Three years and five months after the release of the movie "I Am Not a Medicine God", Patients with Chronic Myeloid Leukemia (also known as "Slow Myeloid Leukemia") in China finally waited for a domestic miracle drug that could save their lives.
On December 18th, sponsored by China Pharmaceutical Innovation Promotion Association, Asunc Pharma (6855. HK) hosted the release of the national "major new drug creation" special results and the global initial listing meeting of orebatinib (trade name: Nelik) held simultaneously in Beijing and Suzhou.
23 days further back, on November 25, Nelik received marketing approval from China's State Drug Administration (NMPA) for the treatment of any tyrosine kinase inhibitor (TKI) resistance and to diagnose adult patients with chronic myeloid leukemia (CML) chronic (CP) or accelerated phase (AP) with T315I mutations using well-validated tests.
"I am very pleased to witness the successful launch of Nelik, because it means that the original drug resistance dilemma of CML treatment in China has been broken, ushering in a new milestone drug, which is of great significance to clinicians and patients." Professor Huang Xiaojun, the main investigator of the Nelik China clinical trial, the director of the Institute of Hematology of Peking University and the director of the Department of Hematology of Peking University People's Hospital, said in his speech.
Chen Kaixian, academician of the Chinese Academy of Sciences and deputy chief engineer of major new drug creation national major science and technology special projects, also gave high praise to this, "As a new drug supported by major national special projects, Nelik represents the strength of China's original innovative drugs, and is the highlight and pride of the implementation of major special projects." The listing of Nelik fully demonstrates the innovation level of China's local medicines, and will encourage more pharmaceutical companies to devote themselves to the research and development of innovative drugs, and continuously improve the innovation capabilities of China's pharmaceutical research and development. ”
If you are resistant to drugs, you can also live
Chronic myelogenous leukemia is a malignant tumor involving the blood and bone marrow, which is characterized by the production of a large number of immature white blood cells, which will accumulate in the bone marrow, inhibiting the normal hematopoiesis of the bone marrow, also known as "blood cancer". In terms of pathological mechanism, the BCR-ABL fusion mutation gene is the most prominent marker of chronic myelogenous leukemia, which is an anti-apoptosis gene and the root cause of excessive proliferation of white blood cells.
△ The picture is from Visual China
In May 2001, Gleevec, a targeted drug for bcr-ABL fusion mutation genes, was launched in the United States, improving the five-year survival rate of patients with chronic myeloid leukemia from 30% to 90%. Since then, second-generation BCR-ABL inhibitors such as dasatinib and nilotinib have also been listed. Since 2013, the generic drugs of major domestic pharmaceutical companies have also been approved, which further improves the accessibility of drugs, and most patients can obtain a survival period close to that of ordinary people.
But resistance is always a sharp blade hanging high above the heads of chronic myelogenous leukemia patients. In the absence of three generations of BCR-ABL inhibitors in China before, once genetic mutation resistance, such as the most common T315I, may mean that there is no cure. "In China, there are just a few drug options, if once the T315I mutation occurs, he will soon go to the accelerated period and the blast period, if you can't do the transplant, life can't be saved." Professor Jiang Qian, the main investigator of the Nelik China clinical trial and deputy director of the Department of Hematology of Peking University People's Hospital, said.
The emergence of Nelik broke this dilemma. At the recent annual meeting of the American Society of Hematology (ASH), Professor Jiang Qian orally presented the latest data on the clinical progress of Nelik, which is also the fourth consecutive year that Nilik's clinical research has been selected for the ORAL report of the ASH Annual Meeting.
Professor Jiang Qian said that before that, only the three-generation BCR-ABL inhibitor of punatinib in the world was approved and was not introduced into China. The listing of Nelik will bring huge survival benefits to the domestic chronic myelogenous leukemia drug-resistant patients. "Especially for patients with T315I mutations, the chromosomal negative rate and the main molecular response are excellent, in fact, once the main molecular response is obtained, it means that the disease of this group of patients has been continuously and stably controlled." I believe that the overall survival ratio will definitely increase in the future. ”
China's innovative medicine through and through
Ten years of grinding a sword is one of the most common definitions in the field of innovative drug research and development, and Nelik is no exception.
The molecular design of The drug was completed in 2008 by Ding Ke, the current dean of the School of Pharmacy at Jinan University. Since then, AXAGON Pharmaceutical has taken over the product, which is still in the laboratory stage, from Dink and is ready to start clinical design.
In 2015, after completing the preclinical pharmacology, toxicology and other related studies, Yasheng Pharmaceutical officially submitted a new drug clinical trial application to the Guangdong Provincial Food and Drug Administration, and submitted an application to the Drug Evaluation Center (CDE) of the State Food and Drug Administration in May of that year after passing the acceptance of the Guangdong Provincial Food and Drug Administration.
