1. Welcome, Disclosures Patrick Sosnay Page 2 Program Goals. 2. Yesterday- Patrick Sosnay Page 5 Overview of Mutation Classes

Transcription

1 Segments 1. Welcome, Disclosures Patrick Sosnay Page 2 Program Goals 2. Yesterday- Patrick Sosnay Page 5 Overview of Mutation Classes 3. Today- Stuart Elborn Page 7 Ivacaftor and Beyond Small Molecule Therapy for Cystic Fibrosis 4. Today- Meghan Ramsay Page 16 Management of Patient Expectations 5. Tomorrow- Joseph Pilewski Page 19 Transforming CF Care One Mechanism at a Time 6. Q&A All Faculty Page 30

2 Segment 1 DR. PATRICK SOSNAY: Good evening, everybody, and welcome. My name is Patrick Sosnay, I m from Johns Hopkins University in Baltimore. I work in the adult pulmonary clinic and do genetics research with Dr. Garry Cutting, I help organize a website, a project called CFTR-2 where we have a database of CF mutations, and I m pleased to welcome you tonight to our Ahead of the Curve celebration of 25 years of CFTR. This meeting is always an exciting event because we get to discuss and celebrate really the hard work that we ve done over the past year, and this year we have an especially great celebration, that 25 years ago CFTR, the gene that causes cystic fibrosis, was recognized. We have some great presentations for you today that celebrates the past, what we ve learned, where we are now and the exciting opportunities for therapies that directly address the mutation and talk about some of the future therapies, the further bit that we have to go to really continue to tackle this disease. A bit about our accreditation, you can get CME credit for physicians and nurses. Some specifics of the CME credit. So our learning objectives tonight: Explain how new CFTR modification advances point to changes that have to be made in clinical practice. Describe the utility of the 2 genotype/phenotype correlations beyond diagnosis in achieving more effective patient treatment. Integrate the patient into an individualized therapy regimen to improve outcomes. A HIPAA disclosure statement. Our disclosures, Dr. Mike Boyle was on the planning committee for this, his disclosures are listed here. And we have to acknowledge really the Johns Hopkins Medicine and Johns Hopkins Nursing CME Departments who help you all get CME credits and help put together some of the educational portion of this talk tonight, and DKBmed who really from start to finish runs a great operation. So we have them to thank for putting this all together. Finally, the money that supports this event was paid for by Vertex, but all the educational content was provided by us. Really us at Johns Hopkins and Dr. Elborn and Dr. Pilewski as well, so Vertex put up the money but they re not at all involved in the message here, that s all directed by us. So stories have beginnings, stories have middles, and stories have end, and really the CFTR beginning is going to be displayed in this video here. So this is a video talking about the initial steps on the discovery of the gene. (Video being played) SUZANNE PATTEE: I remember

3 my parents telling me that the doctors told them that I had a 50 percent chance to be five years old. KATIE REISINGER: My parents just weren t given much hope for me to live a long and healthy life. MARGARET LEIGH: At that time most of the patients became very sick during childhood and a large number died during childhood. SHEREE BERKMANS: We lost children at eight, nine, ten years old. BERYL ROSENSTEIN: We had little in the way of hope, we had little to offer patients, there was tremendous frustration that more progress had not been made. SCOTT DONALDSON: Other than airway clearance and pancreatic enzymes, we didn t have many tools. PAMELA DAVIS: We were pretty much still fighting a rear guard action against cystic fibrosis. We were dealing with the symptoms systematically one by one, each one as they arose, we were behaving aggressively because we believed that the gene would be discovered. FRANCIS COLLINS: I was a junior faculty member at the University of Michigan, got there in 1984, had developed a method to try to travel across chromosomes by jumping instead of walking, which at the time was an important advance potentially because it might enable us to get to the gene for cystic fibrosis from markers that were somewhere 3 nearby but were actually quite a distance away. MITCH DRUMM: A group in Toronto had just found that there were DNA markers that were associating with CF and so Francis got on the phone with Lap-Chee Tsui. LAP-CHEE TSUI: And Francis came in because he had the technology of chromosome jumping. So I said Francis, you re jumping, but you re jumping from a place of quite far away from the gene and so perhaps we can collaborate because we knew exactly where we were and then we have very good psychophysical map of the region, the gene, so we can collaborate. COLLINS: Jack Riordan s lab joined the effort, given his expertise in other aspects that were going to be important like being able to look at sweat glands. TSUI: Jack was very important in the discovery of the cystic fibrosis gene because he had made a number of (indiscernible) libraries. JACK RIORDAN: We had sweat gland samples from patients in the CF Clinic at Sick Kids as well as people without CF and we cultured those cells. TSUI: The first piece of gene that we identified or we isolated was from his library on the so called sweat gland CDNA library. GEORGE RETSCH-BOGART: It really was this extraordinary collaboration between Francis

