China's First Generic of Blockbuster Asthma Drug Salmeterol/Fluticasone Approved: Health Yuan Ends GSK's 23-Year Monopoly as Hengrui, Sinopharm, Bio-Techne Accelerate Market Reshuffle

Jun 14, 2024 19:48 CST Updated 19:48

GSK

Pharmaceutical R&D Manufacturer

The competitive landscape of GSK's star asthma drug, Seretide (generic name: Salmeterol Ticasone), is changing in China.

Recently, Health Yuan announced that its salmeterol xinafoate and fluticasone propionate inhalation powder, reported for production as a Category 4 chemical drug, has been approved. It can be used for the regular treatment of reversible obstructive airway diseases, including adult and pediatric asthma, becoming the first domestically produced generic drug in China. This means that with the approval and market launch of Health Yuan's salmeterol xinafoate and fluticasone propionate inhalation powder, the 23-year market monopoly of the original research manufacturer GSK's blockbuster product in China has come to an end.

Seretide is a compound inhalation powder containing Salmeterol and Fluticasone Propionate. Salmeterol, a long-acting β2 receptor agonist, provides sustained bronchodilation, while Fluticasone Propionate, a glucocorticoid, controls inflammation and reduces acute exacerbations. The combination of bronchodilators and glucocorticoids is the gold standard for asthma treatment. As the world’s first compound inhalation formulation combining a bronchodilator and a corticosteroid, Seretide quickly became an essential product for treating asthma and chronic obstructive pulmonary disease (COPD) after its launch.

In fact, the compound patent for Seretide in China expired as early as 2013, and the reason GSK was able to monopolize the market for over 20 years is due to the extreme difficulty in generic manufacturing of this variety. Among various inhalation preparations, dry powder inhalers present the highest technical challenge, with difficulties in particle engineering, process development, process scale-up, and delivery devices. As Joincare Pharmaceuticals takes the lead in making breakthroughs, domestic pharmaceutical companies such as Hengrui Medicine, China Biologic Products, and Bet Pharmaceutical may also continue to follow suit, accelerating the formation of a multi-layered encirclement against GSK.

Securing the First Generic Approvals for Two Major Varieties in a Row

What are the strategic moves of Health Yuan?

Chronic respiratory diseases (CRD), along with cardiovascular and cerebrovascular diseases, diabetes, and cancer, are listed by the WHO as the four major chronic diseases globally and are the third leading cause of death worldwide. These include COPD, asthma, pneumoconiosis, interstitial lung disease, and pulmonary sarcoidosis, among others. Among these, COPD has the highest mortality rate of all CRDs, while the number of asthma patients is the highest among all CRDs. Currently, the WHO recommends inhaled therapy as the first-line treatment for both asthma and COPD.

GSK's original research product, Seretide, began sales in 1999 and reached its global sales peak in 2013 at $8.243 billion. In 2001, Seretide was first approved for import in China, and subsequently entered the Class B National Medical Insurance Catalogue in 2017. According to annual reports, Seretide’s global market sales in 2023 were approximately £1.139 billion. Calculated at constant exchange rates, favorable pricing in the U.S. market allowed Seretide’s sales to increase by 1% year-on-year, but this was offset by generic drug erosion in European and other international markets.

Currently, Seretide has two forms approved in China: Salmeterol/Fluticasone Powder Inhaler and Salmeterol/Fluticasone Aerosol Inhaler. According to the data from MIRNET on the terminal of public medical institutions in China, in recent years, the market scale of inhalation preparations has maintained at 20 billion yuan, with a year-on-year increase of 8.80% in the first half of 2023. Among them, the sales of Salmeterol/Fluticasone Powder Inhaler exceeded 1 billion yuan in 2022, with a slight year-on-year increase in the first half of 2023, ranking it among the top five products of inhalation preparations.

With the launch of Health Yuan's first generic drug, the future market share of Seretide in China will be further eroded. In fact, Health Yuan’s success in securing the first generic version of Seretide ultimately comes down to its seizing of policy benefits. In December 2020, in order to further standardize and guide bioequivalence studies for generic orally inhaled formulations, and to improve the accessibility of generic orally inhaled drugs, the CDE released the "Guiding Principles for Bioequivalence Studies of Generic Orally Inhaled Formulations."

