Lifetech IBS iron-based absorbable stent: opening the iron-based era of cardiovascular and cerebrovascular interventional therapy

On January 3, 2009, the Bitcoin genesis block was born. On January 10, 2024, the U.S. Securities and Exchange Commission (SEC) approved the Bitcoin spot ETF for the first time in history, and Bitcoin was officially recognized by mainstream funds in Europe and the United States, and in 15 years, Bitcoin has developed from a concept to a market value of more than $1 trillion. Many investors who hold the "Bitcoin Faith" have created a wealth myth in these 15 years. Reaffirming that "great investments require the power of faith"

In the same year, a group of Chinese medical device R&D groups with "iron-based beliefs" were led by Academician Gao Runlin, an expert in cardiovascular diseases, an academician of the Chinese Academy of Engineering, and the former president of Fuwai Hospital of the Chinese Academy of Medical Sciences, as the main investigator, and started the animal experimental research of iron-based absorbable stents of Lifetech Technology.

"Bitcoin believers" believe that Bitcoin will replace the status of gold, reaching a market value of $10 trillion, and "iron-based believers" also believe that iron-based materials are the best absorbable metals implanted in the human body, which will complete the replacement of permanent coronary stents.

IBS is the only BRS that can be used as a comprehensive replacement for permanent stents

Coronary heart disease is one of the most common cardiovascular diseases, with high morbidity and mortality, and seriously threatens human health. In recent years, the number of patients with coronary heart disease in China and the world has grown rapidly, and the number of patients with coronary heart disease in mainland China has reached 11 million, and the number of patients with myocardial infarction is about 4 million to 5 million. Although great progress has been made in interventional treatment of coronary heart disease (PTCA) from balloon dilation (POBA) and bare stent (BMS) to the current third-generation drug-eluting stents (DES), permanent stents as "foreign bodies" still have a series of negative effects in the body for a long time:

1. Target Lesion Failure Rate (TLF): This refers to the proportion of blood vessels that are stretched out by the stent to be blocked again, including cardiogenic death, target vessel myocardial infarction and target lesion revascularization. The popular understanding is the proportion of patients whose blood vessels are blocked again after the stent has been opened for a period of time, resulting in the death of the patient, myocardial infarction or the proportion that needs to be opened twice. TLF is also the only evaluation index for absorbable stents. It is expected that the mechanical and material stimulation of the tissue will be eliminated after the scaffold is absorbed by the body, and the TLF will not increase or slow down.

2. Difficulty in secondary intervention: Once the blood vessel is blocked again, it will be difficult to carry out secondary intervention, and even thoracotomy surgery will be required.

3. Lifelong anticoagulant medication: Patients may need to take anticoagulant medication for a long time due to the presence of stents, and long-term use of anticoagulant medication may lead to an increased risk of bleeding.

4. Limited MRI/CT scans: Traditional metal stents may compromise the compatibility of magnetic resonance imaging (MRI) or computed tomography (CT), leading to imaging artifacts or requiring special conditions to perform these tests safely.

5. Constraining the growth of blood vessels: The presence of stents may limit the normal growth and expansion of blood vessels. Traditional stents may not be suitable for children because children have different blood vessel sizes and growth needs than adults.

6. Calcified deposits in the blood vessel wall: Long-standing stents may lead to calcified deposits in the blood vessel wall, affecting vascular health.

Lifetech's iron-based resorbable vascular stent (IBS) is the answer to this series of problems, as a new type of vascular stent, it is characterized by being gradually absorbed by the human body after a 3-month vascular repair period, avoiding the possible negative effects of the long-term existence of traditional stents. Iron-based believers believe that IBS is the only bioresorbable scaffold that can be used as a comprehensive replacement for permanent stents.

First Principles: Why Iron?

First principles refers to returning to the most basic conditions of things, splitting them into various elements for deconstruction and analysis, so as to find the best path to achieve the goal. The development of iron-based resorbable stents also follows this principle.

Absorbable stent, there are two key words, "absorbable" and "stent", in essence, it is still "stent", first of all, it must be a good stent, and then it is the pursuit of its "absorbability".

