Why are children's oncology drugs forgotten丨 great country creation

Before the interview with the first financial reporter, Wang Jinhu had just accepted a consultation from a child's mother.

Wang Jinhu is the deputy director of the Hematology and Oncology Center at the Children's Hospital affiliated to Zhejiang University School of Medicine, and the mother is looking for a way to alleviate her children with tumors. The lalotinib inhibitor needed by the child has not been approved in China. Recently, due to the impact of the epidemic in Hong Kong, the only channel to purchase drugs has been blocked. After taking the drug for 23 days, the child's tumor shrank significantly, but now because of the dosage form and the purchase channel, the mother is in trouble.

In Wang Jinhu's view, this situation is not uncommon in the field of pediatric tumors. Malignancy has become the second leading cause of child mortality. There are many and more complex types of tumors in children than in adults. At present, there is a serious shortage of drugs for children's tumors, and due to the difficulty and long cycle of clinical research, related drug research and development faces multiple challenges.

Targeted drugs are scarce

How many types of malignancies are there in children?

Yuan Xiaojun, chief physician of the Department of Pediatric Hematology and Oncology of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, said dozens of species in an interview with the first financial reporter, including common leukemia, lymphoma, neuroblastoma and so on.

In 2019, the authoritative medical journal "Lancet Oncology" released the first report evaluating the global burden of disease in children and adolescents, which analyzed that childhood cancer is the sixth largest cancer burden in the world after adult lung, liver, stomach, colon and breast cancer.

The situation in China is not optimistic. The region with the highest global burden of childhood cancer in 2017 was Asia and Oceania. India has the highest burden of childhood cancer, with China ranking second in the world. There are 30,000-40,000 children with cancer in China every year, but there is no consensus on this public data, and too many children have not been diagnosed and counted.

In the distribution of children's tumor types, Yuan Xiaojun shared a set of data: leukemia accounts for more than 30% of children's tumors, brain tumors account for about 20%, and neuroblastoma accounts for 7%-8%. The causes of the formation of children's tumors are different from adult tumors, most children's tumors are more sensitive to traditional chemotherapy drugs, combined with surgery, radiation therapy and other treatment methods, the overall prognosis of children's tumors is better than that of adults.

However, treatment effects vary greatly between countries. From the perspective of cure rate, the cure rate of children's tumors in developed countries in Europe and the United States has reached 80%, and the cure rate in resource-poor areas such as Africa and India is only 20%.

"The cure rate of children's tumors in mainland China is increasing year by year. China's current overall treatment status and treatment of children's tumors belongs to the global medium level, the cure rate of some tumors has been very close to the international advanced level, but there are still about 20%-30% of children's malignant tumors, conventional treatment programs are not good for its effect, that is, the use of all the current chemotherapy, surgery and radiotherapy and other traditional treatment methods, still can not save the lives of these children, so there is an urgent need for targeted drugs to help. ”

For example, Yuan Xiaojun's "children's cancer king" is known as neuroblastoma, the long-term survival rate of low-risk patients has reached more than 90%, and some IVs patients can heal themselves even without treatment, but the long-term survival rate of high-risk patients is less than 30%. In reality, more than 70% of children with neuroblastoma are treated with stage III or ivy, which is "advanced" tumor. She believes that an important reason for the large gap between the overall treatment level of neuroblastoma in China and foreign countries is the lack of targeted drugs to treat this cancer king. Fortunately, since 2022, children with neuroblastoma in China can already use dedicated targeted drugs, but drug development for other high-risk and recurrent children's tumors is still imminent.

"Surgery alone won't solve all problems, and a lot of times, oncology medications may be more important than surgery." Some researchers have found that children's tumors have their own driving mechanisms, and the coincidence rate of mutant genes driven by adult tumors is very low, so many targeted drugs and small molecule drugs found for adult targets cannot be directly applied to children. Wang Jinhu once mentioned.

At present, there are three children's tumor drugs used in the Hainan Boao Lecheng Pilot Zone, the β of datuximab has been approved for marketing in 2021, semmetinib is used for neurofibromatosis type 1, and naxiltimab is used to treat children aged 1 year and older and adults with recurrent or refractory high-risk neuroblastoma of bone marrow. The GD2 monoclonal antibody introduced by BeiGene has also passed the study of the Boao Lecheng Pilot Zone, and finally approved it quickly and applied to the clinic.

According to wisdom bud data, there are about 3,300 patents in the field of pediatric oncology drugs worldwide, and the United States has the highest degree of technology intensity. In recent years, China's research and development growth rate has been relatively fast, ranking second.

Where is the business momentum?

In the development of children's oncology drugs, pharmaceutical companies often lack commercial incentives.

The number of drug studies in children is small, mainly because the number of mutations in children's tumors is much less than that of adults, which is more costly and time-consuming in research and development. Clinical research on children's drugs in the United States generally takes 8 to 14 years to produce results, and the ultra-long cycle poses great pressure on enterprises. Even global pharmaceutical companies such as Novartis will be deterred.

