Patents still matter. An impressive demonstration late last year by Santaris and collaborators from a primate center in Texas was not enough for GSK to exercise its option for SPC3649, Santaris’ lead microRNA therapeutics candidate directed at miR-122 for the inhibition of hepatitis C virus (HCV) infection (discussed on this blog here, and in a review by Mark Kay and myself here). Instead, Alnylam/ISIS-backed Regulus announced today that GSK has decided to side with them in the development of such an miR-122 antagonist for HCV. This is an amendment to an earlier inflammatory disease collaboration between Regulus and GSK with undisclosed upfront and ~$150M in potential milestones plus the usual tiered royalties on drug sales.
GSK’s decision not to exercise the Santaris option led to speculations, also on this blog, whether it is maybe the concern that miR-122 inhibition might be tumorigenic or could have other adverse effects on the liver. While one certainly ought to pay attention to such potential, the pre-clinical safety data and the expectation that any such therapeutic would not be administered chronically would have made this an unusually conservative decision.
It now appears, however, that GSK just could not ignore the fact any more that it is Regulus that got the exclusive license to the critically important miR-122/HCV Sarnow patents. The move can also be interpreted such that while LNAs are certainly an attractive approach to inhibiting microRNAs, there are alternative chemistries of similar potency. A new type of locked nucleic acid chemistry developed by ISIS that was inspired by and looks a bit like Santaris' LNAs but for a few adornments, that supposedly also make it less toxic, is one such chemistry that I could imagine Regulus-GSK to select for their IND-enabling studies. It is worth remarking that it is probably less the miR122-related Esau patent that was the swaying factor here, since as issued in the US, the Esau patent called for a fully 2’-MOE antisense molecule against miR-122…probably not a gate-keeping chemistry for microRNA antagonists.
It will be exciting to further monitor the race between Santaris (already in the clinic) and Regulus in developing a microRNA-based HCV therapeutic, including how the IP will be sorted out. In this context, I can only appeal to the players not to engage in big patent fights at this time and let the better arguments win, but outside the patent appeals courts and civil cases. To paraphrase related comments by the new CEO of Silence Therapeutics, Phil Haworth, yesterday, this is an utter waste of money and management attention. Time to wake up!
PS: Another milestone in the deepening relationship between GSK and Alnylam, and GSK’s move into innovative, high-value medicines.
12 comments:
Could Regulus also pursue an approach similar to Mirrx Therapeutics' Blockmirs?
Has Mirrx effectively blocked all other companies from pursuing that avenue to microRNA inhibition?
I'm not sure about the ISIS version of LNA. From that paper:
"To probe if further increases in affinity could enhance the potency of gapmer ASOs, we replaced MOE residues in the wings with bicyclic nucleic acids such as 2′,4′-methylene bridged nucleic acid (BNA)(11) commonly called LNA (D, locked nucleic acids, Figure 1).(12) While this substitution resulted in improved potency of some ASOs in animals, it was accompanied by a significant increase in the risk for hepatotoxicity.(13) In contrast, the MOE modification employed in second generation ASOs is well tolerated in a variety of animal models and has also demonstrated an excellent safety profile in human clinical trials.(14)"
I think the measely 3 million GSK gave Regulus upfront (followed by 5 million in stock purchase "if certain equirements are met") probably is just GSK covering themselves by getting the use of the patents ... and they'll still go with Santaris' LNA (which by the way showed NO side effects).
I also like the sound of the Mirrx approach better than all of them!!
Alluding to sequence IP is clearly over thinking this; it’s toxicity.
Nucleoside modifications (heterobase and sugar) that don’t occur normally in the cell are just bad news and that goes for ISIS’s lame attempt to seal back the short-term spotlight from Santaris with their LNA-like mers. I’m just a RNA/Protein crystallographer but this isn’t rocket science, if you can’t find it in a t-RNA its bad news. These weird nucleoside modifications never made sense to me, they are the last thing I want incorporated in my nucleotide pools. Stick with nucleosides that make sense and simple phosphorus modification that are negatively charged and hydrogen-bond well: that pretty much means phosphates or phosphorothioates.
