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"From Lab to Life" is a cutting-edge podcast that bridges the gap between groundbreaking medical research and real-world clinical practice. Hosted by leading experts in the healthcare field, each episode delves into the latest innovations in medicine, offering insights on how scientific discoveries translate into practical solutions for patient care. From emerging therapies to case-based discussions, this podcast equips healthcare professionals with the knowledge they need to bring the future of medicine into their daily practice. Join us as we explore the journey from the lab to life.
Hello, and welcome to our program titled, Advancing Cystic Fibrosis, Addressing Disparities, Challenging Perceptions, and Innovating Patient-Centered Care. I'm Dr. Susanna McColley, Professor of Pediatrics and Pulmonary and Sleep Medicine at Northwestern University Feinberg School of Medicine, and Director of Interdisciplinary Research Partnerships at Stanley Manning Children's Research Institute.
and in Robert H. Lurie Children's Hospital of Chicago in Chicago, Illinois. I'm joined today by my esteemed colleague, Alix Wilson, Manager of Cystic Fibrosis Clinical Research at National Jewish Health in Denver, Colorado. Our disclosures are displayed on the screen.
This educational activity is supported by an independent educational grant from Vertex. We would like to thank them for their support of this initiative. The learning objective for this program is displayed on the screen. We're going to talk about CF therapies. And we're going to start with therapies that are focused on treating symptoms. Chest physiotherapy is a manual way to get sticky secretions
out from the airway wall to being within the airway lumens so that they can be coughed out. Bronchodilators, of course, are widely used for many pulmonary diseases and widen the airways to increase airflow through them. There are inhaled therapies that are more specific to cystic fibrosis, including Dornace alpha, hypertonic saline, and inhaled mannitol that help make
thick sticky secretions looser and more able to be cleared from the airways. Pancreatic replacement therapy is essential because most people with cystic fibrosis do not have active enzymes secreted from their pancreas into the intestine to absorb food. In fact, pancreatic enzyme replacement therapy was the
first treatment to be used that allowed kids to gain weight and survive at least for some years with cystic fibrosis. And then we have antibiotics, which are used both to treat and to prevent flares related to chronic respiratory infections in the airway. One of the advances in cystic fibrosis during the past decade plus have been
been new therapies for cystic fibrosis that focus on the underlying genetic defect. These are gene variant specific therapies. And the first one to be approved was ivacaftor. This is a single small molecule treatment given orally twice a day. And it works for people who have specific types of CFTR variants.
that are at the cell surface. So fluoride can pass through them to rehydrate the airway. That was approved initially in 2012 for a single gene variant. Lots of research led it to be approved for many variants, but it's a small percentage of the population that can be treated with that medicine alone. In 2015, combination ivacaftor and lumacaftor was approved.
for people who have two copies of the most common CFTR variant called F5508-DEL. And then another drug combination that had some additional benefits for that same population was approved in 2018. In 2019, we had FDA approval of elexacaftor, tezacaftor, ivacaftor.
which works for people who have just one F508-DEL variant, as well as some other types of variants that respond to that medicine. So we have really expanded usage of these very effective medicines. Now, I talked a bit about modulators and proteins and what the proteins do, so I'm just going to back up and talk a little bit more about that. So using the case of ivacaftor,
There is a protein that sits at the cell surface, that channel, if you will, but the channel is closed. And so these CFTR potentiators help the channel stay open so that chloride ion can flow to the cell surface. The common F508-del variant is a misfolded
protein and it actually never gets to the cell surface. It is caught inside the cell and it gets broken up and cleaned up because it's not a useful protein. So these corrector therapies, lumicaftor, tasicaftor, and elexacaftor actually help the protein folding get to the cell surface. When it gets there, it's not very active and so
IVACAF door can open that channel so that you have the correction of the chloride channel defect. F508-DEL, I've said a couple of times, is the most common gene variant, but many others exist. In fact, hundreds of CFTR variants cause cystic fibrosis. And this is just a list.
from the United States of the percentage of people with CF who have one or two copies of a gene variant. So you see F508-DEL here at the top, about 85 % of people. After that, it falls off greatly. But the important thing to remember is that there are many variants that cause cystic fibrosis.
Many are responsive to treatments, but many are actually not picked up with standard newborn screening tests or even with panels that can be used to confirm a diagnosis by a laboratory. CFTR modulators, as I noted before, are suitable for people who have different types of CFTR mutations or variants. It's not limited to what we talked about earlier.
but keep in mind that because of the protein configuration differences, so these correct the proteins. And so we've talked about ivacaftor, again, many variants, some of which are so rare that uniquely in cystic fibrosis, some of these therapies were actually approved by the Food and Drug Administration based on in-vitro testing. And then going...
all the way over to the triple combination therapy of elexacaftor, tazacaftor, ivacaftor. There are many more people who are eligible and have good results with that treatment. So I'm gonna go through a couple of the studies that have been published. And the first was the pivotal trial of ivacaftor.
And this was a remarkable study because for the first time in a CF trial, we saw a very large increase in lung function measured by forced expiratory volume in one second within two weeks of starting therapy. And this persisted not only through the three months of these clinical trials, but actually well beyond in open label extension trials.
When you look at lumicaftor with ivacaftor, you see that there is a similar pattern. However, it's a much lower increase in FEV1. So this medicine was helpful, but it was not the same boost that people who were ivacaftor eligible got and very similar results for ivacaftor and tasicaftor.
