Huang Ying, CEO of Legendary Biology: Solving the Difficulty of Commercialization of Million CAR-T Therapy

Source of this article: Times Finance Author: Li AohuaDr. Huang Ying, CEO of Legendary Biology

Source of this article: Times Finance Author: Li Aohua

Dr. Huang Ying, CEO of Legendary Biology. Image source: Provided by respondents

On May 10th every year, American girl Emily Whitehead posts a photo on social media to celebrate her healthy year. She is the first child patient with acute lymphoblastic leukemia (ALL) in the world to receive CAR-T Cell therapy, and this year is her 11th year of cancer free survival.

Emily's success story of anti-cancer has become the best endorsement of CAR-T Cell therapy's "one shot elimination of cancer cells".

Since Fred Hutchison Cancer Research Institute first used CAR-T cells to treat B-cell lymphoma in 2008, which has proved the safety of this method, the development of CAR-T Cell therapy has only been 15 years. In the past 15 years, CAR-T Cell therapy has a strong development momentum. It has repeatedly made major breakthroughs in clinical application, and has become the most shining star in the field of cell and gene therapy (CGT).

In 2017, Swiss pharmaceutical giant Novartis Kymriah was approved by the Food and Drug Administration (FDA), becoming the world's first CAR-T Cell therapy. Up to now, 9 CAR-T Cell therapy have been approved worldwide. Among them, Cita cel, independently developed by LEGN. US, has attracted much attention due to its halo of "China's first FDA approved cell therapy product".

Although CAR-T Cell therapy has significant advantages and broad application prospects, its commercialization still faces great challenges. So far, a real "blockbuster" has not yet been born in the global CAR-T Cell therapy field. Due to such factors as large R&D investment, high production costs, limited capacity, and limited scope of indications, the treatment cost of CAR-T Cell therapy remains high, and its accessibility and affordability are still the biggest factors restricting development.

Under multiple pressures, Legendary Biology, which has repeatedly made breakthroughs in clinical research and successfully achieved the first product approved for release abroad, has become a focus of market attention on whether it can create a "legend" in commercialization.

On the breakthrough of CAR-T commercialization, Time Finance exclusively interviewed Dr. Huang Ying, CEO of Legend Biotech. During the interview, "differentiation" and "innovation" were the keywords that Huang Ying constantly mentioned. In his opinion, the ultimate core of a drug is its efficacy, that is, whether it is truly beneficial to patients. For advanced cancer patients, their only demand is to extend their survival time. In this regard, as of now, Sidaki Orense has demonstrated the best clinical data in its class, which is the biggest advantage of Legendary Biology and a prerequisite for successful commercialization.

FIC (First in class) and BIC (Best in class) have always been the principles of Legendary Bio's research and development work. Despite the high risks and long cycles, we are still willing to take risks and spend time and energy doing things that others have not done before, hoping to create differentiated products. Without differentiation, products will not be competitive in the market, "said Huang Ying.

Adventure Journey from Zero to One

In the development history of CAR-T cell therapy in China, legendary biology is an inseparable name. It was incubated by GenScript Biotech (01548. HK). At the beginning of its establishment in 2014, Legendary Biology could almost be described as "having nothing" - no startup funds, no intellectual property rights, even experimental equipment and office space were provided by Jinsrui, and only a research and development team with less than 10 people.

For legendary creatures, the original adventure of choosing a new target, BCMA, to cut into CAR-T track is the beginning of all glory, and the real Moat also comes from the moment of daring to take risks.

The stronger the wind and waves, the more expensive the fish. Although setting new targets significantly increases the risk of clinical failure, the outcome of this risky decision is clearly extremely correct.

At the annual meeting of the American Society of Clinical Oncology (ASCO) in 2017, legendary biology's CAR-T product Sidakiolen Sap surprised four audiences when it appeared. The early clinical data released at that time showed an objective response rate of nearly 100%, and such excellent data immediately attracted global attention. The multinational pharmaceutical giant Johnson&Johnson (JNJ.US) immediately threw an olive branch at Legendary Biology.

