CHIRAL TECHNOLOGIES
often induce innate immune responses via the toll-like receptor pathway, and non-natural protein sequences almost always elicit strong immune reactions in the body through anti-drug antibodies, Spiegelmers do not seem to cause such reactions. The molecular weight of a Spiegelmer (or equally an aptamer) sequence is usually in the range of 10-15 kDa. Therefore, systemic administration will lead to rapid renal clearance within a few hours but elimination from the body can be easily prolonged by days through adding polyethylene glycol (PEG) moieties of different sizes. Such a conjugation reaction is particularly easy for oligonucleotides as, compared to protein scaffolds, it is a site-specific reaction that does not require cumbersome optimisation processes for GMP manufacturing. Other modifications are also possible, for example with hydroxyl ethyl starch.
Delivering drug candidates “The technology platform has now ‘matured’ into a process that is able to not only deliver drug molecules but also to prepare them for clinical development, as downstream processes in terms of bioanalytics (GLP assays), chemical analytics and GMP manufacturing have been established,” says Klussmann.
The technology platform has delivered several drug candidates, three of which are currently in clinical development: NOX-E36 (anti-MCP-1 / CCL2) for diabetic nephropathy (Phase 2a ongoing); NOX-A12 (anti-SDF-1 / CXCL12) for multiple myeloma (Phase 2a ongoing), chronic lymphatic leukemia (Phase 2a ongoing), and glioblastoma; and NOX-H94 (anti-hepcidin) for iron-restriction anemia (Phase 2a to begin in Q3 2012). “NOXXON is very active in terms of collaborating with academic partners, particularly through our provision of very strong proprietary drug candidates. In return, we benefit from the data our partners provide in elaborated animal models that are often not otherwise available,” says Klussmann. “Partnerships are an essential part of
NOXXON’s strategy and will be an important means to develop candidate molecules” he says. “With three compounds in clinical trials across a range of potential indications, risk-sharing approaches will be required to mitigate the expense burden of Phase 3 studies. Based on postive data emerging from one or more of the ongoing Phase 2 studies, we expect to sign a partnership agreement on a clinical programme in the first half of 2013. As to what we hope to achieve with such a partnership, NOX-A12 provides a good example. We have compelling
preclinical data with NOX-A12 in a generally refractory animal model of brain cancer and a clinical trial design that has been reviewed with clinical experts in the field and regulatory agencies in Europe. We would like very much to start a clinical study of NOX-A12 in this indication, and we have similar examples for NOX-E36. “Our short-term objective is to achieve proof-of-concept in clinical programmes,” Klussmann continues. “Therefore, most efforts and capacities within NOXXON are dedicated to this goal and currently less resources are devoted to preclinical research. Since anything beyond a clinical proof-of- concept requires significant resources, it is planned to do further (co)development steps together with a partner.
“Our primary mission is to develop Spiegelmers as drugs and to bring this new and unique chemical class of therapeutics to the pharmaceutical market place. The significant resources that are needed will almost certainly need the buy-in of a pharma partner in order to conduct Phase 3 clinical trials. In five years time, it should be possible to have a Spiegelmer product approved and on the market.
“In the past 20 years, fewer small-molecule drugs and increasingly more biological products or biopharmaceuticals were approved as drugs,” he adds. “That does not mean that chemical drug discovery has become less important, but rather more elaborated approaches in drug discovery have had to be developed for difficult targets. Here, larger molecules that were based on protein scaffolds, for example monoclonal antibodies, succeeded. The latter is precisely an area where NOXXON will position its drugs as a chemical alternative to monoclonal antibodies.”
Klussmann concludes: “NOXXON is at a critical juncture in its development. Three Spiegelmer-based compounds have now advanced through the first stages of clinical development. They appear to be generally safe and well tolerated, and importantly we can already see that they hit their targets because of shifts in biomarkers. “In June and July 2012 NOXXON started Phase 2a clinical trails for NOX-E36 in patients with diabetic nephropathy and for NOX-A12, treating the first cohort of three chronic lymphocytic leukemia (CLL) patients. A trial for NOX-H94, which targets hepcidin, the key regulator of iron metabolism, is also planned to start in 2012, so we hope to get answers to the key question in the coming months, if modulation of those targets in patients will result in the expected therapeutic effect.”
Meet Sven Klussmann of NOXXON Pharma AG
Dr Sven Klussmann is a world leading expert in the field of therapeutic aptamers and one of the original founders of NOXXON Pharma AG. As a PhD student at the Free University Berlin, Dr Klussmann was the first person to demonstrate the principles of the Spiegelmer technology. He received the Carl Ramsauer Award for this work and, following the completion of his academic studies, went on to transfer the Spiegelmer discovery process from an academic environment into a robust, therapeutic lead- generating industrial process. Since the foundation of NOXXON, Dr Klussmann has held positions as Chief Technology Officer and Chief Scientific Officer. Under his scientific leadership, NOXXON automated the drug discovery process and demonstrated in-vivo proof-of-concept for Spiegelmers’ utility as therapeutics in animal models. During this time he has authored more than 40 articles and more than 40 patents on oligonucleotides and their application and has edited a book on aptamers. He is a reviewer for several scientific journals.
From 2006 until January 2008, Dr Klussmann served NOXXON in a twofold function as Chief Scientific Officer and Chief Executive Officer. In this dual role he initiated the transition of NOXXON from a technology-focused drug discovery company into an innovation-driven drug development organisation. To drive this endeavour, Dr Klussmann raised €37 million in venture capital from top-tier
biotechnology investors, completing one of the biggest financing rounds in Europe in 2007. Since beginning of 2008, Dr Klussmann has refocused his efforts on scientific development.
Further information Dr Sven Klussmann CSO NOXXON Pharma AG Max-Dohrn-Strasse 8-10 10589 Berlin Germany Tel: +49 30 72 62 47 0 Fax: +49 30 72 62 47 225 Email:
sklussmann@noxxon.com
Web:
www.noxxon.com July/August 2012 sp2 Inter-Active 39
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44