Severe eosinophilic asthma controlling your life?

Hi, thanks for watching episode #139 of the Doctor Podcast show and I'm your host, Doctor Robert Sichert. Please subscribe to and follow Doctor Podcast. We're on YouTube, Spotify X, LinkedIn, Apple, Amazon, Instagram, Facebook and TikTok and all your other favorite platforms. And please like and repost this and other episodes you enjoy and share. Today we're discussing an important and common medical topic, and that is as according to the CDC, over 25 billion people in the USA have asthma. That's just under 10% of the population.

So it's a lot of people who have this condition. Today, I'm honored to welcome one of the world's leading asthma experts, Doctor Michael E Wexler. Dr. Wexler is the director of the Cone Family Asthma Institute at National Jewish Health in Denver, Co and this is one of the top respiratory centers in the country, and it's affiliated with the University of Colorado as well. He's board certified professor of medicine, the vision of pulmonary, critical care and Sleep Medicine. He's a Harvard fellowship trained in pulmonology or lung disease and critical care medicine and specializes in severe asthma, eosinophilic lung diseases, which we'll spend a lot of time on discussing and related conditions.

Over his career, he has led and participated in numerous major clinical trials focused on new treatments for heart to control asthma, helping bring several important biologic therapies to patients. He joins us today to discuss the exciting recent FDA approval of EXTENSOR, a new long acting treatment for severe eosinophilic asthma, which is made by the GSK pharmaceutical company. So Doctor Wexler, thanks very much for taking the time to join us today and educating us about asthma and eosinophilic asthma.

We really appreciate it. Well, thanks so much. It's great to be here speaking with you today. Thanks. Now everyone's heard of asthma, but few people understand what it is. Can you explain what asthma is, what causes it and how many people are affected by the severe asthma form? Yeah, asthma is a Airways disease. It's characterized by narrowing of the Airways or bronchoconstriction and also by airway inflammation. And the result of both the bronchoconstriction and inflammation is that patients might feel chest tightness, shortness of breath, they may wheeze, and they can have other symptoms like cough and mucus production that can have an impact on their day-to-day lives, cause them to miss work, miss school.

It can cause them to have intermittent exacerbations of their disease where they could be fine one day and then they could get worse and the next day, and this can really have an impact on their day-to-day lives. Right. Do we know what causes asthma? I know there have been different theories and different populations have different prevalence of this. Do we know what what the causes are? Yeah. Asthma is thought to be caused by an interaction between one's genetic background and the environment. So you could have a predisposition genetically to asthma, but it may not become manifest unless you're exposed to specific environmental antigen or allergen.

And there are many different forms of asthma. You can have exercise induced asthma, you can have allergic asthma, you can have occupational asthma. And all of those different types of asthma or phenotypes of asthma really result from a variety of different mechanisms. I see. Now. Specifically, can you tell us what is an eosinophil and what is eosinophilic asthma and how's it different than the regular type of asthma? Yeah, eosinophils are a kind of white blood cell. We all have them, but some people have more eosinophils than others.

And what's the downside of having eosinophils And why do we have eosinophils? Well, eosinophils have granular proteins within them. They're a kind of white blood cell and they have variety of different proteins, including major basic protein eosinophil or cationic protein, eosinophil derived neurotoxin, eosinophil peroxase, amongst others. And those can cause localized tissue damage. Now that's OK if you have a parasite and eosinophils are fighting the parasites. But if they're just sitting in your tissue, in your Airways, in your lungs or in other parts of your body, then eosinophils can cause damage.

So you want to have sufficient eosinophils that they can help you and, and, but on the other hand, you want to avoid having too many eosinophils. And some people are programmed to have more eosinophils than others. So what's the difference between asthma and eosinophilic asthma? Well, eosinophilic asthma is a subtype of asthma. You know, it's the same symptoms. But people with eosinophilic asthma who tend to have higher blood eosinophils, tend to have higher sputum eosinophils. They often have more exacerbations.

