Last week, the cystic fibrosis community celebrated the approval of a new drug from Vertex (VRTX) Pharmaceuticals, a decision that offers the large majority of patients access to cutting-edge treatments.

Those treatments, however, don’t cover patients with certain rare mutations. And they are not cures for anyone.

Seeking to address those issues, the Cystic Fibrosis Foundation on Wednesday unveiled a $500 million initiative aimed at developing treatments for patients who aren’t helped by the Vertex drugs and, ultimately, at finding cures for all CF patients. The message is: Despite the success, there is still work to be done.

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“It’s not the entire story,” Dr. Michael Boyle of the Cystic Fibrosis Foundation said about the Vertex therapies. “The rest of the story is: How are we going to make sure there are treatments for the underlying cause of CF for 100% of patients?”

The new Path to a Cure plan, which was announced ahead of the foundation’s North American Cystic Fibrosis Conference taking place later this week in Nashville, will fund some basic research. But Boyle, the foundation’s senior vice president of therapeutics development, said the majority of the money will go to support clinical programs.

The $500 million will be doled out through 2025, said Boyle, who is taking over as CEO of the foundation come January.

Cystic fibrosis is a progressive disease that damages the lungs, along with other organs, and can ultimately lead to respiratory failure. It occurs when mutations in the CFTR gene form a dysfunctional version of a protein, also called CFTR, setting off a cascade that ends with mucus clogging the lungs and frequent infections.

Vertex’s drugs, the first of which was approved in 2012, have changed the landscape for patients with more common CF-causing mutations. (There are more than 1,700 mutations in the CFTR gene that cause the disease.) The latest medication, Trikafta, is a combination of three therapies that extends the reach of the drugs to an estimated 90% of patients.

All of the drugs, called modulators, work by tweaking the location and shape of the CFTR protein to get it to function properly.

The bulk of the patients who do not respond to the modulators have CF caused by nonsense mutations (also called stop or X mutations), which fail to generate a version of CFTR close enough to the healthy form for modulators to coax activity from.

“Given the urgency of the situation and the fact that unfortunately the research and drug development for nonsense mutations lags so far behind, we need to be throwing our efforts into a ton of different approaches and pursuing all of them with the same intensity and vigor,” said Emily Kramer-Golinkoff, who has nonsense mutation-caused CF and, with her family, started Emily’s Entourage to help develop treatments for patients with nonsense mutations.

The modulators also do not work on some rare CF mutations; in others they have not been tested.

Hispanic CF patients more frequently have these uncommon mutations and, as a result, many have been left without modern therapies, said Dr. Meghan McGarry, a pediatric pulmonologist at the University of California, San Francisco. She estimated that two-thirds of Hispanic patients have mutations targeted by the Vertex drugs, compared to 90% of patients generally.

“For the patients where [modulators] work, it’s amazing,” said McGarry, who has received funding from the Cystic Fibrosis Foundation before. “But there’s a whole group where they don’t work.”

The CF Foundation’s plan outlines a number of clinical approaches that it intends to support. Some, including an approach called a readthrough therapy, would be specific to nonsense mutations. But others, including those involving RNA and DNA, would be “mutation agnostic,” meaning they would work for all CF patients.

While modulators have been transformative for some patients, they are not cures. Gene therapies (delivering a healthy CFTR gene with the help of a harmless virus) or gene editing with tools like CRISPR have potential as one-time therapies that can permanently overcome the underlying mutation, so patients would no longer need to take modulators or other drugs.

Some of the foundation’s funding will also go toward researching how to deliver therapies. Lung cells are difficult targets for two reasons, Boyle said: First, they are more primed than others to attack anything that appears foreign — which could extend to genetic therapies making their way into the cells. And second, lung cells turn over frequently, so the treatments would need to reach the cells that make lung cells to deliver a lasting benefit.

“The lungs are more challenging” than tissues like bone marrow or the liver, Boyle said.

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  • question: are Vertex drugs actually making life of patients normal both in state of health and longevity, or are they just statistically significant, but just marginally, better than no treatment?

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