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Melanie Cole (Host): Cystic fibrosis therapies have entered a new era of protein based treatments that show promise for significant improvements in health. Here to tell us about that is Dr. George Solomon. He’s an Assistant Professor in the Division of Pulmonary, Allergy and Critical Care Medicine at UAB Medicine. Dr. Solomon, explain a little bit about cystic fibrosis today. Tell us what you know about the disease that you didn’t know say 20 years ago.

George Solomon, MD (Guest): That’s a great question. So, Melanie I will tell you first of all, cystic fibrosis is the reason I got into science and into pulmonary medicine. CF is a condition that results from genetic defects in a gene called the cystic fibrosis transmembrane regulator. And what that gene does is it encodes a protein which makes a channel that inserts itself into the cell surfaces throughout the body and helps to regulate the hydration status of the lungs, sinuses, kidneys, pancreas, GI tract, the entire body basically has this protein being expressed. Defects in this channel due to the gene problem result in a very severe illness that people die from prematurely. Years ago, they died in infancy or in early childhood. Now people tend to die more frequently in the third and fourth decades of life with this illness and it is really due to severe progressive pulmonary disease. Because that’s the organ that tends to be the most affected later in life with this condition.

This condition 20 years ago was in it’s infancy of therapies. The first therapies were developed in the 1990s and they were aimed at treating the mucus problem. The mucus in these patients gets extremely thick in the lungs and sinuses because it has the wrong hydration status and that sets off a cascade of problems including recurrent infections and recurrent mucus obstruction. So, most of the initial therapies were aimed at treating these types of chronic and acute infections and dealing with the consequence of the illness like the fact that they don’t make enough pancreatic enzymes to digest food and dealing with acute and chronic infections and the mucus obstruction.

So, that was the impetus for treatment until really ten years ago. Ten years ago, a landmark happened in treating this condition and a company developed and had approval in 2012 was the initial approval of a drug called ivacaftor and what ivacaftor does is it actually turns on the defective protein caused by certain of the gene mutations which cause cystic fibrosis. The patients that had access to ivacaftor initially were a very small group of patients, only about five percent of the patients afflicted with the illness. But it told us there was a way to treat the illness beyond just treating the downstream consequences. There was – we could take an illness caused by a known defect and treat the direct defect head on with a small molecule that can be taken by mouth. So, a pill that takes about five minutes to take once or twice a day could effectively treat this illness and drastically change the outlook for these patients in terms of their lung capacity and in terms of getting sick as frequently.

So, that’s a huge game changer and it set off a huge cascade that I hope we can talk about today in terms of new therapies for the illness.

Host: Then let’s do that. Let’s talk about that. Tell us more about a triple combination drug that is shown to be effective in improving lung function for patients with cystic fibrosis.

Dr. Solomon: Yeah, so, you’ve picked up on the newest and greatest. Let me give you just a little bit more history lesson so we can get to where we are today. So, after the approval of ivacaftor, initially that was for adult patients with a mutation called G551D. G551D is the mutation – is a notation, a particular type of notation for a genetic mutation that causes the protein the CFTR or that I spoke about protein earlier, causes it not to open and close properly. Now, unfortunately, that’s a very minor amount of the patients. A very minor number of patients have that particular type of mutation.

More of them have a mutation called F508del, in fact, in the north American CF population, there’s about 30 or 40,000 people with CF in the US. Those patients more often have this F508del mutation and it’s a much more severe mutation. It causes the protein not only to not open and close properly, but also to misfold. When proteins misfold, they get told in the cell don’t go to where you are supposed to do. Because it’s a recycling process, right, if you have a protein that’s not working, don’t send it to the right place, most of it gets degraded and recycled to save energy in the cell and to turn over the building blocks of the proteins that can be used for other more effective processes the cell needs.

Well, that leaves the patient with a very severe illness because they’ve got less functioning protein than they need to have. So, after the approval of ivacaftor the same pharmaceutical company that had developed ivacaftor began to screen in a very effective fashion thousands of compounds that might be effective at helping to ameliorate the problem of the protein not folding properly in other words, stabilizing that protein to fold a little bit better, escape the cell’s check point and put it where it needs to and maybe that would be enough to make the protein work. And so that was tested.

