After decades of research and a number of setbacks, gene therapy is finally becoming a reality with the recent approval of three pioneering treatments, including two highly anticipated CAR-T therapies, Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) for the treatment of rare forms of lymphoma and, what has been described as the first true gene therapy, Luxturna (voretigene neparvovec‐rzyl), a novel treatment for a rare form of genetic blindness.

Gene therapy is the practice of modifying a patient’s DNA in order to treat a disease. This can include replacing a mutated, disease-causing gene with a healthy copy in order to restore its function, inactivating a faulty gene or introducing a new gene to assist a patient in fighting a disease1.

So, what is all the excitement about? The most tantalising aspect of gene therapy is its curative potential, that is, to offer a patient a complete cure from their disease with a single, one-off treatment. Although most of the gene therapies approved to date cannot boast this, clinical studies have demonstrated the potential of gene therapy to cure a number of genetic diseases including: haemophilia, sickle cell disease and neurodegenerative conditions such as Huntington’s disease.

However, this level of medical innovation does not come without its challenges. The high cost of gene therapies has attracted a lot of attention in recent years and is likely to remain a significant concern for already financially stretched healthcare systems. UniQure’s Glybera, a gene therapy for lipoprotein lipase deficiency, an inherited metabolic disorder was approved in Europe back in 2012, but its $1 million price tag resulted in significant commercialisation challenges and, after limited use, it was subsequently withdrawn from the market.

The issue of pricing for gene therapies is multi-faceted; the high cost of development alongside the often-small patient populations and potential for a single treatment to be curative, means that these therapies are likely to require a higher price point to make them commercially viable. Furthermore, even if this high cost can be justified, the ability of healthcare systems to pay this amount upfront for a single treatment, as opposed to spreading the cumulative costs over many years as they would with conventional therapies, remains to be seen. Another significant challenge for manufacturers is proving the longevity of outcomes in order to support its pricing strategy; will one treatment really cure the disease, or will the effects be diminished in 5-, 10- or 20-years’ time? New therapies are unlikely to possess this level of data at the time of approval and so this remains a big area of uncertainty during pricing negotiations.

But, can we overcome this? New models incorporating outcomes- or annuity-based payments for gene therapies have been proposed. In fact, Spark Therapeutics, the manufacturer of Luxturna, which is priced at around $850,000, has entered into outcome-based rebate agreements with several healthcare providers in the US which will see it only charge for the therapy if patients meet pre-defined outcomes thresholds. Spark has also discussed its willingness to allow instalment payments for the therapy; however, this is not currently possible in the US market. With these novel payment mechanisms in place, Luxturna appears to be enjoying more commercial success than its predecessors, with Spark Therapeutics reporting that 12 vials of the drug were shipped in Q2 2018 and that patients are receiving the therapy in six centres across the US2.

In addition to pricing, there are also logistical challenges associated with gene therapies. Often requiring specialist staff and equipment as well as extended monitoring, sites at which gene therapies can be administered are limited, meaning it can be more difficult for patients to gain access to these therapies. Strimvelis, a gene therapy for ADA‐SCID, was approved in Europe in 2016, however, as the therapy requires ex-vivo manipulation of stem cells extracted directly from the patient, it can only be produced in one hospital in Italy, and, with a shelf-life of only 6 hours, this means patients from Europe must travel significant distances for their treatment. Like Glybera, Strimvelis has only seen limited use since approval, with these logistical challenges, as well as high cost, likely contributing to this.

On the positive side, the gene therapy field is advancing at a considerable pace. Around 2600 clinical trials have been completed, are ongoing or have been approved worldwide, representing a significant increase on the 900 or so in 20043. The majority (around 65%) are focused on finding new treatments for cancer3, however, the potential for gene therapy is also being studied in a wide range of other areas including: monogenic, infectious, cardiovascular and neurological diseases.

New gene therapy technologies are also generating significant interest. A large amount of research to date has focused on introducing genetic modifications to cells, either in-vivo or ex-vivo, using specially-engineered viral vectors. However, another method which has been garnering attention over the last couple of years is the gene editing technology, CRISPR. Considered to be a more targeted method of manipulating DNA, CRISPR is capable of excising specific DNA sequences, which can then be replaced with new ones. Therefore, it is easy to see how this technology may be utilised to replace disease-causing genes with non-mutated or functional copies. After a number of successful proof-of-concept studies in cell and animal models, the first human clinical trial of CRISPR began earlier this year, with CRISPR Therapeutics initiating a Phase 1/2 study investigating the technology for the treatment of the rare blood disorder, β-thalassemia.

With a wealth of molecular and clinical investigation ongoing, the future for gene therapies looks promising. However, the speed at which these innovative therapies can advance into the mainstream of medical treatment depends largely on the pharmaceutical and biotech industry’s ability to overcome both the development and commercialisation challenges associated with producing a safe, effective and accessible gene therapy. It remains to be seen just how valuable gene therapies will ultimately become, but it is a space that should be monitored with great anticipation.

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Jo Adams, ConsultantMake An Enquiry