CAMBRIDGE, Mass. — The tiny round one is vitamin K. There’s a gel cap (vitamin D), a two-tone capsule (that one protects his liver), a square pill (generic Singulair), and more — seven pill bottles sharing space on his dresser with a “Criminal Law and Its Processes” textbook that’s thick enough to be a weapon.
Josh Hillman, a 23-year-old Harvard Law student from Alabama, has cystic fibrosis, the progressive genetic disease that causes frequent lung infections and wears on other organs. He has to pop enzymes with every meal to maximize the nutrients his body absorbs. While he sleeps, 1,200 calories of a nutritional shake drip through a tube directly into his stomach. There are the inhaled drugs — sometimes antibiotics, always a mucus thinner — that he breathes in through a nebulizer, and a blue vest that slips on, inflates, and vibrates, a 30-minute shaking session that he does twice a day to help clear the mucus that gunks up his airway and lungs.
“It makes it a little bit difficult to write,” he said, his Southern accent rumbling like his wheeled desk chair was careening across cobblestones.
But for all that is part of Hillman’s daily regimen — and that’s what he does when he’s healthy — it’s what’s missing that’s just as notable: one of the new cystic fibrosis treatments that have started to transform the lives of others with the condition.
Those medications, the first to be tuned to the genetic mutations that cause the disease, have helped people experience fewer flare-ups and hospitalizations. They have also brought the relief of simply feeling better and breathing easier. The drugs have been touted as a testament to what’s possible with precision medicine treatments, which target the roots of diseases instead of just addressing symptoms.
The catch is that cystic fibrosis is not caused by one mutation, or a handful, but more than 1,500 different rearrangements in the code for the gene known as CFTR. The cutting-edge treatments — there are three available now and a fourth, still-experimental medication expected to be approved, all from Vertex (VRTX) Pharmaceuticals — cover the mutations held by some 90 percent of CF patients.
That leaves up to 10 percent of people whose diseases are advancing without a powerful defense to slow them down. Hillman is among them.
“This is such a concrete fact of your life — it’s always going to be here, it’s never going away,” he said matter-of-factly in describing his condition.
The new therapeutic landscape for CF has created disparities among patients who, until 2012, were all treated the same way. Patients who are not eligible for the new medications have been left wondering if the kinds of treatments available to others will reach them in their lifetimes. And there is a time imperative: Only half of people who are born today with CF will live into their late 40s.
It’s a reminder that with complicated genetic diseases, progress, while rightly celebrated, doesn’t always extend to everyone at the same time.
“It makes me so happy to see other people with CF thriving and getting help. It brings me more joy than I can even explain,” said Stacy Carmona, 32, who works in patient advocacy for a specialty pharmacy, takes more than 40 pills a day, and spoke of the “panic” of feeling left behind. “But there’s that other side of it, where I so desperately want to catch up to them.”
As she’s gotten older, Emily Kramer-Golinkoff, 34, whose lungs function at about 30 percent the level of healthy organs, has started talking with doctors about a transplant.
“Watching them have not just new hope, but like new lives, new capabilities, to start thinking about retirement funds and things like that, I’ve never had that luxury,” she said. “We’re still waiting, and we’re sinking. For us, this disease is still the same killer.”
Cystic fibrosis is mostly known as a disease that affects the lungs and airways of the more than 70,000 people around the world with the condition. Mucus builds up there, trapping bacteria like a mosquito in sap, and leads to repeated infections and, eventually, respiratory failure.
But complications arise in other organs as well. The pancreas can’t produce the right digestive enzymes or sufficient insulin, so patients struggle to keep on weight and sometimes develop diabetes. Liver conditions are also a concern.
The root of the problem involves a protein called CFTR, which shares its name with the gene that is mutated in the disease. Normally, CFTR, which sits along a cell’s surface, serves as a passageway for chloride molecules to exit the cell. In the lungs and airway, the molecules’ movement attracts a coating of water, which in turn prompts tiny chimneysweeps called cilia to clear out mucus that would otherwise settle there.
When there’s a mutation in the gene, however, the protein doesn’t function properly. Different mutations create different mishaps: Sometimes the CFTR channel doesn’t open for the chloride molecules, other times the protein doesn’t make its way to its proper place on the cell’s surface. The result: The chloride molecules can’t make their passage, setting off a chemical cascade that ends with the accumulation of sticky mucus and CF symptoms.
The new Vertex medications — called modulators — aim to restore normal CFTR activity by tweaking errors in the location and shape of the protein that are introduced by the genetic mutation.
But the drugs only work if the protein at least somewhat resembles a healthy version of CFTR. That’s not the case for patients like Hillman, Carmona, and Kramer-Golinkoff. For them, trying the treatments would be like trying to drive a Model T out of the factory when all the assembly line has built is the chassis.
They have what are called nonsense mutations, or stop or X mutations, and make up the bulk of those for whom the modulators are not designed. As their cells’ protein-manufacturing machinery reads strips of the genetic instructions on how to make CFTR, the nonsense mutation prematurely signals it to stop. The mutation can sit early in the gene, or later, but the result is that the CFTR only gets built to, say, piece 493 of the 1,480 pieces it takes to assemble a full CFTR protein.
