Dornase alfa

Pulmonary disease is the major cause of morbidity and mortality in cystic fibrosis (CF). Soon after birth, thick, viscous secretions accumulate in the airway. The viscosity of the respiratory tract secretions is partly from abnormal mucus glycoprotein, the result of the basic gene defect and partly from the presence of high concentrations of DNA. The heavy DNA load is derived mainly from the breakdown of nuclei from polymorphonuclear neutrophils. The neutrophils accumulate in the airway in response to infection and inflammation. A vicious cycle begins that results in bronchiectasis, fibrosis, and ultimately, pulmonary insufficiency and death.

Various mucolytic agents and expectorants have been used in CF patients in vain attempts to decrease mucus viscosity and improve mucocilliary function. Since DNA is a factor in sputum viscosity, naturally occurring enzyme DNase has been proposed as a mucolytic agent. Bovine pancreatic DNase was developed, and in vitro trials showed significantly decreased sputum viscosity. Liberman showed similar mucolytic effects during in vivo studies of bovine DNase, however, significant immunologic complications prevented clinical use.[1]

In 1990, Shak et al[2] developed recombinant human DNase (rhDNase or dornase alfa). In vitro studies documented mucolytic effects similar to bovine DNase. Within minutes, dornase alfa transformed thick, purulent sputum into a flowing liquid. Clinical trials were soon instituted to study the efficacy and safety of aerosolized dornase alfa. A short-term (6 days), place-bo-controlled study documented significant improvement in pulmonary function during the treatment period and decline towards baseline levels 1 week after completion of the trial.[3] Aitken et al[4] studied 14 adult patients with CF (FVC >40%) and 12 normal subjects in a nonrandom trial of dornase alfa. The CF patients responded with improved lung function and dyspnea score. However, bacterial density in sputum from eight CF patients was not significantly decreased. No serious adverse reactions (including the development of serum antibodies to dornase alfa) were found in either group of subjects.

Other clinical trials have established effectiveness and safety of dornase alfa in CF patients. In a study of CF patients with stable disease (FVC >40%, Ranasinha et al[5] showed significant improvement in [FEV.sub.1] (13.3% in treatment as compared to a 0.2% fall in placebo group, p<0.001). Ramsey et al[6] studied 181 children and adult CF patients (FVC [greater than or equal to]. Subjects were randomized to either placebo or one of three doses of dornase alfa (0.6, 2.5, and 10 mg) twice a day for 10 days. FVC improved 10 to 12% (p<0.0001) across all and [FEV.sub.1] improved 10 to 15% (p,0.001) across all doses as compared to placebo. Adverse events were similar in the treatment and placebo groups in both studies.

In a long-term study, Fuchs et al[7] evaluated 968 adults and children with CF (FVC >40% predicted). Subjects were randomized to receive either placebo or dornase alfa once or twice-daily for 24 weeks. Results documented improvement in pulmonary function as follows: [FEV.sub.1], 5.8. [+ or -] 0.7 and 5.6 [+ or -] 0.7 (p<0.01); and FVC 3.8 [+ or -] 0.6 (p<0.01) and 3.0 [+ or -] 0.6% (p=0.01); and FVC and twice daily groups, respectively, as compared to placebo. Dornase alfa treated-patients showed significant decrease in age-adjusted risk of respiratory tract exacerbations and required slightly fewer days of hospitalization, intravenous antibiotics, and sick days at home for CF-related illness as compared to the placebo group. Long-term use of this dornase alfa regimen was well tolerated and, together with previous studies, documents beneficial effects of this drug in patients with moderate, stable lung disease.

