Recently, the launch of Idarucizumab, an expert from the Asian College of Anticoagulation, was held in Shanghai.Idarucizumab, a monoclonal antibody drug, was approved by China Food and Drug Administration on June 8, 2018, for use in emergency surgery/emergency operation or in case of life-threatening/uncontrollable hemorrhage requiring rapid reversal of anticoagulant effect of dabigatran etexilate.During the meeting, Mr. Dirk van Niekerk, head of Boehringer Ingelheim's (BI) human pharmaceuticals business in Greater China, spoke to the media.
I.Face up to the advantages and disadvantages of medicines
Dabigatran etexilate" is a new oral anticoagulant (NOAC) promoted by BI for stroke prevention in atrial fibrillation in recent years.In the onset of atrial fibrillation, blood stasis in the atrium and easy to form intra-atrial thrombus, thrombus shedding can cause peripheral artery or pulmonary artery embolism, is one of the common causes of stroke.In the event of a stroke, the patient's quality of life is affected in mild cases and life-threatening in severe cases, with unimaginable consequences.
The Global Burden of Disease Study 2010 shows that the number of patients with atrial fibrillation worldwide is 33 million, the prevalence of atrial fibrillation in China has increased 20-fold and stroke in atrial fibrillation has increased 13-fold in the past 11 years.Prevention of stroke has become the main content of the comprehensive management strategy for patients with atrial fibrillation, and anticoagulation is one of the effective prevention measures for atrial fibrillation.
The traditional anticoagulant for atrial fibrillation, the vitamin K antagonist warfarin, has a clear antiembolic effect, but it also has certain defects, such as its metabolic susceptibility to food.Drugs and other factors affect the effectiveness of drugs.Long expiry time.The therapeutic window is narrow and requires frequent monitoring, resulting in poor medication compliance.
For patients with atrial fibrillation at risk for stroke, several guidelines no longer recommend antiplatelet therapy for stroke.There are even studies suggesting that aspirin actually increases ischemic stroke and thromboembolic events in elderly patients.For more than a decade, researchers have been working to develop safer.Valid.More convenient use of new oral anticoagulants.
These drugs do not act on multiple clotting factors as traditional anticoagulants do, but rather inhibit only one clotting factor.According to the target of NOACs, they can be divided into two categories: direct coagulation factor inhibitors (factor Xa) and direct thrombin inhibitors (factor IIa).
1) Direct Factor Inhibitors (Factor Xa)
Factor Xa is the intersection of the extrinsic and intrinsic coagulation pathways.Prothrombin is activated by the formation of a phospholipid complex, the thrombin complex, on the surface of the phospholipid membrane.Direct coagulation factor inhibitors exert their anticoagulant effect by binding to the active site of factor Xa and preventing the conversion of prothrombin to thrombin, and the anticoagulant effect is independent of endogenous antithrombin.Representative drugs include: Apixaban.Rivaroxaban.Edoxaban et al.
2) direct thrombin inhibitor (factor IIa)
Factor IIa specifically blocks the activity of thrombin, thereby preventing the cleavage of fibrinogen to fibrin and blocking the final steps of the "coagulation cascade."The anticoagulant effect of direct thrombin inhibitors does not require cofactors and is independent of vitamin K.The anticoagulant effect is concentration dependent.It inactivates both free thrombin and fibrin-bound thrombin.Represents "dabigatran etexilate".
Two.Thinking of developing spear shield
The FDA approved "dabigatran etexilate" in 2010 for the prevention of stroke and systemic thrombosis in patients with atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.So far, "dabigatran etexilate" has been approved in more than 100 countries.According to BI's external data, to date, the clinical experience of thrombin complex in all approved indications worldwide is more than 6.9 million patients per year, and the stroke prevention of "dabigatran etexilate" in patients with non-valvular atrial fibrillation is expected to reach more than 260,000 times compared to no treatment.
No good medicine, no reversal is a very troublesome thing.Patients with atrial fibrillation who are taking anticoagulants in real life are as likely to develop trauma as the general population.Car accidents and urgent cases requiring surgery require reversal agents that can quickly reverse the effects of anticoagulation.Reversal agents currently marketed or under development, such as idarucizumab.Andexanet alfa and Ciraparantag offer new hope for more convenient, efficient and effective control of bleeding risk.
In October and November 2015, the FDA and EMA approved idarucizumab as a specific reversal agent for dabigatran etexilate in patients undergoing emergency surgery.Use when emergency procedures or life-threatening or uncontrolled bleeding require rapid reversal of the anticoagulant effect of dabigatran.
Idarucizumab is a monoclonal antibody designed for dabigatran and the first approved specific reversal agent for the latter.The data showed that "dabigatran" in plasma could be captured in trials in healthy subjects, with peak plasma concentrations occurring 5 minutes after the end of the intravenous infusion, and the majority of "dabigatran" in plasma were captured."Idarucizumab" has a 350-fold higher affinity for "dabigatran" than it has for thrombin, that is, dabigatran dissociates from the bound factor IIa, thrombin, due to its higher affinity for idarucizumab, and binds to idarucizumab.This reversal effect, such as "anti-missile" interception as fast and accurate, can better meet the clinical needs.
three.The original intention of R & D to reassure doctors and patients
Sales of "dabigatran etexilate" in 2017 were 1.438 billion euros worldwide, a steady increase since its launch in 2011.Sales data for idarucizumab are not publicly available.
