Hepatitis B is a common infectious disease. There are 254 million hepatitis B patients worldwide, and more than 80 million patients in China. The cause is the infection of liver cells by hepatitis B virus (HBV) and the resulting autoimmune response. Chronic hepatitis B infection can cause liver cirrhosis, liver cancer and other fatal diseases. According to statistics, about 1.1 million people worldwide die of hepatitis B infection related diseases every year. [1] At present, the therapeutic drugs for hepatitis B mainly include nucleoside analogues, interferon, etc. These drugs can inhibit the replication of viral DNA, but they usually need to be taken over a long period to maintain the efficacy, which is difficult to achieve the radical cure of hepatitis B.
In 2016, the World Health Organization (WHO) released the Global Health Sector Strategy for Viral Hepatitis, which proposed to eliminate the threat of viral hepatitis to public health by 2030. Clearing the cccDNA and HBsAg of hepatitis B virus in infected persons is the most important standard of curing hepatitis B, and also the most fundamental method to block the transmission of HBV.
Gene editing technology may become one of the possible paths to achieving a cure for hepatitis B. In December 2023, the US Food and Drug Administration (FDA) officially approved the marketing of two therapies for sickle cell anemia (SCD), Casgevy and Lyfgenia. In 2024, Intellia Therapeutics successfully completed the clinical proof of concept for the NTLA-2001 system based on CRISPR-Cas9. The advancement of these therapies fully verifies the technical feasibility of treating diseases based on gene editing technology.
The off-target effects of the CRISPR-Cas gene editing system pose a significant threat to the safety of treatment. To address the high off-target issues associated with wild-type Cas nucleases, certain treatment programs have resorted to increasing the delivery amount of gene editing tools, making it more challenging to achieve safe and efficient disease treatment. Currently, the gene editing market is severely lacking in high-precision CRISPR-Cas gene editing tools tailored for specific diseases. Consequently, there is an urgent need to acquire gene editing nucleases specifically designed for particular diseases.
Therefore, gene editing technology has become one of the possible ways to achieve the cure of hepatitis B. This project proposes to use the HBsAg gene fragment of hepatitis B virus as the target sequence, and employ a modified high-precision MAD7 (CRISPR-Cas12a) nuclease for gene editing in vivo to eliminate hepatitis B virus DNA, so as to develop a new treatment for hepatitis B. This therapy has the advantages of high safety, short treatment cycle, and the potential for complete cure, and is expected to become an important means of eliminating the threat of hepatitis B.
At present, the price of some drugs for hepatitis B is very low, which can be used by hepatitis B patients for a long time. However, it is difficult for these traditional drugs to completely eliminate hepatitis B virus and its genetic material in the body, and there are also risks of side effects, drug resistance and other adverse reactions.
Compared with traditional hepatitis B treatment drugs, our treatment products are mainly composed of high-precision MAD7-nuclease, guide-RNA and delivery system (possibly including RNP, LNP, adenovirus vector, etc.), supplemented by isiRNA, interferon and liver protection drugs to form a complete treatment system.
The modified CRISPR/Cas nuclease has the advantages of high safety, complete elimination of hepatitis B virus genetic material, and short treatment cycle. Therefore, if our treatment plan enters the market, the biggest advantage is that it can enable patients to quickly recover and there is no risk of recurrence in the future. At the same time, patients can quickly gain social equity, sense of identity and broader employment opportunities,which eliminates the negative social impact of hepatitis B.
Considering the characteristics and maturity of current delivery technologies, this product may be delivered in the form of mRNA. From a production and application perspective, our treatment plan shares many similarities with mRNA therapy. Therefore, based on the market price of mRNA drugs, the price of this product may range from tens of thousands to hundreds of thousands of RMB. Due to the special nature of in vivo gene editing of products, strict animal experiments, clinical trials, and safety testing are required, which may further increase costs. However, this product is expected to achieve large-scale social promotion by combining measures such as medical insurance.
