Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom
Pharmacotherapeutic group: respiratory system
ATC code: R05CB13
Recombinant human DNase is a genetically engineered version of a naturally occurring human enzyme which cleaves extracellular DNA.
Retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbations of infection. Purulent secretions contain very high concentrations of extracellular DNA, a viscous polyanion released by degenerating leukocytes, which accumulate in response to infection. In vitro, dornase alfa hydrolyses DNA in sputum and greatly reduces the viscoelasticity of cystic fibrosis sputum.
Efficacy and safety was established in double-blind, placebo-controlled studies (Z0342/Z0343) in which patients over 5 years of age and with FVC over 40% predicted received 2.5 mg Pulmozyme once or twice daily over a 24-week period. Overall, 968 patients (mean age of 19 years) with a mean baseline FVC of 78% were randomised in these trials.
Another placebo-controlled double-blind study (Z0713) evaluated the effect of Pulmozyme (2.5 mg once daily for 2 years) on pulmonary function in young patients (aged 6-11 years) with minimum evidence of lung disease as defined by FVC of ≥ 85% predicted. Overall, 474 patients (mean age of 8.4 years) with a mean baseline FVC of 102.3% were randomised in this trial.
Results of the main endpoints are shown in the following tables. A significant increase in FEV1 was observed in the beginning of treatment with Pulmozyme and subsided over time, especially after the first year of treatment; however, the difference with placebo remained statistically significant. Pulmozyme reduced the relative risk of respiratory tract exacerbations requiring parenteral antibiotics by about 30%; this reduction did not correlate with the improvement in FEV1 measured during the first weeks of therapy.
| Studies Z0342/Z0343 | Placebo | 2.5mg QD | 2.5mg BID | |
|---|---|---|---|---|
| N=325 | N=322 | N=321 | ||
| FEV1 (% predicted) | Mean % change from baseline | |||
| Day 8 | - 0.5% | 7.9% | 9.0% | |
| Week 24 | 0.1% | 5.1% | 3.6% | |
| Overall | 0.0% | 5.8% | 5.6% | |
| p<0.001 | p<0.001 | |||
| % patients with exacerbations | over 24 weeks | 43% | 34% | 33% |
| Relative risk (95% CI) | 0.73 (0.57-0.94) | 0.71 (0.55-0.91) | ||
| p=0.015 | p=0.007 |
| Study Z0713 | Placebo | 2.5mg QD | |
|---|---|---|---|
| N=235 | N=237 | ||
| Spirometry | Mean change from baseline (at Week 96) | ||
| FEV1 (% predicted) | -3.10 | 0.03 | |
| p=0.008 | |||
| FVC (% predicted) | -2.88 | -2.23 | |
| p=0.54 | |||
| FEF25-75 (% predicted) | -4.05 | 3.83 | |
| p=0.0008 | |||
| % patients with exacerbations | over 96 weeks | 24% | 17% |
| Relative risk (95% CI) | 0.66 (0.44-0.996) | ||
| p=0.048 |
Post-hoc analysis of the data suggests that the effects of Pulmozyme on respiratory tract exacerbations in older patients (>21 years) may be smaller than in younger patients, and that twice daily dosing may be required in the older patients. The percentage of older patients developing exacerbations over 24 weeks was 44% on placebo, 48% and 39% on Pulmozyme 2.5 mg daily and twice daily, respectively.
Inhalation studies conducted in rats and non-human primates show a low percentage of dornase alfa systemic absorption, <15% for rats and <2% for monkeys. Consistent with the results of these animal studies, dornase alfa administered to patients as an inhaled aerosol shows low systemic exposure.
Absorption of dornase alfa from the gastrointestinal tract following oral administration to rats is negligible.
DNase is normally present in human serum. Inhalation of up to 40 mg of dornase alfa for up to 6 days did not result in a significant elevation of serum DNase concentration above normal endogenous levels. No increase in serum DNase concentration greater than 10ng/ml was observed. Following administration of 2500 U (2.5 mg) of dornase alfa twice daily for 24 weeks, mean serum DNase concentrations were no different from the mean pre-treatment baseline value of 3.5 ± 0.1 ng/ml; suggesting low systemic absorption or accumulation.
Studies in rats and monkeys have shown that, following intravenous administration, dornase alfa was cleared rapidly from the serum. The initial volume of distribution was similar to serum volume in these studies.
Inhalation of 2500 U (2.5 mg) dornase alfa results in a mean sputum concentration of dornase alfa of approximately 3 µg/ml within 15 minutes in cystic fibrosis patients. Concentrations of dornase alfa in sputum rapidly decline following inhalation.
Dornase alfa is expected to be metabolised by proteases present in biological fluids.
Studies in rats and monkeys have shown that, following intravenous administration, rhDNase is cleared rapidly from the serum. Human intravenous studies suggested an elimination half-life from serum of 3-4 hours.
Studies in rats indicate that, following aerosol administration the disappearance half-life of dornase alfa from the lungs is 11 hours. In humans, sputum DNase levels declined below half of those detected immediately post-administration within 2 hours but effects on sputum rheology persisted beyond 12 hours.
Pulmozyme, 2.5 mg by inhalation, was administered daily for 2 weeks to 98 patients aged 3 months to 9 years (65 aged 3 months to <5 years, 33 aged 5 to 9 years), and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. The Pari Baby reusable nebuliser (which uses a facemask instead of a mouthpiece) was utilised in patients unable to demonstrate the ability to inhale or exhale orally throughout the entire treatment period (54/65, 83% of the younger, and 2/33, 6% of the older patients). BAL DNase concentrations were detectable in all patients but showed a broad range, from 0.007 to 1.8 µg/ml. Over an average of 14 days of exposure, serum DNase concentrations (mean ± s.d.) increased by 1.1 ± 1.6 ng/ml for the 3 months to <5 year age group and by 0.8 ± 1.2 ng/ml for the 5 to 9 year age group. The incidence of fever was more frequent in the younger than older age group (41% vs. 24%, respectively); fever is a known complication of bronchoscopy.
Non-clinical data based on standard studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction do not indicate a specific safety risk for humans.
In a study performed in lactating cynomolgus monkeys, receiving high doses of dornase alfa by the intravenous route (100 µg/kg bolus followed by 80 µg/kg/hour for 6 hours), low concentrations (<0.1% of the concentrations seen in the maternal serum of cynomolgus monkeys), were detectable in the maternal milk.
A four-week inhalation toxicity study in juvenile rats commenced dosing 22 days after parturition at doses to the LRT of 0, 51, 102 and 260 µg/kg/day. Dornase alfa was well tolerated, and no lesions were found in the respiratory tract.
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