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