Years of clinical practice have long proven that stent rod thickness has a significant impact on stent handling, safety and effectiveness. Therefore, the drug-eluting stent was reduced from the first generation of stainless steel stents to the second generation of cobalt-chromium alloy stents, and the thickness of the stent rod was reduced from 150 μm to 80 μm, so that the TLF was greatly reduced. The polylactic acid degradable stent represented by Abbott Absorb has a thickness of 157μm due to the poor mechanical properties of the polylactic acid material, which is thicker than the stainless steel stent. Although polylactic acid is a relatively mature resorbable material that is biologically assured, Abbott tries to compensate for the lack of stent rod thickness through stent design or material degradation. However, the global delisting of Abbott Absorb stent in 2017 proves that the road of polylactic acid is not going to work. We still have to return to the road of metal materials.

Obviously, not all metal materials can be used as absorbable scaffolds, Professor Zheng Yufeng of Peking University screened the periodic table with three criteria: biocompatibility, degradability (corrosion) in the human body, and the content in the human body, and believed that only iron, zinc and magnesium have the possibility of being the main elements of absorbable scaffolds.

Biocompatibility: Iron, zinc, and magnesium are all highly abundant nutrients in the human body, and there is a strong balance mechanism in the human body to control their concentration. The amount of one stent is almost 1/1000th of the total amount of the human body. This is something that no other metal element can match, which further guarantees biosecurity.

Degradability: Magnesium is the fastest, zinc is second, and iron is the slowest. From a purely material point of view, magnesium can be degraded in a few days at the earliest, while iron is too slow, and it can be decades. Through in-depth research, the team found that the iron dissolution process can be accelerated by changing the pH value in the human environment. The pH of the human body is 7.35-7.45 (neutral at 37 degrees Celsius, about pH6.8), which is alkaline. Whereas, iron dissolves very easily into iron ions in an acidic environment. The team used large molecular weight polylactic acid as the coating material, which is able to create an acidic environment during degradation, which accelerates the corrosion rate of the iron scaffold and converts it into soluble iron ions. In addition, by adding a 600 nm thick zinc layer to the surface of the iron stent as a sacrificial anode, the iron-based stent will not be corroded at an early stage to ensure effective support for 4-6 months after implantation. After ferroalloy absorbable scaffolds are implanted into the human body, they will be degraded into iron oxide, iron hydroxide and iron phosphate, which will then be phagocytosed by macrophages to become hemosiderosin, which will be transported to the adventitia of blood vessels, and finally enter the spleen through the lymphatic system for reuse.

For magnesium materials, although the corrosion can be delayed by surface coating technology, in practical applications, the integrity of the coating is difficult to guarantee, and the rapid degradation of the entire stent may be caused by small defects. The zinc material will form a zinc carbonate and zinc phosphate layer in the human body, which reduces the corrosion rate of zinc, which is the premise of ensuring the biological safety of zinc materials.

Supporting capacity

The design of the absorbable scaffold must first meet its basic function as a support structure – that is, sufficient support force. On the basis of ensuring the support force, designing a stent rod thinner than the traditional permanent stent is the key to realizing the resorbable stent instead of the traditional stent. By infiltrating 0.05% nitrogen into the pure iron, the strength of the iron is successfully increased to 1000MPa, which is comparable to the strength of the cobalt-chromium alloy permanent scaffold material currently used. This innovative process allows the iron-based bracket to maintain a thinner bracket rod design while still having excellent support performance.

In contrast, zinc and magnesium alloys only have strengths of about 500 MPa and 300 MPa, respectively, which means that bracket rods made with these two materials are necessarily thicker and offer fewer size options. For example, the latest generation of magnesium stents are 99 μm (2.5 mm in diameter), 117 μm (3.0 mm and 3.5 mm in diameter), and 147 μm (4.0 mm in diameter), all of which are significantly higher than the 81 μm thickness of permanent stents currently on the market. Due to the sacrifice of the advantages of the pattern design, the number of specifications of the magnesium bracket is also limited, the second generation only has 6 specifications, and the latest generation can only provide 18 specifications.

