Bonnie Ramsey remembers the dark days of treatment for cystic fibrosis. About 30 years ago, when she devoted her career to the research and treatment of this genetic lung disease, children who were diagnosed had a life expectancy of about 17 years. The outlook is much brighter for patients now, as quality of life has improved significantly, and median lifespans have doubled.
But part of what makes Ramsey more optimistic today is an experimental treatment from Vertex Pharmaceuticals (NASDAQ: VRTX), based in Cambridge, MA. This drug, VX-770, along with a related compound, VX-809, have the potential to be the first drugs ever to fix underlying genetic defects at the root of this condition that affects 30,000 people in the U.S., she says.
Ramsey’s opinion counts for a lot. She’s a clinical researcher affiliated with Seattle Children’s Hospital, and the University of Washington, and serves as executive director of the Cystic Fibrosis Foundation’s Therapeutic Development Network, in which she coordinates a 77-site network of clinical trial sites dedicated to helping companies develop new therapies for this rare disease.
The work for the CF Foundation is how she first got exposed to San Diego-based Aurora Biosciences in 2000, the company that began developing the new drug and was later acquired by Vertex. The CF Foundation has contributed more than $75 million to Vertex to keep the program going over the years, so this is a relationship that’s hugely important to both sides. The drug has now shown enough promise that it has advanced into the final stage of clinical trials needed to win FDA approval.
Ramsey spoke with me in depth about the changing standard of care in cystic fibrosis, why the Vertex programs matter, and how foundations are playing an increasingly important role in financing clinical trials. Here is an edited account of the conversation:
Xconomy: So you got started back in the dark days of treatment for cystic fibrosis, 30 years ago. What have been the major advances since then?
Bonnie Ramsey: There have been advances in terms of research, and those have been phenomenal. Things really turned around in the 1980s. Everyone is aware the gene was identified in 1989, but actually for three to five years before the gene was identified, there had been seminal work in understanding that it was a defect in ion transport, or salt transport, in epithelial lining cells. There had been articles in the New England Journal in terms of what caused the salty sweat in patients. That was because of this abnormal salt transport patients had.
Then when the gene was identified in 1989, they were able to move forward at exponential speed and identify what the faulty protein was, where it was located, and how the protein functions normally, and what was wrong with the dysfunctional protein.
X: Despite all this fundamental, underlying biology that we now know, it hasn’t really added up…
BR: It hasn’t had any impact on treatment. That’s right. We now clearly understand what the cystic fibrosis protein does, and what goes wrong. We also know there are these different classes of mutations. There’s a type 1 mutation, where the protein isn’t transcribed. Those are called premature stop mutations. That’s the type of mutation that [South Plainfield, NJ-based] PTC Therapeutics is working on. Then there are other mutations, the most common type is the Delta F508. That’s one where the nascent protein is made, but doesn’t get properly trafficked up to the surface of the cell. Then there’s the type 3, the G551D, which is what the Vertex product is working on. That’s where the protein gets to the surface, but it’s not properly activated. So it gets up there to the surface of the cell, but it can’t properly transport the salt. Then there’s actually types 4 and 5, in which there are abnormalities in the channel itself.
But I think what’s really key now is that for the first time we’re really looking at therapies that could correct the protein. So, you ask, why has lifespan doubled when we haven’t been treating the underlying defect?
I think it’s because we started looking very systematically at the management of the illness and asked, “How can we improve the management and the secondary consequences of an abnormal protein?” The secondary consequences are where you get this dry, thickened mucus that blocks multiple organs, like the pancreas, the lung, the liver, the testes. You try to figure out better ways to hydrate and mobilize secretions. We know in the lungs that this mucus leads to secondary infections, and so we asked, ‘How do you better treat those infections?’
