So far, the 2024 medical insurance catalog adjustment has announced the drugs and related information that have passed the formal review. From the draft for comments, rare disease drugs are still one of the focuses of the medical insurance catalog adjustment. Rare diseases are also called "orphan diseases". Most of them are congenital diseases, chronic diseases, and may be life-threatening. Although the incidence of rare diseases is low, there are many types of diseases and the number of patients cannot be underestimated. At present, there are more than 7,000 confirmed rare diseases in the world, and there are about 20 million rare disease patients in China1. For a long time, the clinical phenotypes of rare diseases and common diseases overlap greatly, and early diagnosis is difficult, so the misdiagnosis and missed diagnosis rates are high. According to statistics from the National Organization for Rare Diseases in the United States, among the approximately 7,000 rare diseases that have been discovered, only 10% of rare diseases have corresponding treatments, and only 1% of rare diseases have effective treatments for the cause2. Therefore, the treatment field of rare diseases has attracted much attention. As people's understanding of the pathogenesis of rare diseases deepens, innovative drug treatments targeting the complement system have emerged. Taking rare diseases such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD) as examples, as people's clinical cognition continues to improve, related breakthrough treatments have been included in medical insurance. Pay attention to rare diseases and make "rare" visible. At present, the sinking of standardized diagnosis and treatment and the accessibility of innovative drugs require the joint participation of multiple parties. Based on this, on August 24, the "Complement Day-Academic Exchange Conference on Complement-Related Diseases" hosted by the Beijing Bethune Charity Foundation and supported by AstraZeneca was held in Beijing, aiming to actively promote global exchanges on complement-related rare diseases and help standardize the diagnosis and treatment of rare diseases.

So, what exactly is complement? What is the relationship between complement and rare diseases? Professor Ding Xiaoqiang, the incoming chairman of the Chinese Medical Association's Nephrology Branch and director of the Department of Nephrology at Zhongshan Hospital Affiliated to Fudan University, said in an interview that the immune system includes cells and proteins, and there are two major categories of proteins: complement and antibodies. Complement is a very important class of immune-related proteins. In the earliest stage of a disease, such as when bacteria and viruses invade the human body, complement is immediately activated and kills bacteria and viruses. It can also be activated again after antibody activation. Therefore, complement has different pathways to activate, including classical, bypass and lectin pathways. Different pathway activations play different roles in different stages of the disease. Professor Ding Xiaoqiang pointed out that complement, as a mechanism of pathogenesis, does not cause a single disease, but a lot of diseases, so there are a lot of rare diseases related to complement. Complement inhibitors can be said to be groundbreaking and breakthrough progress in the treatment of complement-related diseases, especially complement-related rare diseases. "The treatment of complement can be called targeted therapy, which is very accurate like shooting a target. When a certain link goes wrong, just open this link." Professor Ding Xiaoqiang further stated. From a clinical perspective, complement targeted therapy has played a unique role in the treatment of rare diseases such as PNH, aHUS, gMG, and NMOSD. For example, taking aHUS as an example, according to Professor Ding Xiaoqiang, more than half of the patients have improved renal function in the acute phase or in a relatively short period of time after complement inhibition drug treatment, at least they no longer need dialysis. There are also some patients with renal damage, but not so serious that they need dialysis. If they are treated for a long time for half a year to a year, most patients have significantly improved renal function, and some patients can basically recover their renal function. Therefore, complement therapy is a breakthrough treatment for atypical hemolytic uremic syndrome. In the treatment of PNH, Professor Han Bing, chief physician of the Department of Hematology at Peking Union Medical College Hospital, pointed out that the clinical manifestation of patients is that hemolytic anemia is well controlled, and hemolytic anemia brings corresponding complications, such as renal damage, thrombosis, pulmonary hypertension, and many smooth muscle dysfunction, erectile dysfunction, etc. These problems have been alleviated accordingly. So its survival has changed from the original five-year mortality rate of 35% to the same as normal people, changing the natural course of patients.