As we all know, developing a monoclonal antibody is not easy, and the cost is very high.If, from a pharmacoeconomic point of view, it does not seem to be very cost-effective for drug companies, Mr. von Ned said when the reporter raised this question, the development of this antibody drug is not from a profitable point of view, but on the one hand, it is optimistic about the future market of "dabigatran etexilate", in order to give doctors more peace of mind when using it, give patients double insurance.Second, through the marketing of this drug, people reduce the use of anticoagulants doubts, to enhance the awareness of people with atrial fibrillation stroke prevention.
Attached: Interviews with reporters
Q: Hello Mr. Von Ned!What is the current market share of dabigatran etexilate?
Von Ned: In terms of market value, we are leading the market for stroke prevention in atrial fibrillation, with a market share of about 45%, that is, dabigatran etexilate accounts for 45% of the market share in the new oral anticoagulant stroke prevention market.But dabigatran etexilate is smaller than warfarin, which has been on the market for 20 to 30 years.
Q: How does BI intend to further improve drug accessibility?
Von Ned: Dabigatran etexilate entered Medicare in 2017, I think on the one hand because it has a good advantage as a new oral anticoagulant, on the other hand, the government also realized that some elderly patients taking warfarin do have great dangers, such as more difficult to control coagulation, which is an important reason for the government to include dabigatran etexilate in Medicare.
Idarucizumab is not yet covered by Medicare, a class of biologics that will be marketed at a reasonable price based on manufacturing costs.
Dabigatran etexilate now has a competitive advantage in Medicare prices, and I believe many patients can afford it.As far as I know, many drugs now have some bidding behavior in various provinces in order to get medical insurance.With the pressure of bidding and the availability of generics, I believe that the price of dabigatran etexilate could fall further, making it affordable for more patients.
Q: Idarucizumab is marketed as a rare disease in China. From the perspective of drug company economics, the R & D and final return on investment may not be proportional. What are the initial considerations for the development of Idarucizumab by BI?
P> von Ned: At the beginning of our development of idarucizumab, financial returns were not a priority.So why are we still developing this drug?This is mainly because dabigatran etexilate is still very well anticoagulated, and the number of patients taking dabigatran etexilate worldwide is increasing.China is gradually entering an aging society. In the future, more and more elderly patients with atrial fibrillation will have long-term use demand of dabigatran etexilate. Under the premise of such market, it is necessary to make doctors and patients "more at ease" after using dabigatran etexilate.
When a patient is in an emergency surgical situation, he needs to reverse the effect of anticoagulation quickly and promptly.If we have a drug like idarucizumab that can be quickly reversed, it can greatly reduce the concerns and worries of patients and doctors and make them more at ease.Bold use of dabigatran etexilate allows Pradaxa to be used longer.So, we are not designing idarucizumab for commercial purposes, but to make it easier for doctors and patients to use it in an emergency.
Q: In your opinion, what are the gaps in the treatment of stroke between Chinese and foreign AF patients?
P: I don't really know what dimension to measure the "gap", but what I do know is that China is too big a country to compare with foreign countries, so there are some limitations in treating stroke emergencies.In many small countries in Europe, patients do not come to the hospital for treatment at the onset of a stroke far enough to receive treatment in a timely manner, and hospitals are equipped with very professional doctors and rescue facilities.
However, in China, because the size of the country is really too large, if stroke patients live in rural or remote areas, it will take them a long time to reach the major hospitals that can treat stroke once the disease occurs, which is obviously far less favorable for the "golden 3 hours" required for stroke treatment.
Q: As a participant in AF stroke, does BI have some plans to help China close the gap?
P: In fact, now the Chinese government.Health officials and health care workers are also aware of the problem.We hold hands with the Chinese Stroke Association (CSA) and the American Heart Association/American Stroke Association (AHA/ASA) to fund a training course.
This training course has three modules. Through this course, we strive to provide international training opportunities for stroke doctors in more remote areas and primary hospitals to further promote the standardization of stroke diagnosis and treatment in China.Normalization.The whole project is called "Stroke Comprehensive Training Center", which is sponsored by BI to carry out clinical training bases in Beijing and Shanghai.
As far as I know, each of the two places has 50 doctors training each week, flying over on Friday and returning at the weekend.After training in these three modules, doctors will receive a certificate to provide more stroke patients with safer and more effective treatment.At the same time, these primary care doctors are trained, and their primary hospitals can also be certified, which means that the hospital has the standard of stroke treatment.
Predictably, as training courses continue to deepen, the number of stroke patients in China who can be treated professionally will quickly catch up with the United States and Europe.Therefore, training programs like this one, we will continue to increase investment, so that it can continue to carry on, so that more Chinese stroke patients get more safe and effective.Standardized treatment.