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Transforming cystic fibrosis treatment

Published on 05/04/18 at 10:29am

Fred van Goor, Principle Research Fellow at Vertex Pharmaceuticals, discusses his history of work in cystic fibrosis and how the company’s development of Kalydeco succeeded against all odds.

What is your role at Vertex?

I’ve been working at Vertex since 2001 and they’ve had developmental programmes for Cystic Fibrosis (CF) since day one. There have been some big challenges but we’ve been fortunate to have some successes along the way, as well.

I started out by understanding how our compounds work and then, in the past 10 years, I have also been involved in all of the development programmes and also worked a lot with the regulatory bodies around the world, following the drugs through all aspects of the drug discovery, development and commercialisation.

How did you come to work on developing medicines in CF?

I was post-doc and this has been my first and only industry job. When I first began, I actually wasn’t in CF but I moved into the area, which was only a small project at the time and there were only a few of us working on it. It was an important project though, and in collaboration with the Cystic Fibrosis Foundation. I think what’s unique about working on this programme is that the team that work together on this, based in San Diego, have been involved in the area together for more than 10 years. Once you get into it, you just become so attached to it for a number of different reasons: one of the reasons is that the science is so interesting and challenging; to do what we’ve been trying to do, you’ve got to remember that, when we first started, everybody called it “the fantasy project” because what we were hoping to do was bring a protein from inside the cells to the cell surface, where it’s actually supposed to be. This was considered a fantasy. We’ve always believed in it and believed in targeting the underlying cause of CF, which we always thought would involve developing a combination therapy. From the beginning, it’s been about finding different combination that work together on different mechanisms.

The other thing that makes the role so rewarding is the sense of community you feel as part of the CF community. For many years, from the very beginning, we’ve had people with family members living with CF come to us and visit the site – some of them we’ve grown up with; some started to visit us to cheer us on when they were only five years old. In fact, one individual grew up and even started working with us on an internship, just last year. Those connections that you form, when you’ve been working on a disease for 20 years, are important.

Lastly, one of the things that has kept me going is the team. We’ve worked together in this area for so many years that it’s rewarding to stay a part of it as your working relationship and a level of trust develops. It’s such a hard thing to develop multiple medicines as we have, there’s so much risk and capital involved, that the right team is just so important. We know each other’s strength and weaknesses. These reasons are also what has motivated me to remain working in CF. I’m committed to working on the CF programme until we’re done.

Your base is in San Diego whilst Vertex is based out in Boston, has this been a driver in forming a close-knit team?

One of the things that it has really allowed us to do, and was particularly important in the beginning when we hadn’t had the kind of success that subsequently came along, is to stay focused. It is so easy to get taken off the path and lose that concentration that is required but our San Diego site has always been targeted on finding treatments for CF and developing therapies for the underlying cause.

I think each different site across a company has a different personality and in San Diego, despite being part of a larger pharmaceutical company with all of the experts and knowledge that this brings beyond research, as our base is just a research site we have been able to maintain that biotech culture. We started off as Aurora Biosciences and we were innovating in tackling tough diseases, and I don’t believe we’ve lost that attitude – we thrive on that challenge.

Could you talk about the history of your first major success in CF, Kalydeco?

It’s become harder to develop new compounds. To find the first compound, we had to do a lot of screening – over the years, we’ve screened well over two million different compounds. To flip the whole programme into perspective, for the screens we did for Kalydeco we made about 700 molecules, by hand. To get to Orkambi, we made about 2,500 molecules. For the next generation correctors, that was by far the hardest; we started working on these back in 2008 and actually came from trying to understand how our first-generation correctors worked. We found you could combine two different molecules, working at two different sites, to further improve efficacy.

In 2008, we screened about a million different compounds to identify a next generation corrector and we made about 40,000 molecules by hand – that is way more than we’ve ever made to achieve a breakthrough. It’s not just a needle in a haystack – it’s a significant commitment, it’s the effort and investment to get to the types of levels of benefit that we’re seeing in some of the proof-of-concept studies today, and we’re still working on it. We had about thirty people working on the first medicines that we developed and we now have over a hundred people working on the next generation programmes we’re working on now. In terms of time, we can screen half a million compounds in three months and making 40,000 molecules is a multi-year effort. The real challenge is designing the first hit to go on to make a drug.

Your team has tripled in size since you discovered your first drug. How have the project and your research changed from when you first began?

That’s a big part of our story. We started off as this tiny project that when Vertex first bought Aurora they didn’t know what to do with. We’d always heard that it was impossible to do what we were trying to do and I remember every year at our San Diego campus we would have a science update and all the executives would come across from Boston to check out what we were doing. The CF programme was one of the smallest at the time. Then when we first showed proof-of-concept with Kalydeco, everyone started to pay more attention to our little programme – not just internally.

Kalydeco will always have a special place in the CF world, both internally and externally, because the level of improvement that we saw in that first proof-of-concept study just far exceeded anyone’s expectations. I remember that day like it was yesterday when we first got the results – everyone was sat around the table and everybody just cried because it was so unbelievable, after being told it couldn’t be done. It focused the company on targeting CF and the CF programme, but more importantly it focused the CF community. When we say “Kalydeco-like” that [means] something to people because that’s associated with such a transformative benefit. We’ve been focused on bring that level of benefit to people ever since then.

Where is CF treatment headed next?

We’ve provided a lot of hope over the years but we’re not done yet. We’re continuing to work on different kinds of therapies for the 5-10% of people who won’t respond to our current therapies with nucleic acid therapies and gene editing, through CRISPR, to try to get to all people with CF. There’s still more to do; it’s great that we’ve had success previously but the aim is to bring therapies to all people with CF. We’ve got more to do bring triple-therapy combination to patients and we’ve brought four into the clinic so far, and we’re going to bring two forward to Phase 3 clinical studies. We don’t want to make sure we get the first molecules out there – we want to make sure we get the best-in-class therapies out there.

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