How is the new drug for lupus progressing?

*It is only for medical professionals to read for reference.
You have all you want to know! At the 23rd Asia Pacific Rheumatism Alliance (APLAR) Annual Meeting, Professor Judith James reported on the topic of "Emerging target therapies for SLE"
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As we know, systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations and biological mechanisms, and has a complex pathogenesis
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A survey of the leading causes of death among women of childbearing age in the United States showed that SLE was ranked 7th among all female causes of death in the 15-24 year old population’s cause of death, while African-American women and Hispanic women in the same age group Among them, SLE is ranked 5th in the ranking of causes of death
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In the 25-34-year-old population's cause of death survey, SLE was ranked 11th among all female causes of death, while among African women and Hispanic women of the same age, SLE was ranked 6th
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In the 35-44-year-old population's cause of death survey, SLE was ranked 11th among all female causes of death.
Among African women and Hispanic women of the same age, SLE ranked 9th and 8th respectively.

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In general, the risk of death from SLE is relatively higher in younger/African/Hispanic patients
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We will give an overview of the following 4 parts: Part1: What new drugs are there now? ——Those exciting new therapies Part2: Which drugs can be stopped? Part3: By studying the molecular heterogeneity of lupus, can precision therapy be better developed? Part4: The future direction of lupus treatment Part 1 What new drugs are there now? ——Those exciting new therapies In the 50 years before Belimumab (2011), no new drugs have been approved by the U.
S.
Food and Drug Administration (FDA) for the treatment of SLE, but just in the past few months Here, Belimumab and voclosporin are approved for the treatment of lupus nephritis
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Anifrolumab has just been approved for use in patients with moderate/severe SLE
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Iberdomide has also obtained good data in current clinical studies, and it is hopeful that it will enter the clinical treatment of SLE
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With the development of diagnostic technology and the discovery of new targets, more and more lupus treatment drugs have entered the development process of clinical trials
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▌ Anifrolumab A study to evaluate the long-term efficacy of SLE patients receiving Anifrolumab therapy found that: regardless of the high interferon gene characteristics or the low interferon gene characteristics group, all SLE patients receiving Anifrolumab treatment (300mg/1000mg group) have excellent long-term efficacy In the placebo group
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Study details: A phase IIb randomized, double-blind, placebo-controlled study in adults with moderate to severe SLE evaluated the efficacy and safety of the type I interferon receptor antagonist Anifrolumab
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In addition to background medications, 305 patients were randomly assigned to receive oral corticosteroids (dose <10 or ≥10 mg/day) according to the SLE disease activity index (<10 points or ≥10), combined with intravenous injection of Anifrolumab (300 mg) every 4 weeks Or 1000 mg) or placebo for a total of 48 weeks
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It was found that compared with placebo, the Anifrolumab group had more patients reaching the primary endpoint
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The complete remission rates of the placebo group (n=102), 300 mg group (n=99) and 1000 mg group (n=104) were 17.
6%, 34.
3%, and 28.
8%, respectively
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Subsequently, the researchers regrouped the patients according to their gene expression type I interferon gene status (type I interferon high or low) and found that patients with low interferon gene characteristics had relatively better treatment effects.
The placebo group, 300 mg group and 1000 The complete remission rate of mg group was 13.
2%, 36.
0%, and 28.
2%, respectively
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In addition, at week 52, the incidence of serious adverse events was similar between the treatment groups (18.
8%, 16.
2%, 17.
1%)
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In general, compared with the placebo group, Anifrolumab significantly reduced the disease activity of SLE patients, and showed a greater efficacy advantage in multiple primary/secondary endpoints
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▌ Voclosporin Voclosporin is a new type of calcineurin inhibitor (CNI), based on a unique structure modified by cyclosporine, with less pharmacokinetic variability and better safety than other CNIs
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More than 2000 patients have used Voclosporin in the past, and no major drug-related safety issues have been reported
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In a phase II trial, 265 subjects were assigned to the Voclosporin group (237mg BID or 39.
