With the news that the FDA has approved Trikafta — a triple combination modulator therapy that includes the two compounds that composed the previous generation Symdeko in addition to another corrector titled elexacaftor — there is, for the first time in history, an approved modulator for the vast majority of people with cystic fibrosis. The FDA, in what I consider to be unexpected and great news, approved Trikafta for all people aged twelve and up with one copy of ∆F508, the most common mutation of the more than two thousand mutations of cystic fibrosis. There was concern that the FDA would first approve it only for the mutations of subjects included in the clinical trials. And since there are so many mutations, I was worried it would take some time for FDA approval to trickle down to the more encompassing (and correct, in my opinion) “∆F508 heterozygote” genotype. That concern went unrealized.
Cystic fibrosis is not a lung disease, it is not a pancreatic disease, it is not an organ or tissue disease. It is a genetic disease that disrupts protein maturation which causes thick mucus and results in lung, pancreatic, and other organ problems. This perspective gets to the better root of the problem. CF has been traditionally treated in a reactionary way; always behind the curve. Drugs were taken to fight infections that took hold in the excessively thick mucus, physical treatments were done to try to break up that thick mucus, other drugs were taken to slice up the thick mucus, weird head-tilting sinus rinses were done to “clean” up the sinuses, enzymes were taken to break down foods and help bodies receive nourishment from food. But today, there are now four different FDA-approved drugs that aren’t reactionary. They are prophylactic.
The approval of Kalydeco in 2013 shifted the tides of the future we are reaping today. The mutation Kalydeco was approved for, G551D, is simpler than ∆F508. The subjects in the clinical trial for Kalydeco fared better than most people with CF before they received the modulator. Pre-Kalydeco, protein modulators weren’t a class of drugs for people with CF. Though the CFTR protein was discovered in the late eighties, the hope of “fixing” the underlying issue was a cure through gene therapy or gene editing. Kalydeco opened the doors up for a different drug class altogether.
Cystic fibrosis would be more aptly called a collection of diseases. CF, as a classic disease, is diagnosed through a sweat test. This sweat test measures the amount of salt in a person’s sweat. Usually done a few weeks after birth, the cut-off for diagnosis is 60 mmol/L with golf scores — the lower the better. For some — those of us with “classical” CF — we have a high sweat test. Clinically, it’s manifested by lung damage, thick mucus, pancreatic insufficiency (our body doesn’t produce the enzymes necessary to break down foods), and a litany of other things.
It’d be nice if it were simple. It’s not. There are people with abnormal sweat tests that don’t present as clinical classical CF. They have what appears to be recurring bronchitis, pancreatic, or gastrointestinal issues. And there are people with normal sweat tests that look like normal CF. Cystic fibrosis, as a whole, is complicated. We all know this.
Modulators are a good thing. And yet they muddy the waters. CF is changing. A CF diagnosis is not what it once was. With the advent of Trikafta, it is within reason to assume that kids with CF born today may live full lives. These lives, still full of pills and appointments, will be manageable. They won’t be confined to white walled hospital rooms for months of their lives, and they surely won’t have to fret about what previous generations have worried about. Kids today should expect to see a cure in their lifetime.
Before Orkambi was approved, I began to accept my decline. My appointments, which had been no more than check-ins with my doctor to ensure my lung function was fine and cheery catching up, were becoming grayer and grayer, filled with more difficult conversations as the vibrancy of the world slowly wore off. IV antibiotics were being discussed when in the past oral antibiotics worked wonders. Orkambi dammed that decline, stabilizing me with mild lung disease for the past few years.
We can’t avoid the decline that comes with CF. Bacteria are better at evolving than humans; scar tissue is more resilient than even the most adherent of us; inflammation is working whenever we must be resting. Mild lung disease will still become moderate lung disease and moderate lung disease will become severe. Shortness of breath is a staple of life with CF. When you’re dealing with your disease everyday, you even notice the subtle changes, recognizing that flight of stairs that used to be easy to walk up is now more difficult than it was a few months ago. Orkambi and Symdeko were just another medication in our cabinets.
Trikafta has a better upper limit than any previous generation of modulator. CF progression is compounded; if you can prevent the beginning of the damage, it’s far better than if you prevent middle or late-term damage. Diminishing returns are an inherent lesson for people with CF. As we grow older, we see less return on our buck with antibiotics, with intervention, or with whatever else. Trikafta, once it’s approved for children younger than twelve, will likely prevent a significant amount of the early damage usually inflicted upon on victims of broken CFTR.
And it’s a tremendous win. There is no other way around it: The combination of fundraising, advocacy, medicine, science, and common humanity over the past half century has led us to this moment. It is nothing short of a miracle of superhuman proportions. The victory is built on the backs of hundreds of thousands of people. The victory is also built on a graveyard. When CF is one day cured or at the very least not any different from a diagnosis like diabetes, it will come with the knowing that tens of thousands of young people died without a chance of a full life. They died after a short life where they underwent more physical and emotional trauma than the majority of people will sustain in their two or three times longer lives. Millions of people have grieved the demise of a loved one with cystic fibrosis.
