Crispr/Cas gene scissors – First therapy before approval

“We are on track to apply for approval for Exa-cel in Europe by the end of the year,” Vertex CEO Reshma Kewalramani told Handelsblatt. In the US, Vertex recently began submitting data for a rolling approval process.

According to the Vertex boss, Exa-cel could thus represent a milestone in medicine, which is likely to be followed by further therapies based on gene editing in the coming years. The clinicaltrials.gov database currently lists around 70 clinical studies in which Crispr technology is used, including numerous cell and gene therapies against cancer.

The Crispr/Cas method was researched in the early 2010s and has since been widely used in molecular biology research. It is a system of RNA molecules and enzymes, with the help of which a relatively precise exchange of individual sections of the hereditary molecule DNA is possible.

The process is also known as gene editing. Emmanuelle Charpentier, co-founder of Crispr Therapeutics, and Jennifer Doudna received the 2020 Nobel Prize for their contribution to the discovery.

In the Vertex product, as in most other clinical projects, gene editing occurs outside the body (“ex vivo”). The relatively complicated procedure is similar to stem cell transplantation in the treatment of leukemia. Blood stem cells are first removed from the patient, while the remaining blood stem cells in the body are killed with a special chemotherapy.

The extracted cells are genetically modified in the lab using Crispr/Cas to produce a correct version of specific red blood cells, then multiplied in the lab and reinjected into the patient. Vertex assumes that the defective hemoglobin formation can be corrected in the long term.

Crispr/Cas allows more precise gene editing

So far, the company has published data for 75 treated patients, in whom the occurrence of serious incidents or the need for blood transfusions was almost always significantly reduced.

Vertex boss Kewalramani sees the decisive advantage of the technology in the fact that it allows a much more precise gene modification than competing methods that use gene transfer using viruses. In this way, the aim is to minimize the risk of causing cancer through the integration of new genes and at the same time to increase the durability of the gene changes. “Our goal is a one-time, lasting, and transformative therapy,” she says.

A particular challenge is not only the approval process, but also the subsequent price negotiations with health insurance companies. Because for one-time therapies with the claim to cure hereditary diseases and thus make lifelong chronic treatments superfluous, there are hardly any price models that are accepted by everyone.

The US company Bluebird Bio has failed in the past two years in an attempt to enforce a price of 1.8 million euros for its gene therapy Zynteglo – also against beta thalassemia. Bluebird then withdrew the already approved product from the European market in order to concentrate entirely on the US business.

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Vertex has not yet made any statements about the possible price of its gene therapy, but thanks to good clinical data it sees itself in a significantly better starting position. Unlike Bluebird, Chief Operating Officer Stuart Arbuckle does not want to enter the market with a standard price, but with a more flexible price model. “We are looking for an intensive exchange with the payers and will listen very carefully to the discussions,” said the manager.

Billion dollar business with cystic fibrosis drugs

A successful launch of Exa-cel would be a second major product development breakthrough for Vertex. Over the past decade, the company has pioneered the development of several drugs to treat the hereditary disease cystic fibrosis (CF), also known as mucoviscidosis. This is a metabolic disease in which the formation of secretions in the body is disturbed due to an inherited genetic defect, which leads, among other things, to chronic mucus buildup in the lungs.

In this respect, the company already has some experience in the business with high-priced drugs for rare hereditary diseases. Thanks to Vertex’s CF medicines, the life expectancy and quality of life of CF patients has improved dramatically over the past 15 years.

In turn, the US company’s success in the fight against cystic fibrosis brought it a steadily growing business with sales of $7.5 billion and net profit of $2.3 billion in 2021. For 2022, management expects revenues of $8.8 to 8.9 billion Dollar. Based on the market value of around 82 billion dollars, Vertex is now number three in the US biotech industry after Amgen and Gilead.

In addition to gene therapy for sickle cell anemia, the company is also testing new painkillers, a drug for kidney failure and other active ingredients for cystic fibrosis in advanced clinical studies. In addition, Vertex is also working on several cell therapies for type 1 diabetes.

Strategically, the company is neither focused on specific technologies nor on therapeutic areas, as company boss Kewalramani emphasizes. The focus is on diseases for which the biological causes are very well understood, for which there are clear regulatory conditions for the approval of novel, transformative therapies and which do not require a large marketing effort.

“We want to spend as little money as possible on marketing, but invest the lion’s share of our income in research,” said Kewalramani.

More: Hope for gene therapy: Bayer and Pfizer secure multi-billion alliances.