5mg BID) and the placebo group (Mycophenolate mofetil 2g/day combined with glucocorticoid as background treatment)
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The results of the study found that compared with placebo (19.
3%), the complete remission rate of Voclosporin at 24 weeks was 32.
6% (p=0, OR=2.
02)
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AURORA 1 is a multicenter, double-blind, randomized phase III trial conducted in 142 hospitals and clinics in 27 countries
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Patients were randomly assigned to (1:1) oral Voclosporin group (23.
7 mg, BID) or placebo group.
Both groups received mycophenolate mofetil (1 g, BID) + lowest dose glucocorticoid as background treatment
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The primary endpoint was the complete renal response rate at 52 weeks
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The results of the study showed that at 52 weeks, more patients in the Voclosporin group achieved complete renal response than the placebo group (41% vs 23%, 95% CI 1.
64-4.
27, p<0.
0001)
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The adverse events between the two groups were basically the same
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In general, compared with the placebo group that used mycophenolate mofetil alone and low-dose steroids, Voclosporin combined with mycophenolate mofetil and low-dose glucocorticoids had a higher complete response rate and Sufficient security
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This discovery is an important advance in the treatment of active lupus nephritis
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▌ As a new type of oral immunomodulatory compound, Iberdomide can effectively resist proliferation and promote apoptosis
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Iberdomide has obtained exciting data in the Phase IIb study of SLE patients
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The investigator randomly assigned autoantibody-positive SLE adult (N=288) subjects (in a 2:2:1:2 ratio) to take Iberdomide (0.
45mg, 0.
3mg, 0.
15mg) or placebo; at the 24th week Patients in the placebo group were again randomly divided into Iberdomide 0.
3 mg and 0.
45 mg groups
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The study duration was 52 weeks, and the primary endpoint was the response rate of the SLE responder index (SRI-4) at week 24
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It was found that at week 24, the study reached the primary endpoint: in the Iberdomide 0.
45 mg group, 54.
3% of patients achieved an SRI-4 response, compared with 34.
9% in the placebo group
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Starting from the 16th week, the SRI-4 response of the Iberdomide group was significantly higher than that of the placebo group, especially the 0.
45mg and 0.
15mg groups
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The most common adverse events of Iberdomide (all doses compared with the placebo group) were urinary tract infection (11% vs 4%), upper respiratory tract infection (10% vs 5%), and neutropenia (8% vs 2%).
), influenza (6% vs 4%), nasopharyngitis (5% vs 1%) and diarrhea (4% vs 0%)
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This suggests that Iberdomide has a significant effect in the treatment of active SLE and is well tolerated overall
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Figure 1: Effectiveness and safety of Iberdomide in patients with active lupus Part 2 Which drugs can be stopped? Does mycophenolate maintenance therapy really improve the long-term prognosis of SLE patients? In a multicenter randomized trial of mycophenolate mofetil withdrawal in patients with stable quiescent SLE, a total of 100 patients were included in the trial, and 76% of the patients had a history of lupus nephritis
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Studies have shown that 5 participants (10.
2%) in the mycophenolate mofetil maintenance group reached the primary end point of major disease reactivation, while 9 participants (17.
