"Including 7 drugs for rare diseases at one time"; "The original price of 70 thousand needles is sky high, and the medication for rare diseases is reduced to 30000 at one fell swoop"; The recent annual event in the pharmaceutical circle - the 2021 national medical insurance catalogue negotiation (also known as "national negotiation") once again ignited the use of drugs for rare diseases.
In sharp contrast, a week later, when the rare disease "unicorn" Beihai kangcheng-b (01228. HK) officially landed on the Hong Kong stock exchange, the company fell nearly 30% on the first day of listing.
The market did not "vote with its feet". Because making drugs affordable for patients with rare diseases is a systematic project, and solving the payment problem is only one of them. On the issue of how to do a good job in rare disease drugs, all enterprises in this field, including Hokkaido Kangcheng, still need to find a practical way.
enlightenment of a new rare disease drug to achieve accessibility at a record speed
Rare Disease is often referred to as those with very low incidence rate. According to the definition of the World Health Organization (who), rare diseases are diseases or lesions whose number of patients accounts for 0.65 ‰ ~ 1 ‰ of the total population. At present, there are about 7000 known rare diseases in the world, accounting for about 10% of human diseases. Among these various rare diseases, about 80% are caused by genetic defects.
Due to the low prevalence of a single disease of rare diseases and the small market demand for drugs for a single disease, it is difficult for pharmaceutical enterprises to have sufficient motivation to develop relevant drugs, which leads to the limited treatment methods and drugs for rare diseases at this stage. Statistics show that among about 7000 known rare diseases in the world, only about 5% - 10% of the diseases with real drugs are available.
Therefore, rare diseases have always been a challenge for all mankind, and all countries are actively seeking their own solutions.
The United States is the first country in the world to pass the drug bill on rare diseases, and promulgated the orphan drug act in 1983. The Act provides economic incentives for the research and development of rare diseases, including tax credit for 50% of the R & D cost and exclusive provisions for orphan drug franchise. Therefore, it provides guidance for the research of rare disease treatment drug policies in various countries.
In June 2017, the United States released the orphan drug modernization plan, which aims to solve the problem of a large backlog of orphan drug product project approval. The plan proposes to conduct a complete review of all requests over 120 days within 90 days, and requires that the recognition time of all new orphan drugs should be controlled within 90 days, so as to accelerate the approval and listing of orphan drugs.
China has accelerated the improvement of drug R & D, approval and other relevant policies in the field of rare diseases since about 2018.
On May 22, 2018, the National Health Commission, the Ministry of science and technology, the Ministry of industry and information technology, the State Drug Administration and the State Administration of traditional Chinese medicine jointly issued the first batch of rare diseases catalogue (hereinafter referred to as the catalogue), which contains 121 kinds of rare diseases.
This is the first official definition of rare diseases in China and a milestone in the management of rare diseases in China. With this catalogue, there will be an important reference basis for the construction of China's rare disease diagnosis and treatment system, the basic research of rare diseases, the listing, R & D and medical security of rare disease drugs. At present, the formulation of the second batch of catalogues is also being promoted.
In terms of drug registration and approval, the State Food and Drug Administration launched a total of 78 overseas listed clinically urgently needed new drugs in 2018 and 2019, including 37 rare disease drugs. Listed drugs can directly apply for listing by submitting overseas research materials and be included in the priority review procedure.
For the vast majority of people, the significance of these policies may be strange and distant, but for patients with rare diseases, their feelings may be different.
At the "Pujiang pharmaceutical health industry finance innovation and Development Summit" held in October this year, Li Linkang, executive director of China rare diseases alliance and vice president of China Hospital Association, mentioned such a case:
Deuterium butylbenzazine (trade name: artetam), a drug for the treatment of Huntington's disease (hd), was developed by Teva, Israel.
Deuterated bubenazine was approved by FDA in April 2017. It is the second new drug approved by FDA to treat HD related chorea after bubenazine in recent decades. Deuterium bubenazine is a deuterium substituted product of bubenazine, which can also be regarded as an improved new drug of the latter.