In December 2017, Legendary Biology reached a partnership with Johnson&Johnson's subsidiary, Janssen Company, to jointly develop and commercialize the Western Dakota Olympia. Huang Ying told Times Finance that through cooperation with Johnson&Johnson and Yang Sen, Legendary Biology has strengthened its clinical development, GMP (Good Manufacturing Practice) production and supervision, as well as its ability to apply for registration.

This is a win-win cooperation. Prior to this, we may have strong early research and development capabilities, but there are still shortcomings in later development, clinical practice, production, registration, and other aspects. In this process, Yang Sen gave us great assistance, "Huang Ying said.

Image source: Tuchong Creative

Since then, Legendary Biology has gradually become a benchmark player of domestic CAR-T Cell therapy. With the help of Johnson&Johnson, Sidakiolense has been awarded the qualification of Orphan drug, breakthrough therapy and priority review by the US FDA, and became the first "breakthrough Sex therapy variety" awarded by the Drug Evaluation Center (CDE) of the National Medical Products Administration of China in August 2020.

At the end of February 2022, Sidaki Orense was approved by the US FDA for market launch, becoming a milestone event for China's innovative drug "going global". Subsequently, it obtained a conditional listing permit from the European Union in May and was approved for listing in Japan in September, rapidly advancing commercialization.

According to financial report data, the sales revenue of Sidaki Orense in 2022 was approximately $134 million (equivalent to approximately RMB 924 million), and the sales revenue in the first quarter of 2023 was $72 million (equivalent to approximately RMB 500 million). Based on this calculation, the actual sales of Sidaki Orense have reached 206 million US dollars (equivalent to approximately RMB 1.424 billion) since its listing one year ago.

At present, this adventure is about to reach a new milestone.

In January 2023, according to the information from the Drug Evaluation Center of the State Food and Drug Administration, Sidakiorenza was included in the priority review and approval process. During the ASCO in June, Legendary Biology released the latest phase 3 clinical study data for the Western Dakota Olympia. The results showed that, at a median follow-up of 16 months, compared to the standard treatment regimen (SOC), cedakiolense reduced the risk of disease progression or death by 74% in adult patients with multiple osteomas who had previously received line 1-3 treatment and were resistant to lenalidomide.

This data means that Sidakiolense is expected to become a BIC product in the treatment of Multiple myeloma (MM), bringing new treatment hope to MM patients.

Self production of virus vectors, breaking through production capacity limitations

The full name of CAR-T is ChimericAntigenReceptorT-CellImmunotherapy, which refers to the use of genetic engineering technology to extract T cells from patients and transfer a virus containing a chimeric antigen receptor that recognizes tumors and activates T cells into T cells through a vector. The virus is then transformed into CAR-T cells, which are then amplified and reintroduced into the patient's body, Effectively and quickly identify and accurately kill diseased cells, thereby achieving the goal of treating diseases and restoring patients' health.

From the therapeutic principle of CAR-T Cell therapy, it is easy to see that autogenous CAR-T Cell therapy is a highly personalized customized therapy. Since each product comes from the patient's own T cells, its development, production and use are very complex, and its manufacturing and delivery require precision and speed, which requires a large amount of resources to achieve continuous and standardized production under the conditions of compliance with GMP, Each batch requires strict quality testing. Therefore, facing the widespread clinical needs of patients, how to break through the limitations of personalized customization and achieve large-scale mass production is an urgent threshold for cell therapy products to break through.

Huang Ying admitted to Times Finance that due to the inability to produce on a large scale, over the past year, the supply of West Dakota Olympia has exceeded demand in overseas markets. He analyzed and pointed out that one of the important reasons for the production capacity dilemma of CAR-T is the shortage of lentivirus vectors.

