Domestic generic drugs have been approved one after another, and the original research and innovation drug Noxintuo, an anti-heart failure drug, is facing ＂grabbing food＂ in the market of 3 billion yu

　　21st century business herald reporter Ji Yuanyuan reports from Shanghai Recently, Yixinhe Pharmaceutical Technology Co., Ltd. (hereinafter referred to as "Yixinhe Medicine") developed and produced, and (1) Shakuba Quvalsartan Sodium Tablets (brand name: Yixintan) which was exclusively commercialized was approved by National Medical Products Administration (NMPA). Yixintan is the first generic drug of shakubatravalsartan sodium tablets approved for marketing in the global regulatory market by breaking through the original research patent through innovative crystal forms. The approved indications of this product are for treating essential hypertension and adult patients with chronic heart failure (NYHA II-IV grade, LVEF≤40%) with reduced ejection fraction, so as to reduce the risk of cardiovascular death and hospitalization for heart failure.

　　Immediately afterwards, Unacon also announced that its subsidiary company Shiyao Ouyi developed Shakubatrivalsartan sodium tablets (50mg, 100mg, 200mg) which have obtained the drug registration approval issued by National Medical Products Administration, and regarded them as the adult patients with chronic heart failure (NYHA II-IV grade, LVEF≤40%) with reduced ejection fraction, which reduced the risk of cardiovascular death and hospitalization for heart failure.

　　With the approval of domestic shakubatravalsartan sodium tablets, Novartis, the original drug manufacturer, also released information at the first time, saying that the marketing license for the generic drug of Novartis’ original research product shakubatravalsartan sodium tablets was approved, and Novartis declared that the pharmaceutical active ingredient of the original research product Noxintuo was protected by patents ZL200680001733.0 and ZL201210191052.2 in China.

　　According to the relevant provisions of Article 11 of China’s Patent Law, any enterprise or individual shall not manufacture, use, promise to sell (including applying for online registration, participating in bidding, etc.), sell or import products falling within the scope of the above patent protection before the expiration of the above patent period, otherwise it will constitute patent infringement. To this end, Novartis emphasizes that it will reserve the right to claim its patent right against infringing imitations from relevant judicial and/or administrative organs.

　　Regarding the patent issue, according to the public information, in April 2017, the patent of Shakubatroxobin Sodium Tablets registered by Novartis was declared invalid in China. On July 2, 2021, the crystal patent was also partially invalidated in China. Yixin and Medicine also emphasized in the official disclosure information that in 2022, the domestic sales of Shakuba Quvalsartan sodium tablets totaled nearly 3 billion yuan, and its China patent will expire in November 2026. Yixintan is a first-line drug for the treatment of heart failure and hypertension with independent intellectual property rights, which can legally make the majority of patients with heart failure and hypertension in China use equivalent and affordable innovative drugs three years in advance.

　　It can also be seen that the domestic Shakubatroxobin Valsartan sodium tablets have been approved one after another, which will bring certain market challenges to the original drug.

　　More than 10 pharmaceutical companies compete for the market

　　Shakubatroxobin and valsartan sodium tablets are a new type of eutectic drug composed of enkephalinase inhibitors Shakubatroxobin and angiotensin receptor blocker valsartan sodium tablets in a molar ratio of 1:1. Eutectic structure can make the absorption and elimination rates of shakubarb and valsartan sodium tablets similar, and ensure the synchronous consistency of their efficacy. In addition, compared with independent preparations, eutectic drugs have the advantages of constant composition ratio, good storage stability, and can significantly improve drug solubility and oral bioavailability.

　　As a representative drug of ARNi, Shakubatroxobin sodium tablets have been unanimously recommended by domestic and foreign guidelines in recent years. In 2021, the American Heart Association proposed that ARNi drugs should be given priority to patients with HErEF, and it is recommended to use them to the maximum tolerated dose or target dose (Class I). In 2018, China Heart Failure and Treatment Guidelines also recommended to replace ACEI/ARB with ARNi to further reduce the incidence and mortality of heart failure (Class I).

　　Sakubatravalsartan sodium was originally researched by Novartis Entresto, and was first approved by the FDA in July 2015. It is the world’s first breakthrough and innovative drug in the field of heart failure treatment, and was approved to enter the domestic market for the first time in July 2017. It was included in the national medical insurance category B catalogue through negotiation in 2019, successfully renewed in 2021, and added indications for essential hypertension. In 2021, the global sales of the original research sand kubatroxobin sodium reached US$ 3.548 billion. In 2022, its global sales scale reached US$ 4.644 billion, up 37% year-on-year. In the first half of 2023, the drug also grew into the best-selling drug of Novartis, with sales reaching US$ 2.915 billion, up 31% year-on-year, and it is expected to exceed US$ 6 billion in the whole year.

　　In the China market, the original yanshakubatravalsartan sodium is also a heavy variety. According to the data of the Minenet, the sales growth rate of this product in China’s three major terminals and six major markets has reached triple digits in recent years. In 2021, it exceeded 2 billion yuan for the first time, up 127.62% year-on-year, with full market potential; In 2022, the sales of Shakubatroxobin Sodium Tablets in China’s three major terminals and six major markets exceeded 2 billion yuan. Among them, the hospital market (public hospital terminal+public primary medical terminal) is the main sales channel, with a year-on-year increase of 6.54%.

