Saturday, December 1, 2007

The Confusing World of AtuRNAi, Stealth siRNAs and mdRNAs (III and Final Part): The RNAi Therapeutics Fashion Show

Shortly after Alnylam announced issuance of patent protection for the Kreutzer-Limmer series covering double-stranded RNAs between 15 and 49 base-pairs in Germany this week, the CEO of Silence Therapeutics, Jeffery Vick, shot back at an investor conference presentation reassuring their investors that this development would not affect Silence’s freedom-to-operate, including its all-important ability to close lucrative partnerships based on their proprietary (?) Atu-siRNA technology. Vick’s confidence stems from the observation that the first Kreutzer-Limmer patent had been opposed in Europe before and was consequently reduced to cover dsRNA of 15 to 21 base-pairs in 2006 (see previous Blog entry), and therefore would cover Silence’s blunt, 23 base-pair Atu-siRNAs. He vowed to fight the new patent, which is now likely to be issued throughout Europe in due course, to restrict its scope. My impression is that the patent attorneys will have a feast in the years to come, and just wait until Alnylam sees the time has come to return the favor and go after Silence’s issued patents.

Vick’s views obviously were not echoed by Alnylam’s CEO, John Maraganore, also at an investor presentation, who emphasized that no single patent will give you the right to work on commercializing RNAi Therapeutics. For freedom-to-operate, it takes a whole range of fundamental patents, such as IP covering the use of double-stranded RNAs for gene silencing in humans (Kreutzer-Limmer, Tuschl, Kay), nucleic acid modifications to make them drug-like (Crooke), and even the use of an dsRNAse-mediated mechanism itself (Crooke). It is the view of many, including myself, that it was Alnylam that has understood it very early on to gain exclusive and non-exclusive access to all of the early patents and applications that could even remotely impinge on the use of RNAi in the clinic. What this means is that only Alnylam has a blocking IP estate and that no matter which fundamental (e.g. Fire-Mello) or fringe patents you may have access to, you will still have to pay your dues in one form or another at the Alnylam toll gate. It is worth remembering that at least in the US, a patent does not give you the right to do anything, but the right to block somebody else from using the underlying technology.

So now let’s turn our attention to the RNAi Therapeutics catwalk, looking at the IP and technology strengths and weaknesses of a couple of better known RNAi Therapeutics companies (excluding Big Pharma with RNAi operations):

1) Alnylam Pharmaceuticals: The leader in the translation of the science of RNAi into drugs. Has virtually freedom-to-operate and blocking IP estate, now validated by a number of high-profile partnerships. Ability to gain access to the most promising delivery platforms desirable; IP protection may be sought for knocking down certain genetically validated genes for certain diseases, like they have done for VEGF before. Sorry- “Not-For-Sale”, want to become a top-tier biopharmaceutical themselves.

2) RXi (RNAi subsidiary of CytRx): Has assembled a motley array of patents including access to Tuschl I via UMass and Hannon (both co-exclusive with Alnylam), although many have not issued. These patents may lessen the pain when paying the Alnylam toll. Credible and engaged scientific advisory team including Nobel laureate Craig Mello (UMass) and Greg Hannon (Cold Spring Harbor). Puzzlingly, this company has not made much public progress in moving RNA therapeutics into the clinic. What are they waiting for?

3) Silence Therapeutics: Proven RNAi Therapeutics know-how with already two licensed compounds in the clinic and more to come soon. I am pleased by their progress on siRNA delivery to the vasculature, boding well for their anticipated cancer trials. Their 23 base-pair Atu-RNAi was granted IP protection in Europe and they hope to obtain same in the US soon. This allowed them to close a number of partnerships with Big Pharma, although the upfront payments were not enormous. They are, however, moving on very thin ice if they believe that with this one patent they have freedom-to-operate. It is mostly for their know-how that I believe that they may be one of the next RNAi acquisition targets by Big Pharma. Such a takeover would be “friendly” given Silence’s frequent statements that they would not mind being bought out.