Under the guidance of the new CDE regulations, in February 2023, Health Yuan's first submission of the registration and marketing authorization application for Salmeterol Tiotropium Powder Inhaler was accepted. Health Yuan stated in its announcement at the time that it was the first company in China to submit the marketing application for this product and gain acceptance since the issuance of the new regulations. As of the date of this approval announcement, Health Yuan's total R&D investment in Salmeterol Tiotropium Powder Inhaler has amounted to approximately 88.9057 million yuan.

Notably, the head-to-head competition between Health Yuan and GSK does not end here. In May 2024, Fluticasone Propionate Inhalation Suspension developed by Shanghai Fangyu, a holding subsidiary of Health Yuan, was approved as the first domestically produced generic drug in China for the treatment of mild to moderate asthma attacks in children and adolescents aged 4-16. This product belongs to the class of inhaled corticosteroids, exerting its asthma treatment effect through local anti-inflammatory action. Fluticasone Propionate Inhalation Suspension was originally developed by GSK and entered the Chinese market under the brand name Flixotide in 2017. Data from Menet shows that sales of Fluticasone Propionate Inhalation Suspension in Chinese public medical institutions exceeded 300 million yuan in 2023, with a year-on-year increase of approximately 100%.

Healthcare Yuan's Success in Securing First Generic Versions of Two Major GSK Varieties Linked to Long-Standing Expertise in Inhalation Formulations. In 2013, Healthcare Yuan officially entered the inhalation formulation market by establishing Shanghai Fangyu, becoming one of the earlier companies in China to focus on inhalation formulations. According to the annual report, in 2023, Healthcare Yuan's (excluding Livzon Group and Livzon Monoclonal Antibody) prescription drug segment achieved sales revenue of 1.988 billion yuan, a year-on-year decrease of approximately 6.20%. Among this, the respiratory field, a key therapeutic area for Healthcare Yuan, achieved sales revenue of 1.741 billion yuan, a year-on-year increase of approximately 48.35%.

Currently, Health Yuan has 9 marketed products in the respiratory field, including Terbutaline Sulfate Solution for Nebulization Inhalation, Levalbuterol Hydrochloride Solution for Nebulization Inhalation, Acetylcysteine Solution for Inhalation, Tobramycin Inhalation Solution, Compound Ipratropium Bromide Solution for Inhalation/Ipratropium Bromide Solution for Inhalation, and Budesonide Suspension for Inhalation. These products have quickly opened up the sales market in China by leveraging the opportunities provided by national centralized procurement and are continuously increasing their market share.

Inhalers Approved for Marketing by Health Yuan Pharmaceutical

Source: MiNeiNet China Listed Drugs (MID) Database

In addition, Joincare is also continuously expanding its innovative drug layout in the field of respiratory diseases. In January 2024, Joincare reached product licensing agreements with Quanxin Biotech and Boan Biotech respectively, obtaining relevant rights to two products—an anti-TSLP monoclonal antibody and an anti-IL-4Ra monoclonal antibody—for their development in treating respiratory conditions such as asthma and COPD. In March 2024, Joincare signed an agreement with Bayer for the exclusive license to develop, commercialize, and produce a small molecule inhibitor in China. This marks the first time Joincare has introduced an innovative drug pipeline in the respiratory field from a globally leading multinational company.

It can be seen that in recent years, Jiankangyuan's business development pace has consistently revolved around respiratory diseases as the focal point, accelerating the comprehensive layout of its innovative drug pipeline. In the industry's view, with the continuous strengthening of its R&D pipeline, Jiankangyuan is preparing to enhance its upcoming blockbuster products and performance flexibility. Among these, a rich variety of inhalation preparations are also expected to continue contributing to its sales revenue growth.

China's leading pharmaceutical companies are making a full-scale effort

Inhalation Formulations Market Accelerates Restructuring

According to research reports from Open Source Securities, the expiration of patented original drugs has led to the market entry of generic drugs, causing some price erosion in the inhalation formulation market. In recent years, the global market size for inhalation formulations for respiratory diseases has shown a slight declining trend. However, driven by the increasing clinical demand for inhalation formulations, the market volume of generic drugs is expected to grow further. According to Frost & Sullivan data, the global market for inhalation formulations for respiratory diseases is projected to reach USD 29.3 billion by 2025 and USD 33.7 billion by 2030.

The market potential of inhaled preparations for respiratory diseases in China is also not to be underestimated. According to Frost & Sullivan data, from 2017 to 2021, the market size of inhaled preparations for respiratory diseases in China grew from 12.5 billion yuan to 19.5 billion yuan. With the successive launches of generic drugs, it is expected that the market size of inhaled preparations for respiratory diseases in China will further grow rapidly, reaching 23.9 billion yuan by 2025 and 27.6 billion yuan by 2030.

