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Clinical Trial
. 2018 Apr 4;19(1):55.
doi: 10.1186/s12931-018-0751-x.

A GATA3-specific DNAzyme attenuates sputum eosinophilia in eosinophilic COPD patients: a feasibility randomized clinical trial

Timm Greulich  1 , Jens M Hohlfeld  2 , Petra Neuser  3 , Katrin Lueer  2 , Andreas Klemmer  4 , Carmen Schade-Brittinger  3 , Susanne Harnisch  3 , Holger Garn  5 , Harald Renz  5 , Ursula Homburg  6 , Jonas Renz  6 , Anne Kirsten  7 , Frauke Pedersen  7 , Meike Müller  2 , Claus F Vogelmeier  4 , Henrik Watz  7
Affiliations
Clinical Trial

A GATA3-specific DNAzyme attenuates sputum eosinophilia in eosinophilic COPD patients: a feasibility randomized clinical trial

Timm Greulich et al. Respir Res. .

Abstract

Background: A subset of COPD-patients presents with eosinophilic airway inflammation. While treatment of asthmatic patients with the GATA3-specific DNAzyme SB010 attenuated sputum eosinophilia after allergen challenge, this specific treatment has not been evaluated in patients with COPD. Our objective was to evaluate the feasibility and safety of inhaled SB010 in COPD patients with sputum eosinophilia.

Methods: We conducted a randomized, double-blind, placebo-controlled, multicentre clinical trial in COPD-patients with sputum eosinophilia (≥2.5% non-squamous cells). Patients inhaled 10 mg SB010 bid or matching placebo via the controlled inhalation system AKITA2 APIXNEB for 28 days. Endpoints included the feasibility of the study (primary), patient's safety, sputum eosinophils, FENO, lung function, symptoms, and biomarkers. The study was registered in the German Clinical Trials Register: DRKS00006087.

Results: One hundred thirty patients were screened, 23 patients were randomized (FEV1 49.4 ± 11.5%; sputum eosinophils 8.0 ± 8.4%) and 19 patients completed the study (10 placebo, 9 SB010. After 28 days, SB010 decreased the relative sputum eosinophil count (p = 0.004) as compared to no changes in placebo-treated patients. FENO, lung function, and symptoms were not affected significantly. We found an increase in blood IFN-γ (p = 0.02) and a trend to lower IL-5 levels in patients treated with SB010. SB010 was safe and well tolerated. Thirty five AEs (22 SB010, 13 placebo including 1 SAE) were observed with 3 AEs in each group judged to be possibly treatment-related.

Conclusion: In patients with eosinophilic COPD, sputum eosinophils could be reduced by inhalation of SB010. Long-term studies are needed to demonstrate clinical efficacy.

Keywords: COPD; DNAzyme; Eosinophils; SB010; Sputum; T-helper-2-cells.

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Conflict of interest statement

Ethics approval and consent to participate

The study was approved for all centres by the ethics committee at the University of Marburg as leading ethics committee (AZ: 149/13 A-ff, Jan 2014).

Consent for publication

NA

Competing interests

Dr. Greulich reports personal fees from Astra Zeneca, personal fees from Berlin-Chemie, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from CSL-Behring, grants and personal fees from Grifols, personal fees from GSK, personal fees from Novartis, outside the submitted work; and reports grants from German Center for Lung Research during the conduct of the study.

Dr. Hohlfeld reports personal fees from Boehringer Ingelheim, personal fees from Merck & Co, Inc., personal fees from Novartis, grants from Novartis, grants from Almirall, grants from Takeda, grants from ALK, grants from Boehringer Ingelheim, grants from LETI, grants from GlaxoSmithKline, grants from Sanofi-Aventis, grants from Allergopharma, grants from Astra Zeneca AB, outside the submitted work; and grants from German Center for Lung Research during the conduct of the study.

P. Neuser reports grants from German Center for Lung Research during the conduct of the study.

Dr. Lüer reports grants from German Center for Lung Research during the conduct of the study.

Dr. Klemmer reports grants from German Center for Lung Research during the conduct of the study.