They have more symptoms. They often are refractory to current therapies. And while many people have elevated eosinophils, we now use a threshold of around 300 eosinophils or more to say that you've got a lot of eosinophils. We we recognize that at least 2/3 of patients have elevated eosinophils and you can have other kinds of asthma as well, but eosinophilic asthma, around 2/3 of patients have eosinophilic asthma. Wow, so you can tell this by a blood test right? And see the number of eosinophils in your blood test.

Correct. Yeah, It's a very simple blood test as part of your complete blood count and done routinely. Almost every lab does an eosinophilic count and that is a predictor of worsening asthma. I see. So if someone has asthma and they tend to have severe cases, they need to have that blood test to see if they have eosinophilic asthma. Exactly. Right. So what first drew you to specializing in asthma, and especially the more severe eosinophilic forms that many patients struggle with today? Yeah, well, you know, asthma is a very common disease.

It affects people of all backgrounds. It affects individuals of all socioeconomic statuses. And you know, it's, it's common. It occurs in around 8 to 10% of the population. And patients with severe asthma, they are particularly have a debilitating form with frequent exacerbations with a lot of missed work, missed school. And there's also still over 3000 people in the United States who die every year from asthma. Now that really shouldn't be the case. And so one of the reasons I went into studying asthma is because it's so prevalent, because it's so debilitating in many different individuals.

And my one of my career goals is to really try to establish cures for asthma to see if we can get patients into remission from their asthma, meaning having no exacerbations, no significant symptoms, having stable lung function. Now, what is Extensor, the new drug that's developed by GSK Pharmaceutical company? It's described as an IL 5 antagonist, but without getting too technical, how does this medicine help calm the inflammation and eosinophilic asthma? Yeah, it it's also known as depimokumab and it's an ultra long acting biologic therapy.

So that means it's a monoclonal antibody and it what it does is, is it targets a specific pathway in asthma that's involved in eosinophil development. What does it target? It targets Interleukin 5 or Illinois 5, and there are other Illinois 5 antagonists as that are available for patients with asthma. But what's unique about this therapy is that it has an extended half life, meaning that it can be dosed just twice a year or every six months. What does IL 5 do? What does interleukin 5 do? Well, it's a cytokine that's involved in the maturation of eosinophils, the proliferation of eosinophils, and the activation of eosinophils.

And So what this therapy does is it binds up the IL 5, preventing the activation, proliferation and maturation of eosinophils. So basically it's putting a brake on those eosinophils so that they can't do the damage to the lungs and the Airways. Exactly. It's stopping the production of eosinophils and stopping their entry into the tissue where they cause problems. And by doing so, then you can have a significant impact on preventing exacerbations, modulating symptoms, and having impact on all the other components of eosinophilic asthma.

Right. How is it given? How's this drug extensor given? Yeah, it's a shot. It's given subcutaneously, so it's shot under the skin and it's given every six months. Wow lasts a long time. How often are other asthma medications taken or given just for a comparison? So there are daily controllers where patients take an inhaler once a day or twice a day. And then the newer biologic therapies, the monoclonal antibodies that are really geared for patients with severe asthma, those are administered every two weeks, every four weeks or every eight weeks.

So this isn't a big advance in that it's given every six months. It means that patients will have less disruption of their lives. They won't have to think about their asthma other than when they go in for their twice a year shot. And so that's a big advantage for for patients and it's a great advance for this therapy. That's one of the key things that we're looking for are new therapies. We're looking at therapies that have different mechanism of action that can be given to a broader group of patients and that can be given less frequently because no one wants to take a shot frequently.

No one wants to take their medicine frequently. No one wants to think about their underlying disease, their asthma, as frequently as as as often is required. Right. What age groups is extensor approved for? So I believe it's approved down to age 12 and and so it's for adult eosinophilic asthma. That's so even kids can get this eosinophilic asthma and have bad episodes. So that's great that it works down to age 12. Now you were involved as an investigator in the pivotal swift clinical trials that led to extensors FDA approval.