In 2014, the first of those drugs called lumacaftor was tested in that process and unfortunately it failed. But someone realized at that time wait a minute, maybe the protein needs to be turned on and maybe ivacaftor could turn the properly folded protein on a little bit better and make it work. And in fact, it did. So, thereafter, in 2015, approval for a combination of therapies called Orkambi is the trade name but it is lumacaftor plus the ivacaftor drug. Those were marketed to treat patients with two copies of the F508del mutation. In other words, both the mother and father had given the patient that mutation. And the patients had similar improvements in lung function as to what was observed with ivacaftor.

So, this told us gosh, we can make a stride in a much bigger patient population with cystic fibrosis, but the problem was that the patients didn’t get quite the same level or degree of benefit that had this mutation as did the patients that got the original ivacaftor drug with those original mutations. So, that set across a pathway to discover new drugs that might better fold the protein and help to stabilize it and allow it to work much better where it’s supposed to in the lungs and sinuses etc.

And so that has led us to our current strategy of addition of a new drug two of which are under investigation right now in phase 3 trials. The addition of those two drugs own to a sister drug called Symdecko which is very similar to Orkambi, but a little bit safer, it has a little bit better side effects and tolerability profile. So, that drug was developed a little bit after Orkambi. The Symdecko drug was and now we’re testing the addition of a third drug onto the combination Symdecko which is a drug called tezacaftor plus ivacaftor. So, a two drug combination is now going to become a third drug combination and we hope will go and seek and have successful FDA approval by the end of this year. And those patients, this has been released in press releases so I can discuss it with you. Those patients have dramatic greater than 10% improvement in the lung function and greater than 40 or 50% reduction in their number of flares and exacerbations of their illness. Not to mention, exceedingly good improvements in quality of life with on this drug. So, this is another game changer type condition.

And with the addition of these drugs, we think that 90% of patients who have cystic fibrosis worldwide, will benefit from this therapy. So, that tell us – if it get FDA approval and subsequent approval throughout the other regulatory bodies in Europe, Australia and New Zealand and other countries; we will have a therapy that’s highly effective for almost all of patients with cystic fibrosis. And the estimates are that these kinds of drugs will extend the life expectancy to the 50s maybe even 60s for most of these patients who 20 or 30 years ago would have been expected to live and die in their teenaged years. So, a significant move forward with these types of treatments.

This type of treatment in general, has been called CFTR modulators. CFTR is the abbreviation for that protein name I discussed earlier. And we have to give a basket of terms called modulators which means they modulate dysfunctional protein. That’s what that means. that’s why they are called CFTR modulators.

Just to outline, the ones that we have been discussing are ivacaftor; it’s called a potentiator because it opens the channel’s potential to be open more frequently. It makes the protein open or exist in an open state more than 50% of the time. The other drugs are called correctors because they correct misfolding of the protein and those are the several that I have outlined for you earlier which have been tested wither in isolation or in an approval state for combination with ivacaftor. So, we now have those two classes of drugs that have been added really not even in the last ten years, the last eight or nine years. Those have come to the forefront and have dramatically changed the outlook for patients with cystic fibrosis.

Host: Just incredible. Such a great description and I know there’s a lot of information we could discuss, but before we wrap up Dr. Solomon, please speak about the challenges present as far as being scrutinized for the costs, affordability and any other factors you’d like to discuss in CF patients such as CF related diabetes and where comorbidities might present a challenge.

Dr. Solomon: Yeah, that is - I believe those types of questions are what’s going to consume the next ten years of research in cystic fibrosis. Besides finding better or more effective therapies than these and what not; dealing with the modulators is challenging. One is they are extremely expensive. To be able to get a drug approved for a rare disease population, this drug is not cheap. It took a lot to develop it and therefore, the costs are being pushed onto patients and drug companies to foot that bill of all that cost to have be recounted and brought back from the development of very expensive drugs. That’s one challenge and as a result, the FDA has been early adopters of these medications.

