So, I’m sitting here in Mexico, poolside. It’s almost 9am, and probably already 85 degrees or so. We are going to start drinking soon, because why not? We are on vacation with some close friends, all sharing a house for a few days. All this morning, this song seems to be on a loop in my head, no matter what song is playing through the speaker. Here Comes the Sun is one of my all time favorite songs, one of George Harrison’s gems and part of the opus album that is Abbey Road. It’s such a positive song, with his acoustic melody setting the mood. He said he wrote it in Eric Clapton’s backyard on a nice spring day. They were the best of friends at the time; oddly enough Eric was madly in love with George’s wife Patty Boyd. His emotional pain was the inspiration for the album Layla and accompanying love songs. I digress, but back to the point! Here Comes the Sun just makes me happy, as it should you. George’s wonderful acoustic guitar and arrangement compliment the lyrics. The words speak of a glimmer of hope after despair:
Little darling, it’s been a long cold lonely winter
Little darling, it feels like years since it’s been here
Here comes the sun
Here comes the sun, and I say
It’s all right
As I hear this song of positivity and hope I think about my current state of mood and health. I have been in a clinical trial for some time now, relating to the CFTR modulators (see further explanation below). Look more closely at the next generation modulators since it relates to my current trial. I can’t discuss all the particulars, like the company or drug name, because the data has not been fully collected and submitted to the FDA. However, since I finished the last phase, I recently entered what’s called “open label.” That means that regardless of my double blind group for the trial, I now receive the drug until it is available on the open market. Boy, have I felt the difference right away! I started coughing relentlessly for about 5 days, lots of nastiness coming up that probably had been in there for quite a long time. Once that was over, I feel so clear! It brought to mind a few other songs: I Can See Clearly Now by Johnny Nash, Breathe by Pink Floyd, Sun is Shining by Bob Marley, among others. Suffice to say, it is a drastic improvement. My PFTs have increased quite a bit as well; the FEV1 (forced exploratory volume in 1st second) has gone from 40 to 50% in just a couple of weeks! And my overall volume capacity has improved by 0.5L, which is quite significant. I can exercise much easier, and have a tolerance for more cardio. I want to springboard off this increase, and get back to the mountains for some hiking and climbing. It has been more difficult the past couple of years, which is frustrating since we live in the foothills!
As a result of this increase, I have been able to enjoy this vacation, without CF dominating every aspect of it. That has been the trend lately, we have big plans for a good vacation, and at some point CF rears its ugly head and takes over. Whether I get sick, or have a bad coughing episode, or I am unable to participate fully in the activities we have planned, and on, and on. There have been more times like this than I care to count. But not this time, not this vacation. And that gives me more hope for the future, something I haven’t had in a long time. So a quick thanks to all the people at the National Jewish research clinic and the CF clinic who have made this possible. For continuing to push me, to make me my best so as to qualify for these trials. Because these new meds have let me see a new day ahead. One where I don’t need as many hospitalizations and have less frequent exacerbations. As the song goes, “Here comes the sun, and I say, it’s all right!”
Information about CFTR Modulators (provided by the CF Foundation)
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that affect the production of the CFTR protein. When the CFTR protein is not made correctly, it affects the balance of salt and fluids inside and outside of the cell. This imbalance leads to thick, sticky mucus in the lungs, pancreas, and other organs.
The Cystic Fibrosis Foundation supports the development of drugs that target specific defects in the CFTR protein. As a group, these drugs are called modulators because they are intended to modulate the function of the CFTR protein so that it can serve its primary function: to create a channel for chloride (a component of salt) to flow across the cell surface.
When proper chloride flow is reestablished, mucus becomes rehydrated inside the lungs and other organs. Although modulators can’t yet completely restore proper chloride flow, they can improve the flow enough to relieve symptoms for people with CF.
There are three main types of CFTR modulators:
The first type of CFTR modulator is called a “potentiator.” Potentiators help chloride flow through the CFTR protein channel at the cell surface. The CFTR protein is shaped like a tunnel that can be closed by a gate. Potentiators hold the gate open so chloride can flow through.
The drug ivacaftor (Kalydeco®) is a potentiator. This drug can help patients with gating and conduction mutations in CFTR. It also works on residual function and splice mutations where an insufficient amount of normal protein is present. In all of these mutations, some CFTR protein reaches the surface of the cell. However, either not enough protein reaches the cell surface, or the protein does not allow enough chloride to flow through. By holding the gate on the CFTR protein open, potentiators allow more chloride to flow through and reduce the symptoms of CF.
The next type of CFTR modulator is called a “corrector.” Correctors help the CFTR protein to form the right 3-D shape so that it is able to move — or traffic — to the cell surface.
Almost half of people with CF have two copies of the F508del mutation, which prevents the CFTR protein from forming the right shape. The corrector drugs lumacaftor and tezacaftor help the CFTR protein to form the right shape, traffic to the cell surface, and stay there longer. But, even with lumacaftor and tezacaftor, only about a third of the CFTR protein reaches the cell surface, so by itself it can’t reduce the symptoms of CF.
Additionally, the proteins that do reach the cell surface do not open sufficiently to allow chloride to pass out of the cell. But, if a corrector is used in combination with a potentiator — such as ivacaftor — to hold the gate on the CFTR protein open, enough chloride can then flow to reduce the symptoms of CF. The combinations of lumacaftor/ivacaftor (Orkambi®) and tezacaftor/ivacaftor (Symdeko®) are therefore used to treat people with two copies of the F508del mutation. (Tezacaftor/ivacaftor also can be used to treat people with a single copy of one of 26 specified mutations –regardless of their other mutation.)
The last type of CFTR modulator is called an “amplifier.” Amplifiers increase the amount of CFTR protein that the cell makes. Many CFTR mutations produce insufficient CFTR protein. If the cell made more CFTR protein, potentiators and correctors would be able to allow even more chloride to flow across the cell membrane. Amplifiers, which are being developed and tested, are not yet available.
Ivacaftor and lumacaftor are sometimes called “first-generation modulators” because they were the first modulators approved to treat people with CF. Tezacaftor, approved in Feruary 2018, is also considered a first-generation modulator.
“Next-generation” modulators are new and potentially more effective CFTR modulators. The next-generation CFTR correctors currently in clinical trials target different problems caused by the F508del mutation to further improve CFTR folding and increase the amount of CFTR trafficked to the cell surface. The goal of next-generation therapies, which will likely be part of a triple combination therapy, is to develop treatments that benefit more people, including individuals with a single F508del mutation.
Individually, each of the three drugs (which will likely first be composed of ivacaftor, tezacaftor, and a next-generation modulator) in a triple combination therapy addresses a different aspect of the defective CFTR protein. When used in combination, the results may be better than using one or two of the drugs alone. Already, several next-generation modulators in development have the potential to be significantly more effective than current FDA-approved modulators.
Next-generation modulators may also benefit more people with CF than first-generation modulators. The first-generation drug combination lumacaftor/ivacaftor can only help people with two copies of the F508del mutation, or about 50 percent of the people with CF. But, early clinical trial results suggest that several of the next-generation modulators could benefit people with CF who have only one copy of the F508del mutation. Because nearly 90 percent of the CF population has one or two copies of the F508del mutation, next-generation modulators would enable a much larger number of people with CF to have a modulator treatment.