Thirty years and two months ago, on September 8, 1989, researchers published three papers describing the gene responsible for cystic fibrosis. This was a huge breakthrough, which they hoped would lead to reliable treatment in no time.
It wasn’t a “no time”, but the discovery ultimately led to a drug that dramatically improves the lives of most people with cystic fibrosis. A new three-drug combination called Trikafta was unveiled last week in two articles in The Lancet and The New England Journal of Medicine. And medical professionals who don’t use this kind of language lightly are already calling it a “game changer.
In fact, it looks so promising that the U.S. Food and Drug Administration has accelerated its approval. And this is wonderful news for the more than 70,000 people living with this disease around the world today. However, the high cost could prevent some of them from receiving it. In the first half of the 20th century, when doctors began describing and naming cystic fibrosis, the cause of lung and digestive disorders was a mystery.
They knew that children with CF had difficulty breathing because of unusually thick mucus in their lungs. This thick mucus also made them prone to lung infections and prevented them from breaking down and properly absorbing nutrients… All this meant that they often died before they reached adolescence.
And while we’ve found ways to reduce the effects of these symptoms, people with CF still have a life expectancy of about 40 years. That’s why, in 1989, when researchers discovered the gene responsible for the disease, the story made a lot of noise. They called this gene the gene that regulates the transmembrane conductance of cystic fibrosis, or CFTR gene, and it codes for a protein that normally allows chloride ions to enter and leave cells. Mutations in this gene cause the CFTR protein not to work, cannot find its way to the cell membrane to do its job, or is not made at all. And that explains the thick mucus.
Chloride normally attracts water, so when these ions don’t penetrate the mucus, the mucus becomes thicker and stickier. Thicker mucus in the lungs blocks airflow. And its stickiness catches and holds unpleasant things like bacteria, making people prone to lung infections that damage the lungs over time.
In the pancreas, the thick mucus prevents digestive enzymes from reaching the intestines, making it harder for the body to absorb food and nutrients. Doctors thought that the discovery of the CFTR protein would lead to a general cure for cystic fibrosis fairly quickly. After all, they now knew what the problem was. All they needed were drugs to fix the problem, such as those that would allow the protein to work properly again.
But it turns out that there are more than 1700 mutations in the CFTR gene that can cause cystic fibrosis. So even though doctors found drugs that helped fix the protein, they only worked for specific mutations – and none of them seemed to be effective for the most common one. This is a mutation known as F508del, which causes the CFTR protein to misfold. The cell then sees the misfolded proteins as waste and gets rid of them. But this new treatment works for F508del, and that’s what makes it such a big problem.
Two of the drugs bring the proteins to the cell surface before they are destroyed, and the third helps correct the folding so that they pump the chloride properly.
Based on the results of the two published clinical trials, Trikafta is expected to significantly improve lung function in almost 90% of people with CF. That’s great. It’s not a cure, but the improvement in lung function made a /big/ difference for the people who took it. They reported a much higher quality of life than those who received a placebo. Doctors hope that the drug will work so well that their patients will be able to ease the lengthy daily therapies they currently take to relieve symptoms. And the reduction in the number and severity of lung infections could mean people with CF live longer, especially if the drug is eventually approved for use in young children.
But for the moment, it is only intended for people over 12 years old. And the treatment is not perfect for other reasons. For example, because the drugs correct the specific problem caused by the F508del mutation, the combination of drugs won’t work for people who don’t have it. And, interestingly, this tends to mean that people of color are more likely to have other, rarer mutations because of their disorder. Trikafta is also very expensive. We’re talking about US$311,000 a year, which is obviously a lot to pay, especially if you have to pay it for decades. And it probably shouldn’t cost that much.
Economic review panels have already condemned Vertex, the company that makes Trikafta, for overbilling its cystic fibrosis drugs by as much as 77 percent. So Trikafta has the power to change the lives of thousands of people, but whether it will be primarily dependent on insurance companies is a matter of debate. Ultimately, the goal is to find something that works for everyone, for example, by delivering RNA fragments directly to lung cells to make the right protein. Although Trikafta is a fantastic step in the right direction, which many doctors are rightly pleased about, researchers working on cystic fibrosis say they will continue until they find a universal treatment – or, better yet, a universal cure.