Only highest-dose iberdomide outperforms placebo in SLE; adverse events high
Click Here to Manage Email Alerts
Iberdomide, a novel oral cereblon modulator, was superior to a placebo only in patients with systemic lupus erythematosus who received the highest dose in a phase 2 trial, albeit with a high incidence of adverse events, according to data.
“Lupus treatment development has been problematic because of the diversity of clinical manifestations and pathology in people with this same diagnosis,” Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation, in Oklahoma City, and lead author of the study, told Healio. “Selection and dosing of available treatment remains largely trial and error.
“There is a focus now on developing objective measures that could better predict optimal treatment and potentially guide dosing for individuals,” she added. “Although no conclusions can yet be drawn from the preliminary biomarker observations in this trial, they represent a very necessary step in the right direction.”
According to Merrill and colleagues, iberdomide (Bristol Myers Squibb) is an oral cereblon modulator that binds to cullin-RING E3 ubiquitin ligase 4 complex, “promoting ubiquitination and proteasomal degradation of Ikaros and Aiolos,” they wrote in The New England Journal of Medicine.
“Multiple immunomodulatory effects include increased levels of interleukin-2 and decreased levels of pro-inflammatory cytokines, B-cell differentiation, and autoantibody production,” they wrote. “A phase 2a trial of iberdomide in patients with SLE showed decreased disease activity.”
The study
To assess iberdomide in patients with active, moderate-to-severe SLE, Merrill and colleagues conducted a randomized, placebo-controlled, double-blind phase 2 trial of 288 participants from 117 sites in the United States, Canada, Mexico, Russia, Europe and South America. Eligible participants were adults who met the American College of Rheumatology criteria for SLE, had a score of at least 6 points on the SLEDAI-2K and a score of 4 or higher on the clinical SLEDAI-2K.
In addition, participants demonstrated antinuclear antibody titers of at least 1:40 and were seropositive for anti-double-stranded DNA antibodies or anti-Smith antibodies. Patients with neuropsychiatric SLE, an estimated glomerular filtration rate of less than 45 mL per minute per 1.73 m2, proteinuria greater than 2,000 mg per day, nephritis warranting induction treatment, antiphospholipid syndrome or high-risk antiphospholipid status were excluded.
Participants were randomly assigned 2:2:1:2 to receive oral iberdomide 0.45 mg, 0.3 mg, 0.15 mg or placebo daily for 24 weeks, in addition to standard medications. The primary endpoint was SLE Responder Index (SRI-4) response — defined as a reduction of at least 4 points in SLEDAI-2K score, no new disease activity based on the British Isles Lupus Assessment Group 2004 index and no increase of 0.3 points or more in the Physician’s Global Assessment score — at week 24.
Secondary endpoints included the percentage of patients with at least a 4-point reduction in the SLEDAI-2K score, the percentage of patients with at least a 50% decrease in the Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity Score (CLASI-A), the percentages of patients with no new BILAG-2004 organ involvement and no increase of 0.3 points or more in the PGA score, the mean change from baseline in the number of swollen joints and tender joints in those who had at least two affected joints at enrollment, and others.
According to the researchers, SRI-4 response at week 24 was achieved in 54% of participants treated with 0.45 mg of iberdomide, 40% of those in the 0.3 mg group and 48% of those in the 0.15 mg group, compared with 35% among those who received placebo. The adjusted difference between the 0.45 mg and placebo groups was 19.4 percentage points (95% CI, 41.-33.4). There were no significant differences between the lower dose iberdomide groups and those who received placebo. Most of the secondary endpoints were not met.
Regarding adverse events, the researchers noted that thromboembolic events are a class effect of cereblon-modulating agents. Patients at high risk for thromboembolism were excluded from the trial, and all participants received mandatory thromboprophylaxis. Upper respiratory and urinary tract infections, neutropenia, and rashes occurred more often in the patients who received iberdomide than in those in the placebo group. In all, adverse events were reported in 78%, 78% and 74% of those treated with the high, middle and low doses of iberdomide, respectively, and in 65% of those in the placebo group.
“This small, phase 2 study met its primary endpoint of efficacy at the highest does of iberdomide that was tested,” Merrill said. “There is a great deal more to be learned about this treatment, but there was an intriguing preliminary observation of greater efficacy in patients who entered the trial with an elevated expression of genes relevant to how the drug works — Aiolos and the Type I interferon pathway genes.”
She added: “If these findings are confirmed it would suggest that a more rational approach to treatment selection for lupus patients might be possible in the future.”
‘Red flags’
In an accompanying editorial, Karen H. Costenbader, MD, MPH, of Brigham and Women’s Hospital, in Boston, expressed measured excitement at the “somewhat positive signal” in a trial of a new oral drug for SLE. However, that enthusiasm was tempered by what she referred to as several “red flags.”
In addition to the high incidence of adverse events among patients who received iberdomide, Costenbader pointed to the 24% of participants in the middle-dose group who discontinued treatment due to said adverse events and trial withdrawal. In addition, 72% of the trial’s participants were white, while just 7% were Black.
According to Costenbader, this lack of racial diversity in the study population is a “long-standing and grave problem in the research of therapies for SLE,” particularly as the disease disproportionately impacts, and leads to increased mortality, among individuals of African descent, especially Black women in the United States.
“I am, of course, excited about the somewhat positive signal in this phase 2 trial of a new oral medication for SLE,” Costenbader wrote. “Precision medicine for SLE is on the horizon; soon, therapies may be selected on the basis of specific gene-expression signatures. Nevertheless, the several red flags in this trial, including a high incidence of adverse events and treatment discontinuation, the fact that secondary end points (including one for cutaneous lupus) were not met, small effect sizes, and the potential teratogenicity and thrombogenicity of iberdomide, temper this enthusiasm.”
Collapse
Merrill JT, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2106535.
Costenbader, KH. N Engl J Med. 2022;doi:10.1056/NEJMe2201329.
Read more about
Click Here to Manage Email Alerts