Over those 20 years, we’ve been much more aggressive in general treatment. It used to be you didn’t treat kids at all until they were almost school-age. I’m talking about the lung disease. They started coughing up sputum. We realized by that point, a lot of lung damage had already occurred. I think it’s an approach very similar to what happened in pediatric oncology, where they started getting very aggressive upfront, rather than waiting until they relapsed, and were already too sick. Now we’re very aggressive about starting nutritional supplements and enzyme therapy in the newborn period, because we now have newborn screening that’s nationwide. Children are never allowed to get malnourished and get vitamin deficiencies. That nutritional aspect, and management of it, has had a major impact.
You could say, well, why didn’t you do that 30 years ago? I think a lot of it has to do with the mindset. It’s interesting. A lot of it is a matter of saying, ‘Yes, we can change this.’ This is also what happened with leukemia in the 1960s. People have said, ‘We can do something about it.’ Then you get much more aggressive. I do think that a secondary impact of discovering the gene and the protein in 1989 was that people said, ‘You know, what? There’s a chance we can cure this disease. Therefore, we had better make sure these patients are doing well.’ Hope has a huge impact on the way people approach disease management.
X: Even with the gene, people turned to gene therapy, and it didn’t work.
BR: That’s right, but, psychologically, it changed the way we approached patients.
X: So we’re still benefitting from the fundamental understanding of biology. But what kind of potential does this really offer to patients if lifespan has doubled?
BR: First of all, lifespan doubled, but that means you’re getting into [the mid-30s] or so. And remember, we’re talking about median survival, so there’s a bell-shaped curve. You’re still going to have patients who are getting very sick when they are teenagers. Then other people get sick when they are 30 and 40. Even a doubled life span is not a normal American life span. You still are decades away from the average lifespan, so we need to improve that.
Second of all, although quality of life has dramatically improved, these patients still have to go through a very time-intensive regimen. They have to spend hours just managing all their medications, their airway clearance. They are more susceptible to infections. Most of them will have a couple of major illnesses a year where they have absenteeism from school or work. It’s not a normal life. So it’s intensive in terms of the time a patient spends on it, and it’s intensive in terms of health care.
X: Why are you excited about the Vertex treatment?
BR: This is the first time that a therapy—a small-molecule, not gene therapy—is actually directed at trying to correct the protein. We’ve had other therapies that tried to improve ion transport by going around and using alternative channels. That’s the approach that [Durham, NC-based] Inspire Pharmaceuticals has with denufosol. But this [Vertex’s VX-770] is actually trying to correct the protein. So if it works, we have shown this concept works. You actually can change a dysfunctional protein into a functional channel. Whether it turns out that Vertex is 100 percent successful or not, this is such a giant step forward, it’s like a man walking on the moon.
Now, the CF Foundation has had a long partnership with Vertex. The CF Foundation decided it had to try to go out and find a small-molecule. So they set up a partnership with Aurora, which then got bought out by Vertex. The idea was to do this high-throughput screening. It was really challenging, because they didn’t have the right kind of assays. You’ve got to have an assay to do your screening. To find an assay looking for changes in chloride transport—that was something they had to develop. The CF Foundation, and CF researchers around the country, really worked with Aurora to develop these assays and then develop a drug screening process. They got some hits. Then Aurora, and subsequently Vertex, really did a phenomenal job, with a lot of support from the CF Foundation. They then used combinatorial chemistry to get an initial hit, they’d make changes in the compound, go back and test it again, and all the while developing assays to see if anything was getting better.
I was fortunate enough to be on one of the advisory boards. It was an amazing process to watch. They’d say, ‘Well, we’ve hit another barrier, I’m not sure we can make it any better.’ Then, sure enough, you’d come back six months later, and they figured out a way to make it 100-fold, or 1,000-fold more potent. So it was an amazing process. Then fortunately, as you develop a medicinal product, you can have a very effective chemical, which unfortunately can’t be a drug. It might be toxic, or not properly absorbed, or metabolized too quickly. There’s a lot of things that can go wrong. They really lucked out. These small-molecules were really good drugs. But one thing they couldn’t do was find one drug that could take care of the whole process. So, in patients with the most common type of CF defect, delta F508, the protein is not properly transported to the surface of the cell, and then it doesn’t properly open. It looked like there were different kinds of small molecules needed for the trafficking, and for the opening. They basically came up with two drugs, rather than one miracle drug that could do it all. I think initially, they were hoping it could all be done by one, but so far it looks like two drugs. That’s VX-770, and VX-809.