If, you look at the ivacaftor-elexacaftor-tezacaftor data, what you see is, again, a very large improvement in forced expiratory volume in one second within two weeks of starting the medication that persists for a long time. Now, one of the things about these CFTR modulators is, although they're very effective and many people can take them,
Some people are not eligible for them. And this is primarily people who have a variant that has what's called a stop codon in it. And so it tells the cell to not make any protein. So you can only modulate a protein if there is a protein in the cell. So there are many new types of therapies that are under study. None of these are approved yet.
messenger RNA can be delivered to the cells through inhalation to make protein. So there are studies going on with this type of therapy. There are also CFTR gene transfer vectors to give DNA delivery to cells. And this is an area that has been under research for decades, but as more is learned about gene therapy,
there are more promising systems that are being studied. And then finally, in this era of CFTR gene editing therapies that actually repair the CFTR variant are also under study. This is just a cartoon showing a little bit about how these work. So if you have an incomplete CFTR protein that says stop, and you can give messenger RNA,
You can have a read through so that you get a full length protein to restore CFTR function. Getting back to modulators now, there's been rapid evolution of uses. These drugs are approved. And so as I noted before, by far the one that is used by most people in the United States who are eligible for a modulator is this combination, elexacaptor.
tezacafter, ivocaftor that's shown in the green bar on this slide. Now, one of the issues with health disparities in CF is that because of differences in gene variant distributions across ancestral populations, minoritized people with cystic fibrosis are less likely to be eligible for CFTR modulator therapy.
than white non-Hispanic people with CF. And this is capitulated by particularly the decreased frequency of F508-DEL in these populations, although it is still the most common gene variant in these populations because it is so prevalent worldwide. Even more concerning is that eligible minoritized people with CF are still less
likely to be prescribed the therapy and have delays in the therapy compared to white non-Hispanic people with CF. These are epidemiologic observations from the Cystic Fibrosis Foundation patient registry, and we don't know the causes for that, but it certainly requires those of us who take care of people with CF to be clear in our communication and make sure that everyone who could benefit
from a therapy is offered that therapy. Thanks so much for that information, Dr. McColley Now that we know more about the treatments, can you take us through the current treatment guidelines? Yes, I'm happy to do that. And I'm also happy to say that guidelines are being updated frequently as the field changes.
There are a number of different specific guidelines for people with CF with different circumstances. We have guidelines for indications and what the evidence is for using different medications, for airway clearance techniques, for respiratory support for people who have advanced lung disease and need that, and for lung transplantation.
One of the things that we have discussed in this program is that it's very important to make sure that social determinants of health are screened for. And we think about the traditional social determinants of health that are non-medical factors that affect health. And on average, they affect health more than medical care does.
We have strong evidence that these things are very important in cystic fibrosis respiratory outcomes and require targeted interventions, screening for unmet social needs, making referrals to community organizations to help address them, screening for tobacco smoke exposure and counseling using evidence-based guidelines.
ensuring equitable access to treatment as we discussed with ETI prescriptions, screening and treating for depression and other mental health concerns, and then supporting socioeconomically disadvantaged and minoritized people with CF to participate in clinical trials. Let's dive into a patient case. So let's meet Bree.
Brie is a 34-year-old non-Hispanic white woman recently diagnosed with cystic fibrosis. She has had barriers to regular medical care during childhood. Brie has a history of asthma, frequent sinus infections, nasal polyps, chronic cough, and a recent episode of pancreatitis. And Brie is concerned about the costs of therapies for her cystic fibrosis.
Bri has asked her pulmonologist if there are any natural therapies to treat her cystic fibrosis. How would you approach this conversation with Bri? My approach to these things are twofold. The first thing is really to ask if they had any specific ideas about that or have read anything.
then I generally talk about how to safely use products that may not be really studied or approved for cystic fibrosis safely. The most important thing being clear communication and knowledge that many herbs and other therapies actually can have negative interactions with some medicines
that can be essential to preserve health. Now in your practice, I'm sure that this comes up a lot. So tell me what your approach is. Yes, this has come up frequently. And I think really starting the conversation and asking which therapies they might want to be more natural. And then also the reasons
for wanting a more natural therapy just to get that better understanding and get that good communication going forward. If it's an over-the-counter treatment, there are websites and resources, consumerlabs.com, that providers can utilize to see what the interactions with other medications might be, and then to have a good discussion about whether the
Goals are to only have a natural therapy or if they have other goals that we can compromise. Maybe there are some treatments that they can do more natural and then the other ones that might be really important for their overall health. As an example for pancreatic enzyme replacement therapy to ask them, let's stick with this. Let's stick with an enzyme that we know is effective and doesn't have large interactions.
and then maybe we can consider trying some other things and meeting them halfway. Sitting down with them and talking through the rationale for using the natural versus the provider recommended treatments. And sometimes it can be a perceived concern about cost for the treatments and
truly sometimes sitting down and doing a dollars and cents comparison of what the over-the-counter natural treatment might cost compared to the potentially insurance covered medication might relieve some of that anxiety for that cost concern if that's their rationale for wanting to do natural. And then also asking again, what's
what their definition of natural is and seeing if that is even something that's feasible for them to obtain and then to maintain. We've reached the end of this episode. I want to thank Virtex for their support of this program. Be sure to claim your CME credit by filling out the evaluation and post-test. Also be sure to follow Iridium on X, Facebook, and LinkedIn for more continuing medical education programs.