TESTING SM001 (Tigerase)
RESULTS OF CLINICAL STUDIES
Two studies with Tigerase were conducted as a part of biosimilarity investigation. These studies included phase 1and phase 2 comparative studies with the reference drug Pulmozyme.
A phase 1 open label randomized clinical trial was conducted to compare the safety, tolerability and pharmacokinetics of the biosimilar medicinal product SM001 (Tigerase, AO Generium, Russia) and the reference medicinal product Pulmozyme (F.Hoffmann-La Roche Ltd, Switzerland) in healthy volunteers. Fifty enrolled subjects received inhalations of Pulmozyme (Group 1) or Tigerase (Group 2) at a dose of 2.5 mg daily for 5 days according to the randomisation list (Study №КИ 39/14).
The intergroup analysis showed no statistically significant difference between groups of Pulmozyme and Tigerase in terms of adverse events frequency (p>0.05). All AEs in both groups were mild.
Concentrations of dornase alfa in the blood at different time points were similar between groups of Pulmozyme and Tigerase, no statistically significant differences were found at all time points between groups (p>0.05). After 5 days of inhalations, concentrations of dornase alfa in plasma did not substantially differ from the baseline level, which shows low systemic bioavailability and absence of accumulation (Study №КИ 39/14).
Summarized data on concentrations (including endogenous dornase alfa concentrations) showed no statistically significant differences in terms of Cmax (p>0.05) and significant difference in terms of Tmax (p=0.0122). This difference may be explained by fluctuations of endogenous dornase alfa, since dornase alfa has low systemic absorption after inhalation. It should be noted that median values of Tmax were equal in both groups.
Data on concentrations excluding the baseline endogenous dornase alfa concentrations showed no significant differences (p>0.05) of pharmacokinetic parameters between groups (Cmax, AUC0-t, Tmax).
Thus, in phase 1 study it was established that Tigerase and Pulmozyme are comparable in terms of safety, tolerability and pharmacokinetic parameters after 5 days of inhalations in healthy volunteers (Study №КИ 39/14).
A phase 2 open label randomized clinical trial was conducted to compare the pharmacokinetics, efficacy and safety of the biosimilar medicinal product Tigerase (AO Generium, Russia) and the reference medicinal product Pulmozyme (F.Hoffmann-La Roche Ltd, Switzerland) in cystic fibrosis patients. The study included 100 patients aged 18 years and older with a confirmed diagnosis of CF, who were divided into two groups by stratified randomization in a ratio of 1:1 based on the initial level of FEV1 (40–60% or > 60–100% from due value). SM001 or Pulmozyme were used in a dose of 2.5 mg daily, once a day in the form of inhalations using a jet nebulizer compressor for 24 weeks (Study NCT04468100).
The analysis of the data regarding the primary efficacy endpoint – changes in FEV1 – showed that in both groups (FAS population (Full analyses set) and PP population (Per protocol), similar changes in FEV1 were observed. The average value of changes in FEV1 after 24 weeks of treatment compared with the initial level in the FAS population was –1.3% ± 9.8 % (95% CI (–4.1; 1.6) in Group I (Tigerase) and –1.9% ± 10.0% (95% CI (–4.7; 1.0) in Group II (Pulmozyme). The point estimate for the intergroup difference in changes in FEV1 (Group I – Group II) was 0.6%. The calculated 95% CI for the difference in changes in FEV1 in the FAS population was (–3.3; 4.6%]. In both populations studied, the intergroup difference in changes in FEV1 did not exceed 6%. During long-term treatment of patients with CF, no statistically significant differences were found in terms of efficacy (changes in FEV1 and FVC; number of exacerbations of chronic pulmonary disease and the number of days before its development; change in body weight; quality of life) between medicinal products in both studied populations (FAS and PP).
A safety analysis demonstrated the comparability of Tigerase and Pulmozyme in terms of the incidence of adverse events. No statistically significant differences were found in terms of efficacy or pharmacokinetic parameters (Cmax, AUC0-t, Tmax). The frequency of detection of antibodies to dornase alpha during the study was similar in the treatment groups; the formation of antibodies did not lead to a decrease in the efficacy and safety of therapy (Study NCT04468100).