C. Schade-Brittinger reports grants from German Center for Lung Research, during the conduct of the study.

S. Harnisch reports grants from German Center for Lung Research during the conduct of the study.

Dr. Garn reports personal fees from sterna biologicals GmbH & Co. KG, during the conduct of the study; and is shareholder of sterna biologicals GmbH & Co.KG. Additionally, he reports grants from DZL (German Center for Lung Research) and UGMLC (Universities Gießen and Marburg Lung Center) during the conduct of the study.

Dr. Renz reports grants from Institute of Laboratory Medicine, during the conduct of the study; In addition, Dr. Renz has a patent GATA-3 DNAzyme licensed.

U. Homburg reports other (employee) from sterna biologicals GmbH & Co KG, outside the submitted work.

J. Renz reports other (employee) from Sterna Biologicals GmbH & Co. KG, outside the submitted work.

Dr. Kirsten reports other from Sterna Biologicals, during the conduct of the study; other from Astra Zeneca, other from Berlin Chemie, other from Boehringer Ingelheim, other from Novartis, other from Astra Zeneca, other from Boehringer Ingelheim, other from Roche, other from GSK, other from Novartis, other from Chiesi, other from Takeda, other from Bayer, other from Sterna biologicals, other from Johnson u. Johnson, other from Sanofi, outside the submitted work.

Dr. Pedersen reports grants from German Center for Lung Research, during the conduct of the study.

Dr. Mueller reports grants from Novartis, grants from Allmirall, grants from Takeda, grants from Boehringer Ingelheim, grants from ALK, grants from LETI, grants from Glaxo SmithKline, grants from Sanofi-Aventis, grants from Allergopharma, grants from Astra Zeneca AB, outside the submitted work; and from German Center for Lung Research, during the conduct of the study.

Dr. Vogelmeier reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Chiesi, grants and personal fees from GlaxoSmithKline, grants and personal fees from Grifols, personal fees from Menarini, personal fees from Mundipharma, grants and personal fees from Novartis, personal fees from Teva, personal fees from Cipla, outside the submitted work.

Dr. Watz reports grants from German Center for Lung Research, during the conduct of the study.

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Figures

Fig. 1
Fig. 1
Trial Flow: 23 out of 130 screened patients (screening failure rate 82%) were randomized in a 1:1 ratio to receive SB010 (10 mg bid) or matching placebo. The dropout rate was 3/12 in the SB010 arm and 1/11 in the placebo arm. Reasons for dropout in the SB010 arm were not related to the study drug in 2 cases and may have been study drug-related in one case (mild AE in conjunction with patient’s wish). ITT: Intention-to-treat population; PP: Per-Protocol population. *Numbers for single screening failure reasons do not add up to total number, because two or more reasons could co-exist in one patient
Fig. 2
Fig. 2
In the per-protocol population, SB010 led to a statistically significant reduction of the relative sputum eosinophils [% non-squamous cells], while placebo treatment did not change sputum eosinophil count (a). Comparing the deltas, no statistically significant difference was found (b). Data are displayed as mean ± standard error of the mean (SEM). P values were calculated by the two-sided Wilcoxon signed rank test for pre/post differences and the exact Wilcoxon two-sample test for the comparison of the deltas
Fig. 3
Fig. 3
No statistically significant changes were observed in the FENO measurements during the trial. Data are displayed as mean ± SEM. Pre: Pre-Treatment; Post: Post-Treatment; FU: Follow-up
Fig. 4
Fig. 4
SB010 led to a statistically significant increase of plasma IFN-γ, that was not seen in placebo-treated patients (a). The deltas (pre/post) were statistically higher in SB010-treated patients as compared to placebo-treated patients (b). There was a trend towards a reduction of plasma IL-5 in the SB010 group that was opposite in the placebo group (c), however with no significant difference between the deltas (d). Data are displayed as mean ± SEM. P values were calculated by the two-sided Wilcoxon signed rank test for pre/post differences and the exact Wilcoxon two-sample test for the comparison of the deltas
Fig. 5
Fig. 5
Neither SB010 nor placebo led to statistically significant differences in lung function (a, b), CAT (c), or SGRQ (d) before/after 28 days treatment. Data are displayed as mean ± SEM
See this image and copyright information in PMC

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