Previously, because bubenazine has not been listed in China, Chinese HD patients have been facing the dilemma of no drug availability for a long time. Therefore, later, some patients and public welfare organizations tried to contact the manufacturer in the hope that the enterprise could introduce the drug into China. However, considering the limited number of patients and the high cost of listing registration approval, the enterprise chose to give up.
In contrast, deuterium butylphenazine is much luckier. After it was approved in the United States, it was selected into the list of the first batch of clinically urgently needed overseas new drugs by the State Food and Drug Administration in November 2018. This means that if the drug is to be listed in China, it can enjoy the convenience of priority review, which can greatly reduce the time cost of drug listing.
On December 27, 2019, Teva deuterium bubenazine tablets officially submitted a new drug marketing application (NDA) in China and was quickly approved in May of the next year, becoming the first drug for the treatment of HD in China.
From the public information, based on the price of deuterium butylbenzine tablets in the United States at that time, the price of a box of drugs was about 30000 yuan, but a box of drugs could only be eaten for 100 days. Therefore, the drug cost of patients per month was as high as 10000 yuan, which made many families unable to afford.
Therefore, whether it can be included in medical insurance as soon as possible after breaking through the "listing pass" will also largely determine whether this life-saving drug can benefit more patients.
That is, in the year when deuterium buconazine was approved (2020), after increasing the frequency of national medical insurance catalog adjustment from once in previous years to once a year, the national medical insurance bureau made another major change to the medical insurance catalog adjustment scheme.
In the previous adjustment of the medical insurance catalogue, the access threshold of innovative drugs is generally as of the end of the previous year, so the drugs newly approved for listing in the negotiation year can only wait until the next adjustment of the medical insurance catalogue. This year, the medical insurance bureau extended the time access threshold to the date of the plan announcement for the first time (August 17).
"(doing so) the main purpose is to give faster access to the medical insurance catalogue for those innovative drugs that have just been approved, especially those with independent intellectual property rights. At the same time, it also allows the insured to use innovative drugs with better clinical value as soon as possible and benefit from the catalogue adjustment as soon as possible." The relevant person in charge of the medical service management department of the National Medical Insurance Bureau said in an interview with the media.
Therefore, deuterium bubenazine approved in May 2020 (earlier than the access threshold on August 17) won the admission ticket to participate in the medical insurance negotiation in that year, and was successfully included because of the appropriate quotation.
In the past, it usually took several years or even longer for a new drug to be declared on the market, approved and qualified for medical insurance payment, while deuterium bubenazine only took about one year, which is an unprecedented speed.
In the view of the industry, this reflects the great changes in the policy environment in the field of rare diseases in China. At the same time, it is the result of the joint efforts of policy-making departments, enterprises, patients themselves, public welfare organizations and doctors.
does the payment problem no longer exist?
Although the policy environment continues to improve, at this stage, the development and accessibility of rare disease drugs still face various problems, including difficulty in disease diagnosis, difficulty in promoting clinical trials due to the small number of patients, etc., but the most concerned problem is the payment contradiction.
According to relevant studies, rare disease drugs are currently the most time-consuming, labor-intensive and resource intensive drugs, so their costs and prices are relatively high, exceeding the affordability of most patients. In China, these patients can only place their hopes on medical insurance.
This year's national medical insurance catalogue was adjusted and added 7 drugs for rare diseases, including several high-value drugs for rare diseases, including Bojian's nosinasheng sodium injection and Takeda's agatase α Concentrated solution for injection and Pfizer chlorobenzoic acid soft capsule have achieved a "zero breakthrough" in medical insurance for high-value rare diseases.
