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Executive Summary

Glaxo's fluticasone and Astra's budesonide are "particularly attractive" second-generation inhaled corticosteroids due to their improved ratio of topical to systemic effects for the treatment of chronic asthma, Stanley Szefler, MD, said in a presentation at the March 6-11 American Academy of Allergy and Immunology (AAAI) annual meeting in Orlando. Szefler, from the National Jewish Center for Immunology and Respiratory Medicine in Denver, presented his data on new steroids as part of a seminar entitled "New Medications for Asthma and Allergic Rhinitis: Do Benefits Outweigh the Risks?" Szefler emphasized the importance of inhaled steroids for the treatment of asthma over other current treatments, saying inhaled steroids "have the most remarkable and the most consistent effect on airway hyperresponsiveness (AHR)" and "have a long duration of action." Szefler presented evidence concerning dose-related adverse effects on skin thickness and bone formation associated with the regular use of steroids to back his argument that second- generation corticosteroids offer improved benefits and less risk. Szefler told the AAAI seminar that literature from Europe, where steroids are used "much more aggressively" than in the U.S. for the treatment of chronic asthma, includes test results showing that beclamethasone, in doses as low as 400 mg per day, suppresses plasma osteocalcium, a bone protein involved in bone formation. He also pointed to "some concerning reports" that have concluded that higher doses of steroids can affect a patient's skin thickness. Szefler compared several first generation steroids, such as beclamethasone (Schering's Vancenase and Glaxo's Beclovent) and flunisolide (Forest's Aerobid), to the newer drugs on the basis of several factors that can affect a steroid's adverse effects profile. These factors include: potential for absorption, systemic activity of active metabolites, tissue distribution and elimination parameters. Both budesonide and fluticasone have low bioavailability, 10.7% and 0% respectively, and either weak or inactive metabolites. With rapid rates of metabolization, the two second-generation steroids are eliminated from the body quickly, reducing the likelihood of systemic effects, Szefler said. The U.S. trade name for Glaxo's oral inhaled fluticasone for asthma will be Flovent. Flovent is in Phase III trials; Glaxo previously had predicted a first quarter 1992 filing. Fluticasone is marketed as a nasal spray for the treatment of seasonal rhinitis outside the U.S. with the brandname Flixonase. An inhaled version of fluticasone (Flixotide) for the treatment of asthma is slated for its first overseas filing "in the next few months," the company said ("The Pink Sheet," Dec. 16, 1991, p. 18). Astra's budesonide Pulmicort Turbuhaler also is in Phase III trials in the U.S. The Pulmicort Turbuhaler received approval overseas as early as 1988, in both New Zealand and Sweden, and is now approved and marketed in 12 countries, including Australia, Canada, the U.K. and France. Fluticasone, budesonide and other second-generation inhaled corticosteroids stand to benefit from the changing opinions on the preferred treatment method for asthma. Unveiled at the AAAI conference, the International Consensus Report on Diagnosis and Management of Asthma parallels very closely the recommendations made in the June 1991 National Heart, Lung & Blood Institute ("The Pink Sheet" Feb. 11, 1991, p. 13) report. Both guidelines suggest a near identical step-by-step treatment plan for patients with chronic asthma and emphasize the need to use as little medication as possible. The International Consensus Statement hails corticosteroids as "the most effective anti-inflammatory drugs for the treatment of asthma" and indicates that inhaled steroids "are safe and effective for the chronic treatment of asthma." Similarly the NHLBI report explains that steroids "provide improved asthma care with minimal side effects." Citing studies that connect daily use of inhaled beta-2- adrenergic agonists with increased asthma morbidity and mortality, the International Consensus Statement relegates beta-2 agonists to a secondary position for the treatment of moderate and severe asthma, to be taken on an "as needed" basis in conjunction with steroids. Dosage for the bronchodilators should not "exceed three to four times a day." Beta agonists also are recommended as a first-line therapy for mild asthma, though patients using the drug more than three times a week "should be moved to the next step of care." These recommendations echo those set forth in the NHBLI guidelines. Recognizing the need for nocturnal control of asthma symptoms, the guidelines recommend sustained-release theophylline or beta agonists. Versions of sustained-release theophylline include those marketed by Key Pharmaceuticals (Theo-Dur ER), Rhone-Poulenc Rorer (Slo-Bid), Whitby (Theo-24, licensed from Searle in January) and Geneva Pharmaceuticals. Glaxo filed an NDA for its beta agonist salmeterol (Serevent) in December for the treatment of adult asthma. At a 1990 presentation to analysts, the company said that the twice-daily dosage regimen for Serevent provides 12-hour bronchodilation and "virtually abolishes nocturnal asthma" ("The Pink Sheet," Dec. 10, 1990, p. 12). Serevent has been launched in the U.K. and several European countries and has a patient-use database of more than 24,000 in the U.K. alone. At the same time that Glaxo has been playing up its sustained- release beta agonist salmeterol as a future product with good nocturnal control of asthma symptoms, the company also has found itself having to defend the product in light of recent questions about beta-2 drugs. FDA's Pulmonary-Allergy Drugs Advisory Committee concluded at its Dec. 12-13 meeting that further studies are needed to determine if beta agonist use is actually associated with increased asthma mortality and morbidity ("The Pink Sheet," Dec. 16, p. 16). Glaxo defended the class prior to the advisory committee meeting, at a presentation to analysts, and before the peer review panel, to counter negative data about beta agonists from three studies that were presented at the meeting. In the case of pediatric asthma, both the NHLBI and the new international consensus statements concur in their recommendation that children with moderate to severe asthma be treated with cromolyn, due to the possibility that inhaled steroids may suppress linear growth. As part of the same AAAI seminar on new asthma drug therapies and their risks relative to older generation products, Eli Meltzer, MD, San Diego, highlighted the benefits of Boehringer Ingelheim's anticholinergic drug Atrovent (ipratropium bromide) as an adjunctive therapy for asthma and an effective treatment for severe rhinitis. Atrovent is indicated "as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema," approved labeling states. Meltzer presented test results demonstrating that when Atrovent is used in conjunction with inhaled beta agonists such as fenoterol (Boehringer Ingelheim) or albuterol (Schering's Proventil/Glaxo's Ventolin) as an asthma therapy, "the combination product did better than the individual" anticholinergic or beta agonist. Atrovent's advantage is that "it appears to have very low adverse effects," Meltzer said. Recognizing that there are asthma medications that are "clearly effective," he suggested that Atrovent "might be a good adjunctive therapy." Meltzer also presented data showing the effectiveness of Atrovent in protecting against both allergic and perennial non- allergic rhinitis. When pre-treated with Atrovent, patients with sensitivity to allergens, histamines or methacholine experienced a decrease in the duration and severity of rhinitis after an allergen challenge. Meltzer noted that "there was no real systemic effects, but there were increased amounts of nasal irritation, crusting, and burning in the patients who used a higher dose." He concluded that "for patients with severe rhinitis," using Atrovent "may enhance the quality of life." Atrovent, which is currently approved as an inhalation aerosol, is in clinicals as a solution for chronic obstructive pulmonary disease and as a nasal spray for the treatment of rhinitis.

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