In CAR-T therapy, lentiviral vectors mainly play a role in introducing CAR constructs into patient T cells. Viral vectors are the mainstream carriers in clinical trials of cell and gene therapy. Data shows that over two-thirds of clinical trials currently use viruses as carriers. With the recent outbreak of cell and gene therapy, a large number of therapies have entered the clinical or commercial stage, and the market demand for lentivirus vectors has also increased, leading to frequent supply shortages.

Huang Ying pointed out that most pharmaceutical companies do not produce carriers internally, but rely on third-party suppliers, such as Lonza in Switzerland, ThermoFisher in the United States, and WuXi AppTec (603259.SH, 02359. HK) in China. However, in the past two or three years, COVID-19 vaccine manufacturing has occupied a large amount of production capacity, which is one of the reasons for the shortage of lentiviral vectors.

In addition, the US FDA has strict regulations on the production of CAR-T products, and increasing production capacity is a gradual process.

In order to solve the supply problem of lentivirus vectors, Legendary Biology and Johnson&Johnson have decided to produce virus vectors themselves. In October 2022, Legendary Biology and Johnson&Johnson announced an additional investment of $500 million in their factory located in New Jersey, USA. The production capacity of this factory and another Belgian factory is expected to meet production demand with peak sales exceeding $5 billion.

In April 2023, Legend Biotech announced that it had signed agreements with Johnson&Johnson and Novartis for the transfer of CAR-T product technology, production, and clinical supply services, continuing to increase CAR-T production. According to the agreement, Legendary Biology and Johnson&Johnson will initiate necessary technology transfer activities with Novartis in order for Novartis to execute the production process of the Sidaki Orense.

We have done a lot of work in the past year and expect to make significant improvements in the second half of this year. We have decided to no longer use third-party virus vectors, but instead use all slow virus vectors produced by Johnson&Johnson. We believe that in the near future, the supply of virus vectors can be completely solved, "Huang Ying told Times Finance.

Exploring diversified payment+cost reduction and efficiency enhancement, improving drug accessibility

The characteristic of highly personalized customization determines that self owned CAR-T products cannot achieve large-scale production, which brings another challenge that products are difficult to reduce costs by expanding production. In addition, due to the high investment in research and development and the difficulty in controlling manufacturing costs, the selling price of this type of product remains high, and the payment problem has not been effectively solved.

At present, Sidakiolense is priced at US $465000 per needle in the United States, and other CAR-T Cell therapy that has been approved for listing are priced at more than 2 million per needle in the US market. The two CAR-T products that have already been launched in China have a selling price of over 1.2 million yuan per injection and are not included in the national medical insurance. This price is an insurmountable obstacle for ordinary patients.

In the situation where medical insurance payments cannot be covered in the short term, CAR-T products urgently need to expand innovative payment models. At present, in addition to medical insurance, pharmaceutical companies and people from all walks of life are actively exploring more diverse payment methods, including commercial insurance, special assistance, patient organization assistance, etc., to increase patients' access to medication.

Huang Ying pointed out that solving the payment problem of CAR-T requires the joint efforts of production, hospitals, commercial insurance, and national medical insurance. We hope that the domestic commercial insurance market can mature and provide payment space for slightly higher priced but clinically effective anticancer drugs. At the same time, we are also strengthening cooperation with government and local insurance and commercial insurance in different countries, exploring the possibility of reducing patient payment efforts to benefit more patients, "Huang Ying told Times Finance.

The high selling price of millions of yuan has reduced patients' access to innovative drugs and raised questions about the commercialization prospects of products. What measures should pharmaceutical companies take to provide drugs to more patients? This is undoubtedly a huge challenge, and reducing costs and increasing efficiency is one of the means to address it.

"CAR-T's main cost reduction measures include finding alternative raw materials, improving the automation of production processes, and studying allogeneic universal CAR-T Cell therapy. These measures need time to accumulate and research and development to finally realize the price reduction of products." Huang Ying concluded.