4) Nastech: As RNAi was slowly getting some attention, Nastech quickly assembled a rather large team of experienced nucleic acid scientists that has been busy churning out patent application after patent application with the aim of working around Alnylam’s blocking IP position. Like Silence Therapeutics (and Dicerna) they hope that the scope of Tuschl II and Kreutzer-Limmer will ultimately not cover “long” small interfering RNAs. The ice may be thicker here than for Silence though. Apparently over 150 patent applications, more than Alnylam, according to CEO Steven Quay. Looked up one of their more recent ones on cross-linked peptide-siRNA particles for RNAi delivery. If I understood that one data slide correctly, they only achieved a 15% knockdown (???). Their other applications rather be better in terms of enablement, otherwise I would get the impression that the 150 applications are part of an overblown balloon. Nevertheless, should be considered a takeover candidate for Big Pharma that wants to hit the ground running in RNAi. However, following the P&G disaster, their position in partnership and fund-raising negotiations is quite hurt.

5) Benitec: Australian DNA-directed RNAi company, beaten a hasty retreat from the US after management and dubious patent issues caused them to run out of money. Still, a Benitec-sponsored HIV trial is well and underway at the City of Hope and it can only be hoped that they will remain a force in realizing the promise of DNA-directed RNAi. Only small in-house scientific team, strongly relying on their clinical partners for technology know-how. Major issue is their ability to attract funding when there is a lot of uncertainty surrounding the quality of their IP claims. Nucleonics, which has a phase I DNA-directed RNAi trial for HBV ongoing and is out to raise more funds, considered their arch-rival, but a number of other gene therapy companies, including Targeted Genetics and Introgen, also likely to extend their work in RNAi. DNA-directed RNAi efforts are somewhat less affected by Alnylam’s dominant IP estate, but overlaps exist.

6) Calando (subsidiary of Arrowhead Research Corp.): One of the increasing number of RNAi companies with a focus on delivery, in this case based on cationic cyclodextrin polymers that bind siRNAs for systemic, and potentially targeted delivery. Tox/efficacy data from non-human primate work indicates that this formulation may have promise for cancer applications. Need to license core siRNA patents. Although they may not be a prime acquisition target at this stage, clinical proof-of-concept studies may make them interesting for Big Pharma and Alnylam in 3-5 years.

7) Protiva-Tekmira: Although arch-rivals, I mention them together, because they belong together, both working on cationic liposomal delivery of RNAi. Right now, cationic liposomes are the most advanced systemic RNAi delivery method and both companies consequently had no lack of partnering interest. Unfortunately, IP (Tekmira) and related enabling know-how (Protiva) appear to be split between the companies, and maximal value creation should be achieved through collaboration, rather than wasting their time in the courts. One would hope that both parties realize soon that the whole is so much more valuable than the sum of the parts. If they would face the economic realities they would get back to business and either re-unify or cross-license (I will never get tired of making that plea, in case you have not noticed).

8) Innumerable nanotech delivery efforts, some of which are set to rise to more prominence. One such company is Intradigm that has done some interesting work on RNAi delivery a couple of years ago. Essentially all of them aim to partner their technologies sooner or later. A niche player is Cequent Pharmaceuticals, based on “trans-kingdom RNAi” where orally administered bacteria that express short hairpin RNAs are used to deliver RNAi to the small and large intestine for the treatment of related diseases such as inflammatory bowel disease and cancer. While their Nature Biotech paper showed promise, due to the out-of-the-box nature of this invention and many open mechanistic questions, more data is needed to make me feel at ease with this technology. Nevertheless, the $9M funding round this summer, including the Novartis Option Fund, should be taken as a vote of confidence.

While Alnylam is not-for-sale, many of the other pure play RNAi Therapeutics companies were obviously established and are managed with the intention of being sold off to larger corporations. Sirna Therapeutics was the first one to go and more are likely to follow. Accordingly, John Rossi stated in an interview about the Dicer-substrate start-up Dicerna that this company was basically established with the intention of selling it off to an innovation-starved, RNAi-challenged Big Pharma later on. Consequently, I believe that the RNAi Therapeutics landscape in 20 years will likely largely consist of Alnylam, Alnylam-licensed Big Pharma companies, some of which will have bought in nucleic-acid know-how in the form of small pure-plays biotechs. Those that did not find any suitor will have a difficult time of surviving, and may only survive by hitting the clinical jackpot early on in the game.

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By Dirk Haussecker. All rights reserved.

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