Thursday, August 19, 2010

Is Novartis' Kidney RNAi Drug Deal Part of its Grand RNAi Therapeutics Strategy?

In a reminder that the $100M adoption license option decision is coming close, Quark just announced that it has granted Novartis, for $10M in upfront and another $600M or so in potential milestones, the option to fully license Quark’s drug candidate QPI-1002, an siRNA targeting the famous 'guardian of the genome', p53. Delivered in its naked form intravenously, QPI-1002 is currently in phase I/II studies for the treatment of ischemia-reperfusion-related injuries of the kidney. While the deal is certainly supportive of Novartis’ interest in RNAi Therapeutics, questions remain whether this deal could reflect Novartis’ view of Alnylam’s RNAi trigger IP.

It is possible that this deal has indeed very little to do with Novartis’ general RNAi Therapeutics platform strategy and was largely driven by its therapeutic focus area and commercial groups that simply regarded this candidate as an interesting pipeline addition. As long as the underlying scientific data, market potential, the mechanism of drug action look attractive and the candidate is adequately protected by IP etc, Novartis may not care much about for example whether its core RNAi Therapeutics development group likes the Atu-siRNA structure or not. This would be somewhat reminiscent of the situation at Pfizer where the RNAi drug candidate licensing history does not seem to tell us much about its grand platform strategy.

Nevertheless, given the timing of the license, it is interesting to think that the various departments at Novartis in fact talk to each other occasionally. Such a conversation would probably have been centered around the siRNA structure and IP as well as delivery.

In terms of siRNA structure, QPI-1002 is a 19bp blunt-ended Atu-siRNA that is protected under licenses from both Silence Therapeutics and Alnylam. Since it is an Atu-siRNA structure and patents have actually been issued on this in major markets, there is little question about the need for the license from Silence Therapeutics which it obtained in 2005. In 2006, however, Quark also struck a license with Alnylam for additional patent protection. Because of its size and blunt-endedness, I would agree that such protection may be indeed required due to Kreutzer-Limmer in Europe (15-21bp), although the eventual outcome of the opposition proceedings remains to be seen. Consequently, I expect a decent portion of the Novartis payments to flow to Silence Therapeutics (10%?) and probably also to Alnylam.

In pre-clinical studies reported last year, QPI-1002 demonstrated decent potency with an IC50 of 230pM in tissue culture experiments. Potency has been my biggest concern when it comes to Atu-siRNAs. While I still believe that the rigid Atu-siRNA design makes it quite a bit more difficult to find potent RNAi triggers, at least this study is further support that Atu-siRNAs of clinically relevant potency, let's say an IC50 of less than 50nM, can be found.

The heavily modified Atu-siRNA structure makes QPI-1002 also very stable in biological fluids which is presumably required for the type of naked delivery approach that Quark has taken. Which gets us to the question of delivery.

All of Quark’s RNAi drug candidates are unformulated siRNAs. This raises, of course, a lot of skepticism about their scientific soundness. Quark counters that it just looks at where the naked siRNA goes after various routes of administrations and then select the indication accordingly. Since naked siRNAs following their unformulated administration quickly accumulate in the proximal tubule where the process of the re-uptake of the bulk of the primary urine begins, and since apoptosis in that area is believed by some to be important for the type of kidney injury Quark is targeting, it may explain why the company may have seen success whereas others have apparently failed.

In general, when it comes to target selection, I also like the approach where you carefully match pathophysiology, target, and siRNA pharmacology, instead of having a fixed idea of the target and cell at the start of your project and desperately try and find a suitable delivery technology for it.

Nevertheless, how the siRNA escapes into the cytoplasm of the proximal tubular epithelial cells still remains a mystery although it is always possible that cells in general, especially those with high membrane dynamics, have a general leakiness that allows some siRNA to get through the lipid bilayer when siRNA concentrations are very high. And because siRNAs can be highly potent, this would be sufficient to prompt knockdown.

Similar reasonings may apply to Quark’s eye drugs, one of which, another Atu-siRNA structure, has been licensed to Pfizer and the other one Quark is apparently out to license, too. I guess being too productive in entering the clinic may not be the best way to build value if you are a small and private company.

Overall, this deal is good for the RNAi Therapeutics field as it shows that it is yielding candidates in various therapeutic areas that can attract serious funding by the industry. Not that I need to be convinced of this, but headlines like this should encourage further investments in the space. We shall soon see how this investment will look like in more detail for Novartis. One thing is for sure: delivery has to be a critical part of that equation, and this creates a number of interesting scenarios. I guess I was not the only one wondering about those when I first heard of the news.

4 comments:

steve said...

Hi Dirk,

Could you elaborate a little on the "Interesting scenarios" regarding delivery.
While you see pros and cons with this announcement, what is your gut telling you re, Novartis exercising their option
Love your site,

Steve

Dirk Haussecker said...

Steve- the fundamental question to me is: given that Novartis may already have selected close to 30 targets protected under Alnylam's key RNAi trigger IP, would I spend another $100M (probably includes prepayments of milestones, so $100M can mean many things) for more targets without access to viable delivery and the potential for workaround strategies? Tekmira may be a good start for Novartis, and if it needed more targets down the road, it could always look somewhere else later.

In the current marketplace you can buy a lot of RNAi assets, and I really do hope that Alnylam is not complacent about its position. Other RNAi companies should be fighting tooth and nail for a piece of that $100M pie.

Anonymous said...

Hi Dirk,

Thanks for your hard work on your terrific RNAi blog. I am a frequent visitor and I have learned much. Would it be possible for you to list every single small company focusing in on the RNAi space and then "also" every big pharma looking towards capturing a prominant position in the RNAi space. Thanks for considering the above. IMHO your blog might soon become a "Grand Central Station" for all RNAi traffic. Warm regards, joe

Dirk Haussecker said...

Joe- thank you for your kind comments.

There are far too many small biotech companies that claim to be working on RNAi Therapeutics-related projects for me to list all of them here. If you are mainly interested in publicly traded companies, I would follow Tekmira, Silence Therapeutics, Marina Biotech, RXi Pharmaceuticals, Benitec, Rosetta Genomics, and somewhat Arrowhead Research, too.

Most large pharmaceutical companies also work on RNAi Therapeutics. The most significant efforts probably reside with Roche, Merck, Novartis, Pfizer, Takeda (and a whole range of other Japanese pharmaceuticals) and AstraZeneca. I probably left out some names, but that should get you started.

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