WBUR Special Report on VX-770

by Carey Goldberg, WBUR’s “Common Health”

[Note: This is a “good news” story. It describes the scientific road to the first drug that successfully attacks the underlying defect in cystic fibrosis, bringing dramatic improvements. But the drug appears to work for only 4% of cystic fibrosis patients. CommonHealth plans to write next about the remaining majority, their lives and their prospects.]

The snowdrifts towered before her, taller than she was, dumped by yet another of last winter’s blizzards. The snowblower was broken. Her husband has a bad back. So Roe Van Epps picked up her shovel. When she had cleared her entire driveway, she turned to find her husband behind her, tears in his eyes.

Her first thought was that he was going to critique her shoveling. “What’s wrong?” she demanded.

Nothing was wrong. “Oh my God, you’re shoveling!” he said.

It sank in. “Oh my God!” she echoed.

In her entire 41 years, Roe had never been able to shovel snow. Or to run. Or to go a full winter without getting ill enough to need weeks of intravenous antibiotics.

She was born with cystic fibrosis, a genetic disease that affects 30,000 Americans, gumming up their lungs with dangerously thick mucus that tends to breed bacteria. At birth, doctors told her parents that her life expectancy was age five. Along with school and play, her youth consisted of hospital beds and piles of pills and hours each day of inhalation therapy.

Medical treatments that continually improved in small steps, from new antibiotics to improved enzymes, kept her alive. But she remained a person without a future, told at each life stage not to expect the next. Her husband planned for retirement. She did not.

Now, because of a still-experimental drug called VX-770, made by Cambridge-based Vertex Pharmaceuticals, that has changed.

Roe clearly has a spirit as sparkly-bright as a Roman candle. When she came to speak to the cystic fibrosis team at Children’s Hospital Boston recently, she wore zebra-print stilettos that made the same fun-wild statement as the many shades of red in her hair. But she is openly bewildered by the new possibility of living out a full lifespan.

“Now I’m like, holy cow, I might be 80!” she said. “Maybe I should start using some face cream!” It’s almost like she’s a different person: “I still have cystic fibrosis but I can do things, I can live my life.”

Roe does not use the word “cure.” No one does when they talk about VX-770. Dr. Greg Sawicki, a cystic fibrosis specialist at Children’s, says he would definitely call it a “major advance,” the first drug to come this far that attacks the basic defect in cystic fibrosis. More cause for optimism? Yes. But a cure? No.

Roe still takes antibiotics and does hours of inhalation therapy every day. She doesn’t dare stop. But “this is life-changing,” she said. “I’m very, very careful, I’m trying not to get excited, but I really am, at the same time.”

This is two stories, intertwined. One is Roe’s life with cystic fibrosis and then on VX-770. The other is a tale of amazing science — and a gamble of hundreds of millions of dollars that hit the medical jackpot. Researchers tell it with a hint of disbelieving awe in their voices: For once, nature played no tricks. For once, everything came together just as it was supposed to, from theory to test-tube to human patients.

“It has dramatically changed this disease from one of despair to one of hope and hopefulness,” said Dr. Robert Beall, head of the Cystic Fibrosis Foundation, which was instrumental in the drug’s development.

The story of VX-770 reflects a new scientific era, or at least, aspects of how this new scientific era we’re in is supposed to work. You identify the gene behind an illness. You figure out what the gene’s defect does. You find a way to test for that biological defect in a test-tube, and then screen many, many thousands of chemical compounds for the ability to fix it. You’re not just groping for a needle in a haystack — you’re sifting through a whole big stack. When one or more compounds show enough promise, you develop a drug, run clinical trials, and proceed to save lives.

At least, that’s how it’s supposed to work, but in practice so far, it almost never does. The challenge is just too complex. Genes with links to disease are discovered constantly, but so far, cures stemming from them are mighty few. The gene behind the brain degeneration of Huntington’s Disease was discovered way back in 1993, but a cure remains out of reach.