4 Collins, Lap-Chee Tsui, and Jack Riordan, that pulled together really the most innovative and state of the art teams. COLLINS: And finally, after many fits and starts where many of us began to despair about whether this was a solvable problem, in the summer of 1989 the data emerged to say we found it, this is it. PATTEE: It was amazing the day they announced the discovery of the CF gene. DANNY BESSETTE: Being on the cover of Science magazine and knowing that they were possibly close to finding a cure for CF or at least understanding where CF comes from -- LEIGH: The researchers were excited, the families were excited, the caregivers were excited. BERKMANS: Especially, you know, working with patients day to day on the floor so we were excited for what was to come and what that meant. REISINGER: We were at home and the phone rang, my mom picked up the phone and another CF mom called to tell her that they found the gene and she just started crying immediately because she knew it meant there was hope. ROBERT BEALL: So it was really an exciting, exciting time for our community, for our scientists, but most of all, for the parents and patients. It gave them a new sense of hope. 4 TSUI: The first time I saw the cover of the magazine presented to me in a small celebration at a hospital, I mean I had tears in my eyes. BATSHEVA KEREM: On the day of the publication of the science papers there was a big ceremony in the Hospital for Sick Children, families of CF patients and CF patients, themselves, they came to the hall, and this was really, really touching. When we came into the hall, they were all standing and clapping hands. TSUI: And I felt a little bit of an accomplishment because I finally did something for the patients, for the families. DONALDSON: This was a huge breakthrough, not just for CF, but for genetics and medicine in general. So it was a big deal and I think everybody had a clear appreciation for how special and important it was. PAUL QUINTON: The discovery of the gene for cystic fibrosis was an exhilarating time. DAVIS: And we believed, somewhat naively at the time that from the gene would automatically cascade tremendous understanding of the pathobiology of the disease and then a cure. COLLINS: Shortly after we found the gene I think all of us had the expectation that this was a disease where gene therapy would be particularly appropriate. JEFFREY WINE: Nobody really fully anticipated the tremendous

5 difficulties that lay down that path. MICHAEL BOYLE: Even once people began to realize, hey, this is going to be more challenging, the fact that we knew CFTR, we knew the cause, still said hey, this is the direction we need to go after, it just means it s going to take more than we originally thought. TSUI: Because of the variation of the disease presentation among different patients, even patients with the same mutations, there must be other genetic factors influencing the presentation or the symptoms of the cystic fibrosis. So it was let s look for the so-called modifier genes. COLLINS: It was several more years before the other approach, namely trying to develop a drug, a small molecule, really got fully pushed and I give huge credit to the Cystic Fibrosis Foundation and to Bob Beall for deciding to make a bet on that at a time when I think a lot of people thought the chance of success was going to be very low. But here we are. BEALL: The Cystic Fibrosis Foundation had to change how it did business. We used to support academic institutions, mainly with grants, but then we recognized if we really were going to translate that wonderful knowledge that we had learned from the academics and the test tubes to new therapies, we had to bring in a new partner and that was industry. PHILIP FARRELL: Well discovery of the cystic fibrosis 5 gene opened the door to not only a better understanding of the disease, but the application of the detection of the CF gene mutations for newborn screening. DAVIS: And we re able to identify patients with CF or the vast majority of patients with CF very early in the course of their lives and it gives us an opportunity to intervene. FARRELL: This year over 10 million babies will be screened for cystic fibrosis. DRUMM: Evidence keeps accumulating that the sooner we get in and slow down the progression of the disease, the better off these kids will be. RETSCH-BOGART: Now we have patients who we re seeing right at the beginning of life through newborn screening, we now have the promise of therapies that will be game changing in the sense of preserving lung function and improving nutrition in ways that we previously couldn t do, so it is a completely different landscape. (End of Video) Segment 2 SOSNAY: So starting with what they learned when they discovered the gene that causes cystic fibrosis, it laid out a map that really we were going to use, that we continue to use today, and hopefully I can talk to you a little bit about going from that discovery of the gene to establishing the framework of

6 understanding how different mutations may affect that gene, affect the protein product of that gene, and how we re going to use that to address therapies that are going to fix the mutations. So our learning objectives: Describe how CFTR mutations cam be classified (by type, by class, by therapies). Discuss the variety of CFTR mutations. Other things that happened in 1989, let me put a timestamp on this, 1989 was the year of Tiananmen Square, the Tiananmen Square demonstrations in Beijing was the year that the Berlin Wall fell and the beginning of the reunification of Germany. In 1989 unfortunately the Exxon Valdez spilled oil off the coast of Alaska. And in this momentous year we also heard from our distinguish speakers in the video, 1989 was the year that the CFTR gene was recognized as the cause of CF. So you ve seen these schematics in many different talks in this presentation and previous presentations and it s really become an important guide for us because it helps us group the many different mutations in this CFTR gene into patterns that might be more amenable to group together and think about therapies in the same way. So class I mutations, these are mutations in which the RNA produces a premature termination codon, in other words, the RNA stops short. The RNA is the template that our cells use to 6 assemble the CFTR protein. And that template doesn t go all the way to the end of where the protein should be. So the cell recognizes that it s abnormal, and no protein is made. Class II mutations, the most common mutation, F508del, it s a problem where the protein is made but it is assembled or folds correctly. The cell recognizes that it folds in correctly and gets recycled by cellular machinery so you can t find much of protein in the cell, you can t find really any protein up at the cell surface where it might act to conduct chloride. Class III mutations fold properly, assemble properly and do get trafficked and put in the apical surface, the top surface of the cell, but those particular mutations can t be turned on, so they don t conduct chloride. Class III mutations include the G551D mutation, the success story that ivacaftor is able to open up that particular mutation, conduct chloride, with really some dramatic clinical benefits that you ve been, you guys have heard the clinical successes from that. Class IV mutations represent mutations in which the chloride channel is at the surface and it does conduct a little bit of chloride at baseline, but it doesn t conduct enough chloride. So it s kind of like a class III mutation except there s a little bit more chloride conductance and you actually can turn those mutations on. And example of this is the common R117H mutation.