Taken together, this product will be directly targeted at hepatitis B patients and cooperate with the hospital to realize the direct delivery of the treatment system to patients. The target user is initially identified as a patient with chronic hepatitis B infection whose condition has not worsened and who needs urgent treatment. Based on the information we have collected, we have created a profile of the customers that the product is currently targeting
1. Early hepatitis B infection and serious symptoms: For patients with early hepatitis B infection, their symptoms are quite serious, which will bring a series of additional effects, including deterioration of physical health, social discrimination, reduced employment opportunities and so on. Therefore, patients have a strong demand for radical treatment and are willing to try new therapies.
2. Traditional treatment methods are not applicable and whoever has an urgent need for cure: For those patients who have tried traditional treatment methods but have poor effects, they would rather try this new treatment that can cure hepatitis B radically, since they urgently hope that the disease of hepatitis B can be cured.
The World Health Organization (WHO) has set the goal of eliminating hepatitis B globally by 2030, and mobilized countries to step up their actions to achieve the specific health goals under the 2030 Sustainable Development Goals. The Chinese Center for Disease Control and Prevention has released the National Action Plan for Eliminating hepatitis B as a Public Health Threat (2021-2030), which requires the implementation of strategies and measures to control and prevent hepatitis B to curb new hepatitis B infection, cure hepatitis B infected people, and significantly reduce the number of deaths from related diseases. The "14th Five Year Plan for the Development of Bioeconomy" released by China on May 10, 2022 also clearly proposes to focus on the development of the biopharmaceutical field for people's life and health, which is in line with our original intention of therapy and reflects the broad prospects for the development of this product.
Secondly, in terms of China's medical insurance policy, the National Healthcare Security Administration has been carrying out the adjustment of the national medical insurance drug catalog for six consecutive years since its establishment. According to statistics, the average price reduction of drugs for various diseases included in China's medical insurance negotiations has exceeded 50%. Since 2021, many anti infective drugs including hepatitis B treatment drugs have been included in the medical insurance. At the same time, the national medical insurance also provides special support for innovative drugs. The products of this project belong to the targeted drug category of innovative drugs, and once put into the market, they are highly likely to be included in medical insurance. The increase in sales brought about by medical insurance reimbursement may provide a good buffer for our therapy in terms of treatment costs, thus enabling better promotion in the future.
In December 2023, the US Food and Drug Administration (FDA) officially approved the marketing of Casgevy and Lyfgenia therapies. These two cell-based gene therapies for the treatment of sickle cell anemia (SCD) have milestone significance. In 2024, Intellia Therapeutics successfully completed the clinical concept validation of the NTLA-2001 system based on CRISPR-Cas9. This complete in vivo gene editing therapy has fully validated the technical feasibility of in vivo gene editing therapy for diseases. These cases can demonstrate that major governments around the world have begun to accept gene editing therapies entering the market.
According to the estimation of the World Health Organization, about 254 million people worldwide are infected with hepatitis B. According to the research forecast in 2023, the global hepatitis B treatment market will be valued at 9.4 billion US dollars in 2022, and is expected to grow at a compound annual growth rate of 7.2% during the forecast period from 2023 to 2031, reaching a valuation of 22.1 billion US dollars by 2031. The development and expansion of hepatitis B treatment market reflects the growing development space for the urgent treatment of hepatitis B patients worldwide and high-tech treatment means.
What about the gene editing market? In 2021, the global gene editing market size is 6.11 billion US dollars, and it is expected to have a compound annual growth rate of 17.5% in revenue during the forecast period. The increase in genomics applications and rapid advancements in sequencing and genome editing technologies have become the main factors driving market revenue growth. In terms of regional distribution, North America is currently the largest gene editing therapy market, occupying a significant share of the global market, and Europe is also an important market. The Asia Pacific region is expected to be the fastest-growing market. The booming development of the gene editing market supports the enrichment of gene editing tool libraries and the promotion of gene editing applications. Gene editing therapy is expected to win more public acceptance and development opportunities with this wave.
