麻豆传媒

What could be the first oral medication specific for systemic lupus erythematosus (SLE) was more effective than placebo in a , though the results were something less than a home run.

With 288 patients assigned to three doses of the novel agent iberdomide or placebo, 54% of those taking the highest dose achieved level 4 on the SLE Responder Index (SRI-4, the primary outcome) compared with 35% of the placebo group (difference 19.4 percentage points, 95% CI 4.1-33.4, P=0.01), reported Joan T. Merrill, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City, and colleagues .

More patients in the high-dose iberdomide group (0.45 mg once daily) also showed at least a 4-point decline in the (SLEDAI-2K), a key secondary endpoint. But safety findings were less satisfying.

Rates of urinary and upper respiratory tract infections were both higher with iberdomide, at 0.30 mg and 0.45 mg per day: 10% and 16% of patients, respectively, versus 4% of the placebo group. Along these lines, rates of nasopharyngitis and sinusitis were also increased. Perhaps more concerning, neutropenia and leukopenia were also more common with the two higher iberdomide doses compared with placebo. Overall, treatment-related adverse events were seen in 40% and 44% of the high- and mid-dose iberdomide groups, versus 29% of those receiving placebo.

An by Karen Costenbader, MD, MPH, of Brigham and Women's Hospital in Boston, highlighted these apparent side effects, along with other results, as "red flags" that should "temper ... enthusiasm" for the possibility of an oral drug for lupus. Besides the increased risk for infections and immune deficiency, she pointed to a lack of benefit in a number of secondary endpoints and what she termed a "high incidence" of treatment discontinuation (24% of the 0.30 mg/day group, although the rate was only 10% at 0.45 mg/day).

Iberdomide (formerly CC-220) acts through the ubiquitin pathway to reduce intracellular levels of two transcription factors called Ikaros and Aiolos. It's a member of the immunomodulatory imide drug (IMiD) class, which, Costenbader noted, is believed to carry risk for thrombosis, and the possibility of teratogenicity hasn't yet been excluded for IMiDs.

Only one case each of brain-stem infarction and deep vein thrombosis (DVT) were seen among iberdomide recipients, and none had pulmonary embolism (PE) or myocardial infarction, versus one DVT and one PE with placebo. But Merrill and colleagues were clearly aware of the risk: all patients received thromboprophylaxis with low-dose aspirin or other blood thinners, and those at particularly high risk for thrombosis were excluded.

Study participants were adults meeting American College of Rheumatology criteria for lupus. Baseline SLEDAI-2K scores of at least 6 were required, including scores of at least 4 based solely on clinical parameters. Patients also had to show antinuclear antibody titers of at least 1:40 with seropositivity for anti-double-stranded DNA antibodies or anti-Smith antibodies. Among the exclusion criteria were active lupus nephritis or neuropsychiatric manifestations, as well as the presence of antiphospholipid antibodies or other risk factors for thrombosis.

Mean SLEDAI-2K score at baseline was 9.6. About half the sample had acute lupus, some 30% had the chronic form, and 16% were classed as subacute. Patients were generally in their 30s, 40s, and 50s, and nearly all were women. More than 40% were from Mexico or South America, 35% from Europe and Russia, and 22% from the U.S. and Canada.

Patients were randomized 2:2:1:2 to iberdomide at 0.45, 0.30, or 0.15 mg/day, or placebo. That meant just over 80 each received the two highest doses and placebo, with about 40 receiving the low drug dose.

SRI-4, the trial's primary outcome, was defined as any of the following:

• Reduction of at least 4 points on the SLEDAI-2K
• No new disease activity as rated at level A on the 97-item , or with no more than one BILAG level B score
• No increase beyond 0.3 points on the 3-point Physician's Global Assessment

Secondary endpoints included each of the above standing alone, as well as reductions from baseline in steroid use. Except for a clear difference in rates of 4-point decline in SLEDAI-2K scores, none of these showed a significant advantage for any iberdomide dose. Costenbader, in her editorial, cited the lack of benefit in these outcomes as another reason to be cautious about iberdomide.

"When phase II trials of treatments for [lupus] show positive results, I am delighted but try not to get my hopes up; there have been too many phase III trial failures," she wrote.

"I am, of course, excited about the somewhat positive signal. ... Precision medicine for SLE is on the horizon; soon, therapies may be selected on the basis of specific gene-expression signatures," she added.

Nevertheless, she suggested, that day has not come yet. Indeed, for their part, Merrill and colleagues also showed only mild enthusiasm.

"Longer and larger trials are warranted to determine the effect and safety of iberdomide in patients with SLE," they concluded, after noting a series of limitations to the study, such as the wide swath of exclusions and the predominantly white sample.

has not yet committed to a phase III trial. The company is also in sepsis, multiple myeloma, and several forms of lymphoma, and recently commenced a safety trial in patients with renal impairment.

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