The Bittersweet Downside of Orkambi & CFTR Modulators

In less than a month, it will be the third anniversary of me starting what is arguably the best drug ever created for people with CF. That's a pretty grandiose statement, but CFTR modulators were an entirely new class of drugs in our arsenal of CF drugs. 

CFTR modulators are the drugs that "fix" (I use that term loosely here) the defect that causes cystic fibrosis. Let me digress for a second: I'm speaking personally here, but I would argue cystic fibrosis is more or less a collection of diseases as opposed to a single entity. The reason for this is that there are literally more than a thousand mutations. While some of those mutations may act similarly, the protein misfolding that occurs in the different mutations means that "fixing" that specific defect in each patients' case may be different than a patient with a different mutation. But even within the patients that have the same mutation, we still see variability in their clinical severity, which probably explains why Alyssa and I had such different experiences. My point in all this is that every single person with CF will have varying CFTR function because of many different reasons. What we do in the lab is trying to determine the drug that will work best for the patient. 

"Fixing" the defect essentially means improving CFTR function. A person without CF has good CFTR function, probably at least 50%. People with CF can have any percentage under that, and clinical severity is likely inversely consistent with CFTR function percentage. In sum, CF is a very complicated disease, or collection of diseases if you prefer, and every patient is different. 

My point with all of this is not to dispel any reason for hope. To me, the fact that we have modulators that can improve CFTR function, even with how complicated CF is, is a reason to be hopeful. The likes of Kalydeco and Orkambi, the advent of Symdeko, and the forthcoming triple combo therapies in the pipeline are concrete examples that it's reasonable to assume we may one day have drugs that improve CFTR function to the point where there is no issue with chloride transport in our cells, which would likely mean no clinical presentation of CF at all whatsoever – that unfortunately doesn't mean we'd have no residual scar tissue or fibrosis or bronchiectasis, but it'd mean slowed decline.

Which is why modulators are bittersweet. 

I'm not shy about my struggles with anxiety or depression. I speak openly about the life expectancy conversation with CF and I consider it to be one of my biggest goals to transform the conversation around death through my writings. When I started Orkambi, I knew it had the potential to affect my future, specifically physically, but I didn't really think it'd be life-changing in the way it has been mentally. 

With a chronic disease like CF, you come to accept that your health may fade. Maybe not fully accept, but you understand that it's likely in your future. You come to appreciate the days as they come and be thankful with your health when it's good. But with modulators, there is a new element of hope that's unlike anything else.

With modulators, you start to feel better, you start to realize the decline might not be that imminent. You start to wonder if your future is a little more secure than it has ever been. For me, I even start to feel a bit...normal – a word I desperately hate. 

If Orkambi can significantly slow my decline, it's not irrational to wonder if the next generation of modulators can stabilize my decline. Maybe the generation of modulators after that could even potentially reverse some of the decline of my lung function. This element of hope should be an overwhelmingly good thing.

But compounding a physical disease like CF with the paralyzing mental disease that is anxiety is a recipe for disaster.  

Living with a chronic, terminal disease means you're living on a contracted timescale. 

I've written posts where I've said that it's impossible for anybody to know of their future with any amount of certainty. That's true for everybody. There are unfortunate circumstances that can arise for literally anybody.

But it's different for people that suffer from chronic disease. If you know me personally (and hopefully this is also evident through my writings), I try not to live with bitterness in my heart. I have a really shitty disease that just so happens to be due to a mutation in my DNA. It's hard to not be pissed off about that at times. When I zoom out and realize that my life is the single chance I get at existence, there are times I'm pissed off that I wasn't given a chance to have a life free of constant worry. So I can admit I feel bitter at times. 

Orkambi is a reason to be hopeful that one day, I may have a normal existence, one free from worry that one exacerbation will ruin my lungs. I do have hope that modulators will extend my life significantly. I'm also so sad that Lyss never got that opportunity. She was never able to be excited about modulators because they don't work for post-transplant patients. I'm worried that until my dying days, I will have feel sorrow that my sister never had a chance to be hopeful about these medications for herself. 

I always want to be honest about my experiences. I understand that having CF has taught me a lot of valuable wisdom at a young age, and to be honest, CF has given me an outlet for creativity and a career. For those reasons, I'm grateful. The balance becomes difficult when I try to be the person that learns from his experiences but doesn't become too drawn into those experiences that nothing other than anxiety comes from them. When I write about these experiences, it does seem like I come out on the other side a bit better; I feel as if I've shed some of the extra mental burden and hopefully some good comes from it for those reading my pieces.

Some of my days are filled with a devastating existential dread where I have no interest in doing anything and feel like I will never feel fully fulfilled. Other days I'm hopeful and aspirational, dreaming of a world I'll someday hopefully make better through different avenues. 

I think what I hope people can get from this is that chronic disease is a nonstop physical and mental battle. There is an entire layer of life that most others don't recognize. I don't want to write to make people feel guilty or feel pity for me that I have to deal with this, it's more to be honest about my life and maybe others can become more empathetic through reading about it.