Rare cystic fibrosis mutations limit the benefits of targeted drugs

Research highlights novel causes of the disease in Latinos

At the end of October, the U.S. Food and Drug Administration (FDA) approved Trikafta, a combination of three drugs that shows immense promise for treating the most common genetic mutation in cystic fibrosis (CF). But the news was bittersweet: Just days before Trikafta was approved, a team of scientists from UC San Francisco and the Centro De Neumología Pediátrica (CNP) in San Juan, Puerto Rico, unveiled new research showing that CF patients in Puerto Rico and the Dominican Republic may not benefit from the new therapy.

Cystic fibrosis (CF) is a disease that causes a patient’s lungs and digestive cells to produce an excess of thick mucus, which leads to severe problems with breathing and digestion, and puts patients at an increased risk of infections. While the disease used to be deadly for patients by their teens or early 20s, medical advances pushed the life expectancy of CF patients to nearly 40.

CF is the consequence of mutations to a particular protein, CFTR. Trikafta was designed to counter the most common mutation in CFTR that causes CF, which is known as F508del.

Trikafta is so effective that patients can live nearly normal lives while taking the drugs. But F508del is the underlying cause in only 90 percent of CF cases, while the underlying causes of the remaining 10 percent of cases remain poorly understood—a disparity that the UCSF and CNP teams argue must be addressed to help all CF patients.

In a paper published in Pediatric Pulmonology on October 30, researchers at the two institutions showed that CF in Puerto Rico and the Dominican Republic is typically caused by unusual gene mutations, rather than F508del.

The CF mutations in Puerto Rico and the Dominican Republic are so unique that as many as 25 percent of patients with symptoms of the disease don’t even test positive for it with traditional genetic tests.

Absent the development of therapies designed to work with these rare mutations, Puerto Rican and Dominican CF patients will be left without access to proven, effective treatments.

“By studying more diverse populations with CF, we hope to make it possible to improve early identification of the disease in minority children, and to expand the number of people who can benefit from life-saving new therapies,” Esteban Burchard, MD, MPH, a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine, told UCSF News.

The School of Pharmacy’s editorial director, Grant Burningham, spoke to Angel Mak, PhD, and Andrew Zeiger, two genetics researchers from Burchard’s Asthma Collaboratory team, and Meghan E. McGarry, MD, MAS, a Pediatric Pulmonologist in the UCSF School of Medicine. All three contributed to the recent findings. Zeiger has since moved on to medical school at Thomas Jefferson University.

Burningham: How did you first decide to study this?

Zeiger: This started with Dr. José Rodríguez-Santana [Burchard’s long-time collaborator at the Centro de Neumología Pediátrica in Puerto Rico]. He noticed that 25 percent of his patients weren’t testing [positive] for CF [mutations] even though they had symptoms. He spoke at a conference and Dr. Leandra Cordero Oñate [the leading CF physician in the Dominican Republic] was there, and she said she had noticed the same thing. Patients were testing positive for CF with the sweat tests, and not with the genetic tests. So we recruited CF patients in Puerto Rico and the Dominican Republic and sequenced them to see what was going on genetically.

Burningham: What is a sweat test?

McGarry: The sweat chloride concentration test is the gold standard to diagnose CF. It measures the amount of chloride in sweat. CF affects the chloride channel in the sweat ducts and therefore patients with CF have elevated levels of chloride. Many of the patients in Puerto Rico and Dominican Republic had very high sweat chloride levels, which confirmed they had CF, but they did not have any known CF mutations.

Burningham: What does that mean for people with CF in those places?

Mak: People with CF in the Dominican Republic and Puerto Rico have a different spectrum of mutations causing their disease, and many of the mutations are very rare. Rare CF mutations are not targeted by drugs like Trikafta. These patients need special attention.

Burningham: So these groups are being left out of the latest cures?

Zeiger: Dr. McGarry has been publishing on this for years, showing that minorities aren’t getting represented in clinical trials for CF, and our study gives further evidence to what she’s been talking about.

Mak: Even with new technology, if we don’t study more minorities, it’s only going to make the health disparity gap bigger.

Burningham: How susceptible are these populations to CF? Who normally gets the disease?

McGarry: CF is considered a rare disease and is most common in non-Hispanic whites, but it does occur in other populations. Almost 10 percent of patients in the U.S. are Hispanic and in California a third of new patients are Hispanic.

Burningham: I know there’s a relationship between the disease and cholera?

McGarry: Sort of. CF affects the water regulation channels in the lungs and the gut and causes the channels not to work. When people get cholera, that disease actually turns the channel on, which is how people with cholera die, usually through dehydration as they lose too much water.

The newest CF drugs do exactly what cholera does, and the newest drug (Trikafta) is almost like a cure. Our paper is important because CFTR modulators [like Trikafta] only work on a very specific CF mutation. This is one of the first drug classes targeted to specific mutations, outside of oncology.

Burningham: Your results say many patients in the Dominican Republic and Puerto Rico don’t have that mutation, does that mean the Trikafta is worthless for them?

McGarry: I think the big takeaway is that we need a lot more research on every group affected by CF. Every group needs to get studied and sequenced.

With the new drugs, it’s actually hard to say who it could help and who it won’t. I got into CF research when the first CFTR modulator targeting CF mutations came out. That drug was only approved for one mutation. I had a very sick Hispanic girl with CF who had a different mutation, which was also really rare. We gave her that drug off-label and she had a dramatic response. Before the drug, she was not in school and she couldn’t go to the mall. And in a month she was back in school and in dance class.

We did our own trial and 50 percent of people with different mutations responded to that drug.

But the FDA is only going to approve drugs for mutations that drugs are tested on. So Hispanics who don’t know their mutations, or have only rare mutations, don’t get approved and don’t end up getting the drug, even if it might actually work for their mutations. These drugs are very expensive. Trikafta, for instance is $23,896 a month, so there’s not a big appetite for trial and error with CF patients.


Rare Mutations Drive Cystic Fibrosis in Caribbean (UCSF News)


School of Pharmacy, Department of Bioengineering and Therapeutic Sciences, PharmD Degree Program

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