Although there have been successful examples of CRISPR-Cas9 in treating hepatitis B and other diseases in the scientific community [2-3], because of the uniqueness of gene editing therapy, there is no competitive product in the market that uses similar gene editing therapy to treat hepatitis B. Besides, our project utilizes modified CRISPR/Cas nucleases, which also have their own advantages in terms of therapeutic safety. Our main focus is on individuals with healing needs, which means we won’t directly compete with traditional low-cost drugs. Therefore, our therapy will enter a Blue Ocean Market.
On the basis of the current high-precision MAD7 nuclease, we will continue to utilize research and development funds to design, modify, and produce high-precision CRISPR nuclease mutations, further improving the effectiveness of treatment. We will explore the possibility of gene editing system in vivo delivery using different delivery systems and find the optimal method for achieving efficient targeted delivery. At the same time, simplifying the treatment process and reducing side effects can improve patient compliance and overall attractiveness of the therapy, enhance the stickiness and market position of the treatment, and occupy market share.
This project focuses on high-precision gene editing therapy for hepatitis B. However, similar technology lines and even mutation sites can provide technical reserves for the treatment of similar genetic diseases and gene mutation diseases. By applying the experience of this project, the rapid development of gene editing therapy can be achieved through the design and construction of specific targets and high-precision CRISPR nucleases.
Given the high cost for in vivo gene editing therapy to enter the market, a tiered pricing strategy can be initially adopted to provide different pricing and treatment options for customers with different payment capabilities. In addition, we prefer cooperating with medical insurance related institutions and companies to include therapies in insurance coverage and medical insurance reimbursement, in order to broaden the audience, increase patients' willingness to pay, and improve the market acceptance of therapies. After all, the key to reducing the market price of therapy is to gain the recognition and acceptance of the majority of hepatitis B patients.
Due to the particularity and high-tech requirements of in vivo gene editing therapy, it should mainly be promoted and sold by professional medical institutions. Medical institutions, as discoverers and testers of medical conditions, are the most authoritative institutions in designing treatment plans for patients. The entire process of product delivery should be carried out in medical institutions, and the implementation of treatment plans also relies on the provision of combination therapy drugs by medical institutions. Medical institutions undertake important tasks such as treatment plan design, product performance monitoring, and auxiliary drug supply. Therefore, cooperation should be established with the liver disease or infectious disease departments of large hospitals, so that we can establish a smooth communication and exchange mechanism. The product needs to be recommended by professional doctors to increase the credibility and acceptance of the therapy, and to achieve the best therapeutic effect with the intervention of professional medical institutions.
Due to the progressiveness nature of the therapy, apart from the promotion of the above hospitals and other authoritative institutions, science popularization is essential for product promotion. We utilize digital tools and platforms, such as professional medical websites, traditional social media, and self media platforms such as Tiktok, YouTube, X, and Facebook, to promote science popularization and education online. This can help cover a wider range of potential customer groups and provide immediate interaction and feedback, bridging the gap between therapy and patients, while also serving as a promotional channel to broaden the visibility and influence of therapy. Of course, patients' awareness of hepatitis B cure can also be improved by establishing patient education plans, seminars, online education platforms and other ways. Patient support services, such as treatment management plans, psychological support can be utilized to improve patient compliance and satisfaction.
Of course, we should also cooperate with the government health department, participate in public health projects, promote public health education, and improve the social awareness of hepatitis B treatment.
We mainly focus on the patient population pursuing curative effects, especially those who cannot meet the needs of current treatment plans. We will build our own production line for product manufacturing, achieve systematic treatment through cooperation with hospitals, complete the delivery of treatment methods in patients' bodies, and establish direct channels between products and patients. In the future, we may provide personalized hepatitis B treatment according to the needs of the target 1 household, or provide relevant technical training for the scientific research team [other iGEM teams].
At present, the main costs of the product are research and development expenses and clinical trials, with a relatively low proportion of production costs and equipment costs. Based on the current state of the technology market mentioned earlier, a valuation of 100000 yuan for this product is more appropriate. In the future, if in vivo gene editing therapy is widely recognized in the hepatitis B treatment market, the average production cost will be further reduced.
