A new oral drug for systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is a heterogeneous multisystem autoimmune disease with few approved treatment options and no cure
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Because it affects various organ systems and causes long-term damage, it is commonly known as the "immortal cancer"
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A phase 2 trial in 2017 showed that iberdomide reduced disease activity in SLE, so there is great hope for the drug
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On March 10, 2022, the New England Journal of Medicine (NEJM) published a phase 2 randomized, placebo-controlled, double-blind trial at 117 sites in multiple countries evaluating 3 doses of ibedox Efficacy of amines in patients with moderate to severe SLE
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Its results showed that only the highest dose of ibelidomide in the trial, 0.
45 mg, improved response rates in patients with SLE compared with placebo, but the trial had a high rate of adverse events and high dropout rates
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So it's too early to be optimistic about it
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"NEJM Frontiers of Medicine" specially invited Professor Wu Rui from the Department of Rheumatology and Immunology of the First Affiliated Hospital of Nanchang University to interpret this research
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To read the full text translation, please visit the official website of NEJM Medical Frontiers, APP or click on the WeChat applet picture
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Wu RuiDepartment of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, SLE is a common autoimmune disease, which is more common in young women, with a prevalence ranging from 3.
2 to 5.
175/100,000 people
.

The prevalence rate in China is 70/100,000, and the number of women is as high as 113/100,000.
The number of patients with the disease exceeds 1 million, ranking second in the world
.

The immune mechanism of SLE is complex, involving innate immunity and adaptive immunity, among which the overactivation of B cells, the production of a large number of autoantibodies, and the formation of immune complexes are the main pathological features of SLE.

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SLE can involve important organs and systems such as the kidneys, heart and lungs, blood, and central nervous system, and has a high mortality rate
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Although the 10-year survival rate of SLE has increased to 90% with the improvement of diagnosis and treatment, the current status of SLE treatment is still not optimistic
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Most SLE patients are still in a state of persistent disease activity or recurrent attacks, and long-term use of hormones and immunosuppressive agents can lead to high cardiovascular events and infection rates
.

In terms of other therapeutic drugs, since belimumab (BLyS monoclonal antibody) was approved for SLE in 2011, it took 10 years before tetahcept (TACI fusion protein), anilumab (I IFN receptor monoclonal antibody) and voclosporin have been approved one after another
.

However, the efficacy of the three drugs is limited, and the incidence of adverse events is high, so it is still a challenge to find more safe and effective drugs for SLE
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Ikaros and Aiolos are a class of intranuclear transcription factors containing zinc finger domains, which play a decisive role in the development of hematopoietic cells and are closely related to the development and proliferation of B lymphocytes
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Studies have shown that mRNAs encoding genes for Ikaros (IKZF1) and Aiolos (IKZF3) are overexpressed in SLE patients and are associated with increased susceptibility to SLE
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Iberdomide is a high-affinity modulator of CRBN (a key member of the E3 ubiquitin ligase complex) that binds to the cullin-RINGE 3 ubiquitin ligase 4 complex to promote hematopoietic transcription factors Ubiquitination and proteasomal degradation of Ikaros and Aiolos thus have the potential to play a therapeutic role in SLE
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A phase 2a clinical trial showed that ibelidomide reduces disease activity in SLE
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The investigators re-evaluated the efficacy and safety of ibelidomide in a phase 2 randomized, placebo-controlled, double-blind trial involving moderately to severely active SLE patients
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The NCT03161483 study was published in the New England Journal of Medicine (NEJM) on March 17, 2022 [1]
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The trial was conducted at 117 research centers in the United States, Canada, Europe, South America, Mexico and Russia from July 6, 2017 to January 21, 2020
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Patients were eligible for inclusion if they were at least 18 years old and met the American College of Rheumatology's SLE classification criteria (updated in 1997)
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Patients with a SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) score of at least 6 and a clinical SLEDAI-2K (no laboratory results) score of 4 or more, suggesting moderate to severe disease activity
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Antinuclear antibody titer of at least 1:40, positive for anti-double-stranded DNA antibody or anti-Smith antibody
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Exclusion criteria included severe or unstable neuropsychiatric SLE, estimated glomerular filtration rate less than 45 mL/(min·1.
73 m2), proteinuria greater than 2000 mg/d, nephritis requiring induction therapy, and anti-inflammatory drugs.
Phospholipid syndrome or high-risk antiphospholipid status
.