X: So the CF Foundation has put a lot of money, and a lot of time, into this. Did the foundation have internal debates, or face critics who said, ‘You’re putting too many eggs in this one basket,’ or, ‘Why are you putting all this money in, and letting somebody else make all the money from it?’
BR: You’d have to ask (CF Foundation president) Bob Beall those questions. I must say, first of all, the CF Foundation board was very supportive of the concept. Bob Beall is truly an amazing human being. He’s visionary, and focused. I remember early on, he said, ‘This is going to work.’ You know, I’ve been involved in CF research for 30 years, and I can remember thinking that there was no way this is going to work. But I will say, that once I realized the quality of the team that had been put together, both on the CF Foundation side, and on the Vertex side, if anybody was going to be able to pull this off, they would.
Oftentimes, you’ll hear people going off on these fishing expeditions where they just don’t have the talent to pull it off. But they really, really had a phenomenal team. And a very careful team. This was very methodical, all along the way, and in getting the right people in there to do it. And there’s luck. There’s no question there’s luck. You could do every step right, and you could still end up with a drug that was too toxic.
X: But it hasn’t gone all the way through trials yet. What gives you so much confidence?
BR: That’s absolutely right. We’re in a Phase III study now, which will tell us whether it really works or not. The reason I’m feeling more confident is that it’s gone into humans in Phase I and II. There haven’t been any showstoppers. Often if you are going to see acute toxicity, you’ll see it there. They are able to get good drug levels in the body. It’s an oral tablet, it’s easy to take, easy to tolerate. That’s all very encouraging. That’s been the case for both Vertex drugs. VX-809 is one phase behind VX-770. There hasn’t been a showstopper yet for 809 either. The difference there is we don’t have data yet on how effective it is.
With VX-809, we may not be able to truly tell how effective it is until the time comes when it can be combined with VX-770. Remember, VX-809 does the first step, it gets the protein up to the surface of the cell, and then VX-770 opens it up. So if you just get it to the surface, without anything to open the protein, you may not see a lot. Except that you got it to the surface.
With VX-770, there was a natural selection process that helped them. There’s a genetic defect called G551D, which does the trafficking to the surface itself. So all you have to do is open the protein. If you choose those patients—and that’s why they chose an ultra-small patient population—if you choose G551D patients, their proteins can be opened up.
X: That’s maybe 10 percent of all CF patients, right?
BR: Right. The downside is there aren’t a lot of these patients out there. They are going to test it in the more common patient type, the delta F508s, but they decided to start with this group because they figured the odds would be best.
They did a Phase 2 test in G551Ds, which showed a dramatic improvement in the sweat test. This was incredibly exciting, because there is no treatment—ever—that has been able to change the sweat test. The sweat test is a measurement of the underlying protein abnormality. Also, it showed an improvement in lung function. And it showed a change in the nasal potential difference, which is another measure of the channel, the ion channel. We measure voltage transfer across nasal passages. So the sweat test, and the nasal potential difference, are both measures of the protein function. And both of those changed with VX-770. That, and the fact that the drug is safe and easily absorbed and so forth, is the reason that it’s encouraging.
X: So you saw an alignment between fixing the underlying biological problem, and the clinical outcome? It’s rational.
BR: Absolutely. The whole thing makes sense. The other time I felt like this, way back over a decade ago, was when we developed the inhaled tobramycin [treatment]. It all made sense. The drug killed the bugs. The lung function got better. It was a similar situation. We had seen in Phase II what we thought we’d see. Fortunately we saw the same thing in Phase III and the drug got approved. So we’re hoping the same thing will happen here. If they can just show again what they showed in Phase II, that will be a strong message.
