Author: Qian Tongxin

This week, at the 2023rd Zhangjiang Life Science International Innovation Summit <>, the forum on innovative research and development of rare disease drugs attracted industry attention.

The development of rare disease drugs has always been a common challenge faced by the medical community. At present, the field of rare disease treatment in China is facing two problems: first, whether there is a drug; The second is whether it is accessible and affordable after the drug is developed.

In recent years, under the joint promotion of policy, technology, talents and capital, the field of rare diseases in China has developed rapidly, but there are still a large number of unmet clinical needs. How to make more rare disease drugs accessible and meet the unmet clinical needs of patients is the focus of the industry.

From "not dead", "not painful" to "not crippled"

There are such a group of "glass people" around us, who are genetically affected and are born with a lack of specific clotting factors in the body, which is accompanied by the pain of "blood flow" for life. This disease is hemophilia, which is a very representative rare disease.

Hemophilia is a rare X-linked recessive bleeding disorder, patients will be accompanied by coagulation dysfunction for life, skin, joints, muscles, mucous membranes, internal organs, etc. may occur repeated spontaneous bleeding, there is a risk of disability. Hemophilia can be divided into two types: hemophilia A and hemophilia B, the former because of the lack of coagulation factor VIII., and the latter is the lack of coagulation factor IX.

Due to insufficient ability to pay, the treatment needs of hemophilia patients in the vast number of emerging market countries, including China, are far from being met, and patients are suffering unimaginable pain and hardship physically, physically and mentally, as well as financially.

How can more hemophilia patients have drugs available? Experts in the field of blood diseases call for improving the preventive treatment of hemophilia, using long-acting and ultra-long-acting recombinant coagulation factors to improve patient compliance and reduce patients' injection pain. The so-called "preventive treatment" refers to the prevention of the disease by regular injection of coagulation factors before the onset of the disease.

Professor Sun Jing of the Southern Hospital of Southern Medical University said at the forum that hemophilia treatment has gone through the stage of pursuing "immortality" in the 1.0 era to the pursuit of "no pain" in the 2.0 era, and is currently moving towards the 3.0 era to pursue "zero bleeding and no disability", and patients can live like normal people.

Sun Jing said that at present, there are only standard half-life recombinant eight factors in China, and patients need to be injected intravenously every 2 days, the injection frequency is high, the patient is very painful, and the compliance is poor. Long-acting and ultra-long-acting recombinant coagulation factors only need to be injected 1-1 times a week, which greatly reduces the injection pain of patients and has become the mainstream of prevention and treatment of hemophilia A in Europe and the United States.

"Individualized preventive treatment of long-acting recombinant coagulation factor PK will achieve a continuous drug trough concentration of more than 3-5%, pursue zero bleeding, eliminate target links, and reduce disability." We look forward to the early launch of domestic long-acting recombinant coagulation factors. Sun Jing said.

The research and development of innovative drugs for rare diseases is inseparable from the investment of enterprises. In June this year, Shengsi Biotech's long-acting recombinant coagulation factor 6-FC fusion protein for injection submitted a marketing authorization application and was accepted by the National Medical Products Administration. If this drug is successfully approved for marketing, it will break the situation that there is no long-acting recombinant coagulation factor on the market in China, and improve the technical iteration and drug accessibility of hemophilia patients.

In addition to the above-mentioned long-acting recombinant coagulation factor 8, the company is also developing an ultra-long-acting recombinant coagulation factor 8 and an ultra-long-acting recombinant coagulation factor 9. These products are expected not only to solve the shortage of drugs in the market, but also to significantly reduce the frequency of administration.