SLE patients were randomized in a 2:2:1:2 ratio to oral ibelidomide (at doses of 0.
45, 0.
30, or 0.
15 mg) or placebo once daily for 24 weeks while continuing to use standard of care (Figure 1)
.

Stratification factors included baseline prednisone (equivalent) dose (≥10 mg/d or <10 mg/d) and SLEDAI-2K score (≥10 or <10)
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To address the thromboembolic risk associated with CRBN modulators, patients received at least one form of thromboprophylaxis (aspirin or low molecular weight heparin)
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 Figure 1.
Trial Design Of the 593 patients screened, 288 received treatment, 81 receiving ibelidomide 0.
45 mg, 82 0.
30 mg, 42 0.
15 mg, 83 cases received a placebo
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A higher proportion of patients discontinued treatment in the 0.
30 mg treatment group (20 of 82 patients [24%])
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The main reason for discontinuation was adverse events (19 of 288 patients [7%]), of which 15 patients were withdrawn from the trial
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At baseline, 109 of 288 patients (38%) had a high Aiolos gene signature, and 179 of 288 patients (62%) had a high type I interferon gene signature
.

Aiolos gene expression was higher in patients who received ibelidomide 0.
30 or 0.
45 mg compared to patients who received ibelidomide 0.
15 mg or placebo
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More patients who received the 0.
45 mg dose of ibelidomide had characteristically elevated type I interferon genes compared to the other groups
.

The primary endpoint of the study was 24-week SRI-4 response, defined as at least a 4-point reduction in SLEDAI-2K score, no new disease activity, BILAG-2004 index (British Island Lupus Rating Group 2004 Index, 97 items including 9 organs) score, from A [severe] to E [never cumulative] for each organ system) with no score above A (severe) or 1 B (moderate); or a PGA (Physician's Global Assessment) score (visual analogue scale) table, from 0 [no disease activity] to 3 [most severe disease]) without an increase of 0.
3 points or more
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At week 24, the SRI-4 response rate was 54% in the 0.
45 mg group; 40% in the 0.
30 mg group, 48% in the 0.
15 mg group, and 35% in the placebo group
.

There was a significant difference between the 0.
45 mg group and the placebo group (95% CI, 4.
1 to 33.
4; P=0.
01), and no significant difference between the other dose groups and the placebo group
.

Subgroup analysis according to baseline Aiolos and type I interferon gene expression (Figure 2) showed that in the high Aiolos gene signature subgroup, SRI-4 response rates were 64% and 33% in the 0.
45 mg and placebo groups , while in the high type I interferon gene signature subgroup, the SRI-4 response rates were 60% and 33%, respectively
.

Among patients with high type I interferon and Ikaros gene signatures, there was little difference in the proportion of SRI-4 responses
.

Figure 2.
SRI-4 response rates in patients receiving different doses of ibelidomide and placebo for 24 weeks in subgroup analysis by baseline Aiolos and type I interferon gene expression.
Secondary endpoints included a SLEDAI-2K score of at least Percentage of patients with a 4-point reduction and at least a 50% reduction in CLASI-A response rates
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The CLASI-A score (Ceramic Lupus Erythematosus Disease Area and Severity Index [CLASI] - Activity Score) is a measure of the severity of the skin disease (scores range from 0 to 70, with higher scores indicating greater disease activity )
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A 50% drop in the CLASI-A score is called the CLASI-50
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At Week 24, 45 of 81 patients (56%) in the 0.
45 mg group had a SLEDAI-2K score that decreased by at least 4 points from baseline; compared with 30 of 83 (36%) in the placebo group (difference).
, 19.
3%; 95% CI, 4.
0 to 33.
4)
.

The percentage of patients with a clinical SLEDAI-2K score reduction of at least 4 points was 55.
6% in the 0.
45 mg group and 38.
6% in the placebo group
.

Among 64 patients with a CLASI-A score of at least 10 at baseline, the 0.
45 mg treatment group had a better CLASI-50 response rate than the placebo treatment group at 24 weeks
.

