Three Generic Versions of Sacubitril Valsartan Sodium Approved in China Amid Intense Patent Battles

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Three Generic Drugs Approved Successively

Recently,CHIATAI TIANQINGSacubitril Valsartan Sodium Tablets Approved for Marketing by China's National Medical Products Administration,This is the third generic version of Sacubitril Valsartan to be approved in China.

Figure 1. CHIATAI TIANQING’s Sacubitril Valsartan Sodium Tablets Approved, Source: CDE Official Website

On August 24, F&S Pharma Tech announced that its subsidiaryNanjing Yixinhe Pharmaceutical Technology Co., Ltd.The sacubitril valsartan sodium tablet (brand name: Yixintan) developed by Nanjing Yixinhe Pharmaceutical Technology Co., Ltd. has been approved for marketing by NMPA.This is the first generic Sacubitril Valsartan Sodium Tablets submission in China, and also the first drug of its kind to successfully break through the original patent barriers via independent innovation and gain approval for marketing in global regulated markets.

Figure 2. Yixin Tan approved for marketing, Source: F&S Pharma Tech Official WeChat

On the same day, CSPC Pharmaceutical Group Limited also announced that its subsidiaryCSPC OuyiThe sacubitril valsartan sodium tablets (50mg, 100mg, 200mg) developed have been approved for marketing by the NMPA.

Figure 3. CSPC Ouyi’s Sacubitril Valsartan Sodium Tablets Approved, Source: CDE Official Website

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"Aggressive" SalesEntresto

Novartis' New Drug: A Blockbuster

Sacubitril Valsartan Sodium Tablets (trade name: Entresto) is an angiotensin receptor-neprilysin inhibitor (ARNI) drug developed by Novartis. It was approved by the FDA for marketing in 2015 as the world's first breakthrough innovative drug in the field of heart failure and hypertension treatment. In 2017, Entresto was approved to enter the Chinese market under the trade name "Nuo Xintuo" for the treatment of heart failure and was later included in the 2020 National Medical Insurance Catalog. In June 2021, Nuo Xintuo received approval in China for the indication of treating primary hypertension. Additionally, during the 2021 National Reimbursement Drug List negotiation, Nuo Xintuo successfully renewed its listing with the new indication for primary hypertension added.

Since its launch, the sales of Entresto have been growing rapidly.In 2018, sales exceeded the $1 billion mark, then continued to rise at an average year-over-year growth rate of over 35%. In 2022, global sales reached $4.644 billion, a year-over-year increase of 37%, making it second only to Cosentyx (secukinumab) with $4.788 billion in Novartis' portfolio. In the first half of 2023, Entresto's sales were $2.915 billion, a year-over-year increase of 31%, and annual sales are expected to exceed $6 billion.Entresto has grown to become a "blockbuster" level drug among the new medications developed by Novartis in recent years.

Figure 4. Entresto Sales Data for the First Half of 2023, Source: Novartis 2023 H1 Financial Report

In the Chinese market, Entresto also performed outstandingly. Data shows that in 2021, its in-hospital sales exceeded 2 billion yuan, increasing by 177% year-on-year; in the first quarter of 2023, Entresto's in-hospital sales reached 650 million yuan, and total sales are expected to rise further.

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Full of Market Potential

More than 20 pharmaceutical companies in China are positioning themselves to "seize the market share"

The huge market potential of Sacubitril Valsartan Sodium naturally attracts many generic pharmaceutical companies. As of the end of August this year, the CDE has received 39 product specifications for the marketing application of Sacubitril Valsartan Sodium Tablets, covering more than 20 pharmaceutical companies. In addition to F&S Pharma Tech, CSPC Ouyi Pharmaceutical Co., Ltd., and CHIATAI TIANQING, other prominent pharmaceutical companies such as Kelun, Betta, and Qilu are also involved.

Table 1. Enterprises that have reported the production of Sacubitril Valsartan Sodium Tablets, Source: CDE Official Website

It is worth noting that the two core patents (ZL200680001733.0, ZL201210191052.2) of Entresto will not expire until November 8, 2026. For the domestically approved generic drugs to be marketed earlier, they cannot avoid facing patent challenges. In fact, since Entresto is not a new molecule but a molecular complex formed by Sacubitril and Valsartan Sodium, there have been waves of patent challenges regarding Entresto since 2018.

