gene therapy

This article is a preview from Winter 2019 edition of New Humanist

In May this year, the world’s most expensive drug was licensed in the US. Zolgensma – a gene therapy for spinal muscular atrophy, a muscle-wasting disease that usually kills by the age of two – was approved for a one-time treatment at $2.15 million. If this sounds a bit like an art-market auction price, that’s because pharmaceuticals are as much to do with big capital as healthcare.

Yet if pricing problems can be overcome, we could be at the beginning of a great medical breakthrough. This is the culmination of decades of work, first on sequencing the DNA of human genes and then studying and manipulating their action. Our ability to make planned genetic changes into organisms began in 1973. Within 10 years, we were making human insulin by inserting its gene into bacteria or yeast and getting them to make it for us. This replaced the messy harvesting of sheep, pig or cow insulin from abattoirs. The next stage was to tackle human genetic diseases. All of the body’s processes are run by proteins. Some are hormones like insulin, relatively simple molecules carried through the bloodstream to act on cells throughout the body. Others are much more complex. The structure of all proteins is precise – a single faulty component and it can fail partially or completely. A single incorrect DNA base in the 3 billion we all possess can cause lifelong disease. The incorrect DNA code throws a genetic spanner in the works: the protein malfunctions.

There are several genetic conditions in which only a single DNA base is faulty – for example, haemophilia, cystic fibrosis, thalassaemias or Huntington’s disease. Despite the minor genetic change, the effect of these diseases is crippling and often lethal. The faulty gene in haemophilia prevents blood clotting; in cystic fibrosis the lungs cannot expel mucus properly; thalassaemias restrict the ability of the blood to carry oxygen to the tissues.

The first attempts to correct such defects – gene therapy – began in the 1990s. They were disastrously premature. Knowledge was limited and the attempted gene replacements were crude and led to unpredicted consequences: they caused cancer and people died. The idea was put on hold. Then in 2003 came the completion of the Human Genome: the 3 billion bases of DNA that are the code for a human being. Surely, this monumental achievement would unlock a medical cornucopia? But articles on the 10th anniversary in 2013 reported no medical progress up to that date. Now, as the second decade of the 21st century is coming to a close, something is stirring at last.

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The last five years have seen rapid progress in creating and testing therapies for these genetic conditions. But the mood of optimism has turned to disquiet about the financial implications. Pharmaceutical companies cite the huge costs of research as justification for the prices they charge but this isn’t entirely convincing. For a start, the vast sums of money now floating around in the world of pharmaceuticals sit on the back of decades of publicly funded work in university and hospital laboratories.

So why are these drugs so expensive? The picture is skewed by the inflated economics of the US healthcare industry. Not all of the major pharmaceutical companies are American but the American system sets the benchmark for healthcare economics: Big Pharma prices drugs the American way. All prices in the system are inflated, and matters are made worse by the fact that new drugs are prime vehicles for financial speculation. Money pours into drug development at every stage. Companies have no difficulty raising money to fund many years of research with no sales income. If a new therapy is promising, Big Pharma will pick up a big tab to buy the drug and take it to the next stage. The patent system ensures that for 20 years from its invention there will be no competition from generic copycats, but in practice that might mean only 12 years on the market. So drugs companies have limited time in which to get their money back and turn a profit. There are currently so many different drugs for the same condition in the pipeline that the window to make a profit can be even shorter.

Pharmaceutical companies have traditionally worked hardest on developing drugs for widely prevalent conditions, to the extent that less prevalent conditions have been neglected. But in gene therapy the reverse is true. Early therapies have all been for very low-incidence diseases. One reason these diseases have been targeted is that they are low-hanging fruit in scientific terms: single gene conditions can be treated and multi-gene conditions currently cannot. But the real problem has been caused by financial rather than scientific considerations. Gene therapies have been priced stratospherically high on the assumption that someone – governments, private health insurers, rich people, ad hoc buyers’ clubs – will pay up for a miracle cure.

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Causative genes for genetic diseases involving a single mutation began to be identified and sequenced in the 1980s. Then the search for therapies began. There are currently two main rival strategies: gene silencing and gene therapy proper. In gene silencing, a short synthetic strand of DNA is developed that blocks the action of the faulty gene. This prevents it producing the protein that causes the damage but does not replace the faulty gene. In gene therapy, the faulty gene is edited and replaced by the correct gene. The favoured technique to accomplish this uses viruses, which have the ability to infiltrate an organism’s genome. Doctored “safe” viruses have been developed to carry the replacement gene into the body. Of the two current treatments for spinal muscular atrophy, one involves gene silencing, the other gene therapy.

A dramatic moment in the history of gene silencing came in December 2016, when it emerged that 13 of the 20 babies with spinal muscular atrophy that started treatment in a clinical trial during 2014 and 2015 were alive and breathing on their own, at two and three years old. Typically, half of untreated babies with this form of spinal muscular atrophy would be expected to die or be on ventilators before their first birthday. The gene silencing drug in the trial, Spinraza, developed by the Californian firm Ionis, was bought by Biogen for $75 million. It made $1.7 billion in 2017 and Biogen subsequently invested $1 billion in Ionis to develop further therapies.

Hot on Spinraza’s tail is Zolgensma, the virally delivered one-off cure. Novartis did not research or develop Zolgensma – a firm called AveXis did. Novartis bought it for $8.7 billion, an indication of their inflated expectations. Spinraza and Zolgensma will now fight it out in the market. Novartis announced Zolgensma by claiming that it costs around 50 per cent less than “the 10-year current cost” of Spinraza. But this 10-year costing is misleading for a one-off cure for a condition that usually kills by the age of two; it is being compared with 10 years of treatment with a drug that has to be administered for life. The whole point of the one-off fix is that it avoids the repetitive costs. Incurable diseases place a huge financial burden on families and the state. The cost of new therapies must be weighed up against the savings achieved over a lifetime. But this is not an easy calculation: the price set by the manufacturer is a given, to be paid upfront, while the potential saving is a moving estimate.

