Santaris Initiates First Clinical Trial for a MicroRNA Therapeutic

Another notable milestone has been reached in the history of small RNA-based therapeutics. Yesterday, Santaris announced that it had commenced a clinical trial for SPC3649, an LNA-based antisense molecule against miR-122 for the treatment of Hepatitis C. The phase I trial will be a double-blind, randomized dose-escalation study involving 48 healthy male volunteers.

MiR-122 has been shown to facilitate HCV replication as well as to have a role in cholesterol synthesis. Because of these potential applications and its expression in the liver, the tissue that can be best addressed with today’s systemic delivery technologies for nucleic acid-based therapeutics, miR-122 has become the favorite target for first generation microRNA-based development programs.

Santaris has made rapid progress and appears to be leading anti-miR-122 efforts, at least