Image source: Tuchong Creative

The raw materials for CAR-T products include cell culture media, virus vectors, lipid particles, etc. Currently, most of these raw materials need to be imported from the United States or Europe. If domestic substitution of raw materials and production equipment can be achieved, costs can be reduced to a certain extent. Secondly, CAR-T products have high labor and transportation costs, which can be reduced by improving the automation of the production process.

In addition to relying solely on reducing the cost of labor and raw materials, the most important path to cost reduction and efficiency improvement is still technological innovation. The allogeneic universal CAR-T technology developed on the basis of current autologous CAR-T products is one of them.

The production process of allogeneic universal CAR-T products is similar to that of autologous CAR-T products, except that the donor of T cells has changed from a patient to a screened healthy donor. After the production of autologous CAR-T products is completed, they can only be returned to the patient themselves, while the production of allogeneic universal CAR-T products can produce hundreds or even thousands of CAR-T drugs at once, which can be frozen and used at any time, and can be returned to hundreds or thousands of patients, greatly reducing production costs.

Huang Ying told Time Finance that at present, a large part of R&D resources of Legendary Biology are inclined to allogeneic universal CAR-T Cell therapy. It is understood that Legendary Biology has three universal Cell therapy under development, including two targeted BCMA therapies for Multiple myeloma and one targeted CLL1/CD33 therapy for acute myeloid leukemia, which have entered the phase I clinical stage.

Expanding the population and advancing towards the frontline and solid tumors

Generally speaking, first-line drugs are the first choice for clinical treatment, and after the treatment effect is difficult to maintain or poor (with disease progression), second line and third line drugs are sequentially chosen as alternative treatments. At present, Legendary Creatures is actively promoting the use of Sidakiolense for frontline treatment.

Based on the excellent data of the Phase III clinical study of Sidakiolense, Legendary Biology has submitted applications to the US FDA and the European Medicines Agency (EMA) to expand the indications of Sidakiolense for the treatment of adult Multiple myeloma patients who have received at least one treatment in the past (including a Proteasome inhibitor and an immunomodulator) and who have relapsed and are resistant to lenalidomide.

Once approved, the target audience for this drug will further expand, undoubtedly increasing the sales revenue of the drug.

In addition, although CAR-T Cell therapy has made breakthrough progress in the treatment of hematomas, most of the published cases of CAR-T treatment of solid tumors are still in the early clinical stage, with a small sample size and limited clinical efficacy. The number of solid tumor cases accounts for about 90% of all tumors, and the unmet medical needs are enormous.

At present, Legendary Biology is conducting clinical research on solid tumors such as gastric cancer, esophageal cancer, pancreatic cancer and hepatocellular carcinoma, which is still in the phase 1 clinical trial stage.

Although the overall investment pace in healthcare is slowing down and many investment institutions are holding onto the sidelines, with record breaking clinical data and forward-looking research and development layout, Legendary Biology stands out in the capital market and has successively gained the favor of top investment institutions.

In April of this year, the data of the Phase III CARTITUDE-4 clinical trial of Sidakiolense showed that the efficacy of Sidakiolense in patients with Multiple myeloma was far higher than expected, which could reduce the risk of disease progression or death by 74%. This news instantly ignited the sentiment in the capital market, and the stock price of Legendary Biology skyrocketed, with a total market value quickly exceeding the $10 billion mark. Afterwards, the stock price of Legendary Biology continued to climb and reached a historic high of $75.45 per share on June 22 during the trading session. On July 3rd local time, the US stock market closed at $68.86 per share, with a total market value of over $12 billion.

Legendary Biology also raised over $700 million in just two months. On April 19th, Legend Biotech received $200 million in investment from overseas renowned venture capital RACapital; On May 2nd, Hillhouse Capital purchased $12.7 million in shares of Legendary Biology; On May 6th, Legendary Biology signed a subscription agreement with T. RowePrice, under which investors would purchase $350 million in company stock at a price of $64 per American depositary stock; On May 19th, Hillhouse Capital invested again and purchased $22.2 million in the company's stock.

What new legends will Legendary Creatures create after successfully completing a new round of financing? The following story is worth looking forward to.

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