Silence Therapeutics to Validate Endothelial RNAi Knockdown in Man

This Monday, Silence Therapeutics held an investor evening in London.  To my surprise, interest in the company and technology was such that 80-100 largely analysts, investors, and fund managers crowded the elegant Victorian-style room at the Royal Institution.  In stark contrast to the quaint setting, the main message of the evening was that the company won’t play it conservatively when it comes to this cutting-edge medical technology and is about to test whether their lipoplex-based delivery technologies can knock down genes expressed in endothelial cells…in Man.

Whereas RNAi Therapeutics have more or less conquered the liver, opening up a whole host of indications to RNAi Therapeutics, despite the apparent accessibility of the vascular endothelial system to delivery and promising animal studies, it has proven a more difficult tissue to firmly establish gene-specific knockdowns.  Part of this technical problem is due to the fact that the vasculature, especially the capillaries which are of most functional importance, is tightly interwoven into the tissues that they supply.   This causes experimental difficulties of obtaining pure endothelial cell populations, a particular concern when genes are also expressed in the more abundant host tissue cells.  Moreover, unlike the liver, proteins (and RNA) expressed in the vasculature are not commonly found in the serum.  The latter is of particular importance in clinical studies where taking appropriate biopsies is either not technically feasible or would be deemed unethical.

Similar to how the clinical demonstration of target gene knockdown in the liver has turned around the fortunes of the likes of Alnylam and Tekmira, Silence Therapeutics also wishes to remove remaining doubts by conducting a second phase Ib/IIa study with lead candidate Atu027, this time not in pancreatic cancer (impossible to obtain adequate biopsies in advanced pancreatic cancer patients), but for head and neck cancer (anticipated regulatory submission in 2014).  Head and neck cancer is one of the few cancers for which the tissue is readily accessible.  And while they are at it, they also will take muscle biopsies to look for PKN3 target repression, and look at a whole slew of other assays, some serum-based, for their ability to assess gene expression in vascular endothelial cells.

In addition to the clinical efforts, I also expect the company to more strongly adopt non-human primates for their delivery studies.  When it comes to liver-directed RNAi, non-human primates have been accepted to be a highly predictive surrogate for performance in humans and one can expect the same to be true for endothelial gene knockdown.

The strategic changes are accompanied by continued corporatere-organization of which the most notable overall change may be the increased clinical focus.  This effort is spear-headed by Dr. Michael Khan who is trained in internal medicine and thus has a good feel for selecting interesting indications of unmet medical need and conducting the appropriate clinical studies.  On the scientific front, the most notable change is the departure of long-time CSO Dr. Klaus Giese (due to family reasons), succeeded by long-time comrade Dr Joerg Kaufmann.

In addition to picking up details like the ones above, such investor events are also an invaluable opportunity to gather insights into the investor base and other people associated with the company.  In that regard, the new CEO Ali Mortazavi has done an remarkable job not only at expanding the technical, clinical, and business development expertise of the company, but also at putting the company in a position to become a sustainable stand-alone biotech company which, if you have followed the fate of UK biotech, is not an easy task.  With Atu027 clinical efforts in high gear and Atu111 for acute lung injury likely to join the clinical pipeline in 2014, the coming period will not only test the organizational skills of management, but also their ability to react to share-price moving clinical events.  Expecting success, Silence Therapeutics is striving for a full listing on the LSE thereby opening up the company to an even larger investor base.        

To learn more about Silence Therapeutics and related events, please follow this link.