The race for the first generic version of Seretide (salmeterol/fluticasone inhalation powder) serves as a microcosm of Chinese pharmaceutical companies competing in the market for inhaled medications targeting respiratory diseases. Replicating Seretide represents a peak in the field of inhaled formulations, and among those striving to reach it are several leading domestic pharmaceutical firms. Data from the Mening Network shows that 21 domestic manufacturers have filed applications for salmeterol/fluticasone inhalation powder, with 25 clinical trials still ongoing.

In June 2018, CSPC's subsidiary Chia Tai Tianqing submitted a marketing application for Salmeterol and Fluticasone Propionate Powder Inhaler, becoming the first company in China to report production of this variety. In December of the same year, the product was included in the priority review list. In the field of respiratory medicine, Chia Tai Tianqing has broken through key technical bottlenecks in the treatment drugs and devices for COPD in China. It ranks among the top in the integrated design and manufacturing of inhalation drug-device combinations and in the field of precision diagnostic drugs for asthma. Currently, Chia Tai Tianqing is making comprehensive efforts in indications such as asthma, COPD, pneumoconiosis, and chronic cough and wheezing through core products like Budesonide Suspension for Inhalation.

In October 2018, Hengrui Medicine also filed for the market registration of Salmeterol Tiotropium Powder Inhaler under the new Registration Classification Category 4, joining this first generic competition. Respiratory diseases are one of the key therapeutic areas where Hengrui Medicine has made extensive arrangements. In terms of innovative drug development, the company still has several drugs in clinical trials, targeting popular pathways such as IL-5 and TSLP, for the treatment of diseases like idiopathic pulmonary fibrosis. In April 2024, Hengrui Medicine announced that its developed SHR-4597 inhaler had been approved to commence clinical trials. This is an innovative inhaled biologic product for maintenance treatment of bronchial asthma, with no similar products currently available on the market or in clinical development stages both domestically and internationally.

According to the list of products under review disclosed on the CDE website, so far, four pharmaceutical companies have submitted marketing authorization applications for Salmeterol and Fluticasone Propionate Inhalation Powder. Two of them are classified as Category 4 generics, namely Suzhou Omnia Pharmaceuticals and Sichuan Puretrek Pharmaceuticals, a subsidiary of Chengdu Bright Future Pharmaceutical. The other two are import drug registration applications, filed under Category 5.2 of chemical drugs, namely Fangu Pharmaceuticals, which has partnered with Indian generic giant Cipla, and Hangzhou Jingrui Pharmaceuticals, a subsidiary of Jingxin Pharmaceuticals that has joined hands with Neutec.

In July 2023, the CDE accepted the marketing application for Omnia Pharmaceuticals' (Suzhou) Seretide (salmeterol/fluticasone) Inhalation Powder. Omnia Pharmaceuticals (Suzhou) is one of the few innovative pharmaceutical companies in China with the capability to research and produce all types of inhalation formulations. It has received investments from well-known domestic and international institutions such as Shanghai BioPharmaceutical Fund, Morningside Ventures, Lilly Asia Ventures, Vivo Capital, and SDIC Venture Capital. In addition to the Seretide Inhalation Powder, Omnia Pharmaceuticals (Suzhou) has one inhalation powder and one aerosol product in clinical stages, with expected marketing applications to be completed within the next 1-2 years.

In October 2023, Sichuan Pulitet Pharmaceutical's Salmeterol and Fluticasone Propionate Inhalation Powder was accepted for production as a Category 4 generic drug. Inhalation preparations are the main focus of Chengdu Betta Pharmaceuticals, and Sichuan Pulitet Pharmaceutical is an important part of its strategy. To date, Sichuan Pulitet Pharmaceutical has received approval for nine inhalation products, and several other inhalants, such as Formoterol Fumarate Inhalation Solution, are currently under review for production.

Inhaled formulations for respiratory diseases represent a highly promising and vast market. The "Big Three" of the international inhaled formulations industry—GSK, AstraZeneca, and Boehringer Ingelheim—each hold blockbuster products with annual sales exceeding $1 billion. Due to high technical barriers and significant challenges in generic production, the sales of these products will not experience a cliff-like decline after patent expiration and can continue to generate substantial revenue. With the rise and development of local pharmaceutical companies in China, the inhaled formulations market, long monopolized by multinational corporations, is being rapidly reshaped.

Editor：Cheng Lin