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The Unavoidable "Patent War"

Sacubitril Valsartan Sodium has drawn significant attention in the industry not only because of its huge market potential but also due to its pioneering role in solid-state technology.

From the molecular structure perspective, the active pharmaceutical ingredient LCZ696 in Entresto is a salt complex crystal formed by the combination of sacubitril and valsartan in a 1:1 molar ratio, with each drug molecule containing 2.5 molecules of crystallization water. One of the unique features of LCZ696 is that it is a supramolecular complex with a specific chemical and crystal structure. The combination of two effective drug components within the same unit cell allows them to be released simultaneously in the body. In dogs, after oral administration of LCZ696 tablets, the exposure level of valsartan is three times higher than when sacubitril and valsartan tablets are administered separately. In humans, after oral administration of LCZ696 tablets, the exposure level of valsartan increases by 40% compared to valsartan alone.Compared with the physical mixture of sacubitril/valsartan, the bioavailability of LCZ696 was significantly improved.

Figure 5. Molecular formula of Entresto, Source: Reference 2

Novartis has filed a composition patent (Patent No.: ZL201110029600.7) and a crystal form patent (Patent No.: ZL200680001733.0/ZL201210191052.2) for Entresto in the Chinese market.Especially, the unique crystal form patent allows Novartis' Entresto to maintain its exclusivity in the Chinese market until November 2026.

Table 2. Entresto Registered Patents, Source: China Drug Patent Information Registration Platform

Given the success and vast potential market of Entresto, it faced multiple patent challenges from generic drug manufacturers after its launch. Novartis also frequently attempted to counter these patent challenges initiated by various generic drug companies through litigation.

Before 2019, Chinese pharmaceutical companies such as CSPC Ouyi, Qilu Pharmaceutical, Beijing SiHuan Pharmaceutical, Shandong New Time Pharmaceutical, CHIATAI TIANQING, and Salubris had already challenged the patent validity of Novartis' Entresto, involving two key compound and composition patents of Sacubitril Valsartan Sodium Tablets.

On July 2, 2021, the China National Intellectual Property Administration issued three announcements in a row, stating that the patent challenges against Entresto initiated by Salubris, CHIATAI TIANQING, and CSPC Ouyi Pharmaceutical Co., Ltd. were recognized by the China National Intellectual Property Administration as follows:Part of Novartis' "Entresto" patent rights are invalid, namely the composition patent is invalid, while the crystal form patent remains valid.

The crystalline form patent allows Novartis' Entresto to maintain its exclusive market position in China until November 2026. So, why have domestically produced generic drugs been approved for marketing ahead of schedule?

According to reports,F&S Pharma Tech's Yixin Tan is a new crystalline form containing three molecules of crystallization water, which circumvents the original patent barrier of the crystalline form containing 2.5 molecules of crystallization water, thereby enabling the legal early market entry of the generic drug.F&S Pharma Tech announced that Yixin坦 will be sold nationwide in China through Fosun Pharma.

In response to the approval of generic drugs, Novartis immediately issued a statement indicating that both patents for Sacubitril Valsartan Sodium are currently valid.

Figure 6. Novartis Statement, Source: Novartis Official WeChat

Industry insiders said that since Yixin Tan has successfully bypassed the crystal form patent barriers of Entresto, it may prematurely end Entresto's monopoly status in China. CSPC Ouyi and CHIATAI TIANQING have not yet clearly explained how their generic drugs circumvent the original research’s crystal form patent.

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Summary

The balance between innovative drugs and generic drugs is the fundamental guarantee for maintaining a healthy pharmaceutical industry ecosystem. To strike a balance between encouraging innovation and improving drug accessibility (promoting generics), a sound legal system is essential. In July 2021, China issued the "Implementation Measures for the Early Resolution Mechanism of Pharmaceutical Patent Disputes," also known as China's "patent linkage system." This laid the foundation for encouraging new drug research and promoting the development of high-quality generics, further aligning China’s pharmaceutical intellectual property protection system with international standards.

Driven by the centralized procurement, China's current generic drug companies are transitioning from basic price competition to advanced technology competition.For generic drug companies in China, bypassing certain core patent barriers through independent research and development to seize the first-to-market opportunity is undoubtedly worth encouraging. At the same time, the patent layout of Novartis' Entresto also highlights the importance of crystal form patents, which is worth learning from.