Other secondary endpoints included the proportion of patients with no new BILAG-2004 organ involvement with a PGA score increase of no more than 0.
3 points, no increase in the mean number of swollen and painful joints (at least two involved joints at trial entry), Change in PGA, FACIT fatigue score (ranging from 0 to 52, with higher scores leading to lower fatigue), hormone reduction (prednisone dose reduction at 16 weeks in patients on prednisone doses above 10 mg at baseline [or equivalent dose] was reduced to less than 10 mg per day and maintained through Week 24 without relapse)
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The exploratory endpoint was the SRI-4 response rate in patients with a baseline SLEDAI-2K score ≥10 and high expression of Aiolos and type I interferon genes
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There was no significant difference between the groups in terms of the number of swollen and painful joints compared with the baseline
.

The corresponding mean changes from baseline in the FACIT fatigue score at week 24 were 5.
2, 3.
1, and 2.
7, respectively, compared with 3.
8 in the placebo group
.

With regard to steroid reduction, only 3 patients (2 in the placebo group and 1 in the 0.
30 mg group) met the secondary endpoint
.

Statistical analyses of most secondary endpoints were not clinically significant
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Safety assessments included a 12-lead electrocardiogram, clinical laboratory tests, vital signs assessment, and physical examination
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In terms of the number of patients with adverse events, 63 (78%) in the 0.
45 mg group, 64 (78%) in the 0.
30 mg group, 31 (74%) in the 0.
15 mg group, and 54 (65%) in the placebo group )
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Most events were mild to moderate
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The most common adverse events were urinary and upper respiratory tract infections, neutropenia, and influenza
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Serious adverse events occurred in 13 patients (6%) in the treatment group and 7 (8%) in the placebo group
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Three patients (4%) with serious adverse events in the placebo group experienced relapse of SLE
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There were no deaths in the treatment group
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One patient in the placebo group died of pulmonary embolism after exacerbation of SLE and acute upper respiratory viral infection
.

Of the 2 patients with deep vein thrombosis, 1 was from the 0.
30 mg treatment group and 1 was from the placebo group
.

Brainstem infarction occurred in one patient who received a therapeutic dose of 0.
30 mg
.

Thromboembolic events are a side effect of concern for CRBN modulators
.

In this study, patients at high risk of thromboembolism were excluded and thromboprophylaxis was mandatory in the trial, which showed that upper respiratory and urinary tract infections, neutropenia, and rash were more common in the treatment group than in the placebo group , while thrombotic events are likely to be underestimated
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In conclusion, the 24-week phase 2 trial of NCT03161483, published in this paper, shows that ibelidomide, a novel oral immunomodulatory drug, has demonstrated efficacy and was well tolerated in patients with active SLE
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However, the study also showed some limitations of ibelidomide in the treatment of SLE
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For example, the effective treatment window is small, the primary endpoint is only reached at the 0.
45 mg treatment dose, and most of the secondary endpoints are not reached, and even in cutaneous lupus, it does not show more treatment advantages, and in terms of safety, the risk of infection is high, Most adverse events occurred in the therapeutically effective dose group, and the incidence of withdrawal from the trial due to adverse events was high, and this did not include our concerns about the potential teratogenic and thrombotic risks of IMiD drugs
.

Therefore, data from larger-scale and longer-term trials are still needed to determine the efficacy and safety of ibelidomide in the treatment of SLE
.

References 1.
Merrill JT, Werth VP, Furie R, et al.
Phase 2 trial of iberdomide in systemic lupus erythematosus.
N Engl J Med 2022;386:1034-1045.
The author introduces Wu Rui, chief physician, professor, doctoral student Mentor
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Director of the Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University
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Doctor of Rheumatology from Chongqing Medical University
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Member of the Standing Committee of the Rheumatology Professional Committee of the Chinese Association of Integrative Medicine, a member of the Standing Committee of the Rheumatology Professional Committee of the Chinese Association of Rehabilitation Medicine, and a member of the Rheumatology and Immunology Branch of the Chinese Medical Doctor Association
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He is the executive director of Jiangxi Society of Immunology, the executive director of Jiangxi Rehabilitation Society, the chairman of the Rheumatology Committee of Jiangxi Integrative Medicine Association, the chairman of the Rheumatology Branch of Jiangxi Society of Immunology, and the deputy director of the Rheumatology Branch of Jiangxi Medical Association
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.

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