Depemokimab

Severe eosinophilic asthma is driven by interleukin (IL)-5-mediated type 2 inflammation and frequently requires long-term biologic therapy. Depemokimab was designed to achieve sustained IL-5 neutralization with a twice-yearly dosing schedule, addressing key unmet needs related to treatment burden and adherence. This review summarizes the molecular design, preclinical pharmacology, model-informed drug development (MIDD) strategy, Phase I-III clinical trial program, and regulatory approvals of depemokimab in asthma and chronic rhinosinusitis with nasal polyps. Depemokimab exemplifies how rational antibody engineering, including Fc modification and high-affinity IL-5 binding, can enable sustained pharmacodynamic activity and ultra-long-acting cytokine inhibition. A twice-yearly dosing regimen may offer advantages in terms of treatment adherence, patient convenience, and long-term disease control. The application of MIDD approaches facilitated efficient clinical development and supported the progression of pivotal trials, potentially shortening development timelines by approximately two to three years. Although efficacy and safety data are encouraging, longer-term real-world evidence will be necessary to better define immunogenicity, rare adverse events, and adherence patterns. Comparative effectiveness studies of depemokimab versus other approved anti-IL-5 therapies and type 2-targeted biologics will be critical to establish its relative clinical value. Further investigation into additional eosinophilic diseases, pediatric populations, and diverse healthcare settings may expand its therapeutic utility, positioning depemokimab as a representative example of next-generation long-acting biologics that target cytokine-mediated inflammatory diseases.

This study compared the efficacy of tezepelumab with other approved biologics and endoscopic sinus surgery (ESS) using indirect treatment comparisons (ITCs) in adults with severe, uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP).

Randomized controlled trials (RCTs) identified via a systematic literature review (SLR) were synthesized in a network meta-analysis (NMA). Outcomes included change from baseline in nasal polyp score (NPS), nasal congestion/obstruction score (NCS/NOS), difficulty with sense of smell (DSS), Sino-Nasal Outcome Test-22 (SNOT-22) score, Lund Mackay score (LMS), time to nasal polyposis (NP) surgery decision, proportions requiring NP surgery or systemic corticosteroids (SCS), time to SCS use, and the University of Pennsylvania Smell Identification Test (UPSIT). Mean differences, hazard ratios, and odds ratios with 95% credible intervals were estimated for available treatments at 52 weeks. Not all endpoints were reported across trials; comparisons were conducted only where both treatments reported the outcome.

At 52 weeks, tezepelumab showed comparable efficacy to dupilumab across all evaluated endpoints, apart from the proportion of patients requiring surgery, where tezepelumab was associated with a lower surgery rate than dupilumab. Tezepelumab consistently outperformed mepolizumab, depemokimab, and placebo. In analyses of < 30-week endpoints, tezepelumab outperformed omalizumab for all outcomes except SNOT-22, where no difference was observed. Sensitivity analyses including ESS showed benefits for tezepelumab across endpoints except for NPS, for which ESS ranked highest.

Tezepelumab achieved similar efficacy to dupilumab across all evaluated endpoints with the exception of the proportion of patients requiring surgery, where tezepelumab demonstrated a numerically greater reduction compared with dupilumab. Results consistently favoured tezepelumab and dupilumab over depemokimab, mepolizumab, and omalizumab.