7 And finally Class V mutations are mutations in which the protein functions effectively, conducts chloride effectively, but there s just not enough of it at the cell surface. And often this is due to a splicing defect or the way that different pieces of RNA are put together to assemble the protein. There s a class VI mutation that s been talked about that are fairly uncommon where the problem is that the cell, the CFTR at the cell surface gets recycled more rapidly so it gets inserted into the cell surface but then gets quickly taken down from the cell surface. And the end result, similar to class IV, is that you ve got less functional CFTR up at the surface of the cell. And there are 2,000 different mutations in the CFTR gene that are described, and it s difficult to know with all of those mutations which class they will fit in. In certain cases we can make assumptions. If a particular mutation causes a premature termination or a premature stop, we can group that into class I. But for many of the missense mutations, where you have an amino acid substitution, we can t tell if those are class II, III, IV, or even in certain cases class V mutations. And class is not always a simple assignment, there s some mutations that may fit in more than one class. To make this more complicated, the naming systems change, and this is as we increase the use of genetics in medicine, the geneticists have changed rules with this as far as where we re starting the nucleotide number. 7 And you can see that there are legacy names that you probably are most familiar with but a mutation could also be named by its nucleotide position or by its protein position. And this makes it particularly difficult to interpret new genetic testing reports. A simpler way to think about mutations and a simpler way to think about the classes of mutations, and actually Donna Peeler presented to me, one of the nurses in the pediatric CF clinic, is to think about it very, very simply as is there CFTR, is there CFTR protein at all, that s the first category that needs to be met. And finally, if there is CFTR protein at all, does that CFTR protein work. So thinking about it a little bit more simply into is the protein there in the right place at the top surface of the cell, the apical surface of the cell, and does the protein conduct chloride. So I think the simpler framework is appropriate when we start thinking about some of our therapeutics, especially some of the therapeutics that are closest to being delivered. Segment 3 DR. PATRICK SOSNAY: For our next video we re going to hear about the state of CFTR as of today and some of the exciting therapies that are now available. (Begin video) DONALDSON: Fast forward 20 years into the future, now we have multiple therapies that we can use to take care of patients.

8 We know they work, we know the size of the impact they have in patients, and I think we re at the beginning of having therapies that are truly breakthrough therapies. DRUMM: I can t tell you how thrilled I am about the state we are in CF right now. ROSENSTEIN: The mood among not just the patients but among the staff treating patients with CF has turned around completely because we now have real hope. DONALDSON: You can see huge changes in patients lung function, their survival, their nutritional status, so it s very clear that at a given age patients are doing so much better than they were 20 years ago. FARRELL: We no longer have to worry about children suffering, suffocating, being severely malnourished. STEPHENSON: For nutrition care it s a whole new ballgame. Today it s preventive nutrition, and when I first started it was rescue nutrition. ROSENSTEIN: One can immediately see the nutritional benefits, fewer hospitalizations earlier in life, parents who are part of the team now and come into the CF program not with frustration but with much more of a sense of teamwork and optimism. FARRELL: Fortunately, this is a new day for children and adults with cystic fibrosis. DRUMM: Clearly for patients with 8 gating mutations, we have a drug that s available for them today, ivacaftor, and that is a total game changer. BOYLE: We finally have something that could potentially address and make a difference in our patients with the most common mutations. GUGGINO: Having worked in the laboratory on CFTR and its ion channel properties, to see a treatment come along based on activating this channel, it s truly remarkable for me to see this. TSUI: I was very happy that finally a drug was identified for cystic fibrosis based on the gene discovery. WINE: Without the gene there could be no potentiators, correctors, CFTR-directed therapeutics. The development of all of those therapeutics depended on having cell culture assays made possible by having the gene product, being able to express it, and understanding how it worked. DAVIS: It was a complicated process and it really required I think the collaboration and cooperation of academic labs and industrial-scale screening and medicinal chemistry. It was a remarkable tour de force. CHMIEL: Ivacaftor only affects 4 percent of the CF population, but the reality is it shows that we can do this. BEALL: Our promise to our community is, we have to treat 100 percent of our patients with

