In the movie "I am not a medicine god", the medication dilemma of chronic myelogenous leukemia patients has always touched people's hearts, especially drug resistance is a fate stone hanging on the patient's head at all times, and no one knows when and why it will fall. (Visual China/Photo)
Three and a half years after the release of the movie "I Am Not a Medicine God", the medication dilemma of patients with chronic myelogenous leukemia (hereinafter referred to as chronic myelogenous leukemia) in the film still affects people's hearts from time to time.
Suffering from a malignant blood tumor is very unfortunate, but patients with chronic myelogenous leukemia are still the lucky ones in the tragedy. In 2001, the emergence of the targeted drug "Gleevec" turned the incurable disease into a "chronic disease" - international clinical research data show that if targeted drug therapy is used, about 80% of patients with chronic myelogenous leukemia can survive for more than 10 years, and even enjoy the same life and quality of life as healthy people.
But drug resistance is always hanging on the head of the patient's fate of the boulder, no one knows when, why will fall, once the patient after a generation, the second generation of "Gleevec" drug treatment have failed, or detected T315I gene mutations, often into the situation of no medicine, such as no bone marrow transplantation, will soon enter the accelerated period of the disease, the period of rapid change, and even life-threatening.
The innovative drugs that "break the game" come from China. In March 2021, the third generation of "Gleevec", independently developed by Jiangsu Yasheng Pharmaceutical Development Co., Ltd. (hereinafter referred to as Yasheng Pharmaceutical), was included in the breakthrough treatment variety by the Drug Review Center of the State Drug Administration (hereinafter referred to as CDE), and was officially approved for marketing on November 25 for the treatment of patients with chronic myelogenous leukemia who are resistant to tyrosine kinase inhibitors (TKI) and accompanied by T315I mutations.
In late December 2021, at the national "major new drug creation" special achievement release hosted by the China Association for the Promotion of Pharmaceutical Innovation and the global premiere of orebatinib (trade name: Nelik), Huang Xiaojun, director of the Institute of Hematology of Peking University and director of the Department of Hematology of Peking University People's Hospital, pointed out that the successful listing of Nelik "means that the original drug resistance dilemma in the treatment of chronic myeloid leukemia in China has been broken, ushering in a new milestone drug, which is of great significance to clinicians and patients."
Changing the "no cure"
"Fate this ride, I don't want to get off yet." After surviving with the disease for 18 years, Wood, a chronic myelogenous leukemia patient who participated in the "Nelik" clinical trial, said that he felt very lucky to bet not only on a good attending doctor, but also on a drug. "I've been taking medicine for so long, I even want to have a home, I hope I will have a day when spring blooms."
As early as 1985, overseas scientists discovered in a series of groundbreaking basic studies that the highly active tyrosine kinase (BCR-ABL) protein produced by Philadelphia chromosome translocations is the mechanism that causes chronic myelogenous leukemia. In 2001, the tyrosine kinase inhibitor (TKI) targeting BCR-ABL was officially launched, ushering in an innovation in the treatment of chronic myeloid leukemia and greatly improving the survival rate of patients.
In the movie "I Am Not a Medicine God", the "life-saving medicine" that patients with slow-grain leukemia like wood are hard to buy from India is the generic drug of "Gleevec". "Gleevec", also known as imatinib mesylate tablets, is the first generation of TKI developed by Novartis in Switzerland, as the world's first molecularly targeted drug for anti-cancer, known as a major breakthrough in the history of human anti-cancer.
Most patients with chronic myelogenous leukemia can benefit from Gleevec, but patients must take medication for a long time, and acquiring drug resistance has always been a major challenge in the treatment of chronic myelogenous leukemia – some patients have disease progression or even death due to drug resistance.
"In the process of taking imatinib, about 20%-30% of patients experience treatment failure. Less than 10% of patients progress and have limited survival. Jiang Qian, deputy director of the Department of Hematology of Peking University People's Hospital, said. Among them, BCR-ABL kinase region mutation is one of the important mechanisms of drug resistance after TKI treatment. The T315I mutation is the most common type of drug-resistant mutation, occurring in about 25% of patients with drug-resistant chronic myelogenous leukemia.
According to the Southern Weekend reporter, the approval of "Nelik" is mainly based on the data of two key registration Phase II clinical studies, namely HQP1351CC201 study and HQP1351CC202 study. Jiang Qian introduced that in the 39-month median follow-up, 77 of the 101 patients enrolled in the group were still taking the drug, and the proportion of patients with stable efficacy was very high. In particular, 80% of CML patients with T315I mutations have obtained chromosomal negative transitions, which means that the patient's condition has been continuously and stably controlled.
In terms of safety, drug side effects are also more controllable. About half of patients experience adverse effects of grade 3 or 4 thrombocytopenia, and the side effects become less and less frequent over time. "For example, thrombocytopenia, anemia, white blood cells and granulocytopenia are common and acceptable side effects in the treatment of blood tumors. Other patients may have skin pigmentation (dull skin or the appearance of stains), hyperlipidemia and other adverse reactions, but have little impact on quality of life and will not lead to discontinuation of the drug. Jiang Qian said.
At present, as a special support variety of "major new drug creation" in China, "Nelik" has been officially approved for listing in China, marking the world's second and third-generation "Gleevec" successfully developed by Chinese pharmaceutical companies, and solving the dilemma of domestic drug-resistant patients without drugs to treat.