"Pediatric oncology research is grossly inadequate, and for nearly 30 years, new drugs developed globally for pediatric oncology have been in the single digits. GD2 antibodies are very rare examples. Li Zhizhong, secretary general of the Shiyu Children's Public Welfare Foundation, said in a speech in 2021: "I worked at Novartis for a few years and once wanted to make a children's tumor drug, but it was quickly denied by the boss, saying that this has no market value. ”

The GD2 antibody mentioned in Li Zhi is a specific drug for the treatment of neuroblastoma. At the end of 2020, the pharmaceutical company Y-mAbs Therapeutics' GD2-targeted monoclonal antibody drug was approved for marketing by the FDA, becoming the third GD2 antibody drug approved in the world. Y-mAbs Therapeutics is a small company founded in 2015.

"Many drugs were considered to have no market value in the early stages of development, until a small company made it and was bought by a large company for billions of dollars." Li Zhizhong said: "Therefore, whether there is market value or not depends purely on whether you do it or not, and there is market value when you make it." ”

In 2021, domestic pharmaceutical company BeiGene introduced GD2 monoclonal antibody. It should be known that BeiGene has not been in the field of pediatric tumors for a long time, and due to the uncertain prospects of commercialization, the introduction of this drug once caused controversy within the company.

"We have just entered the field of pediatric oncology, first from the discovery of demand, and then the introduction of GD2 monoclonal antibody, the introduction process is not so smooth." Liu Yan, vice president of BeiGene, said in an interview with CbN: "After all, as a commercial company, from the perspective of profits, the introduction of such drugs is indeed not to make money. ”

Currently, in the field of pediatric oncology, BeiGene has two related products, one is GD2 monoclonal antibody and the other is CD3-CD19 bispecific antibody for the treatment of acute lymphoblastic leukemia.

In recent years, China has issued a number of guidelines and begun to pay attention to the research and development of children's tumor drugs, but because specific incentive measures have not yet been introduced, enterprises still lack motivation for the research and development of children's tumor drugs, and related clinical trials are even more pitiful.

In Wang Jinhu's view, clinical trials of children's oncology drugs should take into account more complex contents, including ethical and informed consent, oral drug dosage forms, etc. For example, capsule preparations for adults, children aged 1-2 years can not be swallowed, the need to develop new dosage forms, thereby increasing the cost. Therefore, in the actual operation of clinical trials, due to the particularity of the age of the children, the expected efficiency of enterprises may be affected.

Domestic pharmaceutical companies are just starting out

"The policy has not yet directly helped pharmaceutical companies. If companies develop new drugs for children's tumors, there is no particularly clear path on how to improve efficiency and reduce costs. Li Zhizhong commented.

Some countries have begun to encourage refractory or recurrent pediatric cancer patients to participate in clinical trials. Wang Jinhu told the first financial reporter that if on the platform of the Clinical Medical Center, there are multiple drugs from multiple pharmaceutical companies that are expanding children's indications or developing new drugs for children, then children will have more opportunities to participate in clinical trials of new drugs. Assuming a target has a 1% positivity rate for a child's tumor and 20 drugs are being clinically tested, the child has a 20% chance of participating in the clinical trial of the new drug.

He believes that China also needs to have more large-scale and high-level research centers as a platform to cooperate with pharmaceutical companies and research and development units. In this way, the patient is more concentrated, which can improve the efficiency of clinical trials and reduce the difficulty of operation. Of course, the establishment of a more mature pediatric clinical trial platform requires active policies to guide.

"Drugs can enter clinical trials, of course, success is very good, even if it is not successful, it will leave very important data, for the future children's recovery, for the future children to grow up to lay the foundation." Li Zhizhong said.

Based on the difficulty of pediatric clinical research, the use of real-world data, that is, relevant diagnosis and treatment data, to supplement the study of children's tumor drugs is expected to shorten the drug development cycle.

Gao Ying, senior medical director of Zero Kr Technology, believes that the process of real-world data (RWD) to generate real-world evidence (RWE) is conducive to the research and development of children's oncology drugs and helps improve the efficiency of research and development, including positive changes in research cycles and research costs. "The biggest difficulty is the quality of real-world data. To maximize the value of existing data, it is necessary to transform diagnosis-level data into research-level data through data governance. ”

In recent years, many domestic pharmaceutical companies have begun to try to develop in the field of children's tumors. Junshi Bio, Beida Pharmaceutical, Chia Tai Tianqing, Hengrui Pharmaceutical, Qilu Pharmaceutical, Fosun Pharmaceutical, etc. are all actively involved.

Wang Jinhu said that in addition to traditional large pharmaceutical companies, there are more cutting-edge small and medium-sized pharmaceutical companies in China, which have begun to pay attention to and invest in the development of children's oncology drugs. "Whether it is introduction or transformation, more and more work is being carried out. With the efforts of many parties, China will slowly form a good atmosphere for research and development, and eventually realize the discovery of corresponding problems, and can have corresponding drugs available. ”