Wang Yali, chairman of Shengsi Biotechnology Group, said at the forum: "Looking at China, due to the inaccurate statistics caused by the insufficient supply of early drugs, the number of hemophilia patients who have been treated and registered in China is only about 4,4, while the actual number of patients is far more than <>,<>, and it continues to increase. At present, what is urgently needed in clinical practice is a stable supply, patient consumption capacity, and a blank long-acting coagulation factor product in the domestic market. ”

There is a huge space for preventive treatment

According to the statistics of the National Bureau of Statistics and the World Federation of Hemophilia, the number of hemophilia patients in China has reached 14,2, due to the shortage and high price of human coagulation factor VIII, most of China's hemophilia patients are on-demand treatment, and patients receiving preventive treatment account for only 3-<>% of the total number of patients. In the future, with the further promotion of preventive treatment in China, it will bring further expansion to the market size of hemophilia drugs.

Earlier this month, Professor Wang Xuefeng of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine and Professor Yang Renchi of the Hematology Hospital of the Chinese Academy of Medical Sciences led the release of the "China Hemophilia Diagnosis and Treatment Report 2023". The report shows that the prevalence of hemophilia in China is about 10 per 3,<> people.

Wang Xuefeng said that although the diagnosis rate of rare diseases in China is low and misdiagnosis has occurred frequently, the diagnosis rate of hemophilia has been greatly improved in recent years, and the tertiary hospitals can basically achieve accurate diagnosis, and the treatment of hemophilia has also shifted from "on-demand treatment" to higher dose prevention and individualized "preventive treatment" with higher efficacy.

However, Wang Xuefeng pointed out that there is still a lot of room for improvement in the diagnosis and treatment of hemophilia, mainly because it is still difficult to classify hemophilia, and if you cannot accurately determine which type of hemophilia, then the treatment of patients will not work.

In recent years, with the development of gene editing technology, gene therapy has also brought more innovative treatment options for patients with rare diseases. For example, Hemgenix, the first gene therapy approved by the US FDA to treat adult patients with hemophilia B, costs as much as $350.<> million per dose, setting a new record for the "world's most expensive drug". The drug requires only one-time treatment.

Earlier this year, Professor Zhang Lei of the Hematology Hospital of the Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences) said that his team's hemophilia gene therapy for the liver targeted adeno-associated virus (AAV) vector has achieved remarkable results through the treatment of nearly 50 hemophilia patients.

At present, in China, innovative biopharmaceutical companies, including Tianze Yuntai, are actively investing in the research and development of hemophilia gene drugs. According to research by research institute Frost & Sullivan, China's hemophilia drug market is expected to exceed 2030 billion yuan by 140.

Regulatory mechanisms and review policies also affect the research and development process of rare disease drugs to a large extent. In recent years, the State Food and Drug Administration has deepened the reform of the review and approval system, accelerated the speed of rare disease drugs on the market, and made drugs available to more patients with rare diseases.

Experts from the Shanghai Drug Review Center pointed out at the forum that rare disease drugs are attracting more and more attention from the international community, multinational pharmaceutical giants are actively deploying rare disease R&D pipelines, and China has also repeatedly introduced policies to promote the research and development of rare disease drugs. As of September 2023, 9, the National Health Commission and other six departments have published the Second Batch of Rare Disease Catalog, which includes 20 rare diseases.

The above experts said that Chinese companies are also paying more and more attention to the research and development of rare disease drugs. Taking the "First Batch of Rare Disease List" as the standard, more than half of the clinical trials of more than 260 rare disease treatment drugs registered in the past decade are domestic enterprises, and the number is gradually increasing.

She also pointed out the difficulties of drug development for rare diseases, including small and scattered patients, difficulty in clinical trial enrollment, limited possibilities for clinical study design and repeated studies; The main factors hindering the research and development of rare disease drugs by enterprises are the uncertainty of the payment process and the unclear prediction of benefits, and the R&D promotion policy needs to be further strengthened.

Taking hemophilia as an example, although the annual treatment cost of patients is as high as 200,000 yuan, most of the alternative treatment drugs for hemophilia have been included in the basic medical insurance, and the development of philanthropy has promoted the formation of multi-party co-payment. In many areas, hemophilia is included in the outpatient special disease, and patients are reimbursed at the same rate as hospitalization in the outpatient setting.