Tuesday, August 10, 2010

SNALP Delivery Taking Off

Just like SNALP delivery has become a staple of this blog, Alnylam has been investing aggressively into its development as exemplified by the one dozen or so presentations by the company and a whole range of collaborators, most notably the University of British Columbia and Old Tekmira spin-off Alcana, at the recent International Liposome Research Days at the world capital of liposomal nucleic acid delivery, Vancouver. It illustrates a theme that I believe we will see repeated over the next decades of RNAi Therapeutics drug development where, once in a while, there will be these pockets of tremendous value creation driven by a few key technical breakthroughs. SNALP is the first of this kind and will be critical for the valuation of the RNAi Therapeutics field over the next 5-10 years.

Seemingly ever increasing potencies with ED50s for knockdown of genes in the liver now in the single-digit microgram (not milligram) per kg range is only one side of the story.

Mechanistic understanding to drive next phase of SNALP development

In fact, more so than ever more potent and smarter lipids, at this point it is the mechanistic understanding of SNALP delivery, together with the ability to sculpt SNALP formulations at will, that will drive the adoption of SNALP for extra-hepatic applications such as in cancer, immune and infectious-related applications, in addition to further improving the overall safety profile.

One important finding, first published earlier this year in Molecular Therapy, is that much of the potency of ionizeable SNALPs can be explained by ApoE association and cellular uptake via the LDL-receptor. Based on this, it is now possible to re-direct SNALP particles from the liver by for example abolishing ApoE association which can be done through increasing the PEG density on the outside. The attachment of targeting ligands can then facilitate the uptake in cells bearing cognate receptors. Combine that with long circulation times and we will see more and more examples of SNALP-RNAi for non-liver tissues. Similar to what has been the case for the ApoB and TTR programs this also means that there will for example soon be cancer formulations that are more potent and selective than Tekmira’s SNALP-PLK1 for which an IND has just been filed. Again, a good problem to have and probably a much better strategy than the one taken by Merck which, after $1.5B or so spent, is to constantly admonish the field of the dangers of innovative drug development while procrastinating forever before collecting valuable clinical data.

So while SNALP potency for the liver is starting to scratch at theoretical limits, based on the rapid progress we’ve been witnessing there is no sign that SNALP technology will have fulfilled its inherent potential any time soon. Alnylam has to be given credit that in the case of SNALP it chose to lead the translational science instead of entirely relying on outside help, and now has results to show.

Given that RNAi Therapeutics in 30 years or so is likely to comprise a number of delivery platforms, is this the right level of investment, or does it risk neglecting potentially complementary delivery technologies that Alnylam likes to emphasize they are investigating, too? From the perspective of the net present value of the pipeline alone, ignoring partnership appeal etc, I believe it is. As an analogy, if you are looking to enter a little explored area at the cutting edge of academic science, it often happens that you will be tapping in the dark for the longest time, and while picking up an interesting signal here or there, this period is very costly if you think in terms of numbers of publications (= clinical candidates). However, once or so often you encounter a strong, robust signal and if you are wise enough you will drop everything to extensively feel out what you’ve just found in a phase that should be very productive. Artefacts (= delivery dead-ends) don’t lend themselves to that type of productivity.

Despite the wealth of exciting data, SNALP delivery probably still has many more skeptics than enthusiastic supporters like myself. I believe this is largely due to the perception that SNALP suffers from many of the same problems that other liposomal nucleic acid delivery platforms suffer from, a perception curiously widespread even among those that get identified as liposomal experts by those undertaking due diligence of the technology, but have yet to read a single paper or patent related to the technology. Immune stimulation, clotting abnormalities and liver toxicity are some of the challenges frequently cited, of course also by a number of competitors.

The reason, however, why competing groups struggle to reach the non-human primate stage while SNALP is enabling now one clinical candidate after another is that these are precisely the areas where Tekmira and Alnylam have invested and made key advances, many of them formulation and process-related, the benefits of which have been now amplified with the more potent lipids. Moreover, with shelf-lives of at least 2 years in the fridge and the improvement in potency decreasing cost of goods and paving the way towards new routes of administration, including subcutaneous, the commercial (and also biodefense) appeal of the technology grows.