If you’re even tangentially involved in the CF community, you know somebody who has died in this way. A CF death is unfortunate in more ways than one. It’s not a peaceful death. It comes with shortness of breath from floppy, damaged airways, thick mucus, low oxygen saturation resulting in hallucinations and delusions, and it comes for people that look and are far too young to die. Every death is tragic; CF deaths are vicious. CF, in its nasty way, telegraphs how it’s going to kill you every day; You’re your own narrator of your decline. The damage being wrought on our bodies is working harder than any of us can hope to prevent. For all previous generations, there was nothing to do other than stifle the impending damage. Those around you witness your decline. It’s impossible for one to not feel pity for the frail. CF bodies tend towards fragility, yet are full of warrior souls.
When my friend (who had been on the Trikafta trials) texted me the drug had been approved, I was having a shitty day. It all turned upside down in a moment. I walked to the lab and shouted, hands shaking, body quivering, voice strained. I was excited, but the full brunt of emotions didn’t hit until driving home.
As I thought about my sister and how she never got to experience this hope, I felt rage. Our time on Earth is transient; In hindsight my sister’s twenty nine years are no different than a blink. She died with somebody else’s lungs failing her, after somebody’s else’s lungs had already failed with hers having failed a few years earlier. It’s strange to consider somebody else’s lungs continued pumping air for years after their souls began their rest. In the way that I think about organ transplant, I can’t help but feel the spirit of those we’ve lost along the way has infused Trikafta and future generations of people with CF.
The way my sister died will resonate with me until my final breaths. Since my sister died, I’ve felt bitterness that there appeared to be no other way. The shortness of life is never so apparent as when you think of the death of someone you deeply loved and how you feel like they could’ve lived longer.
I’m strong, in the sense that I don’t mind to admit what I’m about to admit. I’m scared shitless of dying. But I never feel as in control as I do when I think about my previous struggles with suicidal ideation. I wasn’t given a chance to have CF and the decline that comes with CF is fucking misery personified. It is soul-sucking and it hijacks your autonomy, taking each and every thing you care about one day at a time. I have been in control of my own destiny only once in my life: When I knew I could end life on my terms, not CF’s. I don’t think this is an uncommon experience for people with CF, but it was necessary for me to combat that feeling.
I love to call Duncan my son. I’ve always openly stated that I expected to have kids, but truthfully, it’s something I’ve contemplated a lot. The possibility that I could pass CF to them worries me. What scares me more is the possibility that they will watch me die the same way I watched my sister die. I want to be a father so badly but the potential of that is frightening. Duncan has acted as a stand-in for my future kid; He is my son, because I may never have a real child. It feels unfair and downright insulting that we have to preemptively worry about a future child grieving us.
What Trikafta does is it opens up future paths that did not exist even a month ago for a lot of people. It opens the future for me. It opens the future for me to see many more years. I am twenty five years old and for more than a decade, I’ve doubted that I’d live until forty. It opens the opportunity that I may one day have a kid, and that that kid may not have to see my decline. Forty sounds old, until you realize you wouldn’t have memories of your parents if they died at forty. Forty is short because all life is short and life cut short is a life done, but not finished. I want to live longer than forty. I want to live a long time. Even the most depressed — even those that have died by suicide — want to live a long time. I want others to live long, healthy lives.
Trikafta is also a point we will never be able to return from. It divides the generations of people with cystic fibrosis. As one grows older, the less value they can extract from modulators. Diminishing returns. Thousands of people are still going to die before CF is cured. People who will see some benefit from Trikafta are still going to die from lung disease. There are people that still have no modulators available to them. There are people across the world with CF that will never have a legitimate care team or plan or maybe even diagnosis. There are American and European and Canadian babies, kids, and adults with CF that don’t have the medications they should have. There are people that have had transplants who would receive benefit from modulators but won’t be able to get it since it isn’t approved for them.
I will go on record as saying that I believe the first person that will be cured of CF has already been born. I believe people alive today will have babies that are cured of CF when they are embryos. I believe history books will regard CF in the same way that we view many extinct diseases. I am thrilled and full of emotions to know that the next generations will not have to fear seeing their loved ones suffocate from this wretched fucking disease.
Trikafta would not be possible if it weren’t for the CF Foundation, Vertex, patient advocates, family advocates, the NIH, the scientists and doctors that have been working towards this day for decades, and from more contributors from all over. We’ve lost a lot of people along the way, and the cold reality is we will lose more. For that reason, assessing the advent of Trikafta as singularly positive is a disservice. Every milestone is a reminder of how far we’ve come and how much farther we have to go. We have to acknowledge that part of the CF struggle is the pain that comes with it. It’s absolutely fair to think that it sucks that this drug is becoming available too late for many people, whether they’ve died or their lung function is too low to glean any real benefit. For some ∆F508 homozygotes, this may recover 5-10% lung function which may only lengthen the decline and subsequent misery.
I wish life were simpler. I sincerely do. I want to be wholly optimistic — and I genuinely feel like my future has been opened for the first time ever — but I can’t help but feel that this is more complicated than that.
The announcement of Trikafta feels like a party, and unfortunately, there are those that had to leave a little too early, or weren’t invited at all. I’m proud of this achievement. I’m optimistic for the future, but I’ve not forgotten the past.
A battle has been won, but The War is far from over.