6%) in the discontinuation group reached the primary end point of major disease reactivation
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The median time to reach the end point in both groups was 38 weeks
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Judging from the results of the study, the recurrence rate of the disease in the maintenance group and the withdrawal group is relatively similar
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However, the study found that the adverse reactions (AE) of the mycophenolate mofetil maintenance group, including SAE, TAE, AE severity, and the incidence of infection, were greater than that of the mycophenolate mofetil discontinuation group
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We can't help but question: Can mycophenolate maintenance therapy really improve the long-term prognosis of SLE patients? This is worthy of further study and discussion
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Figure 2: Adverse reactions of the MMF withdrawal trial Part 3 By studying the molecular heterogeneity of lupus, can precise therapies be better developed? A cross-sectional study found that adult SLE patients can be divided into different molecular phenotypes
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Because the diversity of SLE clinical and mechanism hinders the development of diagnosis and treatment, this research attempts to solve the problem of heterogeneous classification of SLE, and identify homogeneous patient groups by analyzing genetic, genomics and proteomics information
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The study collected plasma, serum and RNA provided by 198 adult SLE patients
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The disease degree was scored by the modified SELENA-SLEDAI score
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The results of the study showed that the SLEDAI score was significantly related to interferon, plasma cells, and select cell cycle modules (select cell cycle modules) and the levels of soluble IFN-α, IP-10/IL-1α and other mediators in the circulation
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Figure 3: The correlation between SLEDAI and soluble media The random forest model divides SLE patients with unique molecular phenotypes into 7 groups through co-expression modules and soluble media
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Figure 4: The random forest model divides SLE patients into seven molecular subgroups.
Figure 5: The clinical SLEDAI trends of the third and fourth groups are the highest.
The study found that musculoskeletal and mucosal skin activities are common in all groups; although The third group lacks strong interferon and inflammatory signals, but the clinical SLEDAI trends of the third and fourth groups are the highest; nephritis activities are more frequent in the fourth group, and in the second, fifth, and seventh groups It's even rarer
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Similarly, abnormal serological test results appeared the least frequently in the second and fifth groups
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Figure 6: The proportion of different systems involved in 7 groups of patients Note: Each bar represents patients with disease activity in a specific organ system (100%), and the colored part represents the percentage of patients in each cluster
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The activity in the organ system is defined as at least one corresponding component (for example, thrombocytopenia or leukopenia in the blood; low complement content in the serum, etc.
)
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In terms of predicting efficacy, the responses of groups 1, 2, 4, 5, and 7 to hormones were not significantly different from those of the placebo group, while groups 3 and 6 had significantly better responses to the drug treatment
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The demographic data varies from cluster to cluster, with a higher proportion of European and American patients in group 5 (24.
4%)
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African Americans (n=69) most often appeared in Group 7 (27.
5%) or Group 3 (24.
6%), and rarely appeared in Group 1 (5.
8%)
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In group 1, American Indian patients had the highest incidence (37.
1%)
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Professor Djamel Nehar-Belaid and his team tried to locate SLE at the single-cell level: Through single-cell RNA sequencing, they analyzed 276,000 peripheral blood mononuclear cells in 33 SLE children with different disease activities and 11 controls
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Interferon-stimulated gene signals (ISGs) distinguish SLE child cells from healthy control cells
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High interferon signal expression is derived from a small number of transcriptionally defined subpopulations in the main cell types, including monocytes, CD4+ and CD8+ T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells, especially Plasma cells
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A unique subgroup of ISGs or single gene amplification associated with lupus can distinguish SLE patients with the highest disease activity
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The analysis of approximately 82,000 peripheral blood mononuclear cells from adult SLE patients confirmed that in the patients with the highest disease activity, the subgroups with high interferon signal expression increased significantly
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This research applies precision medicine to the field of disease heterogeneity, laying a foundation for solving the origin of SLE transcription characteristics
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Part 4 Future direction of lupus treatment At present, many new treatment methods are being approved for SLE, and many promising therapies are in the late stage of clinical trials
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Deciphering the molecular heterogeneity of SLE may help improve the results of SLE clinical trials and help better choose appropriate treatments for patients
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The classification of patient subgroups may also be crucial.