9 disease-modifying therapies. BOYLE: And again it sort of shows proof of this whole principle that as we improve chloride transport we see an improvement in outcomes. REISINGER: And seeing my fellow CF patients benefitting from this drug is amazing to me, and I m so happy for them and hopeful for a day that it s available for everyone with CF, not just delta-f508 mutation, but anyone who has cystic fibrosis. PATTEE: I feel very thankful to be alive here at 51. It was very hard to see that age when we were kids. BESSETTE: We re in a new, whole new era. This used to be a pediatric disease and pediatric disease only. REISINGER: My pediatric pulmonologist was so important to my family. We had such a great relationship, and I remember not wanting to transition to the adult clinic at all. I was reluctant to leave. BERKMANS: When we talk to kids about transitioning now they re like, no, I don t want to go, I ve been with you for 20 years, and we say, no, this is a good thing, this is a celebration, this is not a bad thing to be able to go to the adult CF clinic, because like I said, we didn t have one when I first came to work here. DAVIS: None of what we ve seen in CF would be possible without the enthusiastic participation of the patients in clinical trials. And 9 most of them do it with little expectation of benefit for themselves. REISINGER: Being involved in clinical trials is very important to me and I think for the whole CF community. PATTEE: It s just part of my way of giving back to the community and giving hope back and give hope to others with CF. DAVIS: Some of them do it and they say to you right out of the gate, it s for the kids. It s for the next generation of CF patients. I m here taking this chance, taking this risk for the kids. RETSCH-BOGART: Preserving lung function, maximizing nutrition have become even more important so that when a really, really effective therapy becomes available patients will, you know, benefit the most. REISINGER: As an adult I ve been diligent about not only sticking to my treatment regimen, but exercise and making sure that I can stay as healthy as I can for as long as I can, and that s what inspires me to sit with my vest on for hours every day or going running or do all the different things that we have to do. LEIGH: So we ve greatly extended the lifespan of cystic fibrosis patients. We ve greatly improved the quality of life of cystic fibrosis patients. And we have changed their expectations and their dreams. DAVIS: All but one of my patients is over 50, and I had the pleasure

10 of hearing from an emergency room doctor when one of my patients developed acute belly pain and went to his nearest emergency room and we had a call from the emergency room doctor who informed me he could not possibly have cystic fibrosis because he was 62. And, you know, in some ways that s a triumph. (End video) DR. SOSNAY: Now I have the privilege of introducing our first speaker, Professor Stuart Elborn from Northern Ireland. He s here from Queens University and he s going to talk about the present in CFTR. DR. STUART ELBORN: Thank you very much Patrick. Thank you to the team at Hopkins for inviting me to come and talk at this great symposium. Watching those videos has reminded me that my first fellowship involving the care of people with cystic fibrosis started in I was at the North American CF meeting when the first discussion around the discovery of the gene occurred in Washington in that year. I could remember the real sense of excitement that went around that whole conference and the sense of optimism that we could make a difference. The next time I felt that feeling was when the results from the first ivacaftor study were shared. It was a very dark, cold February day, and it was about eight o clock in the evening because Bonnie Ramsey was the other person on the call with some of the team from Vertex, and when 10 we saw the data from that first ivacaftor study, truly the hair stood up on the back of my neck. It was a real sense of, well, the identification of the gene has now led to something that really makes a difference for people with CF. And for the next two or three talks, you re going to hear some of the exciting data that we now have on treatment of people with cystic fibrosis based on understanding of their genotype and directing the right therapy to the right patient. So I m going to try to: Describe how modulating and potentiating CFTR improves clinically important outcomes in CF. Describe indication for potentiator and combination therapy in CF. I m going to talk about the first two classes of CFTR mutations in the context of personalized, stratified or precision medicine for cystic fibrosis, and I ll come back to this concept in a couple of slides to elucidate what we mean by it, because it s a big drive across a number of diseases now, and I think it s important that we understand this concept. But before doing this, I want to get into this groove of history because it is so important that we acknowledge where we come from as we try to figure out how we apply stratified medicine with these new therapies to people with CF. This graph has grown in my slide decks over a number of years. I want to make a couple of points from it. The first ne is that we owe