In the initial stage, our plan is to first promote our products and therapies to first tier cities in China. These areas have abundant medical resources, high patient acceptance of new therapies, and strong payment capabilities. Meanwhile, the medical networks and distribution channels in these regions are relatively mature, which is conducive to the rapid promotion and sales of products. Of course, we will also launch in the medical and economic development zones of developed countries simultaneously. Patients in these regions have a high demand for innovative medical technologies, and the medical security system is relatively complete, which helps to promote market acceptance and insurance coverage of our products.
In the medium term, with the deepening of product research and development and the reduction of costs, the product will be pushed to sub-developed regions. There may be a significant unmet medical need in these regions, and the prices of the cost reduced product may be more in line with the payment levels in these areas. At the same time, we will further explore cooperation with international pharmaceutical companies or distributors, and through their networks and resources, enhance the internationalization process of our products.
In the long run, we will actively explore the possibility of policy and medical insurance cooperation, communicate with government medical insurance departments, strive to include therapies in the national medical insurance catalog, reduce the economic burden on patients, and improve the market acceptance of therapies. At the same time, we plan to conduct comprehensive clinical research, collect efficacy and safety data, and provide support for market promotion and medical insurance negotiations.
Due to the innovation of in vivo gene editing therapy, it is inevitable that there will be social recognition, acceptance, and practical operational risks when it enters the market, which may come from every participant involved in the implementation of the therapy. This risk may manifest as:
(1) Due to the high cost and technical difficulty of the therapy, as well as limited public awareness of professional knowledge such as synthetic biology and gene editing technology, patients may have doubts about the effectiveness, safety, and treatment process of the new therapy.
(2) The use of high-precision MAD7 nucleases obtained from the project for in vivo gene editing has unavoidable safety and ethical issues, and there are unpredictable policy acceptance risks during the project's market launch process;
(3) Doctors and other medical professionals may hold a conservative attitude towards new therapies, especially if medical personnel lack sufficient understanding of the efficacy and safety of the therapy, or if they lack experience related to our therapy in clinical practice, then this therapy is likely to have acceptance barriers.
Therefore, we plan to mitigate this risk from the following aspects:
(1) Enhance patients' and medical professionals' understanding of therapy through educational activities. This may include professional seminars, patient education conferences, online educational resources, and continuing medical education courses.
(2) Collect strong efficacy and safety data through clinical trials and real-world research, including publicly available data from our research and development process, and make this data available to our partners and clients to support the marketing of therapies.
(3) Adopt flexible pricing strategies, such as patient assistance programs and installment payment options, to improve the accessibility of therapies.
(4) Actively communicate with medical insurance institutions, strive to include therapies in insurance coverage, and reduce the economic burden on patients.
When promoting hepatitis B therapy in different countries and regions, enterprises may face diversified market environments and regulatory requirements, which constitute the main part of internationalization risks. There are significant differences in the approval process, registration requirements, clinical trial standards, and market access mechanisms for drugs among regulatory agencies in various countries. For example, drug regulations vary in Southeast Asia, and the drug regulatory agencies and review cycles in ASEAN countries also differ. Therefore, we need to further control these risks.
(1) Before entering a certain market, it is important to have a deep understanding of the laws and regulations of the target market, conduct detailed market research, understand the laws and regulations, cultural customs, and market preferences of the target market, in order to develop strategies that are suitable for the local market.
(2) Adjust the organizational structure, implement a business unit-based planning approach, build teams tailored to different markets, adapt to local development needs, and formulate product strategies that align with regional characteristics, encompassing localized products, marketing materials, website content, and customer services, in order to cater to the demands and preferences of the local market.
(3) Adapt to the changes in the international market through a talent recruitment mechanism, recruit and cultivate talents with international perspectives and local market experience, in order to better understand and respond to the challenges of the local market.
[1] World Health Organization, Global hepatitis report 2024: action for access in low- and middle-income countries
[2] Kostyushev D, Kostyusheva A, Brezgin S, et al. Depleting hepatitis B virus relaxed circular DNA is necessary for resolution of infection by CRISPR/Cas9[J]. Molecular Therapy - Nucleic Acids, 2023, 31(17):482-493.
[3] Gillmore J D, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis[J]. N Engl J Med., 2021, 385(6):493-502.