New Drug Kaftrio

[rdrunner]

Hello, I have read that the new drug Kaftrio has delivered excellent results for cystic fibrosis sufferers. Does any body have any information regarding Kaftrio and bronchiectasis.

[Hidden]

Kaftrio is currently only available worldwide for those with cf who have two of the ‘right’ disease causing, genetic mutations. Whilst it’s strongly believed that ncfbe is part of a spectrum of lung disease originating from the same faulty gene, and we now know that several respiratory diseases also suggest some degree of dysfunction within that gene including COPD and some asthma, nothing has been conclusively proven, so at this point, Kaftrio is not being tested outside of cf, primarily because the principle of how it works depends on the underlying genetics, and it builds on the understanding of the individual components of the drug which have been studied previously. Whilst some ncfbe patients are carriers (meaning they have one identified cf mutation), two genetic flaws are the current criteria for access, and they have to be the right ones. This is the case with all 4 of the cftr modulator drugs that have become available over the last decade, and to date, only one has been trialled outside of cf.

A second phase, larger scale trial looking at whether a drug called ivacaftor (commonly known as kalydeco) is also effective in COPD, specifically chronic bronchitis, began in 2017, but has not yet been completed. The criteria for inclusion were quite strict, though, and only people with a high enough sweat chloride reading and a history of smoking at least 10 cigarettes a day for a year were going to be included. This is partly because smaller lab studies on lung tissue exposed to cigarette smoke showed some response to ivacaftor, and elevated sweat chloride levels are a primary indicator of the dysfunction caused by the genetic defect responsible for cf. A sufficiently high sweat chloride level is still a formal requirement for diagnosing cf, even with 2 identified genes, so they’re using it as an essential marker of whether or not someone is likely to show a response to drugs that modify chloride transport within the cells. The first study was done in 2015/16, but only involved 12 people: it showed that there were grounds to explore it further, but wasn’t definitive. My understanding of this second phase is that it’s primarily a safety study rather than looking predominantly at efficacy, and they were only recruiting 40 patients in the US when the patient group over there is about 4 million, but it will be extremely interesting to see what effects were seen and by how many when the results are published in the next year or two. Without getting into the politics of why it’s overlooked so often, I think if it was found to be safe, and they did see sufficient sustained benefit in chronic bronchitis, it would (should) potentially open up trials for Kalydeco use in ncfbe given that it’s considered to be the most likely ‘close relative’ to cf. Regarding Kaftrio specifically, even studies as to whether or not it works for people with cf with different genetics are still years from completion*, so I would imagine it will be some time yet before they start work outside of cf, and it will almost certainly hinge on the results of the ivacaftor studies: Kaftrio is a triple therapy, with ivacaftor being one of the three compounds making up the drug. *About a tenth of all cf patients are not currently eligible for any of these drugs on the basis of the genetic mutations they carry being more uncommon.

I think it’s really important for people to understand that Kaftrio is not a cure for cf by any stretch, and the results are actually very variable and individualised. Aside from the 10% who don’t have the right genetics, people with liver problems can’t currently take it, and there is a small percentage of people that can’t tolerate the medication itself. With all the modulators to date, they’ve also found that some people see good benefit, yet others see very little at all, and we lack the understanding of the modifier genes involved in the disease to understand why that’s the case. Kaftrio is no different, and the mean increase in fev1 seen is around 10%: some people have had astonishing improvements of 30% or more, but there are others that have actually had a negligible response. For those with chronic lung infections like pseudomonas, it also doesn’t get rid of those, so whilst it may slow the long-term decline in lung function, we know it doesn’t stop it, and there is still a significant treatment burden required to manage things that have already taken root. These would be similar considerations and limiting factors in using them in other conditions like ncfbe if it was ultimately found to have an effect. It’s those factors that have led people to feel these drugs are of most hope to children being born now: if they can stop the lung damage from happening in the first place, life expectancy in cf may well start to normalise for many patients in years to come.

I’ve probably waffled on way beyond what you needed or wanted to know, so apologies there. The take away from me going on forever is that I think it’s going to be several years before Kaftrio is studied in relation to anything other than cf, but they are now starting to look at other applications for the modulators that have been around for a while. Whether or not they trial Kaftrio will to some extent probably depend on the trials of ivacaftor on its own for other groups, and then possibly trials involving ivacaftor/tezacaftor (the dual therapy licensed in the U.K. as Symkevi) as that’s two of the three drugs that make up Kaftrio.

[rdrunner in reply to Hidden]

Thank you Charlie_G for your comprehensive answer. Although I get the gist of your reply it will take me sometime to read and fully understand what you are saying.

[Hidden in reply to rdrunner]

I’m too wordy for my own good sometimes - sorry. If there’s anything not clear or confusing, please let me know. It’s complicated to explain partly because how the drugs work is rooted in the underlying disease mechanism, which is quite complex in and of itself. CF is all about the way chloride is produced and moves inside and between cells in the body being broken, and the role the genetics play with that (different cf mutations break the transport in different ways, or even prevent chloride production to begin with). Everyone with cf has 2 mutations, one from each parent, but there are more than 2500 different mutations that have been identified to date as involved in causing cf when two are present. The modulators like Kaftrio are designed to fix particular fault(s) with chloride production and transport to make the cells function more normally, but will therefore only work if it’s the right type of fault to begin with, which means needing to have the ‘right’ genetic mutations for the drugs to be able to do anything. When it comes to other conditions like bronchiectasis and COPD, what we don’t know is whether they also have broken transport caused by the same gene as a primary cause, or if there are other causes involved. At the moment, it’s still not completely proven it’s the same genetic fault or that broken transport is a big problem in any other respiratory condition: there is evidence to suggest that the gene is definitely involved, like some people with asthma and COPD (and bronchiectasis) having higher than normal sweat chloride levels when tested, but we just don’t know how or how much. If the transport isn’t actually broken, or isn’t broken in the right way, the drugs like Kaftrio etc. won’t help.

Hope that extra explanation makes it clearer and not more confusing, but if it doesn’t, feel free to tell me to shut up!! 😂