Inside View The Long Road To Treatment And Cure For Cystic Fibrosis

Cystic fibrosis (CF) was once considered untreatable. But over 20 years, Paul Negulescu and a team of scientists at Vertex in San Diego have taken steps to unravel and help treat the disease, in which a genetic defect causes a build-up of mucus in the lungs and digestive system. Those milestones led to Negulescu receiving the 2018 Warren Alpert Foundation Prize this month. He discusses his ongoing journey toward a CF cure. What is the significance of your being honored with this award? This Alpert Prize is an example and reminder of what we, as a scientific and medical community, are supposed to do. We are supposed to help people by understanding the cause of diseases and developing therapies that effectively treat or cure them. It’s a tremendous feeling to be recognized for contributing to improvements in human health. It’s why most of us go into this type of research. This was not an easy or rapid path, so it’s wonderful that the work done by so many people for so many years is being recognized. It’s a great feeling to acknowledge that our team has stuck together for so long to work on such a difficult challenge. But there’s still more that we can do.

Isn’t 20 years an unusually long time for a drug discovery project to come to fruition? Most of the time projects don’t get that long to incubate and to deliver. There’s a story here about being persistent as long as the science is moving forward. Vertex really supported that process. Describe Vertex’s commitment to CF research. Our motto is: We are all in for CF. We continue to do research at the same level or higher than five or ten years ago when these compounds were in the early stages. We’re continuing to try and come up with better compounds. What were the signposts that encouraged you? First, we developed an assay that we thought could be used to test and screen for compounds that might rescue the function of CFTR, the protein compromised by the genetic defect underlying the disease. Then we screened that assay over a million compounds and we got a few hits, which we verified. Then we optimized the compounds to make them suitable as drugs. Then we realized that we probably wouldn’t succeed with just one compound. How did you become interested in CF? I first learned about CF while doing graduate work in epithelial biology at the University of California, Berkeley. I was studying the role of CFTR in the stomach. Years later, when I was at a biotechnology start-up called Aurora Biosciences, we were approached by the CF Foundation to develop assays and screen compounds that might rescue the function of CFTR. Vertex then bought Aurora in 2001 and continued the project. So, it was a case of having the relevant training and then being at the right place at the right time. Describe the progress made in CF research since you started working on this disease. In 1989 when the CF gene was identified, the hope was that gene therapy would be the next step. But gene therapy hit some setbacks in the 1990s, so the field tried to focus on symptomatic therapy, like antibiotics. At Vertex, we decided to go after the underlying problems. Tell me about Vertex’s CF pipeline. We have three approved CFTR modulators on the market. One is a single drug that helps about 10 percent of people with the disease. We also have two approved two-drug combination therapies that cover about 50 percent of those with the disease. We now have two triple drug combinations in clinical research trials that we hope will raise the proportion of treatable CF cases to about 90 percent. What is the future of CF treatment? We are moving into the area of genetic-based therapies in terms of thinking about a cure. We have a research collaboration on gene editing for CF. There are better tools available than we had 15 years ago. It’s reinvigorating the field. What’s your relationship with the CF community? The patients have been with us since day one — long before we had any compounds. We’d do fund-raising walks with them. We met some of them as babies or young children and now they are grown up, going to college, and getting treatment. It’s great to be told you are making things better for them. Learn more about the Alpert Prize here.

What is the significance of your being honored with this award?

This Alpert Prize is an example and reminder of what we, as a scientific and medical community, are supposed to do. We are supposed to help people by understanding the cause of diseases and developing therapies that effectively treat or cure them. It’s a tremendous feeling to be recognized for contributing to improvements in human health. It’s why most of us go into this type of research.

This was not an easy or rapid path, so it’s wonderful that the work done by so many people for so many years is being recognized. It’s a great feeling to acknowledge that our team has stuck together for so long to work on such a difficult challenge. But there’s still more that we can do.

Isn’t 20 years an unusually long time for a drug discovery project to come to fruition?

Most of the time projects don’t get that long to incubate and to deliver. There’s a story here about being persistent as long as the science is moving forward. Vertex really supported that process.

Describe Vertex’s commitment to CF research.

Our motto is: We are all in for CF. We continue to do research at the same level or higher than five or ten years ago when these compounds were in the early stages. We’re continuing to try and come up with better compounds.

What were the signposts that encouraged you?

First, we developed an assay that we thought could be used to test and screen for compounds that might rescue the function of CFTR, the protein compromised by the genetic defect underlying the disease. Then we screened that assay over a million compounds and we got a few hits, which we verified. Then we optimized the compounds to make them suitable as drugs. Then we realized that we probably wouldn’t succeed with just one compound.

How did you become interested in CF?

I first learned about CF while doing graduate work in epithelial biology at the University of California, Berkeley. I was studying the role of CFTR in the stomach. Years later, when I was at a biotechnology start-up called Aurora Biosciences, we were approached by the CF Foundation to develop assays and screen compounds that might rescue the function of CFTR. Vertex then bought Aurora in 2001 and continued the project. So, it was a case of having the relevant training and then being at the right place at the right time.

Describe the progress made in CF research since you started working on this disease.

In 1989 when the CF gene was identified, the hope was that gene therapy would be the next step. But gene therapy hit some setbacks in the 1990s, so the field tried to focus on symptomatic therapy, like antibiotics. At Vertex, we decided to go after the underlying problems.

Tell me about Vertex’s CF pipeline.

We have three approved CFTR modulators on the market. One is a single drug that helps about 10 percent of people with the disease. We also have two approved two-drug combination therapies that cover about 50 percent of those with the disease. We now have two triple drug combinations in clinical research trials that we hope will raise the proportion of treatable CF cases to about 90 percent.

What is the future of CF treatment?

We are moving into the area of genetic-based therapies in terms of thinking about a cure. We have a research collaboration on gene editing for CF. There are better tools available than we had 15 years ago. It’s reinvigorating the field.

What’s your relationship with the CF community?

The patients have been with us since day one — long before we had any compounds. We’d do fund-raising walks with them. We met some of them as babies or young children and now they are grown up, going to college, and getting treatment. It’s great to be told you are making things better for them.

Learn more about the Alpert Prize here.