(Laurie Barclay, MD, November 2003)

In 1998, asthma affected 6.4% of the U.S. population, or 17 million Americans including 4.8 million children. Only slightly more African Americans (5.8%) than whites (5.1%) have asthhma, but African Americans are three to four times more likely than whites to be hospitalized for asthma, and mortality is four to six times greater.

Overall mortality from asthma is 5,000 per year in the U.S., and the death rate has doubled during the last two decades. Of 451,000 people hospitalized for asthma in 1994, 169,000 were children under age 15. Of $10.7 billion in health care costs attributable to asthma in 1994, $6.1 billion were in direct health care costs and $4.6 billion in indirect costs, such as lost work days.

Allergic rhinitis is the most common allergic condition worldwide, affecting over 150 million people in North America, Europe and Japan alone, and prevalence is increasing. Inhaled steroids and antihistamines are used most often for treatment, with sales of these products exceeding $2 billion annually in the U.S.

Asthma and allergy in many cases are triggered by airborne allergens, which induce an immune response involving immunoglobulin E (IgE), mast cells, eosinophils, T-lymphocytes, macrophages, and neutrophils. Inflammation and constriction of the airways lead to coughing, wheezing, and difficulty breathing characteristic of an asthma attack, or nasal congestion characteristic of allergic rhinitis.

Variable airflow obstruction in asthma is often reversible either spontaneously or with treatment. Currently available treatments for asthma include inhaled corticosteroids, leukotriene blockers, cromolin, or nedocromil to reduce airway inflammation, and short-acting inhaled beta-2 agonists to relax airway constriction associated with acute attacks. Long-acting bronchodilators include sustained-release theophylline.

Center Watch has identified a pipeline of 45 drugs in various stages of development for asthma and allergy. Many of these involve immune system modulation, whereas some asthma drugs act on smooth muscle within the airway.

King Pharmaceuticals has submitted an NDA for asthma for Intal HFA-227, licensed from Aventis. This hydrofluoroalkane (HFA) aerosol formulation of cromolyn sodium inhibits immediate and non-immediate bronchoconstrictive reactions to inhaled antigen. Its mechanism of action is to inhibit release of histamine and other chemical mediators from mast cells and to prevent activation of inflammatory cells including eosinophils, neutrophils and monocytes. In clinical trials involving 514 adults and children, the overall improvement rate was 65.9%. Reported adverse reactions are rare, and include nausea in 0.15% and throat irritation and coughing in 0.13%.

An oral formulation for cromolyn is in Phase I testing by Emisphere Technologies, offering the potential for greater efficacy and compliance. In early trials, the oral dose produced mean plasma cromolyn concentrations up to 46 ng/mL, higher than those obtained from available non-oral formulations.

Serevent (salmeterol xinafoate), a beta-2 agonist in metered-dose inhaler formulation for asthma, is in Phase III development by GlaxoSmithKline. On January 23, 2003, the Food and Drug Administration (FDA) announced that an interim analysis of a large safety study of Serevent suggests an increased risk of life-threatening asthma episodes or asthma-related deaths in some subgroups. Furthermore, interim analysis did not show a statistically significant result for the primary endpoint, a combination of respiratory-related deaths, intubations, or ventilatory failure.

When all patients in the study were considered, there was a nonsignificant trend toward increased deaths and serious asthma episodes. The risk appeared to be greatest in African-American patients and in those not taking inhaled corticosteroids at study entry. Based on available data, the FDA suggests that the benefits of Serevent in asthma continue to outweigh the risks and that the serious adverse events reported in the trial were rare.

Another beta-adrenergic receptor agonist is Sepracor’s product Xopenex (levalbuterol HC1). This drug is already approved for asthma in other formulations, and is now in Phase III testing as an HFA formulation. Current indications are the treatment or prevention of bronchospasm in patients six years of age and older with reversible obstructive airway disease.

Symbicort pMDI (budesonide/formoterol) is in Phase III testing for asthma by AstraZeneca. This formulation includes the corticosteroid budesonide and the rapid and long-acting bronchodilator formoterol, a beta2-agonist, in a single inhaler (Turbuhaler). It offers adjustable dosing and is available in both standard dose (160/4.5mcg) and low-dose (80/4.5mcg) strengths. Symbicort Turbuhaler is already approved in 68 European countries and launched in 44 countries.

