisms of these transcription factors are associated with the risk of SLE and these transcription factors are overexpressed in the blood cells of patients with SLE [2–4].

In a previously published phase 2, randomised-controlled trial, oral iberdomide has been investigated for efficacy and safety in the treatment of SLE (NCT03161483) [5]. The 247 study subjects were randomised to placebo or iberdomide at daily doses of 0.45 mg, 0.30 mg, or 0.15 mg for the first 24 weeks. The primary endpoint was defined as SLE Responder Index (SRI)-4 response. Mean patient age was between 43.4 and 46.4 years, the vast majority of patients were women. The primary endpoint at week 24 was met by 54.3% of those on the highest dose of iberdomide compared with 24.9% on placebo. In the novel extension trial, sustained efficacy and safety of iberdomide was investigated through week 52. The 80 patients on placebo were re-randomised to iberdomide 0.3 mg or 0.45 mg at week 24, while patients on iberdomide continued their original regimens [1].

Looking at the primary endpoint of SRI-4 at week 52, response rates were either sustained or improved from week 24 in all treatment groups, leading to 51.9% (0.45 mg), 52.4% (0.3 mg), and 50.0% (0.15 mg) of patients achieving this endpoint (see Figure). The percentage of patients in the former placebo group, who were switched to the study drug after week 24, also increased in SRI-4 achievement at week 52: 41.7% versus 61.1% (placebo to 0.3 mg) and 38.9% versus 58.3% (placebo to 0.45 mg). Furthermore, for SRI-6 and SRI-8 achievement in patients with a baseline SLE disease activity index 2,000 (SLEDAI 2K) ≥10, sustainment or ameliorations in efficacy were noted. “The tender and swollen joint count endpoint was not met by any dosing group by week 24, but it continued to improve in all groups between weeks 24–52. However, in the second half there is no ongoing placebo group to compare this to,” Prof. Merrill explained.

Figure: SLE responder index 4 (SRI-4) response up to week 52 in the intent-to-treat population (non-responder imputation) [1]



Infections of the urinary tract (14.9%) or the upper respiratory tract (11.2%), as well as neutropaenia (9.8%) were the highest reported adverse events, with a suggestion of dose response for the latter 2. “The most frequent events leading to discontinuation were rash and neutropaenia,” Prof. Merrill said. Iberdomide was overall well tolerated.

“In conclusion, iberdomide treatment of patients with lupus was associated with sustained clinical benefits in multiple measures of disease activity up to week 52,” Prof. Merrill summarised.

1. Merrill J. Sustained Efficacy and Safety of Iberdomide to Week 52 in Patients with Active Systemic Lupus Erythematosus (SLE) in a Phase 2, Randomized, Placebo-Controlled Study. Abstract 1458, ACR Convergence 2021, 3–10 November.
2. Westra H-J, et al. Nat Genet 2013;45:1238-1243.
3. Lessard CJ, et al. Am J Human Genet. 2012;90:648-660.
4. Nakayama Y, et al. J Immunol 2017;199:2388-2407.
5. Merrill J, et al. Arthritis Rheumatol. 2020;72 (suppl 10).

 

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Posted on 14 January 202217 May 2024