If there is a useful moral to this rare tale of scientific success, it may be the kindergarten maxim: Work together. The Cystic Fibrosis Foundation, founded in 1955, is held up by many as a model disease-fighting group that bridges between researchers, doctors, patients and donors in perpetual quest for a cure. Without the foundation, everyone seems to agree, there would be no VX-770.

The foundation is still far from all it aims to achieve. Though VX-770 is nearing the end of clinical trials, its long-term effects remain unknown, and it only appears to help 4% of people with cystic fibrosis, those with a specific mutation known as G551D. The rest still face lifelong illness and probable premature death. They desperately need more scientific progress, and the foundation just committed $75 million more to Vertex, the drug’s maker, to that end. Vertex pledges its efforts will not flag until it helps the remaining patients.

But still, there is good reason to revel in this particular moment in biomedical history. In key ways, scientists really cracked this brutal disease. That knowledge has been translated into one drug that has seen resounding initial success in clinical trials, and it looks likely to lead still farther. And Roe is wondering if she should go back to school.

‘Something funky about salt’

Let’s begin in 1970, when Roe was born.

Cystic fibrosis had been identified as a distinct disease for more than a generation, but little was understood about the mucus problems that affected multiple organs in patients’ bodies. There was one obvious clue, though: Since the 1950s, to quote Eric Olson, who oversees much of the cystic fibrosis work at Vertex, “People suspected there was something funky about salt.”

People with cystic fibrosis tended to have oddly salty sweat. In fact, testing “sweat chloride” became one way to diagnose the disease. (I can’t resist jumping ahead here: Bob Beall of the Cystic Fibrosis Foundation relayed the tale that recently, in a girl on VX-770, a telltale sign that the drug was taking effect was that her cat stopped licking her skin. It was no longer so salty.)

In 1983, scientists figured out that the central defect in cystic fibrosis involved chloride transport: chloride was getting stuck in cells, and that was thickening the body’s natural secretions, from the pancreas to the intestine to the lungs. Why salty sweat? Eric Olson explains: When you make sweat, it’s very high salt, but normally, as the salty chloride gets near the skin, it gets sucked back in. The defect in cystic fibrosis prevents that sucking-back.

As Roe grew up in Connecticut, she remained resolutely upbeat, but she doesn’t pretend that life with cystic fibrosis was easy. She missed a lot of school, fell behind on schoolwork and had trouble keeping friends — she was “out of sight, out of mind.” She missed prom.

And “Dating — that was a joy! Dating is tough enough without, ‘Oh, by the way, I have this mucus issue? Let’s go out!’”

Through the 1980s, the Cystic Fibrosis Foundation was ramping up its efforts, setting up a network of special care centers and another network of research centers around the country. But it was only in 1989 that cystic fibrosis research reached a major breakthrough: A team led by Francis Collins — who now heads the behemoth National Institutes of Health — pinpointed the cystic fibrosis gene, and the protein it makes. Known as CFTR, it is involved in transporting sodium and chloride ions across the cell membrane.

It was a moment of great uplift in cystic fibrosis circles. A cure seemed conceivably within reach. But first, cystic fibrosis research would take a great big wrong turn.

‘People thought I was crazy’

Roe participated in various studies over the years — for antibiotics, inhalers and supplements — but “It was always like ‘Ooh, this is the next best thing” but “once you got the med, it was just another drug to help me maintain.”

You can particularly understand how Roe was not especially keen on research given that through her twenties, the trendiest direction in cystic fibrosis research was gene therapy, the idea that you could replace the defective cystic fibrosis gene with a good one. Long story short, it fizzled.

There were other advances: a lung drug developed specifically for cystic fibrosis; aerosolized antibiotics that could be inhaled. But no game-changers. And slowly but surely, as with most cystic fibrosis patients, Roe’s lungs were getting worse. She worked full-time in the cosmetics industry but she had to miss work often; she coughed blood; she came to have trouble keeping her blood sugar stable — cystic fibrosis often brings with it diabetes.

Meanwhile, Bob Beall of the Cystic FIbrosis Foundation reached a conviction in 1998 that had him burning up the phone lines. Persuaded that the way forward for developing a cystic fibrosis drug was through high-throughput screening — testing tens of thousands of compounds for effects on CFTR — he called one drug company after another in hopes of enlisting them in the effort.

