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Dual target blockade may be better than one in SLE

Inhibition of B-cell Activating Factor (BAFF) has revolutionised the treatment of patients with systemic lupus erythematosus (SLE). However, outcomes of therapies within the same class (i.e. BAFF-inhibitor) when evaluated in randomised controlled trials (RCTs) have been inconsistent.

Belimumab, a selective BAFF-inhibitor, has been extensively investigated in six major RCTs. It is approved for use in patients with non-renal and renal SLE, as well as children over 5 years old. While the development of another selective BAFF-inhibitor, Tabalumab. was halted due to inconsistent outcomes in two Phase 3 RCTs. Since both BAFF and its homolog, A proliferation-inducing ligand (APRIL) are key drivers in B-cell homeostasis, could dual inhibition (BAFF/APRIL) fare better than belimumab?

At ACR22, Dr Wu et al. (Abstract #L07) will present efficacy and safety data of a novel BAFF/APRIL-inhibitor, Telitacicept in a Phase 3 RCT in China. Adults with positive ANA and/or anti-dsDNA and a SELENA-SLEDAI score ≥8 (N=355) were randomized 1:1 to receive either Telitacicept 160mg or placebo subcutaneously once weekly, as add on to standard therapy. At 52 weeks, 236 (70.4%) patients completed the study. The primary endpoint, SRI-4 was met in 82.6% of patients treated with telitacicept vs 38.1% in the placebo groups; p<0.001. This delta difference of 44.5% was calculated by imputing missing data. However, even if the missing data were assumed to be from non-responders, the response rate was still significantly higher with telitacicept compared with placebo (67.1% vs. 32.7%; delta difference 34.4%. Rates of overall infections were broadly similar between both groups. 

Another BAFF/APRIL inhibitor is Atacicept. Enrollment in the atacicept 150 mg arm was discontinued prematurely due to two deaths in a Phase 2 RCT, APRIL-SLE in 2013. At the ACR 22, Dr Isenberg et al. (Abstract #1001) presented post-hoc analysis on the effect of atacicept compared to placebo on measures of renal function. The study included 285 participants (excluding those with moderate/severe glomerulonephritis) who completed the 52 weeks. This post-hoc analysis suggested a potential for improved renal function with atacicept therapy; UPCR from baseline at week 52 declined in the atacicept groups and increased in the placebo group while the trend of eGFR was stable for the atacicept groups compared to a 4.4% decline in the placebo group from baseline at 52 weeks. 

So what do both results tell us?

Data from the Telitacicept RCT is promising. This is the largest delta difference to date against placebo + standard therapy in SLE compared to the modest effect size of belimumab over its comparator in RCTs (ranging from 9.7% to 14%). It is important to note that the telitacicept trial recruited Chinese patients mainly. Phase 3 RCTs recruiting patients in the US is ongoing and the results will be eagerly. Phase 3 trials of Atacicept in lupus nephritis is also ongoing.

It will be interesting to see how the favourable post-hoc analysis above translate into definitive RCT and whether mitigating strategy including requirement of an up-to-date vaccinations against pneumococcus and seasonal influenza (as applied in another Atacicept Phase 2 RCT, ADDRESS II) could reduce infection risk which halted the APRIL-SLE trial. 

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