Promising new era dawns for cystic fibrosis treatment

Zöe Corbyn

The recent approval of a new drug and the start of a phase 2 gene therapy trial are creating excitement about future treatment possibilities for people with cystic fibrosis. Zöe Corbyn reports.

50-year-old cystic fibrosis patient Rick Cissna knew pretty much as soon as he started taking a drug as part of a clinical trial 2·5 years ago that he was not getting the placebo. Running everyday as part of a regime to try to loosen up and therefore cough out the mucus in his lungs he was only a couple of weeks in when he noticed his cough getting shallower. After about a month on the drug it had all but disappeared. “It was just dramatic”, recalls Cissna who also no longer frets over his lung infections becoming more resistant to antibiotics. “On the drug I haven't had any antibiotics, period”, he says.

The drug is ivacaftor (Kalydeco). This January, the treatment developed by Vertex Pharmaceuticals of Cambridge, MA, received approval in the USA. Approval in Europe is estimated at around July. Additional regulatory submissions are being planned in other countries.

Cystic fibrosis, a rare and lethal disease, affecting about 70 000 people worldwide, is caused by a defective or missing CFTR protein, which controls the movement of salt in the body. Mutations in the CFTR gene cause too much salt and not enough water to pass into the cells, turning the body's secretions, which normally act as a lubricant, into an abnormally thick sticky mucus clogging the lungs and digestive system and making it hard to breathe and digest food. Patients become vulnerable to frequent and severe chest infections which eventually destroy their lungs. People with the condition have an average life expectancy of only around 40 years.

Ivacaftor, a small blue pill taken twice daily, at a list price of US$294 000 per year, is the first drug to treat not the debilitating symptoms of the disease but their underlying cause. But the personalised medicine based on genotype, only works for about 4% of patients, those with a mutation known as G551D. The phase 3 trial results, published last November in the New England Journal of Medicine, showed that compared with a placebo it markedly improved patients' lung function, lowered the amount of salt in their sweat, and helped them gain weight (though it is unclear whether that was a result of a direct effect upon the gastrointestinal system or a reduction in the work of breathing).

The drug has many experts convinced the so-called small molecule approach for the disease—which relies on high throughput screening to find drugs that fix the defective CFTR protein—will see many more patients able to strike at their condition rather than merely its effects. It gives us a “great roadmap” for bringing these drugs to other patient populations, says Robert Beall, president and CEO of the US Cystic Fibrosis Foundation, which is ploughing millions into their development. “We see that small molecules will work.”

Yet it was not supposed to happen this way. For the first decade after the CFTR gene was discovered in 1989 a very different fix was believed to offer the best hope: gene therapy to replace the single faulty gene, which causes the disease. Yet what looked promising in theory turned to dust in reality. Most researchers and funders, particularly in the USA, turned their attention to the small molecule approach.

Yet gene therapy is not down and out. In the UK, things have been different. One consortium of UK scientists has been doggedly pursuing it and they just won funding that will keep its dream alive. Last month it was announced that the second part of a phase 2 clinical trial of gene therapy which had been in jeopardy due to lack of funding would proceed after winning £3·1 million from the Medical Research Council and the National Institute of Health Research. If it goes to plan and gene therapy can stage a comeback, patients will stand to benefit.

The trial, which will use a lipid to deliver the replacement gene, will be the world's largest non-viral gene therapy trial, says chief investigator Eric Alton, an expert in gene therapy and respiratory medicine at Imperial College who coordinates the UK Cystic Fibrosis Gene Therapy Consortium, which brings together researchers at the universities of Oxford, Edinburgh, and Imperial College.

The lipid vector is an alternative to the viral vectors such as adenovirus and adeno-associated virus, which were pursued in the early days of gene therapy but failed to produce the hoped for clinical improvement. Patients will use a nebuliser to inhale molecules of DNA wrapped in fat globules that deliver the replacement gene into the cells in the lung lining. While data to date suggest the lipid vector has a “real possibility of working” and can deliver the 5—10% levels of normal protein needed for a therapeutic effect, says Alton, it is also clear patients will need more than one dose. The new trial will repeat doses once a month for a year for 130 patients. “We will know in about 2 years whether the non-viral route is efficient enough or not”, says Alton, adding not to expect results before March, 2014.