Figure 7 rare disease drugs included in medical insurance this year
"The inclusion of seven rare disease drugs in the medical insurance catalogue will play a positive role in encouraging pharmaceutical enterprises to innovate and develop in the fields related to rare diseases and send a positive signal. We believe that in the future, the field of rare diseases will receive more attention, the treatment needs of more patients will be explored, new products listed overseas will accelerate the introduction of China, and more innovative enterprises will accelerate the development of related fields Research and development in the field to help more patients with rare diseases get due and standardized treatment. " After the announcement of the results of the negotiations, Pfizer told the science and Innovation Board daily.
However, although this year's negotiations on the medical insurance of rare diseases have achieved a lot, it should be pointed out that the coverage of rare diseases by the national medical insurance does not start only this year. In the adjustment of medical insurance catalogue in 2019 and 2020, 9 and 7 rare disease drugs have been included in medical insurance respectively.
In addition, according to the statistics of Beijing pain challenge public welfare foundation, a public welfare organization for rare diseases, up to now, based on the national catalogue of the first batch of rare diseases, 87 kinds of drugs for rare diseases have been clearly registered in China, involving 46 kinds of rare diseases; By 2021, 58 drugs for 28 rare diseases have been included in the national medical insurance catalogue after the national medical insurance negotiation.
According to this calculation, the national medical insurance has covered more than 60% of the drugs for rare diseases involved in the first batch of rare diseases catalogue.
At the same time, we also need to see that a drug with sky high price can finally be included in the medical insurance as a cheap drug, which is not equivalent to that the medical insurance has "opened the gate" to high-value drugs.
As a basic medical insurance, medical insurance has the characteristics of universality, wide coverage and basic insurance, which determines that the first condition that drugs entering the national medical insurance catalogue need to meet is "reasonable price".
"In the process of adjustment, the National Medical Insurance Bureau firmly grasped the functional orientation of 'basic insurance', took the affordability of the fund as the 'bottom line' that must be adhered to, and prevented sky high and expensive drugs from entering medical insurance." Huang Huabo, director of the medical service management department of the National Medical Insurance Bureau, once made it clear.
"According to the limited payment scope, at present, the annual treatment cost of all drugs in the national medical insurance catalogue does not exceed 300000 yuan." After the medical insurance negotiation, at the press conference in early December, Zheng Jie, leader of the calculation expert group of the national medical insurance negotiation drug fund, revealed such a "price benchmark" of medical insurance drugs.
Although the price reduction may not be an easy decision for enterprises at any time. However, this year, Bojian still played the role of a dark horse and hit the floor price of nosinasheng sodium injection in one fell swoop in exchange for access to medical insurance.
At the beginning of being approved for listing in China, the price per unit was as high as 700000 yuan, and the annual treatment cost was as high as millions of yuan. In the medical insurance negotiation this year, the initial offer was 53680 yuan (5ml: 12mg / bottle), which was finally reduced to 33000 yuan after several adjustments.
According to the six injections of sodium nosinogenase in the first year, after the price reduction, the treatment cost of patients in the first year will be reduced to about 200000 yuan. If the reimbursement amount is 70% - 80%, the patient only needs to pay about 40000-60000 yuan. Since then, patients only need to inject three times a year, and the annual treatment cost will be further reduced to about 100000 yuan (before medical insurance reimbursement).
In this regard, some people in the industry believe that the key to the success of the negotiation of sodium nosinogenase is that when the medical insurance extends an olive branch, "the enterprise grasps it in time", and both sides are full of sincerity.
"For medical insurance, we have the sincerity to support qualified rare disease drugs to be included in the payment scope of medical insurance according to regulations; for Bojian, the company also has the sincerity to provide patients with accessible and sustainable treatment, so we choose to reduce the price in place." The other party said to the reporter of science and Innovation Board daily.
An important reason for Bojian to make substantial concessions on price is the competition from Roche.
Public information shows that Roche lisipram oral solution has entered the Chinese market on June 16 this year, which is the world's first oral drug for the treatment of spinal muscular atrophy (SMA).
