Chapter 17

Future Trends in Asthma Therapy

In This Chapter

Looking ahead to improvements in managing asthma

Understanding the importance of continuing asthma research

Volunteering for clinical trials

D uring recent decades, the incidence of asthma has unfortunately risen. That’s the bad news. But the good news is that continuing advances in medical science are providing doctors with increasingly more effective thera-pies to treat asthma patients and improve their quality of life. The even better news is that asthma therapy is only going to improve.

Based on the extensive experience I’ve gained during the last two decades while conducting clinical trials of new asthma drugs, I foresee more effective and innovative products on the horizon. In fact, the pharmaceutical industry, with significant specialty physician guidance and support, continues to develop new approaches to treating asthma.

The newer products will address the underlying airway inflammation that characterizes asthma even more successfully than has been possible until now. As a result, you can expect medications that more effectively treat the root cause of asthma, which would bring doctors and their patients a step closer to the goal of having patients achieve normal lung functions and complete control of symptoms with less need for taking medications on a regular basis.

So get out those sunglasses. As you see over the course of this chapter, the future of asthma therapy’s so bright, you may need to wear shades.

Getting Better All the Time

No matter how good a product is, it can almost always be improved. In that spirit, researchers are continuing to develop more effective formulations and delivery devices for existing asthma medications. In this section, I explain the most notable developments in this area of asthma therapy.

Improving inhaled corticosteroids

The development of inhaled corticosteroids in the 1970s heralded a new age in asthma therapy. For the first time, anti-inflammatory drugs were available that could reduce swelling and mucus production in the airway, decrease airway hyperreactivity (“twitchiness”) in response to asthma triggers, and in some cases even prevent airway remodeling (in which healthy, functioning tissue is replaced with non-functional scar tissue due to chronic airway inflammation).

In recent years, as pharmaceutical researchers have continued improving inhaled corticosteroids, most physicians have come to consider these products the therapy of choice for treating patients with moderate to severe asthma symptoms.

The newest generation of these drugs, which are currently in development or due for FDA approval as this book hits the stores, may provide even more effective therapy by directly targeting the lungs with greater accuracy while also reducing typical adverse side effects associated with inhaled corticosteroids. I’m particularly impressed with ciclesonide (Alvesco) and mometasone (Asmanex). These two drugs have shown great promise in clinical trials, especially in treating children with asthma.

Combining for complementary effect

Another promising trend in recent asthma pharmacology has been the development of products that combine an inhaled corticosteroid with a long-acting bronchodilator in order to achieve a complementary effect. Advair Diskus, which the FDA approved in 2000 and is now one of the most prescribed asthma drugs in the United States, combines fluticasone, an inhaled corticosteroid, and salmeterol, a long-acting bronchodilator.

This focus on complementary therapy is continuing and shows great promise with Symbicort, which the FDA should soon approve. This product combines budesonide, an inhaled corticosteroid, with formoterol, which is the only rapid-onset, long-acting bronchodilator available in the United States. In the near future, expect to see more products that combine formoterol, or other long-acting bronchodilators that are still in development, with some of the newer inhaled corticosteroids.

Special delivery: More effective devices

To really make a difference in effectively managing asthma, as well as other respiratory conditions, the inhaled medications that patients take — whether they’re newly developed drugs or improved formulations of older products — need to reach as deep into the airways as possible. As a result, much of asthma medication development also focuses on improving delivery devices, especially inhalers.

Metered-dose inhalers (MDIs) have been standard delivery devices for asthma medications since the advent of beta ₂ -adrenergic bronchodilators and inhaled corticosteroids. However, many of these devices require a certain level of coordination for effective use (often requiring the patient to also use a holding chamber or spacer for optimal results) and at best only deliver 10 to 20 percent of the spray to the airways where it’s really needed. Additionally, many MDI medications are formulated with ozone-depleting chlorofluorocarbons (CFCs) as propellants.

To overcome the shortcomings of older MDIs, newer inhaled asthma products, both recently approved ones and those still in clinical trials, offer the following improvements:

Environmentally friendly propellants. The FDA approved Hydrofluo-roalkane (HFA), a new non-CFC propellant for use in formulations of albuterol (Proventil HFA, Ventolin HFA) and beclomethasone (QVAR-HFA). Not only are these newer HFA-propelled products better for the ozone layer, but they also deliver medications to the lungs more effectively than the older CFC-based MDIs. You can soon expect to see more formulations of inhaled asthma drugs using HFA, or other soon-to-be approved non-CFC propellants.

User-friendlier MDIs. The recently developed Maxair Autohaler is a prime example of this trend. The Autohaler, which is indicated for short-term relief of suddenly worsening respiratory symptoms, is a breath-activated MDI that delivers the short-acting beta ₂ -adrenergic bronchodilator pirbuterol without the need for a holding chamber and also requires less coordination to use compared to many other MDIs. Look for more delivery devices along these lines in the near future, especially for use with short-term or rescue medications.