This is also the special feature of Yasheng Pharmaceutical, unlike most other domestic innovative drugs, Yasheng Pharmaceutical did not choose to complete phase I clinical trials overseas with more mature conditions, but placed all clinical trials of Nelik in China. Once successful, it will be a Chinese innovative drug in the full sense of the word, and the encouragement to China's pharmaceutical industry is self-evident. But the other side of the coin is doomed to be a long and winding road.
Yasheng Pharmaceutical has set the first phase of the clinical trial in the Department of Hematology of Peking University People's Hospital, which is also the first phase of the first clinical trial of innovative drugs in the history of Peking University People's Hospital, and everyone has a more cautious consideration of the risk of first in human.
"Our first ethics was rejected because we only had preclinical animal data, and we could only prove that the drug was safe in animals, and there was really not enough experience for conducting clinical phase I in China." Later, Professor Huang Xiaojun, director of the Department of Hematology of Peking University People's Hospital, personally went to the ethical defense to pass. Zhai Yifan, chief medical officer of Yasheng Pharmaceutical, recalled.
Another challenge is dose selection. In October 2016, the first enrolled patient began taking the drug, when the first three-generation BCR-ABL inhibitor, punatinib, had been approved, but because of serious cardiovascular side effects, punatinib was once withdrawn from the market by the FDA. In order to avoid risks, in the initial dose selection of Nelik, the research team chose a gradual climbing strategy, slowly increasing from the first 1 mg to 60 mg.
"In the whole Phase I clinical trial, we climbed a total of 11 doses, each time trembling, and we had to have a safety meeting. Because most patients have experienced second-line or multiple drugs, whether it is the side effects of the drug or the symptoms of the disease, we must repeatedly observe and make a balance between safety and efficacy. Zhai Yifan said.
The commercial starting point of Yasheng Pharmaceutical
After being approved for listing, how to improve accessibility is the first problem that Nelik faces.
Zhu Gang, chief commercial operation officer of Yasheng Pharmaceutical, said that in terms of drug laying, Yasheng Pharmaceutical has reached a series of strategic cooperation with a number of domestic head distributors to accurately deliver Nelik to professional pharmacies in demand to ensure that patients across the country can buy life-saving drugs in the first time.
This includes the powerful alliance with Innovent Biologics in July this year. Asunit Pharma and Cinda Bio reached a comprehensive strategic cooperation, which includes the joint development and joint promotion of Nerik in the Chinese market. In addition, Cinda Bio also injected Yasheng Pharmaceutical in the form of equity investment, laying the groundwork for future in-depth cooperation.
In terms of price, Yasheng Pharmaceutical is also actively preparing for the national medical insurance negotiations at the end of next year, and strives to include Nelik in the national medical insurance directory as soon as possible to minimize the drug burden of patients. In addition, in the year before the medical insurance negotiations, Asunit Pharma will also cooperate with third-party payment platforms to ensure the accessibility of drugs through commercial and innovative payment methods such as urban inclusive insurance.
On the other hand, this approval is not the end of Nelik. It is understood that Yasheng Pharmaceutical is conducting a fully approved clinical trial after marketing, and the target indication is for patients with first- and second-generation TKI resistance. The trial has been completed in the first half of this year, and it is expected that new drug marketing applications can be submitted as soon as the first half of next year.
In the longer term, Nerick is equally effective at multiple kinase targets in addition to targeting bcr-ABL fusion genes, so it has the potential to expand to solid tumor indications. One example is that Yasheng Pharmaceutical has launched a phase I clinical trial of Nelik for the treatment of gastrointestinal stromal tumors in China.
Starting from orphan drugs, obtaining policy support from the drug review department, quickly entering the clinical and market, and then expanding other larger indications, this is the market strategy formulated by Yasheng Pharmaceutical for Nelik, and it is also the most recognizable commercial label of this innovative Chinese pharmaceutical company.
Up to now, Yasheng Pharmaceutical has a total of 12 drugs in research, and the main layout focuses on apoptosis targets. Among them, 4 new drugs under development have obtained a total of 12 FDA orphan drug certifications and 1 EU orphan drug certification, as well as 2 FDA approval fast track certifications, which is far ahead of all pharmaceutical companies in China. Among them, the company's follow-up blockbuster variety Bcl-2 selective inhibitor APG-2575 has entered the key clinical phase II for the treatment of relapsed/refractory chronic lymphocytic leukemia/micro-lymphocytic lymphoma. Bcl-2 selective small molecule inhibitors are known as PD-1 in the small molecule field, and there is currently only one drug on the market in the world.
To some extent, The approval of Nelik is not only the starting point for Yasheng Pharmaceutical to open commercialization, but also provides an excellent window for the outside world to observe Yasheng. It remains to be seen how far this innovative Chinese pharmaceutical company, which is committed to "solving the unmet clinical needs of patients in China and around the world," can go.