"Bojiannosin sodium needs intrathecal injection, that is to say, lumbar puncture, which is more painful for patients; in contrast, Roche risperidone is an oral drug, and the patient's compliance is better. In terms of price, the current price of risperidone in China is 60mg / bottle, the retail price is 63800 yuan, plus the free medicine, the annual cost is 650000 yuan, which is before the negotiation with medical insurance The cost of sodium is equivalent. Nosinasheng sodium has no obvious advantage in price, and its compliance is not as good as lisipram. There will be great competitive pressure, so it is inevitable to reduce the price. " According to the aforementioned insiders.
China's rare disease drugs, what should we do?
Different from what most people understand, in addition to those high-value sky high price drugs, there are also many affordable drugs and some low-cost "guaranteed supply drugs".
What connects sky high prices and parity can be said to be "feelings".
Generally speaking, what the high price drugs need to solve is the demand of some patients with rare diseases who have "no medicine to cure", but the difficulty of drug R & D and commercialization is doomed to be a thorny road. Enterprises know that there are tigers in the mountain and still travel to the tiger mountain, and often rely on a feeling;
Although "guaranteed supply" is simple and unsophisticated, it often solves the basic drug needs of patients with rare diseases, but because the price is low, it may not even cover the enterprise cost, so "guaranteed supply" has become a feeling.
Take the "guaranteed supply" penicillamine tablets produced by Shangyao as an example. The price of 100 tablets is 79 yuan. If you calculate that one tablet is only 0.79 yuan, the annual drug cost of patients is about 2300 yuan, and penicillamine tablets still belong to class a medical insurance, that is, patients can be reimbursed by 100% medical insurance. Penicillamine tablet is a first-line drug for the treatment of hepatolenticular degeneration. It is expected to benefit at least 5000 patients every year.
However, according to the reporter of science and Innovation Board daily, penicillamine tablets are mostly sold at a price lower than the production cost, and the number of patients is limited. This drug can only bring more than 10 million sales to enterprises a year. Although such products can solve the urgent needs of patients, they are far from enough to feed the enterprise.
Feelings are valuable, but it is obvious that in the current market environment, the development of Chinese rare disease drugs with feelings will not only become more and more difficult, but also unsustainable, which is the problem in front of "Beihai Kangcheng" and "Shangyao".
As a local star enterprise rooted in the research and development of new drugs for rare diseases earlier, Hokkaido Kangcheng has many praises, including its ability to quickly introduce external projects, the recognition of a number of well-known investors such as Wuxi Apptec Co.Ltd(603259) and Qiming venture capital, and the establishment of a rich product pipeline covering more than 10 products.
But even so, the company's share price still fell all the way after its listing in Hong Kong.
"Beihai Kangcheng's listed products don't sell well." In this regard, an investor in the primary market pointed out to the reporter of science and Innovation Board daily that "due to the limited payment ability of Chinese patients with rare diseases and the insufficient coverage of commercial insurance and medical insurance, the sales of rare disease drugs in China are poor and the value of product pipeline can not support the enterprise valuation."
"Therefore, in addition to innovative technologies such as cell and gene therapy, China's primary market will be relatively cautious in investing in rare diseases. The reason why cell and gene therapy can be favored is that although these innovative technologies are mainly focused on the field of rare diseases at present, they can also be applied to major diseases after the technology is mature in the future." He also said.
According to public information, Hokkaido Kangcheng has three listed products in China, namely, caphosol, neratinib and hunterase β Injection) was approved for listing in November 2018, April 2020 and September 2020 respectively.
Among them, Hercules is the first rare disease drug successfully commercialized by Beihai Kangcheng in China, which is mainly used for long-term enzyme replacement therapy of mucopolysaccharide storage syndrome type II (MPS II, also known as Hunter syndrome). According to the reporter of science and Innovation Board daily, the annual treatment cost of this rare disease drug is more than one million based on the current selling price in China.
From the prospectus of Beihai Kangcheng, although the listing of these three products has a certain pulling effect on the company's revenue growth, the overall sales are still "insignificant" compared with other non rare disease drugs. At the same time, due to the huge R & D investment required for the promotion of other products under research, the company's performance continued to suffer losses.