It will solve the key immune pathway problem and is the future direction of SLE treatment
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In general, through molecular maps, we can divide SLE into different subtypes, even if the current clinical characteristics of patients are not typical
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The prospective prediction methods of these characteristics may be more helpful in evaluating the prognosis of SLE, and provide precise guidance for clinical trial design and precision medicine methods
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Experts comment that SLE is a very heterogeneous autoimmune disease with a complicated pathogenesis and often life-threatening
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The difference in pathogenesis leads to differences in the response of lupus patients to treatment, and the severity of the disease and the different organs involved determine the outcome and prognosis of lupus patients
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Discovering the important pathogenic molecular targets of lupus, developing related therapeutic drugs, precise molecular typing and stratification are the current focus of SLE basic and clinical research
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In recent years, with the continuous deepening of basic research, targeted drugs for type I interferon and its pathways, B cell differentiation and activation (Blys, APRIL), cytokines (IL-2), etc.
are all in clinical research and the real world.
Showed a good therapeutic effect
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Targeted drugs for other molecules, such as IL-12/23, JAK1/2, SYK, sCD40L, etc.
, have also shown the control of disease activity and the protection of organs in their respective clinical studies.
The final results are awaited.
Publish
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The strategies for inducing remission and maintenance of lupus nephritis have been widely studied in the involvement of lupus organs
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From the classic NIH program of the last century, to the comparison between mycophenolate mofetil and cyclophosphamide in the early part of this century, as well as the multi-target induction remission and low-dose cyclophosphamide shock, all suggest the remission scheme of lupus nephritis.
Diversification
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In the maintenance of remission, many studies have shown that the maintenance and remission effects of mycophenolate mofetil and azathioprine are significantly better than the classic NIH regimen of cyclophosphamide once every 3 months
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How to further maintain the remission of lupus nephritis in the long-term, and use the "minimum cost" to maintain low disease activity and remission, or even no hormone remission, remains to be further explored
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The high heterogeneity of SLE has brought challenges to many clinical treatment researches
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Therefore, using modern multi-omics methods to accurately type lupus based on molecular or genetic markers is an effective means to solve this bottleneck
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Through the study of common pathogenic molecules and pathways, such as type I interferon, immune cells, such as monocytes, T/B cells and other transcriptomes, proteomes, etc.
, it is not only possible to further reveal the pathogenesis of lupus, but also for disease transformation.
Both regression and treatment response prediction have important scientific value
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 Expert Profile Zhao Yi Chief Physician Deputy Director, Chief Physician, Doctor of Medicine, Ph.
D.
Supervisor, Department of Rheumatology and Immunology, West China Hospital of Sichuan University Vice Chairman, Chinese Medical Doctor Association, Rheumatology and Immunology Physicians Branch, Youth Committee, Vice Chairman, Sichuan Medical Association, Rheumatology Professional Committee, Designated Chairman, Member of Immunoadsorption Branch of Chinese Medical Doctors Association, Vice President of Sichuan Medical Doctors Association, Rheumatology and Immunology Branch, Undertaking national key research and development 1 project and 3 references from the National Natural Science Foundation of China: [1] Furie R, Khamashta M, Merrill J, et al.
Anifrolumab, an Anti-Interferon-αReceptor Monoclonal Antibody, in Moderate-to-SevereSystemic Lupus Erythematosus.
Arthritis&Rheumatology, 2017,69(2):376-386.
[2]N Engl J Med.
2020 Jan 16;382(3): 211-221.
[3]Schafer PH,Ye Y,Wu L,et al.
Cereblon modulatoriberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupuserythematosus.
Annals of the Rheumatic Diseases,2018,77(10):1516–1523.
[4]Guthridge JM,Lu R,et al.
Adults with systemiclupus exhibit distinct molecular phenotypes in a cross-sectional study.
EClinical Medicine, 2020, 100291.
[5]Nehar-Belaid D,Hong S,Marches R,et al.
Mappingsystemic lupus erythematosus heterogeneity at the single-cell level.
NatureImmunology.
2020.
[6]Merrill JT,Wallace DJ,Wax S et al.
Efficacy and Safetyof Atacicept in Patients With Systemic Lupus Erythematosus.
Arthritis&Rheumatology, 2018,70(2):266–276.