Lifetech's iron-based stents are 55 μm (2.5 mm in diameter), 60 μm (3.0 mm in diameter) and 65 μm (3.5 mm and 4.0 mm in diameter), which are even thinner than the existing permanent stents. At the same time, the number of specifications of iron-based stents is the same as that of permanent stents, all of which provide 56 different size options, providing greater flexibility and precision for clinical applications.

The coating material, the proportion of nitrogen infiltrated, the pattern design, etc., are all tactical options, and the choice of which metal material to choose is a strategic choice, an option to ensure that you do not lose at the starting line, and a first-principle option. The "iron-based believers" are convinced that the iron stent is the only technical path that does not lose to the absorbable stent at the starting line. The results of 18 years of continuous iterative testing also showed that the MR compatibility of iron stents was the same as that of permanent stents, and it was the only absorbable scaffold without calcification deposition.

Latest development: It has been recognized by European and American regulatory agencies, and three academicians have participated

Lifetech's first batch of IBS iron stent products include three indications:

IBS™ coronary stent,

IBS Angel™ Pediatric Pulmonary Vascular Stent and

IBS Titans™.

The fastest progress is the IBS Angel™ iron-based pediatric pulmonary vascular stent, which has been approved for the EU CE certificate on February 23, 2023, and is the world's first iron-based absorbable stent registration certificate. In terms of the U.S. FDA, IBS Angel™ iron-based pediatric pulmonary vascular stent and IBS Titan™ peripheral vascular stent have been approved for compassionate use by the U.S. FDA in 2021 and successfully implanted in the United States. The FDA's compassionate use is the approval of unregistered medical devices for patients with severe disease when existing treatments do not respond well. The approval for sympathetic use proves that it is a much-needed product in the blank market. From this point of view, iron-based materials have been recognized by European and American regulatory authorities as scaffolds. Iron-based brackets are no longer a question of whether they can do it, but a question of how big the market is.

When it comes to the market, the most important product at present is the IBS™ coronary stent. According to Frost & Sullivan's forecast, the global use of coronary intervention stents is expected to exceed 12 million by 2030, and its market size is expected to grow to $9.1 billion, making it the largest medical device in a single market. Absorbable stents cost about twice as much as permanent stents, so the market size is estimated to be $18 billion. Under the endgame thinking, if Lifetech IBS series stents are expected to gain 20% of the market share, sales can reach $3.6 billion, and profits will exceed $1 billion.

The phase I clinical trial of IBS™ coronary stent in China began in March 2018, and the two-year follow-up results of the FIM clinical trial were announced by Academician Runlin Gao at the 2021 American Transcatheter Cardiovascular Therapy Academic Conference. Two-year follow-up data showed no deaths, myocardial infarctions, or thrombotic events. The results confirmed the feasibility of the iron stent, demonstrating its complete resorptibility in the human body. The 3-year results of the FIM clinical trial were published in the prestigious European journal "EuroIntervention", and the 5-year follow-up has been completed, and the results are expected to be published.

Surprisingly, the lumen of the vessel continued to expand after 6 months of implantation of the IBS™ coronary stent, rather than the continuous decrease of the lumen as in the case of permanent stents, polylactic acid and magnesium alloy stents.

The phase II clinical trial of IBS™ coronary stent in China began in March 2022, and the phase II has completed the one-year follow-up of 518 patients, and the results were announced at the EuroPCR conference in Paris on May 14:

The results of one-year clinical follow-up showed that there was no significant difference in the target lesion failure rate (TLF) between the experimental group (Lifetech's IBS™ coronary stent) and the control group (Abbott's Xience™ everolimus drug-eluting coronary stent) (2.3% in the experimental group and 2.7% in the control group, p=0.78). There was no significant difference in the incidence of cardiac death (0 in the experimental group and 1.2% in the control group, p=0.20) and target vasive-related myocardial infarction (0.4% in the experimental group and 1.2% in the control group, p=0.37) in the two groups, and there were no device-related thrombotic events in the two groups, which preliminarily proved that the IBS™ coronary stent was not inferior to the mainstream drug-eluting metal stent in the current market, showing ideal safety and efficacy.

