New drug

[Blue58]

Just been reading up on new drug Kaftrio being used to treat Cystic Fibrosis but as a Bronchiectasis patient myself which I believe is a form of cystic fibrosis, just wondered if anyone else has heard of this drug or know if it will also be trialled on bronchiectasis patients. Sounds like they are getting some good results from this drug.

[Hidden]

It’s an interesting drug. Unfortunately I doubt if they will be trialling it in non cf bronch any time soon. It is currently even limited to use in cf patients who have a specific dna profile and I believe that trials may be taking place to prove its efficacy in other cf patients. As with every drug, we are at the back of the queue.

[Blue58 in reply to Hidden]

Thank you. Got to keep on our toes with educating ourselves though haven't we even though some Doctors find it offensive by us patients having too much knowledge.

[Hidden in reply to Blue58]

Yes it's always a good idea to keep learning.

[Hidden]

I’m a dad to a 12yo with cf not eligible for Kaftrio or any of the precision meds so far available. I’ve replied to Littlepom before with my thoughts on non-cf bronch patients potentially trialling all/any of the precision meds including Kaftrio. I said not that long ago that an ‘easy’ route into testing these for non-cf bronch would be to study those that are known to be cf carriers that carry the appropriate mutations, purely because you could make the case that they have at least one known and provably pathogenic mutation responsible for protein manufacture to justify the study. I still think that’s a decent possibility, but I wouldn’t like to speculate on the likelihood beyond saying that most superlative lung diseases are increasingly being associated with possible CFTR dysfunction. I can also tell you that I was surprised to learn just last week that a pilot evaluation has been undertaken for Ivacaftor, the very first Vertex precision med (and one of the compounds in Kaftrio), with COPD patients, specifically those with chronic bronchitis, back in 2016. From what I can understand, the reason they plumped for that patient group over NCFBE seems to be that initial experiments in the initial stages of drug development showed that Ivacaftor had a clear impact on CFTR in cells exposed to smoke, so they had an evidence base under which to pursue a study. The outcome was the same as all small, pilot studies tends to be: more research required, but it did seem as if there might be some potential benefit, in which case it’s hardly a massive leap to considering trials in non-cf bronch in the longer term, but I strongly suspect it will be the longer term, partly down to cost. The deal struck with Vertex in the U.K. is confidential, but treatment costs in the US are currently $311k per cf patient per year. That’s just shy of a quarter of a million pounds, and whilst we know the NHS haven’t agreed a price anything close to that (they’ve agreed £500m over 5 years for access to all the modulators for all eligible cf patients), Vertex still wanted £100k per patient per year for Orkambi in the UK prior to the deal being struck.

