Research on Asthma

Andrew:

Andrew:

So even though we may have a new way of thinking about asthma and we are learning that some types of asthma are steroid resistant, corticosteroids are the best treatment we have for asthma right now. Let me be sure I understand this, this new line of therapy which will take a number of years to develop will not cause these side effects and will be used for what we now know is a type of asthma that is steroid resistant? Can you tell us more?

Dr. Borish:

Well, the main direction that a lot of this new research is going, is to recognize that steroids are kind of a sledgehammer approach, meaning when you take prednisone, you are literally modifying probably hundreds of biological effects. Some of these biological effects are very useful, like the ones that specifically remove components of the inflammation in the airway, but then there’s those biological effects of prednisone that act to raise blood sugar and lead to diabetic complications, ones that raise blood pressure, that kind of thing. So, one of the things we’re trying to do, is to dissect out what’s really going on in the inflammation of asthma. So if you could figure out that it’s specifically one or two inflammatory molecules that are being overexpressed, well, you can then go in there with, to use one of the medical terms we like to use, sort of a magic bullet to remove the biological effect of that specific mediator and not do all of the hundreds of activities that steroids do and produce their risk for side effects.

Andrew:

Okay. I’d like to ask you in just a moment about the anti-IgE medication approach, but let me ask one general question first. When we talk about airways, most of us probably think first of our lungs, but I wonder, do asthma and allergies affect our upper airways as well, like nose and throat?

Dr. Borish:

Oh, absolutely. No, this is definitely a disease of the entire length of the airway, not only the lungs but clearly also the nasal passages as well, and a lot of the treatments that we’re going to be talking about are anti-allergy treatments that work in asthma to the extent that asthma’s an allergic disease, but they’ll certainly work for allergies of the nose, specifically hay fever. And the other disease that we have to think about is sinus disease. There are 20 or 30 million sinus sufferers in this country, and that’s become a huge problem. It’s almost an irony of some of the success we’ve had of the last decade in the treatment of asthma, which has led to the reduced need for, for example, prednisone, but one of the side effects of that is as we switched all of our patients from dependence on prednisone to dependence on inhaled steroids, we’re no longer getting the systemic effects of taking prednisone as a pill. And what we’re seeing is the asthma’s doing great, and people’s sinuses have become a disaster.

And it’s a huge problem, meaning inflamed sinuses interfere with people’s ability to sleep because they can’t breathe through their nose. It interferes with your sense of smell and taste, and while it doesn’t cause some of the major morbid complications that asthma does, sinus disease greatly interferes with people’s quality of life. So, yes, one of the goals of these kinds of therapies is to see if we can’t block inflammatory disease throughout the entire respiratory tract.

Andrew:

So, Dr. Borish, it sounds like you are saying that asthma is an ongoing inflammatory response. What does this mean in terms of what people call “asthma triggers” that irritate asthma?

Dr. Borish:

Okay. First of all, asthma, when you have it, it’s there all the time. You may be feeling fine. Your airway passages may be clear, you’re breathing well, you’re not coughing, you’re sleeping through the night, but we know from some of the research that we’ve been doing the past several years that if we go into your lungs and collect tissue from the lungs, we can find the inflammation there. So the damage to the airways, the swelling, and the mucus production that I talked about earlier is there. It’s there all the time. This is a persistent, ongoing inflammatory disease. So, when we use the word “asthma trigger,” what we’re talking is about the types of things that will turn that kind of inflammatory process into a symptomatic, potentially life-threatening asthma attack. And really, when you think about that, there are two broad categories. One is allergies. So, you could be doing well, at least feeling well, and not having any symptoms, and then you’ll either go into your allergy season.

If you’re grass allergic, you get exposed to that huge concentration of pollen, and after several days, now you’re symptomatic. Now you’re finding the need for urgent care, perhaps in the emergency room. Or there are people like me who can walk into the home of somebody with a cat and know within five minutes that it’s time to leave because of the intense exposure associated with cat allergen.

Dr. Borish:

And the other category of asthma triggers, probably the scariest for asthmatics, is respiratory infections. What is a cold for everybody else, in the asthmatic becomes bronchitis. Nobody really understands that mechanism, but those typically benign respiratory infections that we all get four, five, six times a year almost invariably spread down into the chest of the asthmatic. They become an attack of bronchitis, and that bronchitis almost invariably produces a very severe asthma attack.

