Long-awaited cystic fibrosis drug could turn deadly disease into a manageable condition

[Jaybee00]

Congrats...but it took 30 years from ID’ing genetic defect to the development of a robust treatment.


https://www.washingtonpost.com/health/2019/10/31/long-awaited-cystic-fibrosis-drug-could-turn-deadly-disease-into-manageable-condition/

 

[Jaybee00]

https://www.washingtonpost.com/nati...094578-19b8-11e5-93b7-5eddc056ad8a_story.html

This is the article that is linked to in the above article.... these guys were able to raise a ton of money for a relatively rare disease.

But note:

Still, venture philanthropy is not always practical — or even realistic. Many organizations don’t have the money to risk significant sums on drug development projects that are more likely to fail than succeed. DeGennaro said he also reminds nonprofits that come seeking advice that the CF Foundation took its leap only after researchers identified the gene behind the condition.

“They no longer had to solve the science problem. . . . What they needed was drugs,” he said. “If you need to solve a science problem, venture philanthropy is probably not right for you.”

 

[Snowdrop]

Even philanthropy isn't philanthropy anymore. It used to be an act that had no financial reward. Now here it simply means high risk-high reward.

 

[Cinders66]

We need philanthropists and. Innovation in our field. A few weeks ago bbc covered a story where scientists had agreed to step in and create a unique drug for a single terriblY affected child. She had gene defects I think and They acted to help her and create a bespoke drug to correct her abnormality. Obviously we can’t all get that but this and the Ebola vaccine speed up really made me feel that as well as resources you need that drive to solve something fast , which I’m sure in real life is being applied to many areas , just not ours. I get frustrated when people in our community are like I used to be and think One study mean we are approaching a cure, we are battling to get on the same running track as other illness, then we have to run and win the actual race.

 

[SNT Gatchaman]

Article in The Atlantic: The Cystic-Fibrosis Breakthrough That Changed Everything (archive)

A cure for cystic fibrosis had supposedly been imminent since 1989, when Jenny turned 2. That year, scientists identified the recessive gene behind cystic fibrosis, which encodes a protein called CFTR that controls the flow of salt and water. The discovery seemed so explosive that a Reuters reporter rushed to publish the scoop more than two weeks before the scientific papers were due to come out; two press conferences followed.

In the decades after, however, researchers came to understand the wide gulf between identifying a genetic problem and knowing how to solve it. Early attempts in the ’90s at using gene therapy to fix mutations failed again and again, both for CF and for other genetic conditions that once seemed tantalizingly close to a cure.

Then, CF researchers changed tack: Instead of correcting the gene, why not correct the mutated protein itself with small fixer molecules? This had never been done before—with any disease—but the nonprofit Cystic Fibrosis Foundation deemed the strategy promising enough to strike an unusual venture-philanthropy agreement with a company that would attempt it, which was eventually bought by Vertex Pharmaceuticals. The foundation funded the research in return for a share of the revenue.

After Kalydeco, the next CF mutation to target was obvious. About 1,700 unique mutations have been found in people with CF, but some 90 percent of patients—including Jenny—carry at least one copy of a mutation, known as F508del, that leaves their protein channels too seriously distorted for Kalydeco alone to correct. Fixing this shape would be a much bigger task. In 2013, Jenny joined the clinical trial for a two-drug combination from Vertex, made up of Kalydeco plus a second fixer molecule. It failed to especially improve her symptoms, though it did work enough to stabilize her falling lung function. “It seemed to push pause,” she said. She stopped getting sicker, but she was still sick. The research went on.

A few years later, word began spreading of a forthcoming three-drug combination from Vertex. In clinical trials, neither patients nor doctors are told who is on the placebo and who is on the experimental drug. But in this trial, everyone could tell. The triple combo made patients’ lung function jump by a shocking 10 percentage points. Overnight, they woke up smelling for the first time the distinctive scent of their home. They could even taste their sweat becoming less salty. This was Trikafta.

 

[Murph]

I really loved this article.

I did a bunch of reading on how they developed the cure. It's worth understanding what pathways to success look like.

1. Success came when they stopped looking for a solution to the most upstream factor: the genetic defect. And started focussing on helping the affected proteins work properly.

2. Then the key thing they had was a benchtop model. Cells they could run drugs on. The same approach was necessary to find a cure for AIDS and I think the reason we are suffering so much is that we don't have one. There's an obvious reason why: we don't understand the key disease processes in mecfs. Until we do we can't create an in vitro model with any confidence.

We can create low-confidence models though, like the nano-needle, or maybe rbc deformability models, or mice with high levels of wasf3 (mice are lower throughput than cells in vitro though). There are other mouse models of mecfs in development by Simmaron Research.

Research on people is just awfully expensive and slow and you really only want to do it at the end, when you're testing drugs you're already hopeful will work. Doing it to find the disease mechanism is a pain. The more time we spend developing models, the better. Even if they're crappy I bet we learn something

3. Reading about cystic fibrosis I began to wonder if their chloride channel problems could be similar in any way to our hypothesised calcium channel problems. I'm well aware this section is a stretch! Their protein folding problem is genetic. Could we have one that is acquired? There is that one study that found high sodium in leg muscles in mecfs. People with CF leak salt like crazy and have to eat more salt. Which reminds me of POTS...

I don't know enough of the biology to rule anything in or out but there's indications that people with CF feel extremely freaking tired. Some of the comments at this next link could easily have been taken from an mecfs forum.

https://cystic-fibrosis.com/living/cf-chronic-fatigue

Of course nobody is going to bother looking for more reasons for people with cystic fibrosis to feel tired. The lung mucus thing appears enough. But it's possible the chlorine channel problem causes fatigue via other pathways that are also important in mecfs? You couldn't rule it out. And Trikafta seems to fix that as the next claim shows.

I have more physical capacity. Cystic fibrosis is an energy-zapper. The body is doing so much extra work fighting infection and trying to breathe that it’s common for people with cystic fibrosis to have chronic fatigue. Though Trikafta hasn’t suddenly given me boundless energy, that capacity to do more without desperately needing a (three-hour) nap is a unique challenge. My mind still tells me to be cautious in expending energy, even though my body says, “You go, girl!”
​

It is probably excessively optimistic but I wonder how a person with mecfs might feel if they took trikafta. I doubt anyone with both has ever got an mecfs diagnosis because the CF diagnosis would appear sufficient to explain anything that's wrong with them. That means nobody who takes this drug will ever identify as a pwme and we won't find out what it does in me/cfs, at least until the patent expires.

4. The last thing to note is that this drug is a combination therapy and by adding 3 active components together they got really good results, far better than using only two active components. This willingness to combine drugs appears to be innovative, perhaps a spillover from approaches to chemotherapy in cancer?

It suggests possible new approaches in mecfs where we do have a short list of drugs that seem barely okay. Could combining them turn them into powerful forces for good? There's the idea of TUDCA + sodium phenylbutyrate that Hwang is planning to test. I wonder what else we could chuck in the mix!

 

[ME/CFS Skeptic]

Thanks for that overview @Murph

Had a quick look at the trials and this looks like the major phase III trial published in 2019 in the NEjM:
Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele | New England Journal of Medicine

The primary endpoint was much air a person can forcefully exhale in one second (forced expiratory volume FEV1), expressed as percentage of predicted score. At the start of the trial patients had 61% of the predicted FEV1 score. But after 4 weeks, the treatment group increased by 13.6 percentage points while the control group decreased by 0.2.