James Huang and Stephen Huang consider the promise and risk of gene therapy

Since the completion of the Human Genome Project in 2003, gene therapy has evolved by leaps and bounds. New emerging treatments are finally reaching its promised potential: providing a one-time lifelong cure for even the rarest and most severe of genetic disorders. Its development alongside other emerging technologies like artificial intelligence (AI), 3-D printing and nanotechnology will eventually alter every aspect of our industry, from R&D to drug manufacture to treatments for patients.

Gene therapy has a complex mix of risks and challenges ranging from exorbitant acquisition costs, ethical dilemmas and unknown long-term side effects. Despite these risks, it is a technological breakthrough that will treat diseases as well as prevent some of them from arising altogether. The high prices linked with gene therapies may have put a damper on their potential to become widely available for the general population, nonetheless it is still a technology which is far from reaching full fruition.

The latest and greatest

The treatment of some rare genetic disorders has seen numerous breakthroughs in the past year alone, and these will fundamentally change how people with these severe diseases are managed.

Philadelphia, US-based Spark Therapeutics is a gene therapy firm focusing on the use of adeno-associated virus vectors to treat rare diseases such as retinal dystrophy, Pompe disease and haemophilia.

Since patients with haemophilia B suffer from a faulty blood clotting mechanism, they need to avoid even minor cuts or bruises and require preventive treatment in the form of daily infusions of clotting factor IX to manage the condition, resulting in a costly and restrictive lifestyle. However, clinical trials of Spark’s fidanacogene elaparvovec, a vector delivering a modified factor IX gene to stimulate the production of the body’s own functioning clotting factor, has shown extremely positive results. A 2017 study involving ten individuals with haemophilia B showed that the annualised bleeding rate was reduced by 97%, and that patients no longer needed daily infusions.

About one in 20,000-35,000 males are born with haemophilia B and the mutations occur on the F9 gene located on the X chromosome. Fidanacogene elaparvovec has received both breakthrough therapy and orphan product designations from the US Food and Drug Administration. Spark has partnered with Pfizer to take the product forward into registration studies, up-scaling and global commercialisation.

A few months later, in November 2018, Spark obtained EU marketing authorisation for another product, Luxturna (voretigene neparvovec), a one-time gene therapy for the treatment of adult and paediatric patients with inherited retinal dystrophy caused by RPE65 mutations on chromosome 1. The progressive condition leads to total blindness in most patients. Novartis has exclusive rights to pursue development, registration and commercialisation in all countries outside the US. The treatment also received FDA approval, in December 2017.

Interestingly, Roche announced plans to buy Spark for $4.3 billion in February this year; it remains to be seen how Roche will manage the aforementioned agreements with its big pharma rivals, especially fellow Swiss-based Novartis.

Elsewhere, Illinois-based AveXis, bought by Novartis for $8.7 billion in May 2018, has made a significant breakthrough with its onasemnogene abeparvovec in pivotal trials for the treatment of spinal muscular atrophy (SMA Type 1), a serious inherited neurodegenerative disease and the leading genetic cause of infant mortality, which one in 6,000-10,000 children. Onasemnogene abeparvovec, a gene therapy that replaces the survival motor neuron 1 (SMN1) gene on chromosome 5, which is missing or mutated in individuals with the condition, seeks to address the condition by modifying the malfunctioning motor neurons. The therapy has obtained fast track designations in three key markets: breakthrough therapy in the US, PRIME (PRIority Medicines) in the EU and Sakigake in Japan. Though this is a remarkable development, its projected price tag of $4-$5 million is seen as exceptionally expensive, even in a high-priced sector where $500,000 to $1.5 million per patient is seen as a norm

Another new treatment promises to treat a disorder while the affected babies are still in their mothers’ wombs. The target of this CRISPR therapy is Angelman Syndrome, a congenital disorder that affects one in 15,000 births and results in many debilitations, including severe physical and intellectual disability. The syndrome is caused by a malfunction of one of the mother’s genes, specifically UBE3A on chromosome 15, which results in malfunctioning neurons due to the gene being either mutated or absent. The new solution, being worked on by the University of North Carolina, involves injecting a harmless virus, which carries molecules, into the brain of foetuses where it then repairs genetic defects by fixing mutations in the organ directly. The treatment, if successfully developed, may offer a one-time fix for this lifelong disease and also allow development of treatments for other similar disorders.

High promise, but also high costs and risks

It is clear that these breakthroughs are significant as they give patients with rare genetic disorders a choice to be given a one-time, lifelong cure of their disorders. While the potential benefits are highly significant, their long-term side effects profile is still largely unknown, and the wider implications in terms of their high costs for payers and equitable access in society need addressing. A notable instance of the technology’s unaffordability was the October 2017 withdrawal of uniQure’s gene therapy Glybera (alipogene tiparvovec) for hereditary lipoprotein lipase deficiency. Its $1-million price tag made it the most expensive treatment in the world during the four years while it was on the market, but throughout this period it was said that only one patient was treated with the company’s commercial stock. The reason given for its withdrawal were the hefty post-approval regulatory obligations imposed by the EMA and more importantly, its failure to secure a US licence.

One of the biggest challenges with gene therapy lies paradoxically with its ‘USP’, that it is the ultimate personalised medicine. Currently, patients with ‘common’ diseases are given medicines that are mass-produced and prescribed using well-recognised ‘standards of care’. However, personalised genetic medicine means that the entire treatment paradigm from analysis of the patient’s genes, designing the individualised treatment, safety assessment, manufacturing and distribution are done solely for each patient. Therefore, with genetic personalised therapy, it is difficult to achieve any economies of scale which would lower prices substantially.

Other challenges that are equally significant include the lack of clarity regarding any long-term side effects, bioethics considerations and re-design of current models of healthcare systems. Modifying people’s genes is a major undertaking and how it will alter a person or society in general over several decades is unclear. Even more controversial is the prospect of hyper-wealthy individuals using genetic engineering to give themselves or their offspring certain desirable physical traits, an extremely divisive and contentious possibility.

Early days

It would be easy to conclude that with its astronomical cost, gene therapy is simply a hugely promising novel technology but one that is unlikely to gain any widespread traction. However, it is important to remember that processes that were once incomprehensibly expensive have gradually become affordable over time for the general population. The Human Genome Project, which began in 1990 and took 13 years to complete, involving geneticists from across the world, required $2.3 billion to sequence the first human genome. Now, there are companies offering to sequence and analyse individuals’ entire genome for less than $1,000. Gene therapy is one of the most exciting medical breakthroughs in recent decades and emerging technologies like AI, 3-D printing and nanotechnology could reduce its production costs in the foreseeable future. In the long term, gene therapy will revolutionise our industry, akin to the impact of monoclonal antibodies now.

James Huang is a policy researcher and Stephen Huang a pharmaceutical medicine consultant, both at SCP Medical