Monday, December 9, 2013

Silenseed Lifts Secrecy of First Clinical RNAi Slow-Release Formulation

Last week saw the first peer-reviewed publication of the LODER RNAi delivery system developed by Israeli biotech Silenseed (Khvalevsky et al. 2013).  Following a ~17-subject phase 0/I study in pancreatic cancer patients that was initiated in 2010 and a more recent phase I study with siG12D in ~100 patients with locally advanced, unresectable pancreatic cancer, LODER (Locally Drug EluteR) had become the first matrix-assisted slow-release RNAi Therapeutic formulation in clinical development.  Nevertheless, I have struggled to understand the basics of the technology largely based on the patent literature which is often ambiguous.

Slow-release RNAi Therapeutics

Slow-release RNAi formulations promise to minimize the need for and frequency of repeat drug administrations.  This is of particular value when systemic delivery options are limited and direct access to the diseased site difficult and/or dangerous to the patient.  Ocular applications are one such area as large molecule drugs are commonly administered by intravitreal needle injections which carry a cumulative risk of injury to the retina and other complications when given every month or two as is common today.  Other areas are wound healing applications (e.g. sites of broken bones) where you basically get the chance to apply the RNAi just once and pharmacology is only needed for a few months, or for diseases of the pancreas where surgical manipulations carry the risk of potentially life-threatening pancreatitis.

While RNAi activity in non-dividing tissues is remarkably extended- it now seems that with stabilizing RNAi trigger modifications and efficient delivery you should be able to achieve potent silencing in the liver for 2 to 3 months following a single administration- slow-release strategies are attractive if the goal is to go beyond that.
Slow-release strategies typically involve matrices with embedded RNAi triggers that dissolve over time thus releasing the RNAi payload.  A major challenge is to find matrices and formulations that are not only biocompatible and bioresorbable, but that do so gradually.  This is because for most matrices you initially get a great burst of activity with a relatively quick drop-off in drug release thereafter.

LODER technology

At the basis of LODER technology is the PLGA (polylactic glycolic acid) workhorse of the medical device industry.  Staying with simplicity, it appears as if the RNAi triggers are simply embedded in the ~1-by-4mm pellets in unmodified Tuschl RNAi trigger format.  As the PLGA dissolves, the RNAi triggers are liberated with about 55% released in the first week, followed by another 25% or so over the next 60 days. 

The release kinetics appear acceptable and it is good to see the RNAi trigger being protected from degradation while inside the matrix (albeit not totally unexpected).  What seems to be far from optimal, however, is the apparent reliance on intracellular delivery by naked, unmodified RNAi triggers alone.  It seems that a combination of the PLGA matrix with self-delivering RNAi triggers or other cellular delivery formulations is called for (shameless self-advertisement : I can always be had for consulting projects).


Nevertheless, the PNAS publication by Silenseed reports good evidence of gene silencing in mouse models, one involving luciferase gene silencing in a transgenic mouse with luciferase expression in the liver, others involving ectopic and orthopic pancreatic tumor masses.

Importantly, performing insightful analyses of the relationship between distance from the implanted pellet(s) and gene silencing, it was found that gene silencing was marked in a sphere up to 2mm away from a pellet.  In the pancreatic cancer models, this was accompanied by local necrosis as expected from the specific knockdown of mutant KRAS which is thought to drive the majority of pancreatic cancers.  

Given that silencing is so locally restricted, this makes me wonder how best to apply the technology in the clinic.  In the pancreatic cancer trials by Silenseed, resectable and non-resectable cancer settings have been tested, in single- and multi-dose regimens.  Intuitively, I could imagine that post-operative settings are attractive, where the pellets are deposited at the border between cancer and normal tissue following the excision of the bulk tumor to kill any remaining cancer cells much in the same way that radiation therapy is often indicated following breast cancer surgery.  In cases of non-resectable pancreatic cancer, it would seem that stuffing the pancreas with LODER pellets once and then hope for the best (maybe in combination with gemcitabine and the like) is the go-for strategy.

I am encouraged by this new way of applying RNAi Therapeutics, but also see a number of simple ways of how to improve upon this first generation LODER formulation.  This would further resolve potential IP issues that come with the use of a prototypical Tuschl-type RNAi trigger. 

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By Dirk Haussecker. All rights reserved.

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