Liposomal RNAi Delivery to the Liver Making Progress

[Disclosure: I chose to own both Tekmira and Alnylam stock, of which particularly Tekmira should benefit considerably from progress on liposomal RNAi delivery due to their IP position on cationic liposomes and relationship with Alnylam.]

Following my blog on the RSV-01 experimental infection results, I received a number of emails noticing my apparently less-than-usual bullish assessment of this Alnylam result, a concern heightened by a falling Alnylam share price.

The problem with calling the results a definite proof-of-concept for RNAi in humans is that this program targets a virus, and it is well documented that particularly unmodified siRNAs can have profound antiviral effects independent of their gene silencing activity, i.e. by inducing cytokine responses. However, I acknowledge that Alnylam and their clinical collaborators have done almost all humanly possible to (statistically) exclude the influence of various parameters such as inflammatory cytokines on the antiviral efficacy, although it is not clear e.g. when and where these markers were measured.

I guess I am just too much of a trained scientific skeptic here when I can agree with proof-of-concept for a clinical effect of an RNAi Therapeutic in man, but remain cautious on proof-of-concept for gene silencing in man. Maybe proof-of-concept should not be seen as a one-time event, but something that will emerge over time.

Especially with some of the other early clinical RNAi trials, one has to be aware that these were entered into the clinic before the entire scope of non-silencing activities of unmodified siRNAs were known (and some of the trials lacking supporting sound scientific data, btw). For those that would like to learn about this topic, I would warmly recommend the freely available, and very critical review article by Protiva’s Adam Judge and Ian MacLachlan from Protiva on the immune-stimulatory potential of siRNAs, including their non-specific antiviral and antiangionic (e.g. relevant for wet AMD applications) potentials. It is important to note that critics, also called “shorts” in stock market lingo, may exploit these issues to portray them as fatal short-comings of the RNAi Therapeutics platform, but like delivery, there is every indication that these will be overcome in a timely manner and the field should not shy away from openly addressing them.

As I indicated in my 2008: Year of the Liver , I believe that the demonstration of RNAi gene silencing in the human liver may very well steal the thunder from the RSV program this year. It was gratifying therefore to hear at today’s Alnylam’s R&D Day that by working together with Tekmira and applying a systematic, industrial-type evaluation of different liposomal nanoparticle formulations (LNPs, aka SNALPs), the potency of these particles has been improved such that only 0.1mg/kg dosages can effect over 50% knock downs. This is very important since these are now concentrations that should be well below the concentrations previously associated with toxicities by these cationic liposomes and likely the cause for delays in filing for the much anticipated liver INDs. Not only was it then confirmed that an siRNA administration led to silencing over an entire month, but equally important was the demonstration that repeat-administration of these particles over 3 months was able to cause sustained gene silencing, meaning that neutralizing antibodies, typically facilitated by concomitant inflammatory cytokine induction, are not generated to blunt repeat administration.

As a result, Alnylam today gave the best indication thus far that they are now ready to enter the clinic with such a systemic RNAi formulation, most likely for treating hypercholesterolemia. In addition to demonstrating safety, this phase I study may indeed provide the most impressive evidence for RNAi gene silencing activity in humans simply by measuring the level of circulating PCSK9, the gene target of this program.

Btw, comparable 0.1mg/kg efficacy and repeat-administration data with the essentially same underlying SNALP technology was also reported on Protiva’s website which I give an ‘A’ for being scientifically engaging, and possibly an ‘A+’ when Protiva and Tekmira can finally come to the realization that it does not make sense to have two companies operating in the same city on the same RNAi delivery technology, while diverting money and attention on lawsuits fighting each other.

As you can see, despite the broad progress in delivering RNAi to many other organs and tissues, based on the available data, RNAi delivery to the liver (not only by SNALPs, but also an increasing number of competing technologies) appears to be the most advanced in terms of efficacy and should be one of the major drivers of the valuation of the RNAi (and also microRNA) Therapeutics space in the next 1-4 years by filling the clinical pipelines with high-quality, promising drug candidates.