Tuesday, June 22, 2010

Regulus and Sanofi-Aventis to Develop MicroRNA Therapeutics for Major Unmet Medical Needs

Regulus Therapeutics and French pharma giant Sanofi-Aventis announced today that they would co-develop MicroRNA Therapeutics with an initial focus on fibrosis (PR by S-A, PR by Regulus, PR by Alnylam and ISIS). The deal demonstrates the need for innovative approaches for the treatment of diseases for which the pharmaceutical industry has long failed to develop meaningful therapies. The deal, valued at potentially over $750M, includes a $25M upfront, relatively realistic $50-60M in mid-term option fees and equity investments and major R&D support by Sanofi-Aventis, and provides Regulus with a nice cash cushion going forward. The ~$50M in realized partnership funding to date from GSK and Sanofi-Aventis should also make shareholders of both RNAi Therapeutics company Alnylam and antisense company ISIS Pharmaceuticals happy which are still the majority owners of Regulus.

Today’s announcement comes less than a month after Regulus Therapeutics secured exclusive access from the University of Wuerzburg to intellectual property related to fundamental work on the role of microRNA-21 in cardiac fibrosis. This should also be the lead program in the collaboration and justify Sanofi-Aventis transferring $25M of hard cash. Beyond the heart, fibrosis, a form of tissue scarring, is also widely observed in other organs such as the lung, kidney, and liver, and new treatment options are desperately sought after. Witness the fate of a drug for idiopathic pulmonary fibrosis (IPF) developed by Intermune of which the data appeared to be somewhat borderline, but which an FDA advisory panel recommended for approval earlier this year essentially because of the very significant unmet medical need (it was subsequently rejected by the FDA).

In addition to miR-21, other microRNAs have also been found to play a role in fibrosis, and both microRNA antisense and microRNA replacement approaches are conceivable. Given that these microRNAs often occur in various tissues, targeted delivery approaches may be preferable. On the other hand, should less specific delivery prove to be well tolerated, it is possible that the same drugs may be of use in other indications such as cancer for which some of these microRNAs, especially miR-21, have also been found to play a role.

The previous deals with GSK involved up to 4 microRNA targets in inflammation and targeting miR-122 for the treatment of Hepatitis C viral infection. Danish competitor Santaris also has an agreement with GSK covering up to 4 antiviral MicroRNA Therapeutics programs. Given that there are significantly less microRNAs than there are genes and microRNA biology is still relatively young, these deals seem to balance the concern of unwittingly giving away too much to Big Pharma with allowing enough flexibility for data-driven drug development.

In addition to proving to be a very good investment for Alnylam and ISIS, being part of Regulus also allows these companies to establish new relationships with major pharmaceutical companies. It is probably not a coincidence that the initial GSK-Regulus partnership was followed by the ISIS-GSK rare and infectious disease deal earlier this year. Of note, Sanofi-Aventis, under the new leadership of CEO Chris Viehbacher, recently entered into a relationship with California company Traversa for the development of protein-based RNAi delivery.

Overall, it is very encouraging to see that a number of companies in Big Pharma do understand the need to invest in potentially transformative new technologies to address major unmet medical needs. I hope that this summer will provide more such proof points.


Anonymous said...

I am hoping you can answer a couple of questions related to RNAi drug delivery platforms:

1. With respect to microRNA based therapeutics, how is the therapeutic delivered to the target? Direct injection, LNP, etc.? If LNP, would Techmira's delivery technology be relevant?

2. It is my understanding that Alnylams ALN-VSP01 is formulated using a 1st generation, SNALP, developed by Tekmira. In a discussion with Alnylam, they referred to a second generation SNALP also... is this an Alnylam proprietary technology, or is the 2nd generation SNALP also Tekmira's technology?

Thank you in advance for your reponse.

Dirk Haussecker said...

Delivery of microRNA-based therapeutics: If you talk about agonist approaches (mimicking the action of microRNAs), it should be very similar to the delivery of RNAi Therapeutics. In the case of inhibiting microRNAs, it is possible that non-targeted antisense technologies can be used such as ISIS uses them at the moment. It remains to be seen what benefits RNAi-like delivery approaches may provide for microRNA inhibition in terms of pharmacology. For tissues, however, where antisense does not distribute well on its own, specific delivery technologies, both systemic and loco-regional will be required.

Both Alnylam and Tekmira have developed more potent, ‘second-generation’ liposomal delivery, both of which however are formulated as SNALPs whether or not they use so-called lipidoids or not. So chances are that Alnylam’s second-generation liposomal programs will also comprise SNALP technology for the foreseeable future.

Anonymous said...

How will the research reported yesterday from Harvard and Memorial Sloan Kettering on interactions between microRNA and mRNA affect microRNA therapeutics efforts?

Dirk Haussecker said...

Certainly an interesting study. It appears that life is more complicated than we had all thought. The study reminds me of the microRNA sponge technology (covered in this blog here: http://rnaitherapeutics.blogspot.com/2007/08/microrna-sponges-gene-therapy-approach.html) whereby RNAs are introduced into a cell with microRNA-like target sites to mop up the availability of a given microRNA so that it cannot target any more its normal gene set. One of these examples where a technology is first invented and the natural correlate discovered only later.

Of course, these types of studies raise a number of issues, also with regard to the application of therapeutic small RNAs. But to be honest, given that one microRNA can regulate over one hundred target genes, the notion that a single pseudogene that is often present in lower abundance than its gene counterpart has the ability and natural function to usurp sufficient amounts of shared microRNAs, is still somewhat puzzling to me. The authors clearly show that the RNAs are regulated by certain miRNAs and that the overexpression or repression of one RNA affects the other RNA in a way consistent with the microRNA sponge model. Moreover, the effect depended on the presence of the microRNA enzyme Dicer. I guess that’s pretty strong evidence for their model, but maybe one experiment that I missed was to mutate some of the microRNA target sites in the pseudogene mRNA and then test whether it was still able to co-regulate the corresponding gene. Because a gene-pseudogene pair will have many more overlapping regulatory RNAs and proteins all of which can affect RNA stability, it is quite important to rule out at various levels non-microRNA effects. I’ll have to think about it more.

Ares said...

Tremendous investment for the development of RNAi terapeutic program. This evidence support the pharmaceutical industry for human rescue missions and need the support of all parties, not just medical experts alone but involve others, especially the government. Hopefully with the support of all parties to produce a more robust method terapeutic again. Thank you.

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