11 a huge debt to the physicians and caregivers who observed what was happening in CF, did early observational studies, made empirical decisions about treatment, applied those decisions, and then tried to figure out how they might be working. The introduction of the sweat test, airway clearance, and then some of the therapies that began to develop around antibiotics and mucociliary clearance have made a huge impact and have been big part of why the prognosis for cystic fibrosis has improved over the last number of decades. The drugs that came out of these observational studies initially, and then in the last couple of decades through well-performed randomized, controlled trials with adequate powering for determining if we were making a difference, have given us a great armamentarium of therapies to treat infection and to improve mucociliary clearance. At the top you can see the last little bit says stratified or precision medicine. And we are moving into a new era where we re not treating the downstream effects of the pathophysiology of CF in terms of infection and mucociliary clearance, but we re getting right to the heart of the disease by being able to use drugs that now modulate the mutant CFTR that our patients have in their lung cells and improve the function right at that basic defect level. This is to remind you of the pathophysiology of CF, because I think that s important as we go through the next number of talks. 11 In the healthy lung the CFTR channel shown in cartoon works properly, it keeps the airways hydrated so cilia work properly. As you go across the normal you can see that the cilia and the EM picture in the middle are nice and straight and they re functioning well. That keeps our airways clear from all of the bacteria in the particulate matter that we breathe in with every breath, so that we don t get infection and inflammation in our lungs. The lower panel illustrates the situation in cystic fibrosis, where we have dehydration, it s a desert in the lower airways in terms of the hydration that s required to keep mucociliary clearance working properly. The particulate matter and the bacteria that people with CF breathe into their lungs, right from the time they take their first breath, is not cleared properly. And that infection sets up an inflammatory response in the lung which for a lot of complicated reasons gets frustrated and is persistent. The immune cells, particularly the neutrophils that come to deal with infection, start to damage the lungs in people with CF and result in inflamed airways, as you can see on the far side of the lower panel, and blocked, mucusplugged airways, which drive this injury in the lungs over many years. In thinking about the treatments we ll now talk about, I wanted to come back to the concept of stratified or precision medicine. This slide illustrates how we have traditionally approached diagnosing disease in people and then how we ve thought about

12 treatment: people present with symptoms, we make a differential diagnosis, we do some tests to confirm that diagnosis, and then we empirically prescribe a treatment. For example, if someone has high cholesterol, we do a cholesterol test and then we put them on a statin. However that means that we end up treating a lot of people with not too much effect, because trials have shown us that there were responders and nonresponders in these sorts of general diseases that have been treated empirically. What we re trying to do in medicine across a range of diseases and has been pioneered by the cancer field, is then when we make a diagnosis, to do some more tests that not tell us what it is, but tell us whether patients are going to respond to the therapies that we have available. That s a diagnostic test that s a bit different because it will drive therapy. And then that diagnostic test allows you to target therapy, which is now the key as it is for treatment for breast cancer, lung cancer, and a number of other conditions. In cystic fibrosis, the understanding of the gene and the understanding of the function of CFTR and the sorting out of the various classes that Patrick described to you have allowed us to develop a precision or stratified approach to therapy. The panel that s come up gives you the sort of principles around what is required for a stratified or precision treatment. You need a biological mechanism that 12 differentiates different groups or stratas, you need multiple treatments that are appropriate to one but not another, and you need a clinical biomarker. In cystic fibrosis we re now in that position: we have a fairly good understanding, although it s still not perfect, of CFTR function; we have a clinical biomarker which is the patient s genotype; and we now have a range of therapies, either licensed or coming through clinical trials that will allow us to select the right treatment for the right mutation in our patient groups. I want to pause for a second, though, and say this is really exciting, but we must remember that the therapies you saw in the first slide, the treatments for infection and mucociliary clearance still are important, because we haven t completely sorted this out, and the mutations of the CFTR gene only account for some of the disease phenotype in cystic fibrosis. So it s important that the conventional treatments that we have available are still used in our patients. Over the next 10 minutes I m going to talk about class I and class II mutations. This is some data from the European cystic fibrosis registry published by Kris De Boeck and colleagues, which gives you some data on the prevalence of class I mutations and class II mutations. Class I are in the top panels, class II on the bottom panels, and the plots are the percentage of patients by country. There s some quite interesting data in this which we won t have time to dwell on. But,

13 for example, in Israel, which is in panel A, the first bar, you can see that class I, which are stop codon mutations, are very common. But in Europe and similarly in North America, class I mutations account for around 10 percent of the mutations and the chromosomes of people with cystic fibrosis. And of those class I mutations, panel B gives you an indication of those that are nonsense or stop codon mutations. The lower two panels show you the prevalence of class II mutations. Panel C is all of class II mutations, and panel D is F508del mutations. And as you can see, these account for the vast majority of CF mutations in people with cystic fibrosis in Europe. Indeed, panel D indicates that the vast majority of these are F508del heterozygotes and homozygotes, and it s about 50/50. So people with F508del account for around 80 percent of the patients, with half of those being homozygote and half heterozygote. Class I mutations are shown on this cartoon, and again, as Patrick has already described to you, in class I mutations, the process of translation in the ribosome to make the protein from RNA is disrupted because the mutation stops the process of making the protein. These are mostly caused by nonsense mutations with the X, which indicates the stop codon, but can also be caused by frame shift mutations. Generally patients with this class of mutations have classical or severe phenotypes. 13 And to show you in a cartoon of how this works, this is the process of translation shown in a cartoon with the stop sign being the premature stop codon. In the situation where this occurs, the protein is not made properly. You may make a small, defective bit of protein that never gets very far and this is brought back into the cell, or no protein may be made at all because the RNA and the ribosome become unstable. To treat patients with this particular class of mutations, an observation with gentamicin by Batsheva Kerem and Michael Wilschanski and Eitan Kerem you saw Batsheva on the video indicated that it might be possible to read through that stop codon. And subsequent to that, a company called PTC developed a drug related to gentamicin called ataluren. Ataluren attaches to the ribosomal complex making the protein. It gets to the stop codon and there it allows the ribosome to read through, and the notion is that you would then get full length protein which would be normal CFTR and get up to the cell membrane. This looked like quite an exciting approach to treatment in some early phase 2 trials that were nasal potential difference, and similar trends were seen in lung function, improved on a couple of different doses of ataluren. This graph shows the nasal PD where a downward deflection is an improvement, suggesting the drug had a positive effect on CFTR function. This drug has now been tested in a phase 3 clinical trial. It was