The revenue of Hokkaido Kangcheng in 2019 and 2020 is 1.47 million yuan and 12.03 million yuan respectively; The losses during the period were 217 million yuan and 846 million yuan respectively. In the first half of 2021, the company had a revenue of 12.19 million yuan and a loss of 344 million yuan during the period.
In addition, there is also a view that rather than defining Beihai Kangcheng as a R & D enterprise of rare disease drugs, it is better to call it a commercial company of rare disease drugs, because in Beihai Kangcheng's existing rare disease and rare tumor product line, all 8 products are imported under license.
"The advantage of authorized introduction is fast, but the disadvantage is expensive. In this case, how can the pricing be obtained?" Another market analyst pointed out.
High value innovative drugs for rare diseases are often affordable by enterprises, but not by patients; The low value guaranteed supply of drugs is affordable for patients, and enterprises "can't afford it". Therefore, to be a rare disease drug that patients can afford and enterprises can afford has become another direction that enterprises hope to break through.
In fact, if the clinical demand is taken as the measurement index, the high-value rare disease drugs are to solve the patient's "no medicine to cure" demand. However, in addition, there are other needs for the treatment of rare diseases, such as the backwardness of existing treatment schemes, the urgent need for more economical alternatives for high-priced drugs and so on. This part of the demand has not been concerned in the past, but it is a real clinical pain point.
"Many patients with rare diseases need long-term or lifelong medication, so medication compliance is very important. This drug should be safe, delicious and easy to use. We think this is a very important consideration, especially in the design and R & D of drugs for rare diseases in children." Jiang Xin, innovation director of Beijing Kexin Bicheng Pharmaceutical Technology Development Co., Ltd. (hereinafter referred to as "Kexin Bicheng"), said.
According to the reporter of Kechuang ban daily, in the treatment of glycogen accumulation, the current mainstream clinical treatment method is to take raw corn starch or modified corn starch, but this treatment scheme has many limitations, including taking it before going to bed and at 3 a.m., and taking it with cold water, even in winter; The dosage is large, and the volume of starch expands after being washed with cold water. It is very difficult for children to take a therapeutic amount of starch at one time.
In view of such clinical pain points, based on the drug R & D ideas provided by pediatricians of Peking Union Medical College Hospital, Tsinghua university designed the preparation, while Kexin Bicheng gave the development fund support and professional systematic drug R & D support, and undertook the work of technological improvement, patent application, animal model construction, clinical experiment application, etc. in the later stage. It is reported that glucose sustained release pellets, an improved new drug for the treatment of glycogen accumulation, has entered the stage of clinical approval.
During the interview, the reporter of science and Innovation Board daily also noted that the importance of rare disease drug research and development guided by clinical demand has been recognized by more and more enterprises involved in this field, including Shanghai Pharmaceuticals Holding Co.Ltd(601607) (601607. SH).
Shangyao established its own rare disease drug platform, Shangyao Ruier company, at the end of December 2020. On the issue of how to make drugs for rare diseases, Shangyao Ruier also has his own thinking.
It is understood that around the clinical needs and pain points, the future development of rare disease drugs by Shangyao Ruier will focus on multiple directions, including generic drugs and improved new drug products arranged for the shortcomings such as too expensive or backward existing treatment schemes, as well as innovative drugs arranged for the drug needs that are urgently needed but the treatment is still blank.
"However, whether it is self-development or authorized introduction, whether the cost is controllable or not will be our key consideration. Only when the cost is controllable can the price be controllable. Therefore, in the future, in the R & D of some rare disease drugs, (we) will make full use of the industrial and transformation advantages of Shanghai Pharmaceuticals Holding Co.Ltd(601607) , carry out the layout of the whole industrial chain, and let patients have more accessible choices." At the recently held 2021 China rare diseases conference, Shangyao Ruier proposed.
(Financial Associated Press)
