Successful testing of new drug for allergic asthma
A novel therapeutic principle is aimed at controlling the airway inflammation in allergic asthma, to mitigate the course of the disease. With its comprehensive expertise, Fraunhofer ITEM successfully performed toxicology testing of the novel DNAzyme-based drug developed by sterna biologicals GmbH & Co. KG and also part of the clinical trials. The results of the proof-of-concept study in man have now been published in the renowned “New England Journal of Medicine”.
Asthma is a highly prevalent airway disease, affecting an estimated 300 million people worldwide. Asthmatics suffer not only from the disease itself, but also from its wide-ranging consequences. The therapeutic options for severe asthma to date are little satisfactory and require a new therapeutic principle. This is what sterna biologicals has developed with the new drug “SB010”. It is based on inhibiting the transcription factor GATA-3 by a so-called DNAzyme – a synthetic DNA molecule with enzymatic action for inhaled administration. It binds to the transcription factor that triggers the inflammatory response and thus the typical asthma symptoms, inactivating it by enzymatic cleavage.
The Fraunhofer ITEM has accompanied development of this first-in-class antagonist with its expertise, from scientific advice and the required toxicity tests (in cooperation with Nycomed GmbH) to clinical trials of phases Ib and IIa. The latter, i.e. the proof-of-concept study, was conducted as a multi-center study in seven German centers under the scientific direction of Professor Norbert Krug, Fraunhofer ITEM Medical Director.
In the randomized, double-blind, parallel-group, multi-center trial, efficacy of the new therapeutic agent was tested. Treatment with “SB010” over 28 days significantly improved lung function after specific allergen challenge as compared to placebo. “SB010” furthermore proved to be safe and well tolerated. The results of this study were presented during this year’s International Conference of the American Thoracic Society in Denver, USA.
“Recent research indicates that approximately 50 percent of all asthmatics suffer from allergic asthma. This type of asthma is Th2-driven across all levels of disease severity. Therefore, developing novel therapeutics specifically for this group of patients holds great promise, in particular of drugs for inhaled delivery. Further clinical trials with ‘SB010’ in a larger cohort of asthmatics are thus warranted,” explains Krug.
Results of the clinical phase-IIa trial (proof-of-concept trial) with “SB010”
In the randomized, double-blind, parallel group, multi-center phase-IIa trial (NCT 01743768) “SB010” treatment over 28 days significantly improved lung function after specific allergen challenge as compared to placebo. In the late-phase asthmatic response, the primary end point of the trial, lung function improved by 35.1% (difference versus placebo, P = 0.02) and in the early-phase asthmatic response by 21.8% (difference versus placebo, P = 0.03). The maximum decline in lung function was also improved, namely by 20.8 % (difference versus placebo, P = 0.09) in the late-phase asthmatic response and by 17.9 % (difference versus placebo, P = 0.04) in the early phase asthmatic response. Mechanistic investigations comprising sputum eosinophils, sputum tryptase, and plasma IL-5 levels support the clinical findings. “SB010” furthermore proved to be safe and well tolerated. No serious treatment-emergent adverse events occurred in either treatment group, and no noteworthy differences in treatment-emergent adverse events were observed between study groups.
Results of the clinical phase-I trials (first-in-human trials) with “SB010”
A summary of the phase-I development program for “SB010” has been published in the “Journal of Allergy and Clinical Immunology”.
Results of the toxicology study with “SB010”
Subacute toxicity, immunotoxicity, and respiratory, cardiovascular, and CNS safety pharmacology were analyzed in rodents and non-rodents in cooperation with Nycomed GmbH (Brunsbüttel, Germany). Genotoxicity was assessed in human peripheral blood. Only marginal reversible histopathological changes were observed in the lungs of rats receiving the highest dose of the inhaled DNAzyme-based compound. No local or systemic adverse effects were observed in dogs. No compound-related respiratory, cardiovascular, or CNS adverse events were observed. The only relevant immunological findings were very slight dose-dependent changes in interleukin-10 and interferon-γ levels in bronchoalveolar lavage fluid.
About the active pharmaceutical ingredient “SB010”
sterna biologicals’ drug candidate “SB010” is a first-in-class inhaled GATA-3 antagonist. GATA-3 is the master transcription factor in regulating Th2-driven inflammatory diseases such as asthma. It is generally accepted that GATA-3 is necessary and sufficient for production of the key cytokines interleukin (IL)-4, IL-5, and IL-13, which are key players in causing inflammation. In pre-clinical development, “SB010” significantly reduced expression of these cytokines and was safe and well-tolerated in a comprehensive phase-I clinical program. “SB010” demonstrated strong clinical effects in a phase-IIa proof-of-concept trial. DNAzymes are single-stranded DNA molecules comprising a catalytic domain flanked by two binding domains. The binding domains attach to a specific sequence of targeted mRNA, in case of SB010 GATA-3 mRNA. After binding to the target, the catalytic domain then cleaves the mRNA, thereby inhibiting relevant cytokine expression.
About sterna biologicals GmbH & Co. KG
sterna biologicals GmbH & Co. KG is an innovative clinical stage biopharmaceutical company developing novel treatments for chronic inflammatory diseases such as asthma, atopic dermatitis, ulcerative colitis, psoriasis, and COPD. By targeting transcription factors that play a pivotal role in regulating underlying inflammatory mechanisms, the company’s DNAzyme-based drug candidates can intervene at a very early stage in the disease formation process.
About the Fraunhofer ITEM
The Fraunhofer ITEM offers contract research in the area of human health, with an emphasis on the respiratory tract as a target organ. Research activities include pre-clinical and clinical studies for drug research and development, GMP manufacturing of biopharmaceuticals for clinical trials, consumer protection, occupational and environmental toxicology, and registration and risk assessment of chemicals and biocides.
The Fraunhofer ITEM is the only institution in Germany’s public research landscape that can offer the whole chain of drug candidate testing as a service – from pre-clinical and toxicology testing (including scientific advice) to clinical trials. If is of great benefit for the client to have the testing done by a single institution – in a test facility that has a basic understanding and a broad expertise. This saves time for repeated briefings and knowledge transfer and can thus help reduce the costs for testing of a novel candidate drug.