　　In this regard, some brokerage analysts told 21st century business herald that the innovative product layout must be aimed at chronic diseases, major diseases, diseases that pose a major threat to people’s health, such as cardiovascular diseases, tumors and major infectious diseases. At the same time, the core of making medicine is clinical value. With the rapid development of life science, many interdisciplinary fields are very active, and the large-scale treatment methods focusing on large populations are worthy of attention.

　　"The successive approval of domestic shakubatravalsartan sodium tablets is a great benefit for cardiovascular patients, although the layout of many domestic pharmaceutical companies is already in the clinical stage, except for the single-minded and pharmaceutical/Fosun Pharma, Shiyan Ouyi, including Sichuan Kelun, Chengdu Beite, Qilu Pharmaceutical, Zhengda Tianqing, etc. are also accelerating the layout. This is due to the accelerated layout of many domestic pharmaceutical companies, and the prices of related products are expected to be further lowered, eventually benefiting more patients. " The above analyst said.

　　According to the data of Minenet, at present, there are three companies that have production approval documents for Shakuba Quvalsartan Sodium Tablets. Among them, Unacon Ouyi Pharmaceutical Co., Ltd. and Nanjing Yixin and Medical Science and Technology Co., Ltd. were all approved on the same day with four types of imitation, which are regarded as over-evaluation, and tied for the first imitation and the first over-evaluation. In addition, 17 enterprises, including Shandong New Times Pharmaceutical, Nanjing Zhengda Tianqing Pharmaceutical and Qilu Pharmaceutical (Hainan), all reported their production under the new classification.

　　An unavoidable patent dispute

　　The competitive anxiety between Chinese and foreign pharmaceutical companies in Shakuba Quvalsartan sodium tablets is also considered to be an important reason for patent confrontation. At the same time, in recent years, patent disputes between original drugs and generic drugs have occurred from time to time. 21st century business herald reporter found through the search of Wisdom Bud database that as of the latest, there are more than 700 drug patents with litigation results in China, and more than 99% of them are invention patents. It can be seen that the handling of drug patent disputes needs urgent attention.

　　Yixinhe Medicine also emphasized in the official information disclosure that Yixintan is a first-line drug for the treatment of heart failure and hypertension with independent intellectual property rights. Compared with the reference crystal form, when the relative humidity changes from 20% to 60%, it absorbs less water and is more stable, and can be sealed and stored below 30℃. This stable crystal form is more suitable for the vast China market.

　　When talking about patents, some pharmaceutical executives also told 21st century business herald that the research and development of original innovative drugs has always been a "three high" industry with high threshold, high risk and high return. According to the latest literature, it takes an average of 12.5 years for a new drug to go on the market, which costs nearly $2.6 billion, and the success rate is less than 10%. Every new drug project is the most important decision of an enterprise, and the project process needs a lot of data research, especially the research on patents, documents and regulations takes a lot of time.

　　"Therefore, how to find a balance between ensuring the innovation enthusiasm of the original drug research enterprises and reducing the burden on patients has been hotly debated. The FDA’s definition of generic drugs is very strict, and the requirements must be consistent with the dosage form, specifications and administration route of the copied products. If it is inconsistent, it will be declared as a new drug. " The above-mentioned pharmaceutical company executives said that for the long-term public interest, the state needs to protect the enthusiasm of the original drug research and development enterprises. At the same time, in order to limit the original drug research and development enterprises, it is necessary to encourage the imitation research and development of the original drug from the level of institutional norms and ensure the interests of generic drug enterprises.

　　In order to better balance the interests of the original research drug and generic drug companies with the system, the new Patent Law, which came into effect on June 1, 2021, established the drug patent linking system in China, aiming at linking the two legal procedures, so as to clarify the interest relationship between the original research drug manufacturers and generic drug manufacturers and avoid the problem of patent punishment when the generic drug research and development is completed.

　　As for how enterprises can avoid patent risks, Hou Xuchao, the founding partner of CIC Consulting, also told 21st century business herald that from the perspective of investment and financing, pharmaceutical companies have five key parameters when choosing product pipelines, including the success rate of products under research, patient base, product penetration rate, product pricing and patent life. With the improvement of pharmaceutical companies’ R&D strength, patent life needs more and more attention.

　　"For the patent situation of unlisted drugs, investors need to hire professional IP lawyers to conduct detailed investigations. Because patent conflicts will directly make it difficult for candidate drugs to be marketed, and even directly affect the product value measured by all the above parameters, it is an essential step for patent investigation. " Hou xuchao said.

　　There is a huge crowd in the chronic disease market behind Shakuba Quvalsartan sodium tablets. In terms of hypertension alone, China, as a big country with hypertension, has 245 million adult hypertensive patients, which means that Shakuba Quvalsartan sodium tablets have a broad market space and are an important direction for the future development of drugs. I believe many domestic and foreign manufacturers will make layouts and list related products one after another.

　　However, it should also be noted that after the appearance of the first imitation drug, the clinical data, approval time and product price of the follow-up drugs and enterprises will all be factors affecting the competition pattern, especially the clinical effectiveness and safety, which will be the key to decide who can go further in this track.