*3.8. SGRMs*

Compared to conventional glucocorticoids, nonsteroidal, selective glucocorticoid receptor modulators (SGRM) preferentially favour transrepression over transactivation [79]. SGRM are designed to activate the GC receptor and suppress inflammation by inhibiting nuclear factor-kappa B (NF-kB) and activator protein 1 (AP-1), whilst inducing less GC response element (GRE)-driven adverse effects [80].

Phase IIb GRANIT RCT [48–50] enrolled patients with inadequately controlled asthma on low-dose BUD to orally receive the SGRM velsecorat (AZD7594) 50–720 μg vs. PCB or open-label fluticasone furoate (FF) 100 μg over 12 weeks. Velsecorat dose-dependently improved trough FEV1 over the entire treatment period. When administered at doses of 320 μg and 720 μg, velsecorat induced a trend towards a significant improvement in trough FEV1 compared to PCB, which was numerically lower compared to the effect of FF vs. PCB. Velsecorat 180–720 μg significantly (*p* < 0.05) improved morning PEF vs. PCB from 9.12 L/min (95%CI 0.20–18.05) to 16.60 L/min (95%CI 8.03–25.17)). Evening PEF was significantly (*p* < 0.05) increased with velsecorat 360 μg and 720 μg vs. PCB, respectively, by 10.26 L/min (95%CI 1.46–19.06) and 11.99 L/min (95%CI 3.57–20.42). The effect of velsecorat on PEF was comparable to that induced by FF vs. PCB [48–50].

Velsecorat administered at doses 90–720 μg significantly (*p* < 0.05) improved the ACQ5 score vs. PCB, by inducing a reduction between −0.19 units (95%CI −0.37–−0.02) and −0.27 units (95%CI −0.43–−0.10), and it was as effective as FF vs. PCB. Velsecorat 50 μg and 180–720 μg significantly (*p* < 0.05) reduced the daily asthma symptom score between −0.14 units (95%CI −0.26 ¬– −0.02) and −0.23 units (95%CI −0.35–−0.11) and improved the percentage of symptom-free days between 8.61% (95%CI 0.30–16.91) and 11.34% (95%CI 2.77–19.91) vs. PCB, to a similar extent as FF. The percentage of asthma control days significantly (*p* < 0.05) increased with velsecorat 50 μg, 360 μg, and 720 μg over the treatment period between 8.62% (95%CI 0.49–16.75) and 10.07% (95%CI 1.46–18.67), similar to FF [48–50].

At doses 50–180 μg, the effect of velsecorat on FENO values was not different to PCB, but when administered at 360 μg and 720 μg, the improvement was significant (*p* < 0.05) vs. PCB (MD 0.81 ppb (95%CI 0.69–0.95) and 0.65 ppb (95%CI 0.56–0.76), respectively), and comparable to that induced by FF vs. PCB [48–50].

Only velsecorat 360 μg significantly (*p* < 0.05) increased the percentage of rescue-free days by 11.79% (95%CI 1.49–22.09) vs. PCB, an effect that was superior to that of FF vs. PCB. Rescue medication use was significantly (*p* < 0.05) lowered with velsecorat 50 μg, 360 μg, and 720 μg vs. PCB (MD between −0.24 puffs (95%CI −0.43–−0.05) and −0.31 puffs (95%CI −0.49–−0.13), an effect similar to that induced by FF vs. PCB [48–50].

Velsecorat 50–720 μg significantly (*p* < 0.05) delayed the time to recurrent CompEx event (a composite endpoint combining severe asthma exacerbations and diary events) vs. PCB (hazard ratio (HR) between 0.20 (95%CI 0.100.38) and 0.58 (95%CI 0.26–0.95)). When administered at doses of 50 μg, 180 μg, 360 μg, and 720 μg, velsecorat significantly (*p* < 0.05) reduced the annualised CompEx event rate vs. PCB (MD between 0.11 (95%CI 0.04–0.25) and 0.44 (95%CI 0.20–0.94)), while at 90 μg, velsecorat induced a strong trend towards a significant reduction in the rate vs. PCB. Overall, no comparative analysis has been performed in the study between velsecorat and FF [48–50].