14 published a couple of months ago in Lancet Respiratory Medicine and somewhat frustratingly, the phase 2 data was not confirmed in the phase 3 study. This is the lung function results from patients treated with ataluren on the green line compared to patients treated with placebo. There was a trend toward a benefit in the patients treated with ataluren, but the difference was not significant. This was looked at in a subgroup of patients who weren t using inhaled aminoglycosides, primarily tobramycin, and there was some encouragement. So we know that aminoglycosides have some effect in themselves on read-through in the laboratory, and when patients who weren t receiving aminoglycosides were looked at, there was a significant but still a small improvement in lung function. There are a number of potential reasons why this drug hasn t worked, and there is some controversy around whether this drug does result in read-through. So there is much work still to be done in class I mutations, but it is encouraging that a further clinical trial with ataluren aimed at patients who are not taking inhaled aminoglycosides is about to start. I m going to move on now briefly to talk about class II mutations. Patrick has outlined the biology of class II mutations where the CFTR protein is made, but it is very defective and most of it is degraded within the cell. However, a small amount does get up to the cell membrane and 14 that s estimated to be around 2 to 3 percent. This is illustrated on this slide. This is the normal situation where normal CFTR gets up to the cell membrane and works, and in class II mutations, particularly F508del, it doesn t get up to the cell membrane in any high number, but is degraded within the cells, thus being called the protease. In F508 there are a few CFTR channels up in the cell membrane, but even those that get there don t work properly; they are blocked channels, even those few that make it. Here is some work from Fred Van Goor and his team at Vertex. He was able to demonstrate that the combination of a drug called lumacaftor in cells that were expressing two copies of F508del in combination with ivacaftor on the far right bar resulted in some increase in chloride transport in this bronchial epithelial cell model, suggesting that this combination therapy of lumacaftor and ivacaftor could get more protein up to the cell membrane, and then ivacaftor could open the pores and get chloride conductance. And this has been through a number of early phase trials, and you will have seen the phase 3 trials I hope at Michael Boyle s plenary session and also presented today by Claire Wainwright. I m going to give you the highlights from these two trials, called TRAFFIC and TRANSPORT that recruited over 1,000 patients and were almost identical in design, comparing two different doses of the combination

15 of ivacaftor and lumacaftor against placebo. This is the, two separate trials with the lung function results showing significant improvements in FEV1 on both doses that were trialed in both studies. It is very reassuring that there s been a consistent response to the combination of lumacaftor and ivacaftor and that both of the doses seem to work pretty similarly and both were significantly better than placebo and were sustained at 24 weeks. We now have data beyond that suggesting that this effect continues up to 48 weeks. There was also a significant improvement in pulmonary exacerbations. This is pooled data from the two studies, and in this slide you can see that the time to next pulmonary exacerbation was reduced in patients who were taking combination therapy. We do have some debates within the CF community about what exactly is a pulmonary exacerbation, and this was broken down in a couple of ways to try and harden this up. And the events requiring hospitalization or events requiring IV antibiotics were also significantly reduced. This is very interesting data, because the improvement in FEV1 is less than what s seen with ivacaftor, but this is still quite a strong signal for reduction in pulmonary exacerbations. I think we now understand clearly that pulmonary exacerbations are a bad thing for our patients, so if we can prevent pulmonary exacerbations, we can reduce the 15 decline in FEV1 and also probably have a significant effect on survival. So this is a very important result from this clinical trial. There were some trends for improvement in body mass index and a modest but nonsignificant improvement in quality of life scores. In summary, the key endpoints from this trial showed a 3 percent improvement in lung function, a reduced time to next exacerbation, fewer hospitalizations, and some improvement in body mass index and quality of life. There is, however, some concern about the stability of this combination therapy on delta- F508 mutant CFTR. This has been a big discussion in the scientific and clinical trial sessions within this conference. But suffice to say that there are still some important aspects of CFTR function and stability that have to be understood so that we can further optimize treatment for homozygous patients with F508del. And it may be that a second corrector is needed to stabilize this molecule to get the best out of it in chloride ion transport, and hopefully further improvements in the clinical outcomes. It is so exciting over the past number of years to have been able to be involved in care and clinical trials in CF when we have a realization that CFTR is a druggable target. We now have treatments that will change the