“I called up nine companies doing high-throughput screening and two returned my phone calls,” he said. “They couldn’t imagine why anyone from the Cystic Fibrosis Foundation was calling — they probably thought we wanted a donation.”

Aurora Biosciences of San Diego — which was later acquired by Vertex — called back. With seed money from the foundation, they built the chemical tools for testing compounds for effects on CFTR. Bill and Melinda Gates came through with $20 million.

“We then committed $40 million to do high-throughput screening to see if we could find one or two molecules that could open up the sodium channels,” Bob recalls. “People thought I was crazy.” (Though, he hastens to add, “my board was 100% behind me.”)

‘This drug is doing something!’

Eric Olson explains about high-throughput screening: “You always find something,” some compounds with some effects. But “they may not be potent enough, they might be toxic — they’re never the drug, they’re a starting point, what we call a scaffold, that you turn over to the medicinal chemists,” for tinkering.

His team figured they were actually after two molecules for two different defects involved in different cystic fibrosis mutations. In one mutation, the CFTR protein has trouble getting to the cell surface. In the other, the protein gets to the surface but has trouble functioning; some call it the problem of the locked or rusty gate.

Work on the two ran neck and neck, but the rusty gate molecule pulled ahead, even though only a small minority of patients had that mutation. “We had to get something into the clinic,” Eric said, “to test the hypothesis: Can you increase CFTR function? It was critical.”

The rusty-gate molecule, VX-770, got a boost from a special source, Eric said: a doctor in Pittsburgh, Dr. Joseph Pilwewski, who just happened to have preserved lung cells from patients with the right mutation. A team of Vertex scientists then used cultured human lung cells for initial testing. In all, the screening ran from 2001, the year Aurora was bought by Vertex, through 2005.

VX-770 went into its Phase I clinical trial in humans — a small, brief initial trial checking mainly for safety — in 2006. In early 2007, the larger Phase 2 opened. The buzz started small. At a cystic fibrosis meeting, a nurse involved in the trial came up to Eric and said, “I know I’m not supposed to tell you anything, but I’m so excited! This drug is doing something! It could be the placebo effect, but I’ve known these patients for years, and this drug is doing something.”

‘I wanted to believe it,” Eric said, “but I didn’t want to go down this path of false hope.”

Word spread. People were saying things like “That patient feels better than he has in years.” But of course it was all anecdotal until the official findings came in. When Eric’s colleagues, Drs. Claudia Ordonez and Bob Kauffman, called him in to a Vertex office to present the first Phase 2 data, it all became real.

“I was in tears,” Eric said, visibly moved even by the recollection. “What was most dramatic was the drop in sweat chloride, because it really meant it was working.”

No one had ever done this before. VX-770 had actually lowered patients’ sweat chloride score, and not by a little. Some scores were cut in half. People had said it couldn’t be done. Eric’s team had responded, “It has to happen, though, if it’s doing what we think it’s doing.” Scientifically, they knew the sweat chloride had to drop, but “when it actually happens in real people — it’s amazing.”

When Eric’s turn came to present the results to Bob Beall and his foundation team, he sealed the results in big envelopes, Academy-Award-style. The foundation team had brought a bottle of Scotch, apprehensive but hoping there would be reason to celebrate. They tore the envelopes open.

“It was one of those great days in your life,” Bob Beall recalled, “one of those aha! moments that just make you glad you made the decision you made ten years before to move in this direction. We could have been wrong — we could have been wrong…”

When the results were presented in the spring of 2008 at a national cystic fibrosis meeting, the crowd was electrified. Eric remembers people saying, “This is the most exciting thing we’ve seen in my 30 years of working on cystic fibrosis.”

Roe wasn’t excited, though — not yet. She passed up her first opportunity to join the Phase 2 VX-770 clinical trial; it just wasn’t the right time for her. Finally, in the fall of 2009, she decided to try the little blue pill at the center of so much buzz. Or rather, she enrolled in a double-blind trial, so she didn’t actually know whether she was on VX-770 or placebo.