For all many eligible cf patients/families are eager to get their hands on Kaftrio, it’s worth remembering that these are novel drugs with no data available as to long-term safety or efficacy, and we do know that they’re pretty heavy on the liver. In some cases, up to 30% of those taking a precision med for cf made by Vertex have had to stop them due to side effects and not being able to tolerate them, particularly with Orkambi, although Kaftrio has been much, much better tolerated and had very little discontinuation in the phase 3 trials. It’s actually a combination of 3 Vertex compounds, two of which existed separately to Kaftrio being formulated and have been used in the other precision meds for cf released by Vertex over the last 8 years. From lab testing, they *think* the drug works on a specific, class II (meaning the defect caused is with protein processing) mutation whereby two of the compounds bind to the faulty CFTR protein to increase the amount that makes it to the cell surface, and once there, the third enables the protein to allow ions in and out more effectively. For Kaftrio to work, therefore, the current understanding is that you have to have a CFTR protein malfunction that prevents protein transit and fails to allow ions in and out of the cells, which means you need to have at least one disease causing mutation that has that effect on CFTR to benefit. The licence in the US meets that, so anyone with at least one copy of the F508del mutation (the mutation known to act in that manner) as part of their disease profile is clinically eligible over there, which translates to almost 90% of patients, but the new licence just issued in Europe is unexpectedly much more restrictive in who can have access, and has caused quite a bit of upset over the last few weeks as a result. The reason for that is that average (mean) increase in fev1 taking Kaftrio is around 14%, but a minority have seen really dramatic increases in fev1 of 30-40% or more, and quite a few report a general sense of feeling better in themselves, even if they have quite severe disease. It’s no surprise people want to be eligible for it, and the understanding had been that it would be issued the same way in the U.K. However, it’s not a panacea, and it doesn’t work for everyone, or to the same extent. Patients with anything more than mild liver disease, which is a common issue in cf, are currently unable to have it (or any of the other precision meds) due to the adverse effect on liver function. As with the other drugs in the class, there is also a highly variable degree of efficacy that reinforces our ongoing lack of understanding of CFTR dysfunction and the role of modulator genes even in cf: patients for whom it should work well on paper don’t always find that to be the case, and some have seen very little benefit, if any at all. It also doesn’t change microbiology: those with chronic infections still have those chronic infections, are still getting exacerbations (albeit at a decreased rate in some cases), and still have the daily symptoms and treatment burden that goes with that. Overall, though, there’s no denying that potentially regaining ‘lost’ fev1 and slowing future loss or re-loss for some patients is an extraordinary and incredibly positive thing. Whilst no one can say for sure, the suggestion is that, in time and if licensed from a young age, there could be large numbers of children that have few (if any) of the lung issues that kids like my daughter experience now. Once cf is more on a par with non-cf bronch in terms of severity, the research and treatment situation will likely be a lot more equal.

Anyway, I’ve had a right ramble, and you probably didn’t want or need to see a lot of that second half, but it’s certainly an interesting area.

[Blue58 in reply to Hidden]

Thank you for passing on such knowledge. A ramble it was not as I thoroughly enjoyed reading it.

[Hidden in reply to Hidden]

Thanks for all of that. Unfortunately after many tests I have absolutely no mutations and so I guess that rules me out for any investigations into its use for me. I do hope though, that your daughter, with all of her life before her, will eventually benefit from one of the new life changing drugs that come along in the pipeline.

[Hidden in reply to Hidden]

I ended up down a research rabbit hole the other night, LP, which is how I stumbled on the chronic bronchitis study: there’s a paper from this year basically asserting the stance that everything respiratory, even asthma, may have its roots in CFTR dysfunction and that they’re all just different elements of a disease spectrum. When you think about it, cf umbrellas almost all obstructive respiratory diseases in terms of symptoms, including asthma, so it would make sense. Carrier screening has now also been found to be positive at a higher ratio in all lung diseases than in the general population, but with NCFB in particular, they increasingly believe there may be novel mutations involved, or that cf gene mutations traditionally considered to be non-disease causing may actually be pathogenic under certain circumstances: I doubt many bronch patients have been screened for all 2000 odd mutations we now know about, so it’s entirely possible if not likely that some of the ‘milder’/atypical/‘inconsequential’ genes are actually relevant in other respiratory diseases, we just currently lack the appropriate understanding. There’s even been a recent prevalence study into 59 clinical aspects of cf disease in ‘healthy carriers’, that would suggest that some degree of CFTR dysfunction is still present with only one faulty gene: going through the list, I certainly have a handful of them on my own medical record, but all the current literature explicitly states that carriers have no associated health problems. Whilst not everything wrong with me could be a feature of cf, I’m about as far from healthy as you can get. I know I bang on about it a lot, (I also know I bang on a lot generally 👀😂) but this is exactly what I mean when I talk about genetic understanding being in its infancy. Practically still newborn, imo. Hopefully they’ll actually get to grips with CFTR dysfunction properly in the not too distant future, in which case they may be able to better help everyone regardless of whether that have a defined cf mutation or not.

As for Bod, her consultant now reckons at least 6 years for something to materialise for the 10%. So we just keep plodding on and work at keeping the decline as slow as we possibly can, and preferably below 2% per annum. The outcome data to date certainly suggests that the better you are when you can access these things, the more noticeable and sustained the improvement seems to be.