Andrew:

So, you’re telling me that not only environmental allergens can cause asthma attacks, but also there are infectious agents – viruses and infections – that can trigger asthma attacks. I’ve also heard that there are new genetic factors involved.

Dr. Borish:

Yes, and actually, the genetics of asthma, I think, is one of the most exciting things that are being developed as we speak here today. We know, from literally work that goes back hundreds of years, that this is a genetic disease. When I see a child in my clinic who invariably asks, “Why did this happen to me?” I can’t answer that question, but what I can tell the child is which of their parents did it to them. You know, invariably you find that one or both has, if not asthma, at least a history of allergies. So, we’ve known that for a hundred years. We’ve known that there is this strong genetic component that as you say interacts with something in the environment – allergens, viral infections, secondhand cigarette smoke, that kind of thing – to trigger the full-blown asthma attack. So, one of the things that’s happening right now, is increasing our understanding of what those genes are for the obvious reason that if we know what genes are dysfunctioning in asthma, then obviously that can clearly lead to focused therapies. So if we know that gene X is way overproduced in asthmatics, and normal people are characterized by the fact that this particular gene is never being expressed in their bodies or in their airway or that it has a different kind of function, then obviously, we can make a drug that will specifically correct that kind of a problem.

Andrew:

I’m thinking about the great strides made with the Human Genome Project. Would you say that the discoveries in that project will impact development of new treatments and shift our thinking about asthma?

Dr. Borish:

Oh, absolutely. And what it really leads to is the concept that has become increasingly popular, that when we use the word “asthma,” we’re probably talking about perhaps dozens of diseases. And what I mean by that is, there are probably dozens of processes that give as a final common pathway the inflammation in the airway that we call asthma. So, in some people it may be purely, as an example, an allergic disease. There are some people, though, who get asthma who have no allergies, have never had hay fever, they don’t have a family history of allergies, but they’re getting their asthma perhaps on the basis of specific exposures to infections. There are some people who have what we call triad asthma where they have asthma, sinus disease, aspirin allergy – that’s the third component of the triad – and that appears to be a disease of overproduction of a very specific type of mediator termed the leukotrienes.

These are all probably very different diseases, but the bottom line is they produce inflammation and swelling and mucus production in the airways, so to the patient it’s the same disease. But the importance is, once we dissect out all of these different diseases, yes, it’s quite possible that each of these diseases is going to require its very own specific therapy.

And I can easily envision a day where the Human Genome Product, as you say, leads us to a situation where people will come in with asthma, we’ll get a DNA sample from them, and we’ll get a read back from the computer a day or so later saying, “Oh, this is a person whose asthma is caused by this and this. These are the drugs you’ll need to use. Oh, and by the way, you should avoid this because this drug won’t work in that particular person,” or “They’ll be particularly responsive to these kinds of drugs.” As I say, it’s a very exciting time.

Andrew:

It is wonderful that we are able to make this progress in treating airway disease. Now can you tell me what is on the horizon for treatment? We’ve been hearing a lot in the press about a new medication called Nuvance. Tell us how it works.

Dr. Borish:

Nuvance represents a naturally occurring anti-allergy, anti-asthma compound. Interleukin-4 is one of the proteins, one of the mediators, that is produced in allergic asthmatic subjects. We can readily identify it in their lungs, and in the nasal passages, and throughout the immune system in people who are developing allergies, and we think that it has a key, central role in the cause of allergies and asthma. In the presence of interleukin-4, one of the things that the body does is it makes the IgE antibodies that we talked about earlier. IgE antibodies are the antibodies that cause allergies. When a non-allergic person is exposed to a cat, for example, typically nothing happens, but if they do in fact make an immune response to the cat, they’ll make IgG antibodies, and that’s never a problem. Allergic people make IgE It can be IgE antibodies to mold, grass, pollen, ragweed, whatever.

And it is the IgE antibody that causes much of the misery. It’s the IgE antibodies that lead to the release of histamine, leukotrienes, and a lot of these other inflammatory mediators that I’m sure most of the asthma sufferers listening are very familiar with that are causing their symptoms. So, IgE gets made because allergic people but not non-allergic people produce interleukin-4.