What did those studies look at and and what were the main findings? For example, in what percentage of cases does it work well? Yeah. So the there were two clinical trials, 2 pivotal trials that were relatively identical in, in, in their pathways and, and, and how they they took place. They were called the SWIFT 1 and Swift 2 trials. And these phase three trials were 52 week randomized, double-blind, placebo-controlled studies that looked at both the efficacy as well as the safety of dipomokumab as add on therapy for patients who had eosinophilic asthma.

And what they demonstrated and was published in New England Journal of Medicine the last year, was that depimokumab reduced the annual rate of clinically significant asthma exacerbations by 54%. That's huge compared to placebo. And and it also showed a 72% reduction in the annualized hospitalization rate. There were improvements in peak flow. There were improvements in symptoms, particularly in those individuals who had low lung function to start with and those who had symptoms to start with. And it had a really good safety profile.

The incidence of adverse events was similar in the depomokumab group compared to the placebo group. So it was safe, it was well tolerated, and it was an effective therapy as well. Wow, that's great. How long does it take to take effect once you get the injection under the skin? Is it immediate or it takes a while? Yeah. You know, we evaluate these patients in the clinical trials usually after a few weeks and we start to see benefits as early as in a few weeks. We see improvement in symptoms, we see improvement in some lung function findings and we see a reduction in the eosinophil counts, which are the key biomarker for this specific therapy.

Wow, that's great. Now it's not meant for treatment of an acute asthma attack, right? That's important to know. Yeah. We didn't study that patient population. It's possible that it might have some more acute effects. And there's actually a study going on now evaluating the efficacy of drugs like depomocumab in the emergency room setting to try to prevent further relapses of asthma. And I think that's a really important area to study is it may not have immediate clinical effects, but the fact that it's such a long term efficacy and safety with this therapy suggests that it might prevent future exacerbations.

Because many exacerbations that occur and many hospitalizations and emergency room visits that occur, they're followed up by subsequent exacerbations once the immediate treatment wears off because we usually treat these exacerbations with steroids, with bronchodilators. But if patients stop taking them and the inflammation recurs, those patients, they're going to end back up in the emergency room. So having a drug like this is likely to prevent recurrent exacerbations in emergency room, business and hospitalizations.

So it's kind of like a snowball rolling downhill. It once it starts going, it gathers momentum and you have more episodes. And if you can block that, it just helps kind of everything, right? Exactly. Now if, if there are any, are there any severe side effects with with this, you mentioned it's very safe, but what what are the side effects in some patients that are important? Yeah, it generally it's very well tolerated in the clinical trials here. It's a shot. So some people can have in discomfort at the injection site or potentially injection site reactions.

Those are rare. But the most commonly reported adverse events were just the common cold. And this trial occurred during COVID. And so there are reported cases of COVID, not necessarily due to the shot, but just happened to coincidentally occur at the time of the clinical trial. With most asthma biologics, there's no increased risk of developing infections like COVID. There's also no increased risk of developing lack of efficacy of the vaccines that we give for flu or for COVID or anything else. It's important to patients continue to get those vaccines as needed.

And also, you know, not to worry that taking these drugs because none of these asthma biologics are really immunosuppressive in any way. And that's a question that comes up all the time. You know, do I need to be concerned about getting infection or I get consults from surgeons? What do I need to do about patients whose patients were on these drugs? They're generally very safe and very well tolerated without significant adverse effects and really no significant effect in terms of immune response.

Right. So suppressing or reducing the eosinophil count doesn't make you more susceptible to other infections or cancer or things like that. Yeah, I know these drugs, the anti Illinois 5 drugs have been given down to thousands and thousands of people and have been shown to be safe and well tolerated from all those perspectives. Right now, before you give this drug, it's important to check the eosinophil count. For example, if somebody doesn't have a eosinophilic asthma but have severe asthma, is is it effective or it's not really meant for that?