Your plea on IP legal manuevers is naive at best; ill advised at worst. While I appreciate that as an academic, you wish that all could just "get along", such pipe dreams would simply slow (stop) BD collaborations (Note: ALNY deals grinding to a halt) and financings will be impossible void of IP clarity (Note: Silence/Intradigm deal). Companies must, first and foremost, defend and won their innovations via a sound IP strategy. This is never a waste of time and/or money.
Which pharma/biotech will be the first to work with Santaris?
Which pharma/biotech will be the first to work with Mirrx Therapeutics?
Can someone take a shot at ranking the 3 microRNA inhibition approaches (Regulus/ISIS antisense oligo, Santaris LNA and Mirrx Blockmir) by 1) Strength of inhibiting the target miR and 2) Least amount of toxicity and off-target effects?
These are all interesting questions/comments.
One quick rebuttal only on the question which level of litigation is healthy for the industry: as a naive scientist, I, of course, abhor litigation that is both costly in terms of money and management attention. Just ask the Alnylam management who would probably prefer spending time on deals and progressing the science rather than litigating half the universities in Massachusetts. A company like Tekmira e.g. has chosen not to go after all the violators of their patents, essentially everybody working on cationic liposomes for siRNA delivery without a license, and these are many companies in the industry, small and large. Tekmira just doesn't have the resources and attention span for this. It would ruin them.
That does not mean, however, that they won't eventually ask for what they are due once products come closer to market. Benitec and Nucleonics are two opposite examples that in the early days spent more time on litigation than science. The outcome was that both companies came close to bankruptcy with one of them, Nucleonics, actually gone bankrupt.
The question is, of course, finding the right balance. However, my plea is based on my observation that litigation has become overly rampant in RNAi Therapeutics, ridiculously so. I am wondering who is ill advising the companies...the scientists or those that are the financial beneficiaries of these lawsuits?
Big Pharma companies, with a few exceptions such as Roche, also ought to be singled out for special treatment here. They make it a business strategy to rebut any patents related to RNAi Therapeutics that comes on their radar, whether meritorious or not. They know that they can easily outspend smaller rivals and that almost any patent that is undergoing review will be narrowed in scope. One way of getting better deal terms eventually.
Coming back to Santaris and Regulus. Probably the best way to settle the dispute is for Regulus to acknowledge Santaris' scientific leadership in HCV-miR122 and make it a collaboration between Regulus, Santaris, and GSK. It would help Regulus as Santaris is much more advanced clinically and would be the price to pay for Santaris for making a risky business decision (they must have seen it coming- even I did). In a way they would even somewhat benefit from such an outcome as they could share development costs, not a minor consideration for an early-stage biotech with limited funding. My advise would be to deal with it without litigation.
What indication do you think Mirrx Therapeutics will select for its' in vivo proof of concept work for Blockmirs?
Which companies will be the most likely partners for this project?
In the latest press release it said that HCV-miR122 would be their lead program. There are many companies interested in new HCV treatment approaches and also those that want to pioneer microRNA/RNA therapeutics, so a potentially large pool of potential partners.
What do you think about the recent study by OSU researchers where they discovered that the loss of miR-328 is probably essential for progression of chronic leukemia to a more life-threatening phase?
They also showed how micrornas can attach directly to protein molecules and alter their function.
Will this discovery accelerate the microRNA therapeutics field?
You are incorrect on the Tekmira (and others) patents. None of these patents (siRNA, cationic lipids, etc.) are yet being infringed, as no commercialized products exist to infringe on the patents. R&D does not infringe patents under international patent laws, specifically as related to drug development. The ALNY litigation is related to the prosecution of filed patents under active reviews, in order to have them issued.
I am aware that as long as there is no commercialized product, patents cannot be enforced even though the work intends to produce commercial products after all. Patents may therefore not be violated in a legal sense, but everybody is aware of what will happen once this is the case and the longer a 'violator' waits, the more expensive the deal will become. It is my interpretation that this threat is what got GSK to go with Regulus after Regulus gave multiple times notice that Santaris was 'violating' Regulus' patents (based on an interview with the Regulus CEO).
I'm confused, however, what this blog entry has to do with the Alnylam litigation. As you seem to agree that this is a totally different matter.?
miR-328...traveling, but reading the paper. Interesting work, will come back to it soon. Thanks for pointing it out.
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