Other effects of IL-4 being produced are a very selective ability to recruit inflammatory cells. Those are white blood cells, but really a very specific type of white blood cell termed the eosinophil. It is the recruitment of these eosinophils into the lungs that produces the inflammation and damage, and a last example of what IL-4 does, is I talked earlier about the excessive mucus production. IL-4 interacting with the airway activates the mucus glands to start excessively producing that mucus.

So, clearly, given that key, central role of IL-4 in causing asthma, it becomes an obvious target. If we could eliminate IL-4 from being produced, we should be able to eliminate these kinds of allergic inflammatory responses. And actually going back to what we were talking about a little while ago, about the genetics of asthma, one of the reasons why this approach is so exciting is that the Human Genome Project and other NIH-funded studies into the genetics of asthma have really pointed to the role of IL-4, both the excessive production of IL-4 and excessive responsiveness to IL-4, as being very important asthma genes in many of our patients.

Andrew:

So Nuvance is aimed at the production of IL-4, so if we can make a medication that stops this IL-4 – which creates the allergic inflammatory response, asthma care will be improved through a mechanism we didn’t even know existed just a few short years ago.

Dr. Borish:

Correct. What I said earlier is that it is a naturally occurring, anti-allergic inflammation product that is present in everybody IL-4 works and causes all of those problematic side effects that I referred to a moment ago because it binds to a very specific receptor that’s present on many cell types in the body, so IL-4 reacts with IL-4 receptors in the mucus cells to stimulate mucus secretion. It acts on IL-4 receptors on other immune cells to stimulate IgE production, and so forth. So, we have these very high binding proteins, if you will, for IL-4. Now, the receptor can trigger all these bad effects because it really has two components to it. On the one hand is the part of it that binds IL-4. On the other is sort of the active site. It’s the site that can turn on all of these biochemical reactions that lead to all of these effects. So, if you imagine a cell floating in the body somewhere, you have on the outer edge of the cell the IL-4 receptor that will bind to IL-4 if it’s present, but on the other side, inside the cell, is the active tail.

The soluble receptor represents only the part of the molecule that can bind to IL-4. These occur naturally, because frequently these proteins that include both the receptor half and the active half get cut in half just because of the natural state of what the body does as cells are broken down and so forth. What we’ve done, and this is work done by the investigators of this project at Immunex, is cloned and administered to our patients just the receptor component, the soluble receptor, that is, the part of the molecule that can bind IL-4 but not the part of the molecule that can activate these bad immune responses.

So, you can think of it almost as a sponge. We now have a protein that can go around and mop up all of the excess IL-4 that’s present in the airways or in the circulation, sequester it, keep it away from the full-length molecules that can trigger the adverse inflammatory responses, and block all of the biological activity thereby of IL-4.

Andrew:

Where are we now in terms of clinical trials with this sponge-like medication?

Dr. Borish:

We are currently in phase two clinical trials, so we have done a number of preliminary studies that have been designed to look at both safety, dosing, and preliminary efficacy studies. In our current studies it’s being administered to approximately 200 people to further establish the clinical efficacy.

Andrew:

Doctor do we know yet who most likely will benefit most from this new approach to asthma control?

Dr. Borish:

Well, it’s a very interesting question. Because of the role of IL-4 in causing IgE production, the obvious initial choice, and the people we’ve focused all of these studies on, are patients with allergic asthma. However, we know that patients with non-allergic asthma – so those are the patients who typically get asthma later in life, don’t have a history of hay fever; when they get skin tested, their skin tests negative, and these are people that are considered to have what’s called intrinsic, non-allergic asthma – we know that these people have asthma characterized by excessive IL-4 production. And because of all the other adverse biological effects of IL-4 like mucus production and recruitment of inflammation to lungs, this drug will almost certainly be helpful in them. As I also hinted at earlier, this is truly an anti-allergy drug. We’re using it in asthma, but it really should block many components of allergic disorders, so in theory at least, it would be effective for people with allergic rhinitis. I don’t think that’s a huge need right now, because we have good hay fever drugs, and patients with hay fever by and large are doing well. But one group that I think will be very excited about this kind of an approach will be the patients I referred to earlier with sinus disease where we don’t have great ways of getting useful drugs into the sinuses.

And the last category that I’m really excited about, are the children especially with atopic dermatitis, allergic skin diseases. This is a disease that probably doesn’t affect more than a million people, but for those million people, it’s a huge, huge problem. These kids are miserable, scratching, not sleeping, and their parents are miserable, watching and not sleeping.