The most expensive medicine is coming! The price is 1908 million yuan! China enterprises are also developing gene therapy for thalassemia.

Recently, the US Food and Drug Administration (FDA) approved the Zynteglo gene therapy of BLUE (stock price: 5.8 1 USD, market value: 448 million USD).

The price of Zynteglo in the United States is as high as US$ 2.8 million (about RMB 654.38+09.08 million), which exceeds the price of Zolgensma, a gene therapy for spinal muscular atrophy of Novartis (NVS, share price of US$ 84.92, market value of US$ 654.38+085.362 billion) and becomes "the most expensive drug in history".

This therapy is a one-time gene therapy, also known as "beti-cel", which is used to treat all β thalassemia genotypes that need regular blood transfusion. This is the first time that FDA has approved gene therapy for patients with β -thalassemia. Bloomberg said that for such patients, this therapy "changed the rules of the game." Prior to this, the only available treatment for this disease was bone marrow transplantation from relatives of patients.

Bluebird was born in the wave of gene therapy. Once, as the darling of biotechnology, Wall Street investors flocked to it, but now, it has fallen to the edge of capital exhaustion.

Stimulated by the news that Zynteglo was approved for listing, Bluebird Bio's share price rose by 24% on August 17, local time, and rose by 17% before the market closed the next day, but closed at 14.3 1%, closing at $5.865438 +0. As of the close of 19, the share price rebounded slightly, rising 2.75% to close at $5.97.

Now, with this "most expensive medicine in history", can Bluebird take off again?

"Changing the rules of the game"

In June this year, the FDA advisory panel unanimously voted to approve the listing of Zynteglo, saying that the advantages of this treatment outweigh the disadvantages. According to the FDA, in later trials, 89% of patients who received Zynteglo gene therapy did not need blood transfusion, and there were no obvious safety problems.

AlexisThompson, head of hematology at Philadelphia Children's Hospital, said that although gene therapy is not effective for everyone, the lives of most patients have changed dramatically. The Philadelphia Children's Hospital used this therapy in clinical trials. Thompson revealed that before that, patients with β -thalassemia who needed blood transfusion had to stay in the hospital for 4-6 hours every 2-4 weeks, and sometimes even needed to stay overnight.

It is reported that β -thalassemia is one of the most common single gene diseases. Due to the mutation of the gene encoding β-globin, the patient's hemoglobin level decreased significantly, or even disappeared. In order to survive, patients have to receive blood transfusion treatment for life. Although blood transfusion can temporarily relieve symptoms related to severe anemia, including fatigue, weakness and shortness of breath, it can not cure symptoms, and may cause serious complications such as iron overload and multiple organ damage.

In the past decade, the average age of death of patients with transfusion-dependent β thalassemia in the United States was 37 years old.

Zynteglo belongs to one-time gene therapy, which introduces β -globin gene into patients' own hematopoietic stem cells through lentiviral vectors, produces normal hemoglobin, and restores red blood cell function, thus significantly reducing patients' blood transfusion needs. Ideally, patients don't even need blood transfusion.

According to Bloomberg News, this therapy "changes the rules of the game" for patients with β -thalassemia who need regular blood transfusion most of the time.

However, the US Food and Drug Administration also pointed out that this treatment has the potential risk of causing blood tumors. Although no cases were found in the study of ZNTEGLO, patients receiving ZNTEGLO treatment should have their blood monitored for at least 65,438+05 years. During taking Zynteglo, patients should also be monitored for allergies, thrombocytopenia and bleeding.

The most expensive in history

If there is no curative effect, 80% of the expenses can be reimbursed.

It is reported that in the United States, according to the current nursing standards, the lifelong medical expenses of patients with blood transfusion-dependent β thalassemia are as high as 6.4 million US dollars, and the average annual medical expenses of each patient are 23 times that of the general population. According to estimates by Bluebird Biology, about 1300~ 1500 people in the United States suffer from β -thalassemia.

The price of Zynteglo in the United States is US$ 2.8 million, but when it was approved to be listed in the European Union in May 2065438+2009, the price of this therapy was 6.5438+0.575 million euros (about US$ 6.5438+0.8 million at the exchange rate at that time). Although the price in the European Union at that time was much cheaper than now, the commercialization of Zynteglo in Europe also faced many obstacles. In April, 20021,due to the failure to reach a price agreement with the German government, Bluebird decided to temporarily withdraw gene therapy Zynteglo from the German market, and then the company gradually withdrew from the European market.

Regarding the pricing of Zynteglo in the US market, FDA believes that its price is within the range of cost performance considered by the independent review team.

According to reports, the payment model introduced by Bluebird Bio in the United States is a one-time advance payment plus up to 80% risk sharing. If the patient fails to maintain the blood transfusion exemption within two years after blood transfusion, the patient or commercial institutions such as insurance will receive 80% reimbursement.

Bluebird Bio said that about 70%-75% of patients with β -thalassemia who rely on blood transfusion in the United States enjoy commercial insurance. The company is in the late stage of negotiations with major commercial organizations, including drug welfare management agencies, and is also cooperating with some state Medicaid agencies.

Zynteglo will be officially listed in the United States in the fourth quarter of this year. As it takes 70 to 90 days to collect cells for intravenous injection, it is expected that the formal treatment will begin in the first quarter of 2023.

