FDA Approves New Cystic Fibrosis Treatment for 4% of Patients

Similar Drugs May be on the Horizon for Other Sufferers
The FDA has just approved a new drug called ivacaftor that will almost certainly be a godsend for 4% of cystic fibrosis (CF) sufferers in the U.S. While this translates to just 1,200 patients, it may eventually prove to be an important step towards better treatments for all CF patients. Right now doctors can only deal with the symptoms of CF. So there are treatments to clear lungs of mucous build up, prevent lung infections, replace lungs with a lung transplant when they become too damaged and so on.

A new CF drug does
more than treat
CF symptoms.
Image by PJ Lynch and
CC Jaffe
Treatment with ivacaftor is different. In essence, it deals directly with the results of the broken gene that causes CF. So ivacaftor is getting at the underlying cause of CF not just the symptoms. But it only works for patients whose gene is broken in exactly the right way. That is why only 4% of U.S. patients are helped with the drug. Obviously this is great news for these patients. But it is also good news for all CF sufferers. And frankly for everyone with an untreatable genetic disease. Up until now, scientists have been very good at finding the genetic differences that lead to inherited diseases. Where they have been lagging is translating that knowledge into treatments. That is why ivacaftor is such a big deal. Researchers used an identified genetic difference (called G551D) to find a drug to treat people with that specific genetic difference. More specifically, they translated their genetic knowledge of one form of CF into the medicine ivacaftor. And other CF drugs may be coming soon. Scientists are working hard on finding new drugs that target other genetic differences that lead to CF. The good news is that at least two of them are pretty far along in clinical trials. It is still too early yet to tell if these will pan out but the success of ivacaftor gives scientists cause for hope that even if they don't, other, better drugs can be found. Ivacaftor opens the door to trying similar approaches with other diseases too. Hopefully it is the first of many such discoveries with many such genetic differences. We may be on the threshold of better treatments for a variety of genetic diseases.
How Ivacaftor Works
Cystic fibrosis (CF) is usually caused by certain genetic glitches in the CFTR gene. Different glitches lead to CF by slightly different routes. This has to do with how genes work. Like most genes, CFTR has the instructions for making a protein. In this case, CFTR has the instructions for making the CFTR protein. This protein sits on the outside of cells and controls the movement of chloride ions into and out of the cell. People with CF usually have genetic differences in their CFTR gene that cause it to make a CFTR protein that doesn't work properly. This is what causes all of a CF patient's symptoms. There are lots of ways to get a broken CFTR protein. Sometimes its gene isn't read properly. Sometimes it only gets partially made or ends up in the wrong part of the cell. And sometimes it just can't do its job. The version that ivacaftor works on, G551D, fits into this last category. The G551D version can't open up very well and so chloride ions flow sluggishly. Ivacaftor causes the CFTR protein to stay open a bit longer. Now more ions flow making the patient's protein work better (although scientists don't really know how it works). The end result is a great improvement in the symptoms of a patient with the G551D version of CFTR. Given how ivacaftor works, it makes sense that it wouldn't work on CFTR proteins that are broken for different reasons. That is why scientists are working so hard on finding new drugs to treat these other patients.

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Potential New CF Treatments
In around 10% of CF cases, only part of the CFTR protein gets made. Helping a sliver of CFTR stay open longer probably won't help...there isn't enough of the protein made to form a channel for the chloride ions to flow through. This is why ivacaftor doesn't work for people with these glitches. But a drug that causes these patients' cells to make a complete CFTR protein would help them. And that is just what a drug called PTC124 does. It causes patients to make full length CFTR protein instead of their usual short one. Again it makes sense that PTC124 wouldn't work for people with the G551D version of CFTR. It does no good to try to make a sluggish but long enough protein even longer.

PTC-124 helps cells make
full length CFTR.
Neither drug works with the granddaddy of all CFTR glitches, deltaF508. Which is a shame since around 70-75% of people with CF have this particular glitch. The deltaF508 version of the CFTR gene makes a protein that gets lost on its way to the outside of the cell. Once lost, a protein tends to get destroyed by a cell or end up as a useless heap. To make matters worse, the little bit of deltaF508 protein that does manage to get to the right place works poorly as well. Obviously helping a destroyed and/or useless heap of a protein stay open longer won't help much. Nor would it help to lengthen it. This is why neither ivacaftor nor PTC124 alone works with deltaF508. But there is some hope. A compound called VX-809 that is currently in clinical trials shows some promise for people with the deltaF508 version of CFTR. It basically helps deltaF508 find its way to the right part of the cell. Unfortunately even if VX-809 makes it through clinical trials, it probably won't be enough to help patients with the deltaF508 version of CFTR. A drug for deltaF508 needs to direct the protein to its proper place AND it needs to get the protein to work better when it gets there. In CF lingo, it needs both a corrector (something that gets it to the right place) and a potentiator (something that gets it to work better). One way to do this might be to combine ivacaftor and VX-809. The idea is that VX-809 would get deltaF508 to the right place and ivacaftor would get it working better. One bit of evidence that this approach might work is that scientists have shown that the small amount of deltaF508 that does make it to the right place works much better in the presence of ivacaftor. Get more of it there and there might be enough working CFTR protein to keep CF at bay. Or at least make a patient's symptoms less severe. It will be years before the results are in for this sort of combination therapy. But these three drugs are definitely the best news CF patients have heard in a long, long time.