“And that protein isn’t going to cut it,” said Kevin Foskett, a physiologist at the University of Pennsylvania’s Perelman School of Medicine.
To be a patient with nonsense mutations is to find yourself trapped in a therapeutic past that so much of your community has left behind. While conferences and social media burst with the stories of patients whose lives have been opened up with the new treatments — and while you share so much vicarious excitement for them — you face a constant unease about your own health.
“It’s a really strange emotional place to be in,” Kramer-Golinkoff said.
Even before the modulators made it to market, improvements in treating CF-related infections and more specialized care were helping patients live longer and healthier lives.
But now, “there is this sense that some people are getting these great therapies and are really benefitting, and some people are not,” said Dr. Bill Skach, senior vice president of research affairs at the Cystic Fibrosis Foundation.
And those in the latter group are still dealing with too-frequent hospitalizations, already-high anxiety about infections that gets amplified during cold and flu season, and ever-present calculations about what to do with their lives.
For Hillman, who had to withdraw from college one semester because he was so sick, pursuing law school was an investment he had to weigh. Was it worth taking on so much debt? If he could land the type of job that would help pay off his loans after graduation, would he even be healthy enough to work full time?
“It’s just total uncertainty,” he said. “In every decision, even if it’s not the major factor, I definitely have to think: Will I be around to pay this off? How does this affect my parents? What is the health insurance situation of whatever this is, particularly with job prospects?”
Hillman, a first-year student, made it through his first semester without any serious flare-ups or trips to the hospital. But CF scaffolds his days: He’s up well before his classmates to get his treatments in before class, and he often has to call it a night earlier than friends because CF wears you out.
Along with her family, Kramer-Golinkoff, who lives in the Philadelphia area, in 2011 started Emily’s Entourage, which has raised more than $4 million to fund projects that could lead to treatments for people with nonsense mutations. Part of her advocacy is grounded in explaining to people — including those who work in drug development — that despite the positive headlines they’ve seen about CF, not everyone has shared in that good news.
“I worry about the perception that CF is done,” she said. “There is an outlying 10 percent of us for whom it is not at all done.”
Plus, she and others note, CF is not “done” even for patients with the mutations that the Vertex drugs target. While some people are helped greatly, others see more muted responses — and are still left struggling with infections and symptoms. Better modulators are needed, they say, as are, eventually, cures.
The Cystic Fibrosis Foundation has recognized the splintering of the community and last year dedicated $90 million for research and drug development programs for CF caused by nonsense or other rare mutations. Advocates argue there’s an extra incentive for researchers and drug companies to pursue treatments for these patients, even if the market seems small: Nonsense mutations cause forms of other genetic conditions as well, so if a company can find a way to sidestep the premature “stop” signal sent by the mutations, it could unlock treatments for a number of diseases.
The dearth of options for people with nonsense mutations belies the promise that many patients once felt.
Just a few years ago, a drug called ataluren that was designed to treat people with nonsense mutation CF made it to final-stage clinical trials. Carmona, who took ataluren in combination with Kalydeco, one of the Vertex modulators, said it improved her lung function and decreased inflammation.
“I could breathe. I wasn’t coughing,” said Carmona, who is married, has two dogs, and lives in Southern California. “I always feel some amount of chest tightness and all of that went away.”
But in March 2017, the company behind ataluren, PTC Therapeutics (PTCT), announced the drug failed to significantly improve lung function for patients in the trial overall. It pulled the drug from development, and pulled the rug out from under people with nonsense mutations.
“For so long that was the one hope,” Kramer-Golinkoff said. “When the light of that one extinguishes, it’s a big disappointment. It wasn’t like there were other options.”
There still aren’t.
A company called Translate Bio (TBIO) has started an early clinical trial of a CF treatment using mRNA, the genetic instruction guide that cells look to to make CFTR. Its therapy aims to help patients churn out full and functional copies of the protein.
An mRNA therapy would be “mutation agnostic” — meaning it could work no matter what type of CFTR mutation a patient has. Similarly, gene therapies — in which a normal CFTR gene would be ushered into cells — would also apply to everyone with the disease.
For now, though, all those approaches remain experimental or pursued within the confines of laboratories.
Some patients with nonsense mutations do try taking the modulators, and there are case reports of some success. It’s possible that, if the mutation occurs late enough in the gene, patients can produce enough of a CFTR protein for the modulator to coax some activity from.
“We’re just trying to push the limits here until we can get to a better drug,” said Dr. Steven Rowe, the director of the Cystic Fibrosis Research Center at the University of Alabama at Birmingham, who has run trials testing therapies for patients with nonsense mutations.
When patients with genetic diseases think of a cure, and what a difference it would make in their lives, they generally think in terms of hypotheticals. But patients with nonsense mutation CF have living proof all around them of what a targeted treatment — even if it’s not a cure — can do.
“If I was able to take a drug that would make me feel better, that would change everything,” Carmona said. “I wouldn’t feel so limited. I wouldn’t be so afraid to dream big or make plans that I feel like I deserve. But I just feel like it’s so unknown.
“Yeah, it would change everything.”