But the regulatory agencies in Oceania in like Australia and New Zealand they have not approved all these drugs yet. And only more recently did the EMA which is the FDA equivalent for the European Union, did they approve many of these drugs for therapy in patients. So, in other words, regulatory agencies are struggling with the cost benefit analysis of these drugs. We know there’s a long-term benefit, but the costs are exceedingly high. The drugs cost upwards of a few hundred thousand dollars a year. So, that’s going to be an ongoing problem for these drugs moving forward but thankfully, they happen to be highly effective. So, we think that will help to ease the cost benefit analysis and the burden of that.

Now, you brought up other questions about comorbidities of the illness. Conditions like pancreatic endocrine and exocrine insufficiency which are very common presentations in people as they get older with cystic fibrosis especially CF related diabetes which is a condition – we don’t know if it will reverse or not. There are case reports and there are reports by physicians of improvement of control of diabetes when patients are on highly effective modulator therapy. But there’s not yet been a study suggesting that in fact, you can reverse the diabetic consequences these patients have by giving them a modulator because the pancreas is not as reversable in it’s illness. In other words, the destruction to it is more permanent and so whether or not the modulator can help to improve that function or not is an unknown question at this point. We think there is some evidence that it may. But we just don’t know yet at this point.

Now the other circumstance is pancreatic exocrine insufficiency or exocrine function and that’s really the release of digestive enzymes. And I will tell you that some of the trials of more recent modulators including the Symdecko there were studies done embedded into those pivotal trials that suggested that some patients have improvements of some laboratory values that suggest return of some pancreas function. So, we’re very hopeful that if we tune the right modulators to the right patients we may recover and improve some of these comorbidities of the illness. But we don’t know yet.

The final unanswered question is what’s going to happen to people that have chronic infections. We’ve encountered in patients that take ivacaftor that show them clear of very common and chronic infection called pseudomonas aeruginosa, but we don’t yet know if those patients are going to sustain that and if they clear it, if their lung in the new state in which it’s under being treated with the modulator; is it going to cause it to acquire new infections, to have lower or increased susceptibility to acquiring new infections? We just don’t know these answers to those yet and so those are – we are conducting a large number of observational studies of patients on these modulators where they are taking them for prolonged periods of time, three, four, five, six years and longer so we can really get an idea of what the natural history of the illness is going to be in light of taking these drugs long term.

Because long term therapy is not studied in the pivotal trials. Usually they are six months to one year studies. So, we don’t have a long term efficacy and natural history by studying them for FDA approval. But we do have these long term studies which under way or being planned for subsequent drugs we hope will reach approval. So, the answer to your – the long answer to your question is that we are trying to look at all these aspects and we are hopeful, but more studies are going to be necessary to answer those questions.

Host: Then wrap it up for us. What would you like other providers to take away from these incredible studies on cystic fibrosis therapies and when you want them to refer to one of your trials or even for a second opinion?

Dr. Solomon: Sure. So, cystic fibrosis is commonly treated by CF specific providers and we have a large center here at UAB and many other states have one or more centers for cystic fibrosis. There are a couple of reasons why we would love to have referrals to our center from people that may be practicing in the region. One is if you have a difficult diagnosis, okay so if you suspect cystic fibrosis but you don’t know, we have advanced diagnostic techniques here that can be employed that are not available at other centers in the region. It can help us to decide if the patient has the condition and then is there a trial, we can work them into to get them early access to therapy.

So, I think that second of all, I would say that we are a heavy enroller in clinical studies and also are initiating some studies of early access to modulator therapies for that kind of untreated group I discussed, that 10% that are not available at other centers in this region. So, if you have a patient that you think may have cystic fibrosis, you are having trouble making a diagnosis, having trouble treating their known cystic fibrosis or they want access to research for these types of therapies, we need referrals for those patients, and we would open and welcome those and they can be done also at the MIST line as you talked about earlier.

Host: Thank you so much Dr. Solomon for coming on with us today. It’s a very exciting time in this type of research. Thank you for sharing it with us today. A community physician can refer a patient to UAB Medicine by calling the MIST line at 1-800-UAB-MIST. That’s 1-800-822-6478. This is UAB Med Cast. For more information on resources available at UAB Medicine you can go to www.uabmedicine.org/physician, that’s www.uabmedicine.org/physician. I’m Melanie Cole. Thanks so much for tuning in today.