Efficacy and safety of CM310 in severe eosinophilic chronic rhinosinusitis with nasal polyps (CROWNS-1): a multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial

Yuan Zhang; Bing Yan; Shen Shen; Xicheng Song; Yan Jiang; Li Shi; Changqing Zhao; Yi Yang; Luyun Jiang; Jiping Li; Jing Ye; Jinfeng Liu; Lijia Wan; Yucheng Yang; Jianjun Chen; Feng Liu; Lizhong Su; Yu Xu; Guolin Tan; Shaoqing Yu; Yu Zhang; Lin Wang; Shengyang Liu; Hongyue Yan; Wei Liu; Bo Chen; Chengshuo Wang; Luo Zhang

doi:10.1016/j.eclinm.2023.102076

Efficacy and safety of CM310 in severe eosinophilic chronic rhinosinusitis with nasal polyps (CROWNS-1): a multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial

EClinicalMedicine. 2023 Jul 5:61:102076. doi: 10.1016/j.eclinm.2023.102076. eCollection 2023 Jul.

Authors

Yuan Zhang¹, Bing Yan^{2

3

4}, Shen Shen^{2

3

4}, Xicheng Song^{5

6}, Yan Jiang⁷, Li Shi⁸, Changqing Zhao⁹, Yi Yang¹⁰, Luyun Jiang¹¹, Jiping Li¹², Jing Ye¹³, Jinfeng Liu¹⁴, Lijia Wan¹⁵, Yucheng Yang¹⁶, Jianjun Chen¹⁷, Feng Liu¹⁸, Lizhong Su¹⁹, Yu Xu²⁰, Guolin Tan²¹, Shaoqing Yu^{22

23}, Yu Zhang^{5

6}, Lin Wang⁷, Shengyang Liu⁸, Hongyue Yan²⁴, Wei Liu²⁴, Bo Chen²⁴, Chengshuo Wang^{2

3

4}, Luo Zhang^{1

2

3

4}

Affiliations

¹ Department of Allergy, Beijing TongRen Hospital, Capital Medical University, Beijing 100005, China.
² Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing 100730, China.
³ Beijing Institute of Otolaryngology, Beijing Laboratory of Allergic Diseases, Beijing Key Laboratory of Nasal Diseases, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing 100005, China.
⁴ Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing 100005, China.
⁵ Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong 264000, China.
⁶ Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong 264000, China.
⁷ Department of Otorhinolaryngology, Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.
⁸ Department of Otorhinolaryngology, Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250000, China.
⁹ Department of Otorhinolaryngology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030000, China.
¹⁰ Department of Otorhinolaryngology, Beijing Hospital, Beijing 100730, China.
¹¹ Department of Otorhinolaryngology, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China.
¹² Department of Otorhinolaryngology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
¹³ Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, China.
¹⁴ Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
¹⁵ Department of Otorhinolaryngology, Jingzhou Central Hospital Affiliated to Yangtze University, Jingzhou, Hubei 434020, China.
¹⁶ Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, Sichuan 400042, China.
¹⁷ Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
¹⁸ Department of Otorhinolaryngology, West China Hospital, Sichuan University, Chengdu, Sichuan 610066, China.
¹⁹ Department of Otorhinolaryngology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 314408, China.
²⁰ Department of Otorhinolaryngology, Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
²¹ Department of Otorhinolaryngology, Head and Neck Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
²² Department of Otolaryngology Head and Neck Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
²³ Department of Allergy, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
²⁴ Clinical Department, Keymed Biosciences (Chengdu) Limited, Chengdu, Sichuan 610219, China.

Abstract

Background: Severe eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remains the most relapsed subtype of uncontrolled CRSwNP. CM310, a humanised anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits IL-4 and IL-13 signaling which underlying eosinophilic inflammation. This study aims to evaluate the efficacy and safety of CM310 in patients with severe ECRSwNP.

Methods: A multicentre, randomised, double-blind, and placebo-controlled phase 2 clinical trial was conducted. 56 eligible adult patients with severe ECRSwNP were randomised 1:1 to receive subcutaneously either CM310 (300 mg) or placebo every 2 weeks under the background therapy of mometasone furoate nasal spray (MFNS) for 16 weeks, with 8 weeks of follow-up. Coprimary endpoints included the changes from baseline in nasal polyp score (NPS) and nasal congestion score (NCS) at week 16. Key secondary endpoints included sinus Lund-Mackay CT score, change in sinus volume occupied by disease, University of Pennsylvania Smell Identification Test score, 22-item Sino-nasal Outcome Test score, and total symptom score. Safety, pharmacodynamics, and changes in type 2 inflammation biomarkers were assessed. This study is registered with ClinicalTrials.gov, NCT04805398.

Findings: Between April 6, 2021, and March 18, 2022, 27 patients respectively in both the CM310 and placebo groups completed the study. Findings suggested that CM310 improved the coprimary efficacy endpoints of decreasing nasal polyp size and alleviating nasal congestion compared with the placebo. Least squares (LS) mean differences (CM310 vs placebo) of change from baseline in NPS and NCS at week 16 were -2.1 (95% CI -2.9, -1.4; p < 0.0001) and -0.9 (95% CI -1.4, -0.5; p < 0.0001), respectively. Sinus CT scan revealed that Lund-Mackay CT score (LS mean difference [95% CI] -7.6, [-9.4, -5.8]; p < 0.0001) and sinus volume occupied by disease (LS mean difference [95% CI] -37%, [-47%, -28%]; p < 0.0001) were significantly improved with CM310 compared with placebo. In addition, CM310 significantly relieved the daily symptoms of patients with CRSwNP and improved their quality of life reflected by the improvements in the TSS (-2.6 [95% CI -3.5, -1.6]), UPSIT (10.4 [95% CI 6.8, 14.0]) and SNOT-22 score (-19.1 [95% CI -29.8, -8.5]). Compared with placebo, CM310 administration significantly reduced type 2-related biomarkers including the serum TARC and total IgE, and tissue eosinophils. The most common adverse events were upper respiratory tract infection, blood cholesterol increased, and tinnitus, but none were considered drug-related.

Interpretation: These findings support CM310 as an effective additional treatment option to the standard of care in patients with severe ECRSwNP.

Funding: KeyMed Biosciences (Chengdu) Limited.

Keywords: Anti-interleukin-4 receptor alpha monoclonal antibody; Chronic rhinosinusitis with nasal polyps; Double-blind; Placebo-controlled; RCT.

Associated data

ClinicalTrials.gov/NCT04805398