Bluebird creatures are expected to be "reborn"

In 1970s, the concept of gene therapy was first put forward. In the 1990s, clinical trials of gene therapy in the United States were in full swing. From 65438 to 0995, the first successful clinical case of gene therapy appeared in the United States, and gene therapy began to attract much attention.

Bluebird was born in this wave. 1992, two researchers from Massachusetts Institute of Technology founded GenetixPharmaceuticals, the predecessor of Bluebird.

In the following decades, the development of gene technology gradually matured, and biotechnology companies were increasingly favored by the capital market. Bluebird pursued the victory and landed on Nasdaq on 20 13. The pre-listing price was $ 17 per share, which rose by 50% on the day of listing, approaching $26 per share. By 20 18, the company's share price rushed to the highest point-231USD/share, while Bluebird Bio had not officially launched its products at that time.

It was not until 20 19 that Zynteglo, the gene therapy of Bluebird, was conditionally listed in the European Union, but it withdrew from the region in 20021year after a major setback. Subsequently, Skysona, another gene therapy for cerebral adrenal leukodystrophy, also withdrew from the European market.

It never rains but it pours. In May, 2020, the CAR-T therapy bb2 12 1 jointly developed by Bluebird Bio and BMS for patients with refractory multiple myeloma was delayed by FDA due to insufficient data. In June of the same year 165438+ 10, the application for the marketing of gene therapy for sickle cell anemia (SCD)-soybean protein was also delayed for a whole year.

After many setbacks, Bluebird began to decline, and its share price also went down all the way. As of Thursday's US stock market close, its share price plunged 97.5% from the peak of 20 18.

The reporter checked the financial reports of Bluebird Bio in recent years and found that the company's net losses reached 790 million US dollars, 620 million US dollars and 820 million US dollars in 20 19, 2020 and 20021year respectively. Bluebird Bio's 20021financial report shows that the company has only about $442 million in available cash and related current assets.

Zynteglo's approval in the United States may help revive Bluebird's business. MarcEngelsgjerd, an analyst at Bloomberg, wrote in a report that "after the failure of Europe and the delay of US regulation, licenses provide a way to earn considerable income".

According to the financial report of Bluebird Bio-202 1, the three gene therapies of Bluebird Bio-Znteglo, Skysona and LentiGlobin will all reach a new milestone, which is expected to bring new revenue growth. At present, Zynteglo has taken an important step to the market. The company believes that Skysona is also expected to be approved and given priority review in 2022, and LentiGlobin is expected to submit a license application in the first quarter of next year.

China enterprises are also developing gene therapy for thalassemia.

β -thalassemia is common all over the world. Similarly, in China, the number of thalassemia patients is increasing.

According to the data of "Blue Book of Thalassemia in China (2020)" released in May of 20021year, there are about 345 million people with thalassemia gene in the world, while there are about 30 million people with thalassemia gene in China, and there are about 300,000 patients with moderate and severe thalassemia, which is increasing at the rate of about 10% every year.

Due to the limited blood resources and the high cost of iron chelating agent, only a part of thalassemia patients in China can maintain standardized blood transfusion and standardized iron removal treatment, and the survival rate of thalassemia patients is significantly lower than that of developed countries.

At present, domestic enterprises are also developing gene therapy for thalassemia.

According to the First Financial Report, on August 16 this year, Shanghai Bangyao Biotechnology Co., Ltd. (hereinafter referred to as "Bangyao Bio") announced that its clinical trial application for the gene therapy product "BRL-1kloc-0/autologous hematopoietic stem cell injection" for blood transfusion-dependent β -thalassemia was approved by the US Food and Drug Administration in China on the same day.

Although BRL- 10 1 of Bangyao Bio and Zynteglo of Bluebird Bio belong to gene therapy products, they are still different. The former belongs to gene editing therapy products, and the latter belongs to lentivirus gene therapy products.

Bangyao Bio said that in the traditional treatment of thalassemia, hematopoietic stem cell transplantation is the only way to cure β -thalassemia, but it is expensive and difficult to match. Only a small number of patients can receive transplantation. If autologous hematopoietic stem cells can be genetically modified and returned to patients, the problems of insufficient source and difficult matching of hematopoietic stem cells can be solved, and the progress of CRISPR gene editing technology provides the possibility for this treatment strategy. BRL- 10 1 is a gene therapy product developed based on the hematopoietic stem cell platform independently developed by the company. The platform mainly uses the gene editing system to transform the patient's hematopoietic stem cells, and the transformed hematopoietic stem cells return to the patient's body through self-renewal and differentiation reconstruction to transform the cell population, so as to achieve the purpose of treating blood system diseases.

Bangyao Bio also said that compared with other gene therapies for β-thalassemia, the company's hematopoietic stem cell gene therapy is more efficient, convenient and safe, with the advantages of good targeting, high safety, wide range of action and remarkable therapeutic effect. It can be cured once for life, and the cost can be greatly reduced, which is expected to become a treatment that benefits the public.

Before BRL- 10 1 of Bangyao Bio announced its clinical approval, in 20021,Boya Yin Ji's research product ET-0 1 was also approved for clinical trial in China. Similarly, ET-0 1 also belongs to gene editing therapy products.