Substances tested

Reduced chemotherapy-induced febrile neutropenia: at least one episode of fever with neutropenia in 40 percent of the G-CSF group versus 77 percent on placebo (p less than 0.001). Median duration of grade IV neutropenia (ANC under 0.5 x 10^9 per L) was one day with G-CSF versus six days with placebo.

Reduced clinically significant exacerbations in severe eosinophilic asthma from 2.40 per patient per year on placebo to 1.24 at 75 mg (48 percent reduction, 95 percent CI 31 to 61, p less than 0.0001), 1.46 at 250 mg (39 percent reduction) and 1.15 at 750 mg (52 percent reduction, 36 to 64, p less than 0.0001).

Exacerbation rate reduced 47 percent (95 percent CI 29 to 61) with intravenous and 53 percent (37 to 65) with subcutaneous dosing versus placebo (p less than 0.001 for both). Exacerbations needing emergency care or hospitalisation fell 32 percent (intravenous) and 61 percent (subcutaneous). FEV1 at week 32 rose 100 mL more than placebo on the intravenous arm.

In patients with blood eosinophils at least 300 cells per uL, the annual exacerbation rate over 48 weeks fell versus placebo on both schedules: rate ratio 0.55 (95 percent CI 0.42 to 0.71, p less than 0.0001) every 4 weeks and 0.49 (0.37 to 0.64, p less than 0.0001) every 8 weeks.

Nine of 11 patients with hypereosinophilic syndrome had responses lasting more than three months with the eosinophil count returning to normal. The FIP1L1-PDGFRA fusion, from an interstitial deletion on chromosome 4q12, was found in 9 of 16 patients and in 5 of the 9 durable responders. A T674I mutation at relapse confirmed the fusion kinase as the drug target.

Histologic remission in eosinophilic esophagitis reached 60 percent (25 of 42) on weekly dupilumab versus 5 percent (2 of 39) on placebo in Part A (difference 55 percentage points, 95 percent CI 40 to 71, p less than 0.001), and 59 percent weekly versus 6 percent placebo in Part B.

In two replicate phase 3 COPD trials, annualised moderate or severe exacerbations among former smokers fell from 1.90 to 1.34 events (rate ratio 0.71, 95 percent CI 0.57 to 0.88, p = 0.002) in OBERON and from 2.07 to 1.37 (rate ratio 0.66, 0.55 to 0.80, p less than 0.001) in TITANIA. There were no eligibility criteria related to blood eosinophil count.

Across 19 trials with 2565 participants, dornase alfa probably improved FEV1 versus placebo in trials from one month to two years, with a decrease in pulmonary exacerbations in trials of six months or longer. Voice alteration and rash were the only adverse events reported at increased frequency. Evidence was insufficient to place it above other hyperosmolar agents.

PAD4 knockout neutrophils cannot form NETs after chemokine stimulation or incubation with bacteria and are deficient in NET-mediated bacterial killing, establishing PAD4 as essential for NET-mediated antibacterial defence. This is the target rationale behind PAD inhibitors; no inhibitor compound was dosed in this study.

On activation, neutrophils release granule proteins and chromatin that form extracellular fibres binding Gram-positive and Gram-negative bacteria. These NETs degrade virulence factors and kill bacteria, and are abundant in vivo in experimental dysentery and spontaneous human appendicitis.