X: We hear a lot from biotech companies, in the downturn, increasingly turning to disease foundations like the CF Foundation and others for help in development. Why does this model make sense, and what makes for a good partnership?
BR: The reality is that while CF is one of the more common rare diseases, it’s still a rare disease. In the past—and I will say this is changing, because somebody like Vertex could potentially be very profitable here—traditionally, big companies like Pfizer or GSK didn’t want to touch rare diseases. There’s just not a big enough market. With something like this, where else are you going to use it besides with CF? If you’re developing a blockbuster, you want to be able to use it for multiple indications, or across millions of people. The only way rare diseases could really attract a company to work in this area would be to go to them and say, ‘We’re going to reduce every possible barrier you might have.’ So we take the financial risk early on. We let you get a profit later. As long as we get the drug. And we’ll have a system set up so that you can get access to the patients.
There are two big risks that companies have. There’s the financial risk upfront. But second of all, they need to get patients enrolled in studies so they can get their drug approved. There are many barriers to doing trials in a pediatric population, because they’re a vulnerable population. But I think that with rare diseases, the families are more motivated to get treatments. They sign up for studies.
But that’s largely because the CF Foundation has done a huge job of putting together this clinical trial network called the Therapeutics Development Network which we run. There are 77 sites now around the country. That means the doctors, and nurses, and researchers are all very well trained in how you conduct trials. The other thing the foundation has done is set up a huge national education effort for families. It’s set up to explain to them why they need to participate in research. How do you tell whether a research study is a good study, or one that’s worthless? The program is called “I am the key.” They have all this education material to get families to enroll.
X: How has that played out in the Phase III trial for Vertex?
BR: Everybody knows within the network who the patients are. They are all being followed in the clinic. It’s not like a hypertension trial, where you go out and put ads in the newspapers and hope people start coming in. This is a very captured audience. But, it’s a tiny audience. So each center will only have probably less than five patients. So they have to go to many sites to get enough patients. But that wasn’t a problem, enrollment, in the Phase II trial.
X: Do you get many companies knocking on the CF Foundation door trying to get into the network?
BR: A lot of companies are interested. They have obviously heard the CF Foundation will support some companies. The foundation has had to get more selective, because we can’t support everybody. Companies know it’s a good system.
X: What about other disease foundations? Are they studying your model?
BR: I’ve talked to the autism group, the hydrocephalis group. Years ago I talked to a sickle-cell anemia group, pediatric nephrology. Over the years I’ve talked to lots of groups about it. Rare disease networks are now pretty commonplace.
X: But are there still people donating to the cause in a way that it enables enterprising biotech entrepreneurs to turn to groups like this, as a viable way of keeping their pipeline moving forward?
BR: Yes. The foundation is still supporting several biotech companies, and is still extremely active. Things are moving forward.
The NIH, as well, particularly now that Francis Collins is going to take it on, he’s been close to the CF community for years. As you may remember, he found the gene. He’s very interested in this model, the CF drug development model. I don’t know, I haven’t talked to him about this, but he may work on how can NIH better partner with industry to help with developing new therapies.
But it’s the federal system, so it’s got to be a rigid system, and it’s been hard for industry to partner for that reason.
X: So five, or 10 years out, what kind of prognosis or life expectancy will CF patients have?
BR: I hope in five or 10 years, one of the therapies is available and working, and we’ll see about it’s impact on lifespan and quality of life. I hope that both VX-770 and VX-809, or drugs with similar modes of action will be approved and available. I don’t like the word ‘cure,’ because I don’t know what that means. No matter what they get, they will have to be on treatment for the rest of their life. To me, a cure is like taking a vaccine and you’ll never get an illness. But these are treatments that will significantly alter the course of the illness.
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