At first, she thought maybe she was just having a good week, or month. Then, she started to bring up more mucus. “Actually, it felt like a flash flood,” she said. “I would cough and it would just come flying out of me, not to be too gross. It was just everywhere. It was much thicker than it used to be. It was constant, all day long, and I thought, ‘Oh, crap, I’m getting sick,’ but I never actually got sick.”

“And as time went on, my amount of mucus decreased, and my cough decreased. Then I started noticing bigger and bigger changes. I was sleeping. I was able to maintain my blood sugars. I could basically eat and not have to worry. I no longer needed any medication for constipation. And the biggest thing for me was, that year was the first year in my entire life that I never got sick.”

Roe has a port in her chest for intravenous antibiotics. She hasn’t used it since she started the trial in 2009. And more: before she started on the trial, she had a “huge mucus plug” in her chest so bad that she was considering surgery to remove part of her lung; now it appears to be gone.

As she spoke to the Children’s Hospital cystic fibrosis team, she mentioned that her FEV, a measure of her lung function, had been 62%. Now it’s 81%.

“Oh my God,” exclaimed Nancy Shotola, who runs the pulmonary function lab.

Roe still has a bit of a cough, but it’s more like throat-clearing than the old hacking. She still wheezes a bit, with asthma. But she never coughs blood anymore. She can clean her house. She runs two miles every other day. She feels so normal that sometimes, amazingly enough, she almost forgets to take her blue pill.

Looking Ahead

Roe is still taking VX-770 as part of a clinical trial, but now it’s “open-label,” and she knows she’s on the drug, not placebo. Vertex is planning to apply to the FDA later this year for permission to market it. Somehow, she says, until a doctor can pull out a pad and write her a prescription for whatever VX-770 ends up being called, “it’s not completely real.”

Vertex is not saying at this point how much the drug will cost — though she has asked. It is expected to be expensive.

Vertex is hot hot hot these days. Its new drug for Hepatitis C, just officially named Incivek, is expected to receive FDA approval later this month and many predict it will be a blockbuster. The company’s stock is soaring, and earlier this year, when it announced it would move from its sprawling headquarters near the Charles River to the Boston Seaport, Cambridge fought openly to keep it.

It is testing VX-770 in children, with excellent results. In February, it announced the data from a second Phase 3 study on VX-770, this one in children as young as six — also predictably excellent. And it’s testing a combination of VX-770 and a different drug, VX-809, a “corrector” aimed at bringing CFTR to the cell surface instead of just unlocking the gate, in adults with a far more common mutation.

(The “corrector” molecule problem involves faulty folding of a defective protein. It’s more complex than the rusty gate because many different steps are needed to ensure the protein is folded into the right shape.)

In its announcement last month that it would invest another $75 million in Vertex drugs over the next five years, the Cystic Fibrosis Foundation said the new program would develop a second “corrector” drug, also aimed at helping the 90% of patients who have the more common mutations.

All good news. But it brings more “a sense of responsibility than elation,” Eric Olson said. “Now that you know the answer, but you’re only getting to 4%, and nobody else has anything in the clinic for the rest of these patients, it’s a big responsibility. We’ve got to move faster, harder. It’s almost like you’ve got the golden ring, and you know what it can do, but then you’ve got to figure out the way to do it.”

It’s a painful topic for Roe, the other 96%. Already, she’s a senior citizen by cystic fibrosis standards. A friend recently had a double lung transplant. To friends with cystic fibrosis, and even to family, she doesn’t tend to talk much about how VX-770 has changed her life.

But she’s so naturally open that you only have to ask to get a glimpse of the huge emotional dislocation she’s now navigating. She is reimagining her life. It’s the opposite of the typical mid-life crisis in which people suddenly see death looming. Suddenly, she sees a whole unexpected second half of her life on the horizon.

“Hello,” she said, “I’m here! Now what?”

On her wrist is a tattooed reminder, in graceful cursive, “breathe.”

She may need it now as much as ever — though for different reasons.

Source: WBUR.org (click here to view the article and video clips)