High-dose iberdomide shows promise in phase II SLE trial

In a phase II trial evaluating three doses of the high-affinity cereblon modulator iberdomide, the 0.45-mg dose demonstrated superiority over placebo for individuals with active, moderate-to-severe systemic lupus erythematosus (SLE).

“In this trial, the primary endpoint of an SLE Responder Index (SRI-4) response was met in a higher percentage of patients in the group that received the highest dose of iberdomide than in the placebo arm, but the criteria were not met in the groups that received lower doses,” said the researchers.

A total of 288 participants (mean age 44.7 years, 97 percent female, 72 percent Caucasian) were randomized 2:2:1:2 to receive oral iberdomide 0.45, 0.30, or 0.15 mg or placebo QD for 24 weeks, on top of standard-of-care medications. [N Engl J Med 2022;386:1034-1045]

At week 24, more than half (54 percent) of iberdomide 0.45-mg recipients had an SRI-4 response. Only a third (35 percent) of placebo recipients were able to achieve this endpoint (adjusted between-group difference, 19.4 percentage points; p=0.01).

No significant differences were seen between the iberdomide 0.30-mg and the placebo arms (adjusted difference, 5.0 percentage points; p=0.51), as well as between the iberdomide 0.15-mg and the placebo arms (11.4 percentage points; p=0.21).

Up to 78 percent of patients across all iberdomide arms reported adverse events (AEs) compared with 65 percent of those receiving placebo, but most were mild to moderate. The most frequent AEs reported with iberdomide were urinary tract and upper respiratory tract infections, neutropenia, and influenza. Other AEs tied to iberdomide use were dose-dependent (herpesvirus infection, fungal skin infection, and varicella-zoster virus infection [0.45 mg]; pneumonitis and oral herpesvirus infection [0.15 mg]).

Across the iberdomide arms, the 0.30-mg dose had the highest incidence of withdrawal owing to AEs (13 percent); the other two doses had a similar discontinuation rate (5 percent in each arm). No deaths were reported with iberdomide.

Red flags despite partially positive signal

“I am … excited about the somewhat positive signal in this phase II trial of a new oral medication for SLE … [which] is challenging to diagnose, treat, and study … Precision medicine for SLE is on the horizon. Soon, therapies may be selected based on specific gene-expression signatures,” commented Dr Karen Costenbader from Brigham and Women’s Hospital, Boston, Massachusetts, US, in a separate editorial. [N Engl J Med 2022;386:1085-1086]

However, the study has limited patient diversity – with an underrepresented Black cohort – which may restrict generalizability of the results. “The lack of racial diversity in the trial population is a long-standing and grave problem in the research of therapies for SLE, a disease that disproportionately affects and causes increased mortality among persons of African descent, particularly young Black women in the US,” Costenbader pointed out.

“[T]he several red flags … including a high incidence of AEs and treatment discontinuation, the fact that secondary endpoints … were not met, small effect sizes, and the potential teratogenicity and thrombogenicity of iberdomide, temper this enthusiasm,” she continued.

Larger, longer studies are thus warranted to further ascertain the benefit of iberdomide for SLE patients.