16 function of this protein. Ataluren has a limited impact at present, but I think there is still some optimism that drugs can be developed for class I mutations. Finally, the lumacaftor/ivacaftor data indicate that this is a very promising combination. We still have a way to go to get the best combination or combinations of drugs to continue to make a significant impact on this class of mutations in cystic fibrosis. Thank you very much. Segment 4 DR. PATRICK SOSNAY: Next I get to introduce my coworker, Meghan Ramsay, who is a nurse practitioner in the adult clinic. She started as a nurse practitioner when I was a fellow, so much of what I learn about taking care of patients with CF patients is from Meghan. She s going to talk a little bit about the context of these exciting new therapies in respect to everything else with the burden of treatment that our CF patients have. MEGHAN RAMSAY: Thank you all. I hope everyone s enjoying their evening. I m going to talk with you about managing patient expectations. So to get started, we ll go through the learning objective: Define better ways to manage patient expectations about new therapies. I ll give a little bit of insight, and I probably won t have the full 16 answer, but I will work as hard as I can. This slide was used by Dr. Mike Boyle at a plenary session a few years ago, and bits of it have always been pulled out for talks, but this is why it s not an easy question, there s no one answer. Because when we look at the genotype and genetics, CFTR is, yes, part of the equation for the variation in lung function, but we still know and have heard, that even if we know the genotype, we still can t predict heir lung function. Part of their variation in lung function is from CFTR, but it s also modifier genes. The other whole 50 percent of their variation in lung function is environment, and we all know adherence is a big issue. A lot of research is going on about that right now. We also know that environmental exposures play a big portion, and their treatment and their access to medications and to care also plays in. There is also a whole other random element that s we re not even sure we have the full answer to in the variation to what s causing the variation in the lung function. When I was putting this together I was thinking, when ivacaftor first came out, everyone heard the headline, the nurse coordinators and probably other people in the facility, and I got multiple s, multiple calls. Everyone wanted to know when they could get started, what this meant for them, or they wanted to know what genotype they were. Many people didn t know their genotype, I feel patients have become much more

17 educated since ivacaftor has come out. We ve also been able to find more genotyping in our patients, so we ve had a lot more discussion about it. We knew some of the information that had come out from the research on ivacaftor. Obviously, everyone was extremely excited, and we were able to relay the research finding to our patients, but what were the patients hearing? What they d been hearing now has been more buzzwords about new treatments coming out there. I did a quick Google search and found some of these words that we re going to be up against about what our patients are hearing and somewhat expecting. One of them was that it s a dream come true. As a parent this is such a dream come true, Camille said, she s the mother, Dylan has started growing and gaining weight and he s missing fewer schooldays, and overall he s feeling much better. And then another title of an article was it s a new wonder drug that can heal lungs of CF sufferers. So what brings us to this miracle or hope idea that I ve written about here? I asked a couple of our patients who have gone on ivacaftor, and I asked them for one word they could tell me about being on the medication. Well, I didn t get one word, I got probably two pages worth of information from both of them. I ll go through their stories and we ll talk about this miracle or hope. One patient who started on the medication had been preparing 17 herself for years ahead of the drug so that her lungs could be the healthiest they could. She nailed down her treatments, she started exercising aggressively, she improved lung function on her own before she went on this treatment. And a lot of this is because she had a sister who had cystic fibrosis and she saw her dwindle and wait three years for a lung transplant, and then she eventually did get the lung transplant and is still alive. So she had this in the back of her mind that some day, cystic fibrosis was going to cause this progression for her. So she wanted to get her lungs in the best state she could, she got as healthy as she could, she got on the medication and she says that everywhere in the community that she sees about cystic fibrosis on the blogs, on the Internet, is that the drug is a miracle. She says it has given her hope. She says she has been able to have hope. She has a family. She has recently become a new parent, and she feels that she has a hope to control her destiny with the hope that she is so grateful for for the CF community with the drug. She said she still works hard every day, she still exercises and does all of her treatments. Another patient was part of the clinical trials, and she decided about six months into it that she didn t feel CF sick anymore. One of her online friends who had CF it was not a person-toperson friend and I do trust this patient had told her that she had lost her CF card, because she was on a therapy that was correcting the underlying defect.

18 Our patient said, I didn t quite feel like I lost my CF card, but I finally feel like for the first time I m not CF sick. She says it s still a trial every day because she still does her treatments, she is also married and has a child, as well, and she also said that this has given her hope. It helps her with her treatments and it s given her hope for the future with her family. So what are we to do with hearing our patients who go online and hear about a medication? They hear these case stories from other patients, they hear that it s a miracle and we know that only a little bit over 4 percent of the patients right now are on this therapy, and obviously on the horizon there will be more. Well, unfortunately we won t be able to put a lot of people on the drug right now, so we ve got to keep up with the treatments and do what we ve been doing. A lot of that involves adherence, which is very difficult. We all know that s what we struggle with every day with our patients, letting them know that we ve got to keep their lungs healthy. This drug s only going to help their lungs if they can get on a medication that s going to help with the underlying defect; it s going to help their lungs for the future. So we ve got to keep them as healthy as we can, a lot of this is communication and the explaining what their genotype is and what we know about their genotype and possibilities. We let them know about the Cystic Fibrosis Foundation pipeline and where the research is. 18 I feel keeping them informed has been very helpful. I think it also decreases a lot of anxiety when you re talking with your patients and communicating with them about what you know about the drug and what that means to them. This also means they re coming together as your team and trying to figure out how you are going to disseminate the information to your patients. When a new article or headline comes out, suddenly you get a bombardment of s asking is this for me or what more do you know, thinking I have a whole lot more information than what s out there, you can proactively send them information or have a communication plan for your patients, or tell them what you are going to do when a new drug does come out. And I think that will help allay a lot of the patients fears and help us as providers tackle this. A lot of it is communicating with the patients and families and educating them on what genotyping is and what that means to them. We can also let them know we don t always necessarily know the answer and we re not hiding it from them, but we re still working on it. In summary, I don t have that miracle answer. There are some things that we can t change when we look at the CFTR. Some patients are going to be eligible for certain medications and some aren t, but we know that there are some environmental factors we can change. We might be able to change some

