Sunday, September 9, 2007

Regulus Rx, Where One and One Equals Five

One has to be impressed by the way John Maraganore, chief astronomer and CEO of Alnylam, and his team are maximising the value of their company’s scientific know-how and intellectual property. Last week’s launch of Regulus Therapeutics, a joint venture with ISIS Pharmaceuticals focussed on the development of microRNA-based therapeutics, is the latest in a string of strategic decisions that positions Alnylam to lead and participate in the very promising field of RNAi-related therapies while wisely managing the company’s resources and respecting the scientific challenges ahead. The scientific and financial results speak for themselves and are starting to catch the attention and respect of Wall Street and beyond.

Forming this joint venture not only consolidates and complements much of the IP in microRNA-based therapeutics, it also allows the respective companies to focus on their core operations in RNAi and antisense while giving the new company a distinct identity and independence that should incentivise their employees and help attract 3rd party funding, particularly in the form of alliances with larger partners. The joint venture also acknowledges the fact that microRNA therapeutics sets a new paradigm for treating disease with its unique set of challenges and risks.

Based on pioneering work by Regulus SAB member David Bartel and his group at the MIT, it is now believed that the approximately 1000 human microRNAs regulate around one third of our genes, “that is one third of our genes” (Stanley Crooke). It follows that each microRNA targets multiple genes. Targeting a microRNA for therapy is therefore based on the premise that the functions of these genes are linked to a common biological process hence limiting the potential for unwanted side-effects by disturbing unrelated pathways. In this sense, microRNA- and RNAi-based therapies are opposite philosophies where siRNAs seek to surgically target single disease-associated genes, whereas microRNAs are aimed at whole networks. Genetic research supports both approaches, and a number of microRNAs have been shown in animal models and human cells to specifically affect discrete regulatory pathways, a fact that is arguably best understood by two key SAB members of Regulus Rx, namely David Bartel and David Baltimore. A recent catalogue of microRNAs established by yet another Regulus SAB member, Thomas Tuschl from the Rockefeller, however, suggests that many microRNAs are constitutively expressed in a number of tissues, thereby slightly questioning whether this is the case for most microRNAs. Although a truly exploding field of research, compared to RNAi Therapeutics where there are already an abundance of well-defined targets, the development of Regulus Rx will heavily depend on progress made in elucidating the exact role of specific microRNAs.

Regulus Rx’s first development program, targeting miR-122 for the treatment of Hepatitis C Virus (HCV) infection is a particularly interesting case. This program has been licensed from Stanford University where Catherine Jopling from Peter Sarnow’s group has shown that miR-122 specifically interacts with part of the HCV genome and thereby stimulates HCV replication. MiR-122 is by far the most abundant microRNA in the liver, and it is surprising that no obvious toxicities have been associated with its inhibition in vitro or in vivo, as demonstrated by work from both Alnylam and ISIS scientists. It is even thought that inhibiting it may have applications in managing cardiovascular disease. Earlier this year, Alnylam and ISIS were issued a patent covering miR-122 as a therapeutic target. I am quite curious to learn whether last week’s announcement of HCV miR-122 as the first development program of Regulus is also based on results targeting HCV replication by miR-122 inhibition in vivo. In this regard, it is notable that a leading group in HCV biology, the Rice group at Rockefeller only recently confirmed miR-122’s importance in HCV replication in a paper jointly published with Thomas Tuschl from the same institute.

Regulus Rx will be based in Carlsbad, CA, not only because of the better weather, but also because this is where ISIS Pharmaceuticals is located. This acknowledges the fact that antisense technology, pioneered and long dominated by ISIS, is the key enabling technology for antagonising mature microRNAs many of which are processed out of introns of RNA Polymerase II transcripts and therefore not a target for RNAi. This underscores the importance Alnylam has attributed to ISIS’ patent estate, also demonstrated by their exclusive licensing ISIS’ oligonucleotides modification patents for the use in double-stranded RNAi Therapeutics. It also sends out the subtle message that as Alnylam respects other parties’ IP it expects anybody interested in RNAi Therapeutics to follow this example by licensing from Alnylam.

The 50:50 joint venture also speaks volumes to the negotiating leverage Alnylam has gained in recent years, made possible in large part by its solid financial position. Only 3 months ago, the financial strength of Alnylam has allowed it to revise a partnership agreement with Medtronic that has given Alnylam a larger stake in the financial success of any drugs coming out of that collaboration in return for increased funding by Alnylam. Unlike ISIS which not long ago had to repeatedly issue debt to fund their operations and is biting its nails to gain financial freedom by partnering its ApoB100 antisense program, Alnylam could easily pay the $10M to equal the companies’ stake in the new venture. In addition to its financial muscle and Tuschl III which gives Regulus exclusive access to some of the most important microRNA targets, Alnylam further brings to the table its invaluable access to leading scientists in academia and Big Pharma alike.

Finally, it is notable that the otherwise wide-ranging technology access licenses that Alnylam has granted Novartis and Roche did not include microRNAs. It would therefore be appropriate that following last week’s development the newco be put on a solid financial footing through a significant partnership. But let’s give them some time for this as although the day may never end on Alnylam, on earth their day still has only 24 hours.

(For more on the scientific rationale for microRNA therapeutics, please read my Blog from 26 May, 2007: “MicroRNAs as Therapeutic Targets”)

PS: Once the dust has settled, we should learn more about the exact scope of Regulus Rx. Specifically, it is not clear to me yet whether in addition to antagonising microRNAs by antisense, the scope of Regulus will encompass the microRNA agonist approach as well where microRNAs mimics are introduced for therapeutic purposes. While this would strengthen Regulus’ portfolio, it would be a significant contribution of Alnylam IP since such mimics would essentially be based on siRNA technology.

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By Dirk Haussecker. All rights reserved.

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