Efficacy and safety of twice per year depemokimab in chronic rhinosinusitis with nasal polyps (ANCHOR-1 and ANCHOR-2): phase 3, randomised, double-blind, parallel trials

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) symptoms are frequently driven by type 2 inflammation. Depemokimab is the first ultra-long-acting biological drug engineered with enhanced interleukin-5 binding affinity, high potency, and an extended half-life, enabling twice per year dosing and sustained type 2 inflammation inhibition. The ANCHOR-1 and ANCHOR-2 trials investigated the efficacy and safety of depemokimab in people with CRSwNP. Methods: ANCHOR-1 and ANCHOR-2 were randomised, double-blind, placebo-controlled, parallel-group, replicate phase 3 trials conducted concurrently at 190 centres (hospitals, specialised clinics, and clinical trial sites) in 16 countries (Argentina, Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Romania, Spain, Sweden, Türkiye, the UK, and the USA). Individuals aged 18 years or older at the time of consent, with inadequately controlled CRSwNP, an endoscopic bilateral nasal polyps score of 5 or more, previous surgery for CRSwNP or previous treatment with or intolerance to systemic corticosteroids, and severe symptoms were stratified by previous CRSwNP surgery and randomly assigned 1:1 to receive either depemokimab (100 mg subcutaneously) or placebo every 26 weeks (with standard of care). Allocation was computer generated. The trial sponsor, site staff, and participants were masked. The coprimary endpoints were change from baseline in total endoscopic nasal polyps score (0-8) at week 52 and mean nasal obstruction score (verbal response scale [0-3]) over weeks 49-52, assessed in the full analysis set. Integrated analyses were conducted. Adverse events on treatment and after treatment were monitored. The trials are complete and are registered with ClinicalTrials.gov (NCT05274750 and NCT05281523). Findings: Between April 18, 2022, and Aug 7, 2023, 540 individuals were randomly assigned across ANCHOR-1 and ANCHOR-2; 528 participants comprised the full analysis set (depemokimab, n=272; placebo, n=256). Depemokimab had statistically significant improvements from baseline versus placebo in the coprimary endpoints of total nasal polyps score (treatment difference: ANCHOR-1, -0·7, 95% CI -1·1 to -0·3; p<0·001; ANCHOR-2, -0·6, -1·0 to -0·2; p=0·004; integrated, -0·7, -0·9 to -0·4) and mean nasal obstruction verbal response scale score (ANCHOR-1, -0·23, -0·46 to 0·00; p=0·047; ANCHOR-2, -0·25, -0·46 to -0·03; p=0·025; integrated, -0·24, -0·39 to -0·08). Adverse events were similar between depemokimab and placebo in ANCHOR-1 (74% [n=106] vs 79% [n=101]) and ANCHOR-2 (76% [n=98] vs 80% [n=102]). Interpretation: Depemokimab significantly improved clinically relevant coprimary endpoints versus placebo and was well tolerated, supporting its use as a twice per year treatment option, with the potential to reduce treatment burden for people with CRSwNP.