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“Big Pharmaceuticals” has been committed to producing a wide range of innovative drugs for many years. For them, gene therapy may be the place to give birth to the next “miracle.” Gene therapy, as its name implies, is a treatment that replaces defective genes with normal genes and has become a potential treatment for hundreds of hereditary diseases, such as hemophilia and muscular dystrophy.

Sequence-specific nuclease technology represented by ZFN (zinc finger endonuclease) and TALEN (like transcription activator effector nuclease) enables efficient site-based genome editing, including gene research, gene therapy, and genetic improvement. The aspect shows great potential. CRISPR/Cas9 is the third generation of “genomic fixed-point editing technology” that emerged after these two technologies. Whether it is excitement or fear, almost everyone expects to see the miracle of gene therapy curing a series of diseases, and multinational pharmaceutical companies are naturally reluctant to miss the field.




How do multinational pharmaceutical companies lay out gene therapy?


In view of the huge application potential and broad commercial market, multinational giants compete in the field of gene therapy.

On March 8, Roche announced the acquisition of Spark Therapeutics, a gene therapy manufacturer for rare eye and hemophilia, for $114.50 per share ($4.8 billion, 122% premium). On March 11, Biogen also announced that it will acquire Nightstar Therapeutics, a London-based gene therapy company, for approximately $800 million. On March 25, Thermo Fisher announced the acquisition of Brammer Bio, a leader in viral vector manufacturing focused on gene and cell therapy, for approximately $1.7 billion in cash.

If traced back, Novartis also acquired AveXis, a manufacturer of spinal muscular atrophy (SMA) gene therapy, for $218 per share (a total of $8.7 billion, a premium of 88%) in April 2018.

In addition to “buy and buy”, another way for multinational pharmaceutical companies to lay out gene therapy is to reach a “development or commercialization” cooperation agreement with genetic editing. For example, on March 21, Pfizer announced that it would pay a $51 million down payment (up to a total of $630 million in cooperation) with the French gene therapy company Vivet. In February of this year, Merck of Germany reached an exclusive R&D license agreement with Vertex in order to further promote drug development based on gene editing. The former introduced two compounds from Vertex for $230 million in 2017. The latest agreement is to increase the development rights of the two compounds, but the specific price has not been disclosed.

Novartis has reached an agreement with Spark to launch Luxturna in the European market, which is priced at approximately $850,000/year in the United States and $27 million in revenue in 2018. Novartis’s one-time gene therapy, Zolgensma, from AveXis is expected to be approved in 2019, and the product has been submitted to the US FDA and EU EMA for review. Novartis has said on the 2019JP Morgan that Zolgensma’s pricing is expected to be around $4 million, which is probably the most expensive treatment in history.

Although the pricing of gene therapy is expensive, its commercial potential is enormous. The data show that there are currently more than 5,000 rare diseases in the world caused by single gene mutations, so that targeted treatment of targeted “genes” can be performed. Analysts predict that despite the limited number of patients with individual diseases, many treatments are likely to generate sales of $1 billion or more due to their high pricing.

Some investors said, “Although the science related to gene editing has been researched for decades, large-scale investment in gene therapy is the wave that began in the past two years. Large pharmaceutical companies are waking up and believe that gene therapy is a The real technology, the patient needs to be there.”



Which gene therapies are progressing faster?


Although multinational pharmaceutical companies have seen the potential of gene editing and treatment, there are still a handful of companies in this field. Things are rare, which may be another reason for large pharmaceutical companies to buy at a high premium. The following is a list of biotech companies that have progressed rapidly in the field of gene therapy.

uniQure, based in Amsterdam, the Netherlands, has been developing gene therapy since the end of the last century, mainly around the study of adeno-associated virus (AAV). The company’s Glybera, which was launched in 2012, is the first gene therapy drug approved in Europe and the United States. It was also criticized for its $1 million price, a genetic drug for the treatment of lipoprotein lipase deficiency genetic disease (LPLD). Some media have reported that the drug was only used once in four years.

Although the first product has been smashed in the market, uniQure has not yet died, and has started the late study of A-type B hemophilia gene therapy AMT-061, and strives to be listed in 2020. The industry’s M&A boom has made uniQure the scent of many pharmaceutical giants. Some analysts predict that if the therapy is approved, it will generate more than $1 billion in annual sales.

Also attractive is Regenxbio, a leading developer of viral vectors and a developer of gene therapy methods. More than 20 partners currently use its vectors, including Novartis’ SMA gene therapy. Regenxbio also has a number of independently developed treatments, such as a treatment for wet age-related macular degeneration or AMD.

Sarepta’s antisense nucleotide therapy Exondys 51 for Duchenne muscular dystrophy (DMD) can treat DMD patients due to dystrophin gene mutations (deletion 51 exon deletion), which accounts for approximately 13% of DMD patients. The drug generated about $300 million in sales last year, but the therapy is administered once a week and needs to be used regularly.

Audentes’ primary treatment goal is the deadly muscle disease X-linked myotube myopathy (XLMTM), which last October reported a “significant improvement in neuromuscular and respiratory function” in an early trial involving 7 XLMTM patients. So that the baby in the test can take off the ventilator.

Others that are making progress faster are Crispr and Editas. Vertex has also initiated an I/II human clinical study with Crispr in Germany to evaluate the potential of experimental CRISPR/Cas9 gene editing therapy CTX001 for the treatment of beta thalassemia.

An official from the Canadian Ministry of Health told reporters that although gene therapy is currently expensive, the significance of its improved treatment is enormous. Take Spark’s ophthalmology gene therapy Luxturna as an example. The company’s video on multiple occasions shows that a gene therapy for clinical subjects that are invisible from birth has helped them to see the light again. Shocked.

Still others believe that the cost of treatment for each patient, such as hemophilia, SMA, and DMD, may cost more than $500,000, but is cumulative compared to the need to receive various other therapies throughout life. Up to several million dollars in cost, potential disposable treatment is also relatively cheap.

The application of gene editing can be divided into two major parts: diagnosis and treatment. Although the current cost of gene therapy is still comparable to the “high price”, technological breakthroughs have significantly reduced the cost of sequencing (note: in less than 20 years, the cost of gene sequencing has dropped from $10 million to less than $1,000). Although the current CAR-T or gene editing is expensive, after 5 to 10 years, these therapies are expected to become civilian treatments, benefiting more patients.

In summary, the broad application market, rapid iterative technology, declining cost, and increasingly clear regulation may be the main reasons why multinational giants have invested in gene therapy related technologies. I hope that the related treatment costs will also drop rapidly like Moore’s Law.

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