Somewhat similar to Alnylam when it talks about the other delivery technologies in its stable, Marina Biotech and Silence Therapeutics are often also keen to stress that lipid-mediated siRNA delivery is not everything, cautioning against making a single technology platform, i.e. [SNALP], fit for various therapeutic applications, although it is quite clear from their own activities that liposomes/lipoplexes play a very critical role for these companies, too. Just recently, Marina Biotech bought the IP for Novosom’s amphiphilic liposomal delivery platform and they also presented improvements in liposome potency at the Vancouver meeting with ED50s down to 80ug/kg in rodents.

It is still unclear to me whether this communication strategy is simply to reach out to Big Pharma to whom the supermarket concept appeals, or whether they have actually made internal progress with other delivery platforms to back up such statements. Anything else would be either corporate suicide or trying to mask deficiencies in formulation and scale-up, areas where Tekmira dominates and (still) enjoys a gate-keeping position. I say ‘still’ because it is obvious that since Alnylam has moved so close to Tekmira’s quarters, it may be a question of time until sufficient know-how has moved over to Alnylam’s allies in Vancouver to make Alnylam’s SNALP efforts independent that of Tekmira’s at least in terms of know-how. Instead of an adversarial relationship, one may also speculate that such a transfer of know-how would make sense if Alnylam and Tekmira were scheming to sell Tekmira as part of a larger Alnylam alliance, in which case Alnylam would want to make sure that it can stand on its own SNALP feet first.

Of course, advertising their RNAi capabilities, particularly in delivery, to potential platform collaborators is one aim when Alnylam impresses at a meeting like this with a full range of presentations. Notably, the accompanying press release states (paraphrasing now) that progress such as this will form the basis for future platform partnerships as, I’m convinced, it has for the Roche and Takeda relationships. Within 2 months or so, we should know how much in particular SNALP delivery is worth to Novartis after exercising the $100M adoption license option or whether it will adopt a different approach to RNAi Therapeutics drug development altogether.


Anonymous said...


Well said....However, why is big pharma so low to act. TKM would cost them almost nothing in terms of what their research budget is...

Are they that dumb?

Dirk Haussecker said...

Let's discuss this in 5 months' time. A lot should be happening right now. Also keep in mind that the herd instinct is widespread in Big Pharma. Merck, Roche, Takeda were all linked events. I believe the Novartis decision could well force some hands this time around.

Anonymous said...

Thanks....I have been patient with ALNY and have been a TKM owner for some time. I think the Ebola results were an eye opener, but the caution exhibited by big pharma is amazing. In 2005 all biotechs could have been bought with the R&D money the top 10 drug companies spent. I have personally seen the bureaucratic nightmare in big pharma as the CSOs try to protect in-house research which in the case of RNAi delivery seems a waste compared to the results outside of their efforts.

Thanks for your ansers and commentaries. You educate me every time you post.

Anonymous said...

My question is do yu still think the viral vertor is better solution for neurodegenerative diaease like Huntington or SCA ?
Or you have any else thinking?

Warren Yen

Anonymous said...


When do you anticipate the first marketing of RNAI therapeutics assuming that the current clinical trials are successful.

Dirk Haussecker said...

Warren...I'm not very familiar with the pathophysiology of SCA, but for HD I tend to agree that virally delivered RNAi could be very interesting.

First commercialization of RNA Rx...I'm hopeful that the ALN-RSV01 could yield data confirming the results of the fist phase II study and that makes it approvable for the lung transplant patient population. There is not much else available for these patients and it is an acute treatment. It wouldn't be a huge seller, but may draw some attention. Similarly, Marina speculates that their FAP tkRNAi drug candidate could be approvable after phase II.

After that, Ebola might have a chance of moving relatively quickly through the clinic (3-4 years?).

Quark and Pfizer have RNAi Rx for ocular diseases that could enter phase III soon. I'm a bit skeptical about how these candidates are supposed to work (no specific delivery tech) and would expect similar concerns by Pfizer.

I could imagine TKM-ApoB and ALN-TTR finishing phase III in 2015/16.

Anonymous said...

As the article, Alnylam/Tekmira annouces their SNALP based RNAi can reach microgram per kilo potency, I don't see any reason that SNALP can not be injected into spinocerebelar fluid, say less than 1 miligram for an adult.
Why you think viral based is better? Is there any reason that I don't know?

Dirk Haussecker said...

I have to admit that I don't know enough about the pharmacology of drugs administered intrathecally. ISIS believes it works for their antisense technology in neurodegenerative diseases. Alnylam, however, I believe is using direct intrastriatal infusion for their Huntington's program. If intrathecal administration can reach cells affected by SCA, then I'd think SNALP has a chance there, too.

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