Dupilumab Improves Nasal Polyp Burden and Asthma Control in Patients With CRSwNP and AERD

In the difficult-to-treat subgroup of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and comorbid aspirin-exacerbated respiratory disease, dupilumab significantly improved CRSwNP disease outcomes, along with asthma control and lung function. This is preliminary evidence of the effect of dupilumab in patients with CRSwNP and comorbid aspirin- exacerbated respiratory disease

344 Dupilumab significantly improves itch and skin lesions in patients with prurigo nodularis: pooled results from two phase 3 trials (LIBERTY-PN PRIME and PRIME2)

Abstract Prurigo nodularis (PN), a chronic inflammatory and pruritic skin condition with severely itchy skin nodules, substantially affects the quality of life and is often inadequately controlled with topical medications. Recently, the US Food and Drug Administration approved dupilumab as the first systemic therapy for PN. Two randomized clinical trials with similar designs, LIBERTY-PN PRIME (NCT04183335) and PRIME2 (NCT04202679), demonstrated the efficacy and safety of dupilumab in adults with PN inadequately controlled with topical medications or for whom those who were inadvisable. To report the efficacy of dupilumab on pruritus and skin lesions in PN, as well as its safety, by analysing pooled data from PRIME and PRIME2 trials, given their similar trial design. PRIME and PRIME2 were multicentre, randomized, placebo-controlled, double-blinded, phase 3 trials, which comprised a 2–4-week screening, 24-week treatment and 12-week follow-up period. Itch severity was measured by Worst Itch Numerical Rating Scale (WI-NRS), ranging from 0 (no itch) to 10 (worst itch imaginable). The severity of skin lesions was assessed using Investigator’s Global Assessment for PN-Stage (IGA PN-S), as score 0 (no nodules), 1 (1–5 nodules), 2 (6–19 nodules), 3 (20–99 nodules) or 4 (over 100 nodules). To be eligible for enrolment patients had WI-NRS ≥7, and IGA PN-S score of 3 or 4. Patients received subcutaneous dupilumab 300 mg (loading dose, 600 mg) or matched placebo every 2 weeks for 24 weeks. Efficacy endpoints were the proportion of patients with a WI-NRS score reduction of ≥4 points, the proportion of patients who achieved an IGA PN-S score of 0 or 1, and the proportion of patients who achieved concomitantly WI-NRS reduction of ≥4 points and IGA PN-S score of 0 or 1, at week 12 and at week 24. At baseline, demographic and disease characteristics were balanced between the PRIME and PRIME2 pooled dupilumab (n = 153), and pooled placebo groups (n = 158). All but 1 patient had used prior topical medications for PN, and 66.2% had used off-label systemic medications. Despite prior therapies, at baseline, the overall mean (standard deviation) WI-NRS score was 8.5 (1.0); 66.3% of patients had 20–99 nodules, and 33.7% had over 100 nodules. At week 12, the ≥4-point reduction in WI-NRS in the dupilumab group was achieved by 62 patients (40.5%), and at week 24, by 90 (58.8%), compared with 30 patients (19.0%) in the placebo group at each time point (P < 0.0001 for both). An IGA PN-S score of 0 or 1 was achieved by 44 (28.8%) patients in the dupilumab group vs. 19 (12.0%) in the placebo group at week 12 (P = 0.0002), and, respectively, by 71 (46.4%) vs. 27 (17.1%) patients at week 24 (P < 0.0001). The concomitant reduction in WI-NRS by ≥4 points and IGA PN-S score of 0 or 1 was achieved by 28 (18.3%) patients in the dupilumab group vs. 11 (7.0%) in the placebo group at week 12 (P = 0.0021), and, respectively, by 54 (35.3%) vs. 14 (8.9%) patients at week 24 (P < 0.0001). The rate of treatment-emergent adverse events was 59.9% with dupilumab and 51.0% with placebo. The most common adverse events were headache (5.3% vs. 5.7%), neurodermatitis (2.0% vs. 5.7%), skin infections (3.9% vs. 7.6%) and injection-site reactions (3.9% vs. 5.7%) in dupilumab vs. placebo groups. Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions vs. placebo in patients with PN, confirming the findings from individual PRIME and PRIME2 studies. The safety profile of dupilumab was consistent with the known safety profile in its approved indications