And the cost-benefit analysis is vastly different in countries with different healthcare systems. In the US, healthcare insurers are concerned about the cost of these new therapies but since they are used for very rare diseases, a high price for a limited population makes sense. In the inflated world of US healthcare (which sucks up 20 per cent of GDP) they can live with it. In Europe, however, the state provision of healthcare runs counter to America’s fundamentally capitalistic orientation, and it can be difficult to justify buying such expensive treatments. Given that the US healthcare industry sets the benchmark for costs, this is a real issue. Spinraza was only licensed in the UK in May 2019 after a long stand-off between Biogen and the NHS.

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In Europe, out of 10 approved gene therapies, four have already been withdrawn on economic grounds. Perhaps the most notorious case is Glybera, approved in 2012 to treat the rare disease lipoprotein lipase deficiency. Glybera, developed by a leading Dutch firm, was withdrawn in October 2017. The disease affects one in a million people and Glybera is a one-off solution. You don’t have to be a genius to work out that a treatment that cost billions to develop and is given once to one person in a million might be hard to make a profit on. And what healthcare authority could afford it at £1 million a shot?

Several conditions with a much larger patient population are now coming into the frame: haemophilia, thalassaemias, Huntington’s disease and cystic fibrosis. These not only have much larger patient populations, they also have very active support groups. Cystic fibrosis is the frontrunner, having been at the centre of a four-year running battle between the NHS and the US pharmaceutical company Vertex. This standoff was finally resolved on 24 October when the NHS and Vertex agreed a two-year deal, which will make the drugs Orkambi and Symkevi available to all sufferers who can benefit from the treatment within a month. The deal includes a fast-track licensing path for Vertex’s future drugs, previously withdrawn during the standoff.

Cystic fibrosis is a well-known condition with around 10,400 sufferers in the UK. The genetic error creates a defective protein that interferes with mucus clearance in the lungs. In 1962, life expectancy for sufferers of the condition was just 10, and it is now around 40. Several treatments are currently either available or in the pipeline. Orkambi and its sister drug Symkevi modulate the protein produced by the aberrant gene and are effective in about 70 per cent of cystic fibrosis patients (those carrying two copies of a particular mutation). Orkambi is given twice a day, and, before the NHS deal, was offered at an annual price of £104,000 per year. That price – multiplied by the several thousand patients who will now live for many decades longer – clearly made no sense. The NHS initially made Vertex the biggest offer in its history: £500 million for 10 years’ treatment of all eligible patients in the UK.

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This is one breakthrough, but as more treatments for major diseases arrive, these problems will become acute. Before the Orkambi deal, the UK Department of Health and Social Care had floated the idea of a Crown Use licence. This is the nuclear option, enabling the NHS to sideline the licence holder and import a cheaper generic version. As it happens, Vertex failed to patent Orkambi in Argentina and a generic equivalent is being made there. British patient groups took matters into their own hands, forming a buyers’ group to import the generic drug.

The Labour Party, at its annual conference this autumn, floated the creation of “democratically owned pharmaceutical companies with specific missions to serve the needs of the NHS”. The idea would be to produce generic equivalents for drugs such as Orkambi. The pharmaceutical industry will object that such proposals threaten research: why spend billions on developing new drugs when anyone can steal the results?

A therapy in the pipeline for Huntington’s disease will be an important test case. Huntington’s disease is a terrible scourge, inherited from a dominant mutation – only one parent needs to have the mutation to cause the disease. It tends to hit around the age of 45, and causes a progressive loss of motor control and cognitive functions, usually resulting in death around 15 years later. The gene responsible was identified in 1993 and more than 25 years of subsequent research have led to a large phase-three clinical trial on HTTRx, developed, like Spinraza, by Ionis Pharmaceuticals. There are reasons to hope that if this gene-silencing drug proves itself in the trial, the outcome might be better than in the case of cystic fibrosis and Vertex.

Roche, a major pharmaceutical company, bought HTTRx (now known as RG6042) from Ionis for $45 million – significantly less than the $8.7 billion Novartis paid for Zolgensma. The financial impact of Huntington’s disease, with working careers cut short at 45 and expensive care delivered for around 15 years, means that the saving achieved by eliminating these and allowing a productive life to continue for decades could offset the price of treatment for healthcare providers.

One long-term economic problem with gene therapies is that if they work, they will reduce the number of people needing treatment, making the drugs even less profitable. Gene therapy that targets the germline – eliminating the condition in future generations – is currently not permitted. But there are already procedures that are reducing the incidence of many diseases: foetal diagnosis and pre-implantation genetic testing, a form of IVF in which only healthy embryos are implanted. Eventually, a combination of these and really effective gene therapies is guaranteed to create a declining market for gene treatments, as aberrant genes are removed from the population. This has already happened with some diseases. Incidence of Tay-Sachs, which mostly affects the US Jewish population, has fallen by more than 90 per cent since mass screening was introduced in 1971.

Whatever the economics of gene therapies, the goal of eliminating these horrific diseases must override finance. When vaccines for polio and smallpox became available, the World Health Organisation made global eradication a goal. Smallpox was eradicated in 1977. I approached major figures in the development of gene therapies for this article but the response was either guarded or silent: everyone recognises that there is a problem, but the way out is unclear. The cost of the Orkambi cure? We don’t know, because it is “commercially sensitive information”. The deal is good news, but the money is still winning.