Previous trials of dornase alfa in CF patients with advanced lung disease (FVC <40%), failed to detect clinically significant improvement in lung function.[8,9] However, the drug was well tolerated in this group of patients. In this issue of CHEST (see page 889), McCoy and colleagues present the results of a multicenter, placebo-controlled, double-blind, study of dornase alfa in CF patients with severe lung disease (FVC <40% predicted). Three hundred and twenty patients from 65 centers in the United States were randomized to either placebo or dornase alfa, 2.5 mg once daily for 12 weeks. The mean improvement in [FEV.sub.1] was 9.4% in the dornase alfa group as compared to 2.1% in the placebo group (p<0.001); and for FVC was 12.4% as compared to 7.3% (p<0.001; in the two groups, respectively. No significant difference was found in the mean dyspnea score or in the number of days requiting IV antibiotics or hospitalization. The overall frequency of serious adverse events was similar between the two groups and was expected for patients with advanced lung disease. Minor adverse events such as fever, rhinitis, decrease in FVC, voice alteration, and dyspepsia were reported more frequently in the dornase alfa group. A concern that excessive mobilization of airway secretions in patients with advanced lung disease might result in worsening of pulmonary function was not substantiated. These findings suggest that patients with severe lung disease do benefit from dornase alfa therapy.

Dornase alfa has been approved for use in clinical practice for over 2 years, and a large number of patients with varying severity of lung disease are currently receiving this drug. Many patients report decreased cough, easier expectoration of sputum, fewer pulmonary exacerbations, and overall improved sense of well-being while receiving dornase alfa therapy. On the other hand, some patients are unable to tolerate therapy secondary to adverse effects or refuse treatment as they find the risks and/or cost outweighs the benefits. Several factors need to be considered prior to the institution of dornase alfa therapy:

* What is the appropriate patient age or disease

severity to consider initiating therapy? * Does the patient have a large enough infectious

component (excessive DNA load) to justify therapy? * Is the cost approximately $10,00 a year) of dornase

alfa therapy affordable for the patient? Will this

costly therapy result in a patient with a chronic illness

reaching his/her health insurance lifetime limit

sooner? * What is the appropriate dose and duration of therapy? * How can adherence be monitored? * How should an individual patient be monitored for

efficacy? * Can other current forms of therapy be decreased or

discontinued? * Are there interactions with other therapeutic interventions? * Will additional side-effects be observed as more

patients use dornase alfa for longer intervals?

The answers to many of these questions are not known. Although, a large epidemiologic study currently in progress may help resolve these issues, until more data are available, decisions regarding therapy should be made on an individual basis. Once therapy is instituted, the patient should be followed closely for efficacy and compliance. In light of the available data, denial of therapy on the basis of age or severity of lung disease (often dictated by third party payers) is not justifiable.

References

[1] Liberman J. Dornase aerosol effect on sputum viscosity in cases of cystic fibrosis. JAMA 1968; 98:597-98 [2] Shak S, Capon DJ, Hellniss R, et al. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 1990; 87:9188-92 [3] Hubbard RC, McElvaney NG, Birrer P, et al. A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. N Engl J Med 1992; 326:812-15 [4] Aitken ML, Burke W, McDonald G, et al. Recombinant human DNase inhaled in normal subjects and patients with cystic fibrosis. JAMA 1992; 267:1947-51 [5] Ranasinha C, Assoufi B, Shak S, et al. Efficacy and safety of short-term administration of aerosolized recombinant human DNase (rhDnNse) in adults with stable stage cystic fibrosis. Lancet 1993; 342:199-202 [6] Ramsey BW, Astley SW, Aitken ML, et al. Efficacy and safety of short-term administration of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis. Am Rev Respir Dis 1994; 148:145-51 [7] Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary, function in patients with cystic fibrosis. N Engl J Med 1994; 331:637-42 [8] Shah PL, Scott SF, Hodson ME. Report on a multi-centre study using aerosolized recombinant human DNase I in the treatment of cystic fibrosis patients with severe pulmonary disease [abstract]. Pediatr Pulmonol Suppl 1993; 9:157-58 [9] Wilmott R, Amin RS, Collin A, et al. A phase II, double-blind, midticenter study of the safety and efficacy of aerosolized recombinant DNase I (rh DNase) in hospitalized patients with CF experiencing acute pulmonary exacerbations [abstract]. Pediatr Pulmonol Suppl 1993; 9:154

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