Deucravacitinib ‘very likely’ best small molecule for systemic lupus erythematosus
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Key takeaways:
- Among targeted small-molecule drugs, deucravacitinib had the best efficacy and safety in SLE.
- Dose and course of the drugs overall “had little effect” on their efficacy.
Deucravacitinib is “very likely to be the best” targeted small-molecule drug for the treatment of systemic lupus erythematosus, according to data published in Arthritis Research & Therapy.
“Due to such advantages as convenient administration, low production cost and no immunogenicity, targeted small-molecule drugs have broad clinical application prospects,” Shiheng Wang, of the China Academy of Chinese Medical Sciences, in Beijing, and colleagues wrote. “Many clinical trials have been published to investigate the efficacy and safety of targeted small-molecule drugs. However, the difference in their efficacy and safety is still unclear.”
To compare the efficacy and safety of various targeted small-molecule drugs for SLE, Wang and colleagues conducted a network meta-analysis of 13 randomized controlled trials. The analysis included 13 studies involving 3,622 patients and nine targeted small-molecule drugs, including baricitinib (Olumiant, Eli Lilly), deucravacitinib (Sotyktu, Bristol Myers Squibb) and iberdomide (Bristol Myers Squibb).
The researchers employed Bayesian network meta-regression to compare how different dosages impacted efficacy and safety. They examined how the drugs impacted several disease activity measures, including the Systemic Lupus Erythematosus Responder Index (SRI-4) and the BILAG-based Composite Lupus Assessment (BICLA).
According to the researchers, baricitinib, deucravacitinib and iberdomide “were significantly superior” to placebo in terms of SRI-4 improvement (P < .05), though deucravacitinib significantly outperformed baricitinib (RR = 1.32; 95% CI, 1.04-1.68). Deucravacitinib also significantly bested placebo in BICLA response (RR = 1.55; 95% CI, 1.2-2.02).
The targeted small-molecule drugs did not significantly increase the risk for adverse events vs. placebo (P > .05). The researchers added that dose and course of treatment “had little effect” on the drugs’ efficacy and safety, but noted that result “may differ from reality.”
“Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant,” Wang and colleagues wrote. “Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of [adverse events]. Therefore, deucravacitinib is very likely to be the best intervention measure.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Although we are familiar with Janus kinase inhibitors and are becoming familiar with TYK-2 inhibition (approved for psoriasis), other mechanisms of action (MOA) are not at present being used in rheumatology and are less well known. These MOA include Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), and sphingosine-1-phosphate (S1P) receptor inhibitors.
BTK inhibitors are a class of drugs that target and inhibit the activity of BTK, an enzyme crucial in the signaling pathways of B cells. This inhibition leads to reduced survival and proliferation of B cells, particularly those that are malignant or autoreactive. There are four BTK inhibitors currently approved by the FDA, for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenström’s macroglobulinemia. BTK inhibitors are also now being investigated for rheumatoid arthritis, multiple sclerosis and SLE.
SYK plays a key role in signaling pathways initiated by the B cell receptor and Fc receptors on immune cells. Inhibiting SYK disrupts these pathways, reducing immune cell activation, proliferation and inflammatory responses. There is one SYK inhibitor approved by the FDA, for the treatment of chronic immune thrombocytopenia. SYK inhibitors are currently under investigation for RA, SLE, CLL, non-Hodgkin lymphoma, allergic diseases and asthma.
S1P receptor inhibitors bind to the surface of lymphocytes and modulate egress from lymph nodes, resulting in fewer lymphocytes in circulation and diminishing the immune response. Three S1P receptor inhibitors have been approved by the FDA, for the treatment of relapsing forms of multiple sclerosis and ulcerative colitis. They are additionally being investigated for RA and psoriasis.
The era of small molecules is here.
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