Data mining of free-text responses : an innovative approach to analyzing patient perspectives on treatment for chronic rhinosinusitis with nasal polyps in a phase IIa proof-of-concept study for dupilumab

Purpose: Patient perspective is an important and increasingly sought-after complement to clinical assessment. The aim of this study was to transcribe individual patients' experience of treatment in a dupilumab clinical trial through free-text responses with analysis using natural language processing (NLP) to obtain the unique perspective of patients on disease impact and unmet needs with existing treatment to inform future trial design. Patients and Methods: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) who were enrolled in a Phase IIa randomized controlled trial comparing dupilumab with placebo (NCT01920893) were invited to complete a self-assessment of treatment (SAT) tool at the end of treatment, asking, "What is your opinion on the treatment you had during the trial? What did you like or dislike about the treatment?" Free-text responses were analyzed for the overall cohort and according to treatment assignment using natural language processing including sentiment scoring. In a mixed-methods approach, quantitative patient-reported outcome (PRO) results were utilized to complement the qualitative analysis of free-text responses. Results: Of 60 patients enrolled in the study, 43 (71.6%) completed the SAT and responses from 37 patients were analyzed (placebo, n = 16; dupilumab, n = 21). Word analyses showed that the most common words were "smell," "improve," "staff," "great," "time," and "good." Across the whole cohort, "smell" was the most common symptom-related word. The words "smell" and "experience" were more likely to occur in patients treated with dupilumab. Patients treated with dupilumab also had more positive sentiment in their SAT responses than those who received placebo. The results from this qualitative analysis were reflected in quantitative PRO results. Conclusion: "Smell" was important to patients with CRSwNP, highlighting its importance as a patient-centric efficacy outcome measure in the context of clinical trials in CRSwNP. Trial Registration: ClinicalTrials.gov, NCT01920893. Registered 12 August 2013, https:// www.clinicaltrials.gov/ct2/show/NCT01920893

Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS‐52 is unaffected by eosinophilic status

Background The human monoclonal antibody dupilumab blocks interleukin (IL)-4 andIL-13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS-52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS-52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy. Methods Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund-Mackay score assessed by CT (LMK-CT) at week 24. Patients (n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm. Results Dupilumab significantly improved NPS, NC, and LMK-CT scores versus placebo at week 24 in all ECRS subgroups (p 0.05), except LMK-CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups. Conclusion Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP

Dupilumab improves health related quality of life:Results from the phase 3 SINUS studies

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2-mediated inflammatory disease with high symptom burden and reduced health-related quality of life (HRQoL). This report aimed to comprehensively understand the effects of dupilumab on domains of HRQoL, their individual elements, and health status in patients with severe CRSwNP from phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) trials. Methods Patients were randomized to dupilumab (n = 438) or placebo (n = 286) for 24 weeks (SINUS-24), or 52 weeks (SINUS-52). Disease-specific HRQoL using 22-item sino-nasal outcome test (SNOT-22), and health status using EuroQoL-visual analog scale (EQ-VAS) was evaluated in the pooled intention-to-treat (ITT) population (Week 24), SINUS-52 ITT (Week 52) and in the subgroups with/without asthma; non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD); and prior sinus surgery. Results At baseline, patients had poor disease-specific HRQoL and general health status and identified "Decreased sense of smell/taste" and "Nasal blockage" as the most important symptoms. Dupilumab significantly improved SNOT-22 total, domain (Nasal, Sleep, Function, Emotion, and Ear/facial), and 22-item scores, and EQ-VAS, at Week 24 vs placebo (all p < .0001), with continued improvements to Week 52 in SINUS-52. Improvements occurred irrespective of comorbid asthma, NSAID-ERD, or prior surgery. A significantly greater proportion of dupilumab-treated patients exceeded clinically meaningful thresholds for SNOT-22 total score and EQ-VAS vs placebo (all subgroups p < .05 except patients without surgery at Week 24). Conclusions Dupilumab treatment led to significant clinically meaningful improvements across all aspects of disease-specific HRQoL, and general health status in patients with severe CRSwNP

Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS‐52 is unaffected by eosinophilic status

Background The human monoclonal antibody dupilumab blocks interleukin (IL)-4 andIL-13, key and central drivers of type 2 inflammation. Dupilumab, on background mometasone furoate nasal spray (MFNS), improved outcomes in the phase III SINUS-52 study (NCT02898454) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). This posthoc analysis of SINUS-52 examined whether eosinophilic status of CRSwNP was a predictor of dupilumab efficacy. Methods Patients were randomized 1:1:1 to dupilumab 300 mg every 2 weeks (q2w) until week 52; dupilumab 300 mg q2w until Week 24, then 300 mg every 4 weeks until week 52; or placebo (MFNS) until week 52. Coprimary endpoints were change from baseline in nasal polyps score (NPS), nasal congestion (NC), and Lund-Mackay score assessed by CT (LMK-CT) at week 24. Patients (n = 438) were stratified by eosinophilic chronic rhinosinusitis (ECRS) status according to the Japanese Epidemiological Survey of Refractory Eosinophilic Rhinosinusitis algorithm. Results Dupilumab significantly improved NPS, NC, and LMK-CT scores versus placebo at week 24 in all ECRS subgroups (p 0.05), except LMK-CT at week 24 (p = 0.0275). Similar results were seen for the secondary endpoints. Dupilumab was well tolerated across all ECRS subgroups. Conclusion Dupilumab produced consistent improvement in symptoms of severe CRSwNP irrespective of ECRS status. Therefore, blood eosinophil level may not be a suitable biomarker for dupilumab efficacy in CRSwNP

Indirect treatment comparison of biologics in chronic rhinosinusitis with nasal polyps

BACKGROUND: Among patients with chronic rhinosinusitis with nasal polyps (CRSwNP), randomized clinical trials (RCTs) of biologics, such as anti-interleukin-4/interleukin-13 (dupilumab) and anti-immunoglobulin E (omalizumab), have demonstrated efficacy compared with intranasal corticosteroids (INCS). However, no head-to-head RCTs exist between biologics. OBJECTIVE: To perform an indirect treatment comparison (ITC) of the efficacy of biologics plus INCS versus placebo (INCS) as a common comparator. METHODS: Embase, MEDLINE, and Cochrane were searched for RCTs of biologics in CRSwNP. Bucher ITCs were performed for outcomes at week 24: nasal polyp score (NPS) (range, 0-8), nasal congestion (NC) (range, 0-3), loss of smell (range, 0-3), University of Pennsylvania Smell Identification Test (range, 0-40), total symptom score (range, 0-12), 22-item sinonasal outcome test (range, 0-110), and responder analyses based on NPS or NC improvement of 1 point or greater. RESULTS: Assessment of trial design, baseline characteristics, and outcome measures suggested that ITC was feasible with four phase 3 RCTs: dupilumab SINUS-24 and SINUS-52 (NCT02912468/NCT02898454) and omalizumab POLYP 1 and POLYP 2 (NCT03280550/NCT03280537). In the intent-totreat population, dupilumab had significantly greater improvements from baseline to week 24 versus omalizumab across key outcomes: NPS (least squares mean difference [95% confidence interval], -1.04 [-1.63 to -0.44]), NC (-0.35 [-0.60 to -0.11]), loss of smell (-0.66 [-0.90 to -0.42]), University of Pennsylvania Smell Identification Test (6.70 [4.67-8.73]), and total symptom score (-1.18 [-1.95 to -0.41]). Improvement in the 22-item sinonasal outcome test was greater in dupilumab versus omalizumab but was not statistically significant. Dupilumab patients were significantly more likely to achieve >= 1-point improvement in NPS (odds ratio [95% CI] = 3.58 [1.82-7.04]) and NC (2.13 [1.12-4.04]) versus omalizumab. CONCLUSIONS: Although ITCs have limitations, these results demonstrated that dupilumab had consistently greater improvements in key CRSwNP outcomes versus omalizumab at week 24. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology