Cell and gene therapies are certainly not new but have seen a serious shift in the past 5 years. Fueled by the FDA regulatory approval of the CAR-T cell therapies and gene therapies in 2017, the USD 1 billion in sales from 2017 is currently expected to reach USD 44 billion in 2024, a staggering 65% compound annual growth rate. Together with several multibillion-dollar acquisitions in the space, it is safe to say that the field is graduating from a niche market into the mainstream.
Cell and gene therapies:
Gene therapy refers to the modification, introduction, or removal of the genetic material (typically a gene) in the cells of a patient to treat a genetic disease. Gene therapy can be given either inside the body (in vivo) or outside of the body (ex vivo). In contrast, cell therapy involves the cultivation or modification of cells outside the body before being injected into the patient. The cells used in cell therapy may originate from the patient or a donor. Both gene and cell therapies aim at treating or preventing genetic diseases but through different approaches.
What’s the current status of these therapies?
A review in the Journal of Gene Medicine from 2018 shows that almost 3,600 gene therapy clinical trials have been undertaken in 38 countries by the end of 2017. Since then, close to 800 studies have been registered in the US alone. Many pharmaceutical companies have targeted small and defined populations of patients with limited or no treatment options; for example, those suffering from relapsed pediatric refractory acute lymphoblastic leukemia. The success of these small-population targeted therapies has led to the increasing interest of many biopharmaceutical companies and spin-offs in targeting larger patient populations.
One of the most promising therapies has been in the field of cancer immunotherapy, using CAR T to target tumor-associated cell surface antigens. Since the first reported success of this treatment in 2011, hundreds of leukemia and lymphoma patients have been treated with this therapy, with high remission rates being observed. In 2017, the US Food and Drug Administration (FDA) approved the first CAR T cell product, Kymriah. Doses of Kymriah are optimized by using a patient’s own T cells, making it an excellent addition to the quickly growing field of precision medicine.
Traditionally, the US FDA and the European Medicines Agency (EMA) have been in agreement on drug approval more than 90% of the time, but that could be changing. A recently conducted study suggests that the EMA may be less likely to approve new drugs than the FDA. Notably, there have been only 10 cell and gene therapies approved by the EMA (first one being approved 9 years ago), much less than the US FDA approved ones. Interestingly, China being the first country ever to approve a gene therapy, has been lagging in this field due to a lack of clear regulatory pathways and inadequate financial incentives.
As reported in Frontiers in Genetics in September 2019, a total of 20 gene therapies have been approved so far worldwide, including both in vivo and ex vivo gene therapy drugs. Various other gene therapies for life-threatening genetic diseases, including cancer, neurodegenerative diseases, and coagulation disorders, are in the pipeline to be evaluated for clinical use in the near future.
Besides targeting rare disorders, this field is also now advancing towards discovering and developing treatments for common genetic diseases. Bluebird Bio was granted approval from the European Commission in June of this year to market its ex vivo gene therapy Zynteglo, for treating β-thalassemia, one of the most common blood disorders globally . Additionally, a recent study published in Nature Communications reports that the researchers at the National Institutes of Health have developed a new viral vector for use in gene therapy for sickle cell disease, which affects around 100,000 people in the United States.
Today’s trends and what to expect:
With the increasing success of these therapies, big biopharma companies also have started showing interest. Novartis acquired AveXis in mid-2018 for USD 8.7 billion, a bet that would soon start to bear fruits with the company securing FDA approval of Zolgensma for the treatment of pediatric patients aged up to two years old with spinal muscular atrophy (SMA) in May of the following year.
Similarly, there have been major acquisitions or partnerships this past year, such as by Roche acquiring Spark Therapeutics, with a total transaction value of USD 4.3 billion. Philadelphia-based Spark Therapeutics had the first FDA-approved in vivo gene therapy (Luxturna) for inherited retinal dystrophy and is currently pursuing gene therapies for various genetic disorders, including blindness, hemophilia, lysosomal storage disorders, and neurodegenerative diseases. Roche has further entered into a USD 1.2 billion collaboration with Sarepta Therapeutics for the Duchenne muscular dystrophy gene therapy.
Another major investment took place by Bristol-Myers Squibb acquiring Celgene, with an equity value of approximately USD 74 billion. The acquisition aimed at creating a biopharma company that addresses the needs of patients with cancer and cardiovascular diseases as well as inflammatory and immunological disorders.
With big companies, there also seems to have come big price-tags. Novartis’ one-time treatment Zolgensma has been priced at USD 2.125 million, making it the most expensive treatment worldwide. Other in-development gene therapies such as Biomarin’s hemophilia drug have also been rumored to be priced around the 2 to 3 million USD range. While these prices may seem absurd, there is a case for it. Take for example Biogen’s Spinraza, the current approved treatment for SMA, it has a price of USD 750,000 for the initial year, followed by USD 375,000 annually thereafter. Considering that Novartis’ Zolgensma is a one-time treatment, the company argues that it would be more valuable than the expensive long-term treatments that cost several hundred thousand dollars annually. Others argue that the values are just excessive and are going to exacerbate an already unsustainable system. If the treatments show to hold long term effectiveness as a true one-off intervention, it is likely that this multi-million price tag will stick. That is a big if. Biomarin’s initial data suggests the effect might only last eight years and Novartis recently had to suspend their Zolgensma trial due to some safety concerns.
Outsourcing to contract manufacturing organizations (CMOs), and contract development and manufacturing organizations (CMDOs) has been on the rise in the last decade. Only one-third of manufacturing is estimated to be conducted in-house, the rest being outsourced. This is expected to be exacerbated with the growth of gene therapy and personalized medicine. Finding the right CMO and CMDOs can streamline the supply chain and minimize the time to market in a space where experts might still be limited. CMDOs are expanding into full service providers and are able to take over a larger share of the development and manufacturing process.
Although it has been a little over 2 years since the FDA made its first approval of gene therapy, the market for these therapies has been expanding rapidly. With such fast growth, not everyone managed to jump on board. So far, only six companies that are considered established large pharma players are included in the top 20 by 2024 sales by Evaluate Pharma (Novartis, Gilead, Biogen, Celgene, Roche and Takeda). All these six players acquired a strategic partner in this space within the last 2 years.
Gene and cell therapies have shown great potential for decades now but have only now shown that they can be successful not only tackling incurable rare diseases but also replacing traditional pharmaceuticals.