Dry-powder inhalers (DPIs). Rather than dispensing their product as an aerosolized spray, as do MDIs, these newer types of inhalers deliver asthma drugs in special dry-powder formulations. DPIs are also designed for easy use, and if operated properly, are very effective at delivering medication to the tiniest airways. The FDA has thus far approved DPI formulations of four inhaled products:

• Budesonide, an inhaled corticosteroid (Pulmicort Turbuhaler)

• Fluticasone, also an inhaled corticosteroid (Flovent Rotadisk, used with the Diskhaler device)

• Salmeterol, a long-acting bronchodilator (Serevent Diskus)

• Fluticasone and salmeterol in combination (Advair Diskus)

More DPI formulations are also in the pipeline, so breathe easy. Your doctor will continue to have a wider choice of simpler and more effective ways for delivering medications deeper into your airways than ever before.

Under Your Tongue: Swallow Immunotherapy

European researchers have recently developed a potential alternative to allergy shots, known as sublingual-swallow immunotherapy. Doctors in a few European countries are currently using the therapy to reduce symptoms of pollen allergies, a common trigger of asthma (see Chapter 5 for details on asthma triggers). This treatment, known by the less than lovely acronym of SLIT, consists of patients holding up to 20 drops of allergen extract under the tongue for as along as two minutes before swallowing.

Although some studies indicate that SLIT can indeed help reduce symptoms associated with allergic reactions to certain pollens, this exact form of the therapy still needs more research. For one thing, holding the required number of drops under your tongue for a definite amount of time isn’t always that easy to do.

Perhaps more importantly, SLIT has mainly been prescribed as a self-administered therapy, with patients taking the drops at home rather than in a medical setting where doctors and nurses can make sure that the extract is taken properly. As a result, doctors and nurses can’t monitor the patients to make sure that they get proper and immediate medical attention if the extract triggers a rare, serious adverse side effect (see Chapter 11).

However, I am intrigued by further advances in this concept of immunotherapy, especially the development of a disintegrating tablet form of SLIT, which gradually dissolves under the patient’s tongue. Although this approach to SLIT is still at the trial stage in Europe, it could possibly simplify administration of immunotherapy and ensure that patients on their own would consistently adhere to the proper dosage and method of taking the extract.

Based on what my European colleagues have told me, and the studies I’ve seen, a disintegrating tablet form of SLIT could turn out to be the next potential breakthrough in immunotherapy in the United States, especially if the treatment can be developed to also provide effective treatment for a much wider range of allergens.

Blocking IgE: A Biotech Breakthrough

One way of effectively managing asthma and improving the quality of life of asthmatics is to attempt to block or interrupt the immune system’s response to allergen exposure. (See Chapter 6 for an in-depth discussion of the immune system and its key players, including IgE.) To that end, the first-ever anti-IgE medication, a recombinant human monoclonal antibody , or rhuMab, known as omalizumab/rhuMAb-E25 (Xolair), has recently been developed and was approved by the FDA in June 2003.

This novel and more targeted form of therapy for asthma (and other allergic conditions) is specifically designed to block IgE — which the vast majority of people with allergies tend to overproduce — from playing its key role in triggering symptoms of allergic reactions. This anti-IgE antibody is designed to be administered in your physician’s office once every two to four weeks by injection, with the exact dosage tailored to each patient’s body weight and baseline levels of circulating IgE, as measured by a simple laboratory blood test.

As I explain in greater detail in Chapter 6, when a person’s immune system with allergies is exposed to an allergen to which he or she has been previously sensitized, IgE antibodies prompt mast cells and basophils (among others) to initiate a complex chain of events that culminates in the release of potent chemical mediators of inflammation, such as histamine and leukotrienes. The action of these chemicals is the main cause of symptoms such as coughing, sneezing, watery eyes, and shortness of breath.

Omalizumab/rhuMAb-E25 (Xolair) represents an exciting advance in asthma management. Studies show that patients with moderate to severe allergic asthma who used Xolair had less frequent respiratory symptoms overall, and more than half of participants not only experienced fewer asthma episodes, but they also were able to stop using their inhaled corticosteroid medication.

Anti-IgE therapy provides an innovative way of treating asthma and other allergic disorders at an earlier stage, rather than after the allergic reaction and resulting symptoms have occurred. Researchers are also working on other promising monoclonal antibody medications, such as anti-IL-5 and perhaps anti-IL-8 (see the following section for more information).

Exploring the Frontiers of Asthma Therapy

Some of the most exciting and promising ongoing medical research focuses on the actual blocking of the immune system response that leads to airway inflammation and resulting airway hyperreactivity — the underlying cause of asthma. Although we’re still years away from seeing FDA-approved products, the concept of isolating and neutralizing allergic reactions at the cellular level seems particularly promising.

Inhibiting interleukins

Among the key regulators of immune system functions, interleukins are a class of compounds produced by lymphocytes (which constitute 20 to 30 percent of the white blood cells in most human beings), by macrophages (cells that protect against infection and noxious substances), and by monocytes (large white blood cells formed in the bone marrow, which turn into macrophages after they enter the blood).