[Hidden in reply to Hidden]

The trouble with non cf bronch is that it has so many causes. I was born perfectly ok. I started having pneumonias at 18 mths which led to the lung damage. There has been a theory that the diptheria vacc at that time could have been the culprit and then of course there are those who were ok until they had whooping cough. Bronch is the end result, not a disease in itself. Of course I am sure that there are many causes including lots of so far undiscovered or untested for mutations. So for me and many other ncfbe s it is too late and we do have to plod on, doing as well as we can.

My hopes are for bod and her contemporaries. With parents like you and the help of good doctors she can be kept as well and strong as possible to take advantage of anything that comes along. Six years is no time in the scale of things and I have very positive feelings about her outcomes.

[Hidden in reply to Hidden]

But that’s the thing: increasingly the argument seems to be that all sources of chronic respiratory illness, whether that’s something problematic from birth, or something that only emerges in later childhood or adulthood like asthma and COPD, may stem from CFTR dysfunction. It may be that the diphtheria vaccine or whooping cough weren’t causative for you and others like you, but instead may have accelerated or altered an existing CFTR related disease process somehow. The root cause of many respiratory issues, or at the very least the genetic predisposition to respiratory diseases, may well be defective CFTR, and if you google ‘CFTR function and (insert respiratory disease of choice)’ you’ll find multiple, peer reviewed papers that support that to be the case. There’s a growing school of thought that the only condition in which fixing CFTR dysfunction may not be ‘the answer’ is PCD, and only because they know from experiments that fixing protein dysfunction in that cohort will thin mucus to more normal consistency, but won’t restore cilia movement to transport it up/out. My rabbit hole has given me increased hope for almost everyone with respiratory problems, to be honest, which is how it should be: no one condition should take major priority over others.

[Hidden in reply to Hidden]

It’s very interesting Charlie but for me at my stage very exhausting as I have had a lifetime of ideas and promises of new treatments which have all come to nought. I do hope that the CFTR theory proves solid and that it leads to positive improvement for all with lung conditions. How wonderful it would be to be free of the daily struggle.

[Jaybird19 in reply to Hidden]

You mention the diphtheria vacc as possible problem. Interesting because i found out in 1980s that i was not vaccinated , and that my mother had had to go to swear before a magistrate to avoid this. I was using a toxic strain as a control at work . It turned out that both I and a colleague of similiar age were both not vaccinated. Do you know if there was a there a problem with that vaccine in late 1930's.

[Hidden in reply to Jaybird19]

I don't believe that vacc was available in the 1930s, especially as diptheria was rife until the 1950s. I was given it in the early 1950s. The first batch was floated in a substance which could cause pink disease which in turn damaged the lungs. The formulation was quickly changed and my sister had no problem 3 years later. Of course, nobody picked this up as the cause of my bronch. No govt has ever admitted the problem and many do not know about it. There is quite a lot of anecdotal evidence amongst those of us still alive who were vaccinated against diptheria at that time, had repeated pneumonias and developed bronch.After reading of someone else who was convinced that her problems started after the dip vacc, I asked my very good bronch consultant and said ' you must think I am mad'. Her reply, ' No you aren't mad, it is a distinct possibility but no govt is going to admit it'.

[Elaiworthy in reply to Hidden]

I’m find this very interesting

[Ergendl in reply to Hidden]

I can understand the drug developers investigating whether one of the Kaftrio active agents can treat COPD patients, as that would open up a huge market for them. Large sales would reduce costs and recoup the costs developing the original drug as well as its spin-off.

[Hidden in reply to Ergendl]

Yes far more copd patients than ncfbe. This was the case when the Blair govt poured millions into copd programmes in the 90s and stopped even the most meagre funding for bronch. One can only hope that when somebody benefits it eventually finds its way to the back of the queue. Too late for me though.

[Bronchi1]

Looks interesting. They wont allow it in Scotland I see. Insufficient evidence and excessive cost.

[Hidden in reply to Bronchi1]

Kaftrio will be available in Scotland, it was agreed at the start of August. All 4 home nations now have independent deals with Vertex for access in line with the most recent EMA licence.