Just as Bitcoin will not benchmark against Ethereum and Tether but directly against gold, Lifetech's IBS™ coronary stent clinical trial does not benchmark against polylactic acid degradable stents, but against Abbott's Xience™ Everolimus drug-eluting permanent stent, which is currently the most mainstream in the market, which lays the foundation for IBS™ coronary stent to be the only comprehensive replacement for permanent stents. Congratulations to the Xianjian Yuanxin team. (There should be applause here)

In China, coronary stents are the only medical devices that require phase III clinical trials.

The phase III clinical trial of IBS™ coronary stent in China was officially launched in February 2023, which lasted only 5 months, and completed the enrollment of more than 800 subjects, with a success rate of 100%. After the results of the 1-year follow-up of phase III are available, the certificate can be obtained in China. At the same time, due to the continuous good communication with the EU regulators, the company's 23-year annual report has disclosed that the IBS™ coronary stent has submitted the EU CE registration application, if there is no accident, the EU CE approval will be earlier than the domestic one.

As a world-class innovative medical device product, it should not only look at the support of regulatory agencies in China, the United States and Europe, but also the support of cardiovascular and cerebrovascular doctors. From the progress of the three clinical trials, it can be seen that Chinese cardiovascular and cerebrovascular doctors are becoming more and more confident in Lifetech iron-based absorbable stents. It took 10 months to enroll more than 60 patients in the Phase I clinical trial, 9 months to enroll 518 patients in Phase II, and more than 800 patients in only 5 months in Phase III.

In addition, all three major academicians in the field of cardiovascular and cerebrovascular diseases in China participated, and the confirmatory clinical study of IBS™ coronary stents in China (i.e., phase II and phase III clinical studies) was led by Academician Gao Runlin as the principal investigator (PI), and Academician Ge Junbo and Academician Han Yaling, as well as clinical experts from nearly 40 clinical research centers across the country were invited to participate. Globally, it has reached clinical cooperation with 93 hospitals in 9 countries, including Beijing Fuwai Hospital, Yunnan Fuwai Hospital, Zhongshan Hospital affiliated to Fudan University, PLA Northern Theater General Hospital, PLA General Hospital, Guangdong Provincial People's Hospital, Beijing Anzhen Hospital, etc. Children's Hospital of Wisconsin, PIMA Heart and Vascular, USA; European Hospital of University of Florence, University Hospital Leipzig, etc.

epilogue

What is the chemical element that accounts for the largest mass of the Earth?

The answer is iron, which makes up 30% of the Earth's mass. As the most abundant element, iron has also been deeply involved in the evolution of all living things on earth for hundreds of millions of years, and the most important biological function of iron is to participate in the synthesis of hemoglobin and the transportation of oxygen. Our bodies need iron to transport oxygen to all parts of the body, and oxygen binds to fats and sugars to produce energy and heat. This is the common sense of "iron-based beliefs", and with the advancement of the clinical trials of iron-based stents of Lifetech, more and more regulators, doctors, patients, and researchers have joined the consensus of "iron-based beliefs".

As an investor, with the lessons of "Bitcoin faith", it is better to believe early than later, and iron-based materials have opened a new market of tens of billions of dollars. After deducting the net cash of 1.5 billion yuan on the account and the property assets of 3 billion yuan in Shenzhen and Dongguan, the latest research report of CICC predicts that the net profit deducted from the non-attributable parent company in 2024 and 2025 will be 487 million yuan and 585 million yuan respectively, with a valuation of less than 10PE. It can be seen that Yuanxin's iron-based pipeline is not valued at all in the current market. Yuanxin has introduced two rounds of investment, the goal is to spin off and go public, iron-based bracket is a business with a profit of 1 billion US dollars, such as listed in the US stock market or A-shares, the market value may reach 100 billion.

As the time for IBS coronary iron-based stent certification approaches, the market will eventually reflect the valuation of iron-based pipelines. The current undervaluation is the bear market benefit of Hong Kong stocks falling for four consecutive years, and Lifetech Technology is a ten-bagger medical device company with the highest value betting rate.