Since the discovery of complement in the 19th century, people have never stopped developing and researching the complement system and its drugs. In 2007, the first C5 complement inhibitor developed by Alexion was officially launched as a complement drug. At present, the application of complement drugs in China is still in its early stages. However, this blue ocean market is attracting more and more pharmaceutical companies to join. AstraZeneca, a leading pharmaceutical company, took the lead and spent $39 billion to acquire Alexion, a leader in the complement field. Today, AstraZeneca's layout of the complement system is mainly reflected in "endogenous and exogenous" and the mutual cooperation of medical affairs. The first is "endogenous". AstraZeneca actively develops related drugs for listing and builds a complement platform. At present, AstraZeneca's first complement inhibitor has been approved for 4 indications in China. On the other hand, it is "external". Through acquisitions, investments and cooperation with innovative companies, a "medical system ecosystem" is established, and the field of rare diseases is naturally an important part of it. Hu Yiqing, head of AstraZeneca's rare disease business unit in China, said: "Rare diseases are a very important strategic treatment area for AstraZeneca. We are open-minded and are very willing to cooperate with the world's leading innovative companies if there are good products." In terms of medical affairs, Yang Haiying, head of AstraZeneca's Medical Affairs Department in China, revealed that AstraZeneca China is also actively participating in global disease registration research and has launched a disease registration study for Chinese patients with rare diseases to assist clinicians in clarifying the diagnosis and treatment pathways of the disease. At the same time, AstraZeneca is also continuing to support the construction of medical centers of excellence in various treatment fields, supporting the establishment of a cross-departmental MDT rare disease diagnosis and treatment mechanism, helping each center to cultivate experts with diagnosis and treatment experience in a single disease, allowing advanced and scientific diagnosis and treatment concepts to sink, and also promoting China's clinical practice and innovation to the world.

"No drugs available" is the norm for most patients with rare diseases. The demand for rare disease drugs has always been hot. According to Frost & Sullivan data, the global market size of rare disease drugs will increase from US$135.1 billion in 2020 to US$383.3 billion in 2030, with an annual compound growth rate of up to 11%. The Chinese rare disease drug market will increase from US$1.3 billion in 2020 to US$25.9 billion in 2030, with an average annual growth rate of 34.5%3. The vast drug market has attracted a large number of pharmaceutical companies to enter the market. In recent years, in addition to spending heavily on rare disease businesses and related pharmaceutical companies, domestic and foreign pharmaceutical companies have also increased their research and development investment to expand their own rare disease drug research and development pipelines to further increase their strength in the field of rare diseases. The same is true for AstraZeneca, a leading company in the field of rare diseases. In the field of complement alone, AstraZeneca has extensively studied the cascade reaction of the complement system, covering more than 30 proteins, and has also announced five major complement platforms: C5, C3, D factor, P factor, and H factor. Hu Yiqing introduced that AstraZeneca will adopt different drug modalities according to the characteristics of different complement targets, including monoclonal antibodies, siRNA, oral small molecules, VHH nanoantibodies, and fusion proteins targeting the kidney, and is committed to bringing breakthrough treatment solutions to multiple rare disease fields. On the C5 platform, AstraZeneca already has two drugs worldwide, and the third-generation drug is also under development. At present, AstraZeneca has two rare disease drugs approved in China, covering five indications. Hu Yiqing said that in the future, they will continue to increase investment in the fields of nephrology, neurology, cardiovascular, blood, metabolism and rare tumors, and bring more than ten new products or indications to Chinese patients. At the same time, AstraZeneca also plans to increase investment in gene therapy to explore rare disease treatments. Today, AstraZeneca China actively participates in rare disease clinical projects around the world, and basically achieves synchronous research and development with the world. "We will continue to accelerate R&D innovation and cooperation to allow more rare disease patients to have treatment options, so that they can live longer, better and more dignified." In addition, AstraZeneca attaches great importance to disease registration research for Chinese rare disease patients. "In China, there are still few rare disease patients who use complement treatment, and the data collected is relatively early. We hope to accumulate more "Chinese data" for complement treatment to help us develop new products and new indications, verify the effectiveness and safety of the treatment, and then benefit more Chinese patients," said Yang Haiying. In recent years, driven by national policies, the field of rare diseases has achieved unprecedented development, bringing new treatment hope to the majority of rare disease patients. "With the continuous emergence of innovative treatments for rare diseases, we always have a vision: we hope that patients with rare diseases can return to normal life." Hu Yiqing said, "As a leading global pharmaceutical company, AstraZeneca will continue to work hard to achieve this goal."

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