Yeah. Well, someone who's got bad asthma, you have to do an extensive work up and you have to figure out what type of asthma does the patient have. Part of that is looking at the different biomarkers. And currently we look at eosinophilic counts in the blood. You can look at eosinophils in the sputum as well. Either of those would indicate eosinophilic asthma. But there are other biomarkers of what we call type 2 inflammation, including elevated exhaled nitric oxide. So OR patients, we also look at the propensity to have allergies and IG levels.

So, you know, a good pulmonologist or allergist who see a patient with asthma will do those kinds of things. They'll confirm a diagnosis of asthma. They will address other issues that could be complicating asthma. For instance, people who aren't adherent to their inhalers. You know, those patients might get worse asthma just because they're not adhering. Third of all, you have to look for other complicating comorbidities. Do patients have bad reflux disease? Are they aspirating? Do they have chronic respiratory tract infections?

They have sinus disease to that vocal cord dysfunction. So you want to do a good work up and then after evaluating all those different factors and looking at eosinophils, nitric oxide levels, the excel of breath, and IG levels, then you can decide what type of asthma the patient has and give the most appropriate therapy. If someone has a low eosinophil count, it's unlikely that they'd benefit from a drug like depomocimab. So we're looking for eosinophil counts of at least 150 and you can go back and look and see did they have a history of eosinophilic asthma?

Did they have elevated eosinophils in the past? Right now, if you're on corticosteroids, if you're on Prednisone, that might lower the eosinophil count. So current guidelines say that if you're on oral steroids, one should presume that you have eosinophils if you have bad asthma. I see now, based on what you just said, can general primary care doctors or paediatricians treat with extensor? Or should patients be seen by a pulmonologist or a lung specialist like you? I mean, there are many excellent primary care doctors, internists who see a lot of patients with asthma.

But my recommendation is if you have a patient who has severe asthma, who's got low lung function, who has frequent exacerbations, who is symptomatic, you know, several days a week, has nighttime awakenings several nights a month, those patients ought to be referred. Because maybe it isn't just asthma, maybe it's something else. Could it be, you know, another inflammatory airway disease? Could it be sarcoidosis? Could it be a lung cancer? Could it be emphysema? Could it be cardiovascular disease?

I think that the physicians who are best equipped to do that kind of work up, who are also equipped to evaluate for the other comorbidities I mentioned, like reflux and aspiration and vocor dysfunction, are generally allergists and pulmonologists who have expertise in asthma. And those should be the ones who should try to figure out what type of asthma a patient has and be the ones to prescribe drugs like depomokumab and the other monoclonal antibodies that are currently approved for asthma. Right.

I mentioned earlier you were involved in these clinical trials and and many other ones. Are there ongoing clinical trials now for drugs that are even more effective than extensor, even though it's hugely effective or maybe can be given even less frequently? What? What's the future for this type of treatment? Yeah. You know, I like to say it's, it's a good time to have bad asthma because we have a lot of good therapies. We have now 7 biologic therapies that are approved for asthma and those include omalizumab, which blocks IG, mepalizumab, which blocks Illinois 5, similar to depomochemab, rezlizumab, which blocks Illinois 5, benlylizumab, which blocks the Illinois 5 receptor.

We have dupilumab which blocks the Illinois 4 and 13 receptor and tezipilumab which blocks TSLP or thymic stroma, lymphopoietin. There's so many other therapies that are in development including combinations of these targeted therapies. Just in the last couple of days there was. Announcement of positive results from a drug called Luncecamig which which blinds Illinois 13 and TSLP. So it's targeting 2 specific cytokines. There are ultra long acting TSLP therapies. There's one called Varecatug, which is a TSLP receptor therapy that is administered every three to six months.

That just had some positive results. Then there are newer newer pathways that are being evaluated. Anti Illinois 33 therapies like itekamab and tozeracamab. There are Jack inhibitors like frevacitinib and other inhaled Jack inhibitors. And then there are other therapies that target T cells like the OX40 ligand, targeted therapies like amlitellemab. And then other there recently published, there was something that targets BTK or Bruton tyrosine kinase drug called rosabrutinib was just published on this past week and also offers hope for our patients with bad asthma.