19 of their exposures and improve their adherence, and this is something to be aggressive about, to talk with them about adherence to their treatments, because it does go a lot longer way than they may think it does. And again, communicating with the patients, getting them familiarized with the CFF.org, the pipeline, getting them familiarized with research and where we re at and what their genotype means to them. Hopefully in the future of our patients and in the future of this presentation we ll have a lot more hope when we leave here tonight. Thank you. Segment 5 DR. PATRICK SOSNAY: Our next video talks about tomorrow and the future, and what are the next steps to hopefully make cystic fibrosis as much as possible a disease of the past. (Begin video) BOYLE: It s great to look back 25 years at the discovery of the gene. I guess the real question is, what about looking forward? FARRELL: I ve never been more optimistic or hopeful in my entire career. CHMIEL: We are at the precipice, and I think the advances that we re going to see in the next 5 to 10 years are going to be exponential. WINE: The rate at which the 19 discovery process is moving forward here, and the fact that it s now clearly a combination of industry and academic research labs, is unlike anything I ve ever seen before in the CF field. DONALDSON: Now we know what can be achieved, and that tells us where we need to go. RETSCH-BOGART: I see the discovery of the gene, understanding the protein, understanding how the cell processes the protein, and the variations in the protein from all the different CF mutations that we now are aware of, these are all tightly linked, and continued success in developing therapies is going to be that tight understanding between protein structure, cell biology, and drug therapy. BOYLE: The results from the trial that were announced this summer basically demonstrated clearly that we can do the same thing in patients with F508del. The results showed an improvement in FEV1 and showed an improvement in how frequently patients were sick. Now, it s not to the levels we saw with ivacaftor and patients with G551D, but we re not surprised about that because we knew this was going to be a harder nut to crack. The reason we re so excited, though, is obviously this is a much bigger group of patients that we have a chance to impact. KEREM: Probably ivacaftor could help other mutations from class III and class IV, and maybe can be even combined with a corrector

20 for delta-f508 or an agent that will promote read-through for nonsense mutations. DRUMM: About 2,000 different mutations in this one gene can cause disease, and we know very clearly that one size won t fit all. So a compound that works for one individual or one mutation may not work for another, but the fact that all these other drugs are in the pipeline means that we re probably going to keep hitting more and more and more of these patients, getting us to the point where we re going to be talking about semantics to say we have a cure versus we have a treatment for it. And we re making really big strides, and I think that s incredibly exciting. BOYLE: We know we re not done yet. We know we need to get stronger agents, we know we want to increase to patients who have just one F508del mutation, the most common group, but we ve been waiting for this for a long time. It couldn t be more exciting to treat the underlying cause and see a difference in how they re doing, it s exactly what we were hoping for. TSUI: I m quite hopeful because now the high throughput screening and the drug libraries are all available. It just requires a magic moment to identify this particular drug. BEALL: Obviously, now there s hope that lumacaftor and ivacaftor will be approved by the Food and Drug Administration for homozygotes, we re working on heterozygotes, and we ve got a pipeline for the nonsense 20 mutations. RETSCH-BOGART: To me the excitement comes from the width and depth of the pipeline in terms of the kinds of agents that we are now looking at, novel approaches to managing lung infection, because that will probably still be an issue for patients even if they have a great protector potentiator drug that improves their CFTR function. LEIGH: I have worked with patients with cystic fibrosis for a long time and I, as much as they, I want to see the day when there s a cure for cystic fibrosis. BESSETTE: Hopefully the next generation of patients with CF won t even have to acknowledge they have CF because we ll have found something to take care of it. VON BERG: My hopes for the future are that we have the magic pills to not help the 4 percent of people living with CF, but that we can help everyone living with CF. PATTEE: That might be what keeps me going, that hope and passion for the future, that we re going to be have better treatments and be able to help more people with CF live longer. RIORDAN: The hope is to be able to restore enough normal CFTR function in any individual who has a mutation. REISINGER: It s given so much hope for the CF community, and that inspires me to stay healthy, knowing that there are new drugs on the horizon.