Altana Pharma and Aventis have completed Phase III testing of Alvesco (ciclesonide), an inhaled corticosteroid used once-daily for asthma, and have submitted it in May 2002 for approval in Europe, Australia, Canada and Switzerland.

The MPL vaccine adjuvant is in Phase III testing by Corixa and GlaxoSmithKline, targeting allergic symptoms caused by pollens from grasses, trees and house dust mites. This proprietary form of monophosphoryl lipid A is a highly potent immunostimulant and a derivative of the lipid A molecule extracted from gram-negative bacterial cell walls. MPL activates monocytes and macrophages and stimulates release of cytokines including IL-1, IL-12, TNFa and GM-CSF, enhancing recruitment of lymphoid and antigen-presenting cells to the local lymphoid organs. It thereby enhances immune responses to a variety of viral and bacterial antigens, such as peptides, proteins, polysaccharides and tumor cell lysates.

Results from Phase II multicenter clinical trials suggest that adding MPL adjuvant to desensitization products allows more rapid response to treatment, fewer treatments with lower dosages, and a higher response rate. Thus far, MPL has been well tolerated in all clinical trials in which thousands of doses have been administered. There has been no systemic toxicity, and reactogenicity is usually similar to that of the antigen or vehicle alone. The MPL adjuvant is also being evaluated in vaccines for development in cancer and infectious disease targets.

Loteprednol etabonate is in Phase III testing for allergy by IVAX. This drug is structurally similar to other soft corticosteroids, as it is synthesized through structural modifications of prednisolone-related compounds. In a recent study published in Ophthalmology, this site-active corticosteroid appeared to be safe and effective in treating ocular allergy symptoms. Because it is not absorbed systemically, it does not cause increased intraocular pressure or other adverse effects typically associated with steroids.

Dynavax Technologies has completed Phase II testing of AIC as immunotherapy for ragweed allergy. This anti-allergy vaccine candidate consists of the major ragweed allergen, Amb a 1, linked to a proprietary 1018 immunostimulatory DNA sequence (ISS). In the Phase II study, 27 ragweed-allergic adults with a history of seasonal rhinitis received a series of six subcutaneous injections at three different dosing levels, ranging from 2.4 micrograms over a three-week period to 15 micrograms over a six-week period.

Except for self-limited local reactions, the AIC injections were well tolerated, with no serious, vaccine-related adverse systemic reactions observed. The antibody responses to ragweed allergen showed marked dose-related increases in allergen-specific IgG levels, similar to those observed with successful conventional immunotherapy with licensed ragweed extract. However, the latter therapy usually involves 60 injections of allergen administered frequently over a two-year period.

TNX-901 is an anti-IgE monoclonal antibody for which Tanox, Genentech and Novartis have completed Phase II testing for severe peanut allergy. In a four-month, placebo-controlled trial reported in the March 13, 2003 issue of the New England Journal of Medicine, once-monthly dosage of TNX-901 increased the average threshold for allergic reaction from half a peanut to about nine peanuts. This reduced response to challenge should help protect against many accidental exposures.

Another inhibitor of the IgE receptor on mast cells is R112, in Phase I/II testing for allergy by Rigel Pharmaceuticals. Unlike other allergy drugs such as antihistamines or antileukotrienes that block only a single mediator, R112 is designed to block all major pathways that are triggered in an allergic attack, potentially improving efficacy and applicability to a wider range of allergens. Although steroids also block multiple mediators in the allergic response, they have a slow onset of action and globally block immune function. Intranasal administration of R112 prevents systemic exposure.

In a Phase I/II study, a single intranasal administration of R112 in volunteers with asymptomatic seasonal allergic rhinitis reduced the release of chemical mediators involved in mast cell activation within minutes after allergen challenge. No clinically significant adverse effects were reported. On September 10, 2003, Rigel began a multidose safety trial of R112 to establish the longer-term, multi-dose safety of R112 in various dosing regimens for allergic rhinitis.

Because both asthma and allergy involve common mechanisms within the immune system triggering chronic inflammation, immunomodulators may offer considerable potential in targeting the pathophysiology and thereby reducing symptoms. Local administration and use of drugs with more selective sites of action may prevent adverse systemic reactions seen with steroids and other nonspecific antiinflammatory drugs.