So there are a lot of therapies in the pipeline. I'm only mentioning a few, but there's so many others that are in development. Combinations of Illinois 45 and 13, TSLP and Illinois 33, and many, many others. You mentioned about a dozen different medications with tongue twister names. I'm very impressed you could say them all so quickly. How do you decide which drug to put a patient on? Is there a algorithm that you used to to figure out what's best for a specific patient to customize their treatment?

Yeah. You know, you have to use a mix of looking at the biomarkers, looking at the effects of these drugs on other comorbidities like chronic sinusitis, like atopic dermatitis, like eosinophilic esophagitis and others. You have to evaluate the frequency that these drugs are administered and also the cost to the patient and what the papers are going to say. And then you need to use shared decision making with the patients to discuss what are the pros and cons of each therapy based on what those drugs can do for those patients specifically and for the specific type of asthma that the person has and for their other comorbidities.

So for instance, if a patient's got bad atopic dermatitis, you might have them give them one drug. If they've got bad allergies, you might give them a different drug. If they've got really high nitric oxide levels, you might give them one drug. They've got really high eosinophils. You'd give them another drug. So you have to evaluate each patient carefully and and figure all these things out. Now you read my mind. I was going to ask you is, is this covered? Is extensor covered by insurance at this point?

Yeah, these are expensive therapies. All the monoclonal antibodies that we have now are expensive therapies. They cost anywhere from 40,000 to $52,000 a year. Fortunately, most payers recognize that if someone goes to the emergency room and has a hospitalization and has frequent doctor's office visits, that those are costly as well and that these therapies that can prevent exacerbations, you know, you could have some cost savings by administering these therapies. So most payers will approve these therapies if you give a strong rationale and the approval process isn't too complicated.

Normally you have to say, OK, this person has these biomarkers, they've got severe asthma, they've had X number of exacerbations, they're already taking their inhalers. And so they will generally approve those kinds of therapies. Well, that's good to know. Anything else in the future about asthma or are we ever going to be able to figure out how to prevent it completely, you think? Or the combination of genetics and environment is is something that continues and we just figure out better ways to treat it.

No, I, I think we're, it's really exciting actually. We're working towards not just treating the exacerbations, but also preventing exacerbations. You know, it's akin to, you know, yes, we can put the fire out, but don't we want to prevent the fire from happening to start with? So we're starting to do studies now where we're administering these therapies earlier on in the course of disease to see if we can prevent exacerbations from happening, to see if we can prevent the progression of asthma, to see if we can get patients into remission earlier.

And then our goal is to try to get patients off of therapy and what we call disease modification. What's exciting to me are not only the use of our current biologic therapies, but we're also doing even some genetic studies where we're trying to reprogram one's genetics to try to address the underlying asthma, like using car T cell like therapy to try to really prevent asthma and cure asthma with a single shot. Wow, so maybe you can inject a new eosinophil that has different genes in it and then it populates a patient's body and they don't have the problem with eosinophils anymore?

Yeah, or maybe giving a drug that that stimulates the body to make its own anti Illinois 5 for instance, and preventing eosinophils from that perspective. Sounds like a great future, so I'm excited. It's really exciting. And also we're also starting to use these therapies in other areas like COPD, chronic obstruction problems, patients with chronic bronchitis and emphysema. And we've now had two approvals of these biologics that we use in asthma in COPD. And we just got some positive results from another COPD trial, an anti Illinois 33 therapy called tozoracomab and that offers some promise as well for patients with COPD.

So it's an exciting time to be managing these patients and offering them these new therapies. That's great. Great to know. I'm only an ophthalmologist, so I didn't know much about asthma, but now I feel like I'm almost an expert in it. Not not quite as good as you, but I appreciate you taking the time to share your knowledge and wisdom and experience about asthma and these new drugs that are available, and I'm sure the audience will appreciate this as well. Such a pleasure to talk to you. I'm sure you know much more about asthma than I know about glaucoma and cataracts and retinal diseases.

Navy. Navy. But it takes all of us, takes a village, as they say. Exactly. Thank you. Thank you so much.

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