In recent years, researchers have identified two interleukin compounds, known as IL-5 and IL-8, as key components of the inflammatory process. Check out the following sections to read about research into new therapies using these compounds.

Anti-interleukin-5

Studies indicate that IL-5 plays an important role in the production of specialized white blood cells known as eosinophils. Chemical mediators attract eosinophils to the site of inflammation where these white blood cells in turn stimulate a prolonged response, which contributes to the late-phase reactions that asthma patients often experience (see Chapter 6). Studies also show that many people with allergic asthma have higher than average numbers of eosinophils in their bone marrow and bronchial mucosa (the internal lining of the airway).

Patients in recent clinical trials who were treated with mepolizumab, a newly developed anti-IL-5 monoclonal antibody, showed a marked reduction in the number of mature eosinophils and eosinophil progenitors (cells that can become eosinophils) in bone marrow, and an important decrease in levels of bronchial mucosa.

These results suggest that anti-IL-5/mepolizumab therapy may someday be an effective way of preventing the immune system from unleashing chemical mediators of inflammation when exposed to allergens.

Anti-interleukin-8

This interleukin compound seems to play a crucial role in cases of severe persistent asthma and sudden-onset fatal asthma. Many patients who suffer from these more serious forms of the condition produce above-normal levels of IL-8 and also of neutrophils (large white blood cells that appear under a microscope to be neutral-colored, hence the name). By attracting neutrophils to the airway epithelium (the membranous tissue that covers most of our internal surfaces and organs), IL-8 appears to foster airway inflammation, leading possibly to airway remodeling.

Although research is ongoing into ways of inhibiting or preventing the action of IL-8, some studies have also shown that salmeterol, an already approved and widely prescribed long-acting beta ₂ -adrenergic bronchodilator (see Chap-ter 15), may be effective in reducing the activity of IL-8.

Toll-like receptors (TLRs)

These proteins, which acquired their unusual name because the German scientist who first discovered them yelled out “toll” (German for great ), alert the immune system to the presence of infectious agents such as viruses and bacteria. Toll-like receptors (TLRs), which reside on the surface of certain immune system cells, can also recruit other cells to attack infectious agents.

According to some researchers, TLRs can be used to enhance your immune system’s response against actually harmful diseases, thus boosting your overall well-being. Conversely, this could help reduce the immune system’s tendency — in those people with a genetic susceptibility to develop hypersensitivities and produce antibodies to otherwise harmless allergens — to trigger allergic responses when exposed to allergens.

Gene therapy

The completion of the U.S. Human Genome Project in April 2003 means that scientists are now much closer to identifying the proteins that make up human life. They’re perhaps on the brink of isolating and blocking the inherited genetic mutations and abnormalities that can lead some people to develop hypersensitive immune systems and resulting conditions, such as allergic asthma.

One recent study of the DNA of asthmatics has shown that the process that leads to inflammation, and thus to characteristic respiratory symptoms of asthma, is actually due to a mutated gene. When the makeup of proteins produced by this sort of gene is established, scientists may be able to develop therapies that block the action of those proteins and keep the inherited condition from actually having an adverse effect.

Gene therapy may even make it possible to develop a vaccine for infants or young children that would provide them with a lifetime’s immunity from asthma.

Keeping Research Alive: Clinical Trials and You

Studies around the world continue to show that asthma is almost always a life-long condition. The condition’s extent and character may vary over a patient’s life, but after a person has the disease, it will likely never go completely away. Medical researchers in New Zealand have recently confirmed this finding. (New Zealand is one of the countries hardest hit by asthma and a center of expertise in treating the condition.)

Even with new and improved treatments, those few patients who may actually outgrow their asthma will continue to be exceptional cases until doctors can pinpoint and correct the exact immune system malfunction that leads some people to develop asthma.

In order to keep improving asthma therapy, continued research into what causes the disorder and how to treat it more effectively is essential. And, in order for this research to be successful, the participation of human subjects is crucial. The more patients volunteer for studies and clinical trials, the quicker doctors can bring new and more effective treatments to market.

I encourage asthma patients, based on their physicians’ advice, to consider enrolling in clinical trials of therapies that are still in development. In my own work as a principal investigator on many asthma and allergy research projects, I know the challenges of organizing and conducting the studies that are required in order to bring new medications to market.

One of the main reasons that pharmaceutical companies spend an average of $700 to $800 million dollars bringing new drugs from laboratory to market is the need for extensive clinical trials, which can often take seven years to complete. And at the end of this arduous process, only a small fraction of drugs actually receive FDA approval.

The high cost and financial gamble of pharmaceutical research and development (R&D) is, in turn, one of the main reasons the prices of prescription medication in the United States are so high. Pharmaceutical companies need to make back their investment in all their R&D from a relatively small number of products that do finally make it to market.

If more asthma patients participated in clinical trials, the process of developing new and more effective drugs and delivery devices could be accelerated to the benefit of asthmatics everywhere and may also result in products that would be less costly.