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The future of lupus treatment is oral therapies?

There has been an explosion of trials in SLE, including nonrenal and glomerulonephritis studies.

Importantly, several drug approvals in lupus have occurred recently: belimumab (high dose) for lupus nephritis, anifrolimumab for non-renal SLE, and in glomerulonephritis in lupus there is a phase 3 high dose anifrolimumab where results won’t be available for a couple of years. Voclosporin can benefit nephritis in addition to standard of care.

But, what about the JAKis and Tyk2 oral drugs in SLE?

Upadacitinib 15 mg daily vs a BTKi vs both vs placebo showed that upadacitinib was effective in the treatment of active non-renal SLE and is enrolling for a phase III study (SLEEK RCT). The BTKi did not give added value. More data are presented at EULAR 2023 (POS1133, Gaudreau, et al) showing the modulation of Type I IFN affecting pathogenic pathways in SLE, but in the RCT, some disease activity markers in SLE actually worsened or did not improve making the results difficult to interpret until it is understood what is happening to complements and antiDNA when a JAK1i is used.

Deucravacitinib vs. placebo as an add on to standard of care was more effective than placebo in non-renal lupus in a phase2 RCT (PAISLEY trial). The phase 3 study is enrolling.

POS0112 explored the mechanism of action of deucravicitinib in SLE and found that interferon production was reduced in SLE patients from the phase2 RCT vs placebo, as were B cells and other biomarkers.

And, should baricitinib be brought back to explore benefit in renal lupus? The non-renal Phase2 study in SLE with baricitinib was positive but the phase3 RCT was negative. Questions have circulated that the baricitinib trial may have been negative due to the selection of outcome measures and there were some hints of efficacy in some outcome measurements in the phase2 trial. However, OP0053 by Hassanien et al has a small single site RCT of baricitinib 4mg daily vs IV cyclophosphamide in renal lupus which showed that baricitinib improved disease activity, proteinuria, C3 and anti-DNA but there will need to be a large RCT before this would be considered as a new standard of care. 

So, move over IV and sc drugs and make room (hopefully) also for oral JAKis and TYK2i treatments in SLE.

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