AstraZeneca's PARP Inhibitor Olaparib Recommended for Priority Review in China; Benralizumab and Tezepelumab Granted Clinical Trial Approvals

On December 22, the latest public notice on the website of the Center for Drug Evaluation (CDE) under China’s National Medical Products Administration indicated that olaparib, submitted by AstraZeneca for approval in China, is proposed to be included in the priority review program. The intended indication is metastatic castration-resistant prostate cancer. Additionally, two new biological drugs, benralizumab and tezepelumab, received implicit approval for clinical trials. Olaparib is a “first-in-class” PARP inhibitor; benralizumab is an IL-5Rα inhibitor; and tezepelumab is a potential “first-in-class” TSLP inhibitor.

1. Olaparib

Mechanism of Action: PARP Inhibitors

Proposed Indication: Monotherapy for adult patients with specific metastatic castration-resistant prostate cancer

Olaparib is a “first-in-class” PARP inhibitor jointly developed by AstraZeneca and Merck & Co. (MSD), and it was the first PARP inhibitor to receive regulatory approval. This drug targets the DNA damage response (DDR) pathway, leveraging the principle of “synthetic lethality” to kill cancer cells while sparing healthy cells. Olaparib was first approved in the United States in December 2014 for the treatment of patients with advanced ovarian cancer harboring germline BRCA mutations.

Olaparib is proposed for inclusion in the Priority Review Program in China, with the intended indication being: monotherapy (proposed) for adult patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations (germline and/or somatic) who have experienced disease progression following prior treatment with novel hormonal agents.

Source: CDE Official Website

Based on the results of the Phase 3 PROfound clinical trial, olaparib significantly improved overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 or ATM mutations (a subgroup of homologous recombination repair [HRR] gene mutations), thereby meeting the key secondary endpoint of the trial. Previously reported results demonstrated that, in mCRPC patients with BRCA1/2 or ATM mutations, olaparib treatment significantly prolonged radiographic progression-free survival (rPFS) compared to abiraterone or enzalutamide, thus meeting the primary endpoint of the trial.

In China, olaparib (brand name: Lynparza) was first approved in August 2018, becoming the first targeted novel drug for ovarian cancer to be approved and marketed in the country. In November 2019, olaparib received further approval from the National Medical Products Administration (NMPA) for first-line maintenance treatment of patients with advanced ovarian cancer harboring BRCA mutations who had achieved a response following platinum-based chemotherapy.

2. Benralizumab Injection

Mechanism of Action: IL-5Rα Inhibitor

Approved Clinical Indication: Chronic Obstructive Pulmonary Disease (COPD)

Benralizumab (Fasenra) is a monoclonal antibody developed by AstraZeneca that binds to IL-5Rα expressed on the surface of eosinophils. By binding to IL-5Rα, it recruits natural killer cells to rapidly eliminate these cells by inducing eosinophil apoptosis. Studies have shown that its selective anti-eosinophil effect can reduce the rate of acute exacerbations in patients with COPD, an effect that appears to be more pronounced in patients with high baseline blood eosinophil counts.

Previously, benralizumab was approved by the U.S. FDA in November 2017 as add-on maintenance therapy for patients aged 12 years and older with severe asthma exhibiting an eosinophilic phenotype. Furthermore, it was granted orphan drug designation by the FDA for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) in 2018 and for hypereosinophilic syndrome (HES) in 2019.

Benralizumab injection has been approved for clinical trials in China, with the proposed indication being chronic obstructive pulmonary disease (COPD). COPD is a progressive disease that causes airflow obstruction in the lungs, leading to breathing difficulties. It affects approximately 384 million people worldwide and is the third leading cause of death globally. Improving lung function, reducing acute exacerbations, and managing daily symptoms are key therapeutic goals in the management of COPD.

According to the clinical results of the WINDWARD study, patients with severe asthma who received an 8-week benralizumab dosing regimen showed significant improvement in lung function, with a 159 mL greater increase in forced expiratory volume in one second (FEV1) compared to the placebo group. Differences were observed as early as 4 weeks after initiation of treatment, indicating a rapid onset of action. The study demonstrates that benralizumab has robust clinical performance, including the ability to improve lung function after the first dose, the potential to reduce or even discontinue the use of oral corticosteroids, and the convenience of an 8-week dosing interval.

Source: CDE Official Website

3. Tezepelumab Injection

Mechanism of Action: TSLP Inhibitor

Approved Clinical Indication: Severe Chronic Rhinosinusitis with Nasal Polyps

Publicly available information indicates that tezepelumab is a thymic stromal lymphopoietin (TSLP) inhibitor jointly developed by Amgen and AstraZeneca. As a potential first-in-class novel drug, it has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA). TSLP is an epithelial cytokine that serves as an upstream regulator of multiple inflammatory pathways in various diseases, including asthma, and plays a critical role in the initiation and persistence of airway inflammation. Studies have shown that TSLP is actively involved in regulating type 2 (T2) immunity. Additionally, it contributes to non-T2-driven inflammation by activating or signaling to various cell types, such as mast cells and basophils.

The approval of tezepelumab injection for clinical trials in China marks its intended development for the treatment of severe chronic rhinosinusitis with nasal polyps (CRSwNP). Chronic rhinosinusitis with nasal polyps affects up to 4% of the global population and is characterized by the presence of benign inflammatory polyps (nasal polyps) on the lining of the sinuses or nasal cavity, which can obstruct normal airflow and lead to symptoms such as nasal congestion, runny nose, facial pain/pressure, and reduced or lost sense of smell.

Studies have shown that TSLP expression levels are positively correlated with the expression of Th2 cytokines in sinus mucosa. In cultures of human primary nasal mucosal epithelial cells, TSLP can induce ST2L expression. In eosinophilic chronic rhinosinusitis with nasal polyps, the positive feedback loop formed by TSLP and its receptor, along with Th2 cytokines, can promote the initiation and progression of Th2 inflammatory responses. Therefore, biologics targeting TSLP hold promise as a novel therapeutic option for chronic rhinosinusitis with nasal polyps.

Currently, surgery and systemic corticosteroids are the main treatment options for this disease following standard therapy with intranasal corticosteroids. However, due to the regrowth of nasal polyps, they often fail to effectively control chronic symptoms over time.

References:

[1] Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Nov 27, 2019, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=3

[2] Positive Phase 2 Results for AstraZeneca’s New Drug Fasenra: Near-Complete Elimination of Pathogenic White Blood Cells. Retrieved April 8, 2019, from https://med.sina.com/article_detail_103_2_64050.html

[3] Jiang Wenzhong. (2004). Increased airway eosinophils and exacerbation of COPD. Journal of Modern Clinical Medicine and Bioengineering, 79-81. doi:CNKI:SUN:XDLC.0.2004-01-043.

[4]Tezepelumab Significantly Reduced Asthma Exacerbations For A Broad Population Of Patients With Severe Uncontrolled Asthma. Retrieved September 7, 2018, from https://www.amgen.com/media/news-releases/2017/09/tezepelumab-significantly-reduced-asthma-exacerbations-for-a-broad-population-of-patients-with-severe-uncontrolled-asthma/

[5] Zhang L. (2017). Prospects for precision treatment of chronic rhinosinusitis with nasal polyps. Chinese Journal of Otorhinolaryngology Head and Neck Surgery doi:10.3760/cma.j.issn.1673-0860.2017.02.001.

[6] Liao Bo. Interaction of TSLP, IL-33 and Their Receptors in Epithelial Cells of Eosinophilic Chronic Rhinosinusitis with Nasal Polyps [D]. 2015.

Source: Yiyao Guanlan

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