Iberdomide Improves Systemic Lupus Erythematosus Response in Phase 2 Trial

Joan T. Merrill, MD

Iberdomide provided greater therapeutic response to patients with systemic lupus erythematosus (SLE) than placebo, according to new phase 2 findings supporting the continued investigation of the novel drug.

Led by Joan T. Merrill, MD, of the Arthritis and Clinical Immunology Research Program at the Oklahoma Medical Research Foundation, investigators sought to evaluate the clinical benefit of iberdomide in patients with active, moderate to severe SLE. A previous phase 2A trial showed the agent’s association with decreased SLE disease activity; its components imply it could provide unique benefit for patients with the rheumatic disease.

“Iberdomide is a high-affinity cereblon modulator that binds to cullin-RING E3 ubiquitin ligase 4 complex, promoting ubiquitination and proteasomal degradation of Ikaros and Aiolos,” Merrill and colleagues wrote. “Multiple immunomodulatory effects include increased levels of interleukin-2 and decreased levels of pro-inflammatory cytokines, B-cell differentiation, and autoantibody production.”

Investigators randomly assigned patients 2:2:1:2 to either once-daily oral iberdomide (0.45, 0.30 or 0.15 mg dose, respectively) or placebo for a treatment period of 24 weeks. Patients were permitted to continue standard medication during the trial. The team sought a primary end point of SLE Response Index (SRI-4) response among treated patients.

SRI-4 was defined by reductions of ≥4 points in the 24-item, weighted SLE Disease Activity Index 2000 (SLEADI-2K) score. Investigators additionally assessed for no new disease activity per British Isles Lupus Assessment Group 2004 (BILAG-2004) index, as well as no increase of ≥0.3 points in Physicians Global Assessment (PGA) score for disease activity.

The trial’s 288 patients were randomized to once-daily oral iberdomide 0.45 mg (n = 81), 0.30 mg (n = 82), 0.15 mg (n = 42), and placebo (n = 83). Mean patient age was 45 years old, with 72% being White. Mean disease activity at baseline, per SLEDAI-2K, was 9.6.

A majority of patients to receive 0.45 mg iberdomide achieved SRI-4 response (54%) after 24 weeks; another 40% and 48% of patients to receive 0.30 mg and 0.15 iberdomide achieved the endpoint, respectively. Just 35% of patients to receive placebo achieved SRI-4 response, providing an adjusted difference of 19.4 percentage points with 0.45 mg iberdomide (95% CI, 4.1 – 33.4; P = .01).

Investigators additionally observed insignificant improvements in BILAG-2004 scores between iberdomide 0.45 mg and placebo (8.0; 95% CI, -3.9 to 19.7) nor PGA (6.8; 95% CI, -5.2 to 18.6).

“However, numerically more patients in the iberdomide 0.45-mg dose group had a decrease in the SLEDAI-2K score of at least 4 points and an SRI-4 response only with a sustained decrease in the use of glucocorticoids, although no conclusions can be drawn from these secondary end-point results because the widths of confidence intervals were not adjusted for multiple comparisons,” investigators explained.

Adverse events associated with the investigative therapy included urinary tract infections, upper respiratory tract infections, and neutropenia.

Despite limitations including the exclusion of patients with increased thrombotic risk, active lupus nephritis or neuropsychiatric manifestations of SLE—as well as generalizability of trial results based on lacking patient population diversity—the findings provided more interest in assessing the absolute value of iberdomide for patients with SLE.

“In patients with SLE, iberdomide at the highest dose, but not at lower doses, was superior to placebo with respect to the primary end point of an SRI-4 response at 24 weeks,” investigators concluded. “Longer and larger trials are warranted to determine the effect and safety of iberdomide in patients with SLE.”

The study, “Phase 2 Trial of Iberdomide in Systemic Lupus Erythematosus,” was published online in The New England Journal of Medicine.