Domestic new drugs "from have to excellent"
"At the American Annual Meeting of Hematology (ASH) a few days ago, when we announced the updated results of the orebatinib Phase I study data, the applause was warm and lasting. European and American experts have come to the email to inquire, and the expectations are very high. The drug is very promising for the world. Jiang Qian said.
How to develop safer and more effective drugs to solve the clinically urgent drug problems of chronic myelogenous leukemia resistant patients is one of the most high-profile issues in the hematology and oncology community. In the past, there was only one three-generation "Gleevec" in the world, Ponatinib, which was listed in the United States, and because of the risk of "life-threatening thrombosis and severe stenosis of blood vessels", it had received a black box warning from the US FDA and had not entered the country.
Previously, based on the clinical efficacy and safety evidence of "Nelik", the drug has successively obtained orphan drug qualification in the United States and the European Union, becoming a best-in-class drug in the same category.
Song Ruilin, executive chairman of the China Pharmaceutical Innovation Promotion Association, said that from the "Eleventh Five-Year Plan" to the "Thirteenth Five-Year Plan", the number of new drugs on the market has reached more than 80 new drugs of class 1. "And I think 'Nelik' deserves attention because it really has a unique point in filling the clinical gap and showing clinical value." Song Ruilin said.
Song Ruilin also pointed out that the emergence of many "Me too" and "Me better" generic drugs in China has led to excessive congestion on the track, fierce competition, and the inability to highlight innovation and innovative value. "From the past there were no innovative drugs, to now there are innovative drugs, how to achieve the transformation of 'from having to excellent' in the next step, and doing more high-end innovative drugs that truly fill the clinical gap is a question that must be answered in front of the interface of China's pharmaceutical innovation." Song Ruilin said.
Promote participation in health insurance negotiations and improve access to drugs
Since the launch of a generation of "Gleevec" in China in 2003, the annual treatment cost of patients with chronic myeloid leukemia was as high as 300,000. In recent years, with the expiration of drug patents, the emergence of generic drugs and a series of changes such as national medical insurance negotiations, patients only need to pay about 1500 yuan a year.
The anti-cancer drug "Gleevec" (imatinib mesylate tablets) used to treat chronic myelogenous leukemia is a very good targeted drug, which is a "life-saving drug" for patients with chronic myelogenous leukemia and is expensive. (Visual China/Photo)
After the patient appears to be resistant and the treatment fails, the second-line drugs such as dasatinib and nilotinib need to pay a higher fee, according to different medical insurance reimbursement policies in different places, the price of domestic or imported drugs is different, and the amount of patients' self-payment ranges from 20,000 to 100,000 yuan.
"Patients will have different mutations in the treatment process, which is also the reason for drug resistance, the worst mutation is the T315I mutation, and only Nelik is currently effective." Huang Xiaojun said in the interview.
In the past, slow-myelogenous leukemia-resistant patients with T315I mutations could only buy punatinib that was not listed in China from overseas, because of its high price, many patients could only buy cheaper generic drugs produced by The Mont Everest Pharmaceutical Factory in Bangladesh, and there were risks of illegal drug purchase and drug safety hazards.
According to the price of drugs displayed on the drugs.com website, the price of a single box of punatinib (30 tablets, 10mg each) is 18,711 US dollars, which is about 120,000 yuan. "The retail price of orebatinib is about 1/3 to 1/4 of punatinib." Zhu Gang, Chief Commercial Operation Officer of Yasheng Pharmaceutical, introduced. That is to say, the retail price of a single box is about 30,000 yuan.
But even so, if patients are to pay for the drug entirely out of pocket, there may still be many families who cannot afford it. Some patients told the Southern Weekend reporter that "Nelik" has a high degree of attention and discussion in the patient group, he has taken two days of medicine, need to eat a box every month, and is very much looking forward to this drug being able to enter the medical insurance directory as soon as possible and benefit more patients.
At present, it is difficult for a new drug to enter the hospital if it cannot enter the medical insurance directory. "And if the newly developed and marketed innovative drugs are indeed to solve the urgent needs and lifesavers of the clinic, we should still try to achieve the accessibility and affordability of these drugs as much as possible." Yang Dajun, chairman and CEO of Yasheng Pharmaceutical, told Southern Weekend that this is a problem at the level of the whole society, not just involving a certain department.
Chen Kaixian, academician of the Chinese Academy of Sciences and deputy chief engineer of the "major new drug creation" technology of the national major science and technology project, said in an exclusive interview with the Southern Weekend reporter that pharmaceutical research and development is a typical high-input and high-risk industry. Enterprises may need to invest billions, it takes ten years or even more to develop a drug, if it can not get a reasonable return after listing, it is very unfavorable to the future survival and long-term development of the enterprise.
"Many domestic enterprises will aim the market overseas, but if the pricing of products in the domestic market is low, it will also have an impact on the global market pricing of enterprises, and I hope that the relevant domestic departments can pay attention to these problems and promote the continuous improvement and development of relevant policies." Chen Kaixian told Southern Weekend reporters.
Yang Dajun revealed that in the second half of 2022, it will actively promote the participation of "Nelik" in the national medical insurance negotiations, and is currently exploring innovative payment paths, including cooperation with commercial medical insurance and urban huimin insurance, etc. At the same time, the drug has been invested in professional pharmacies across the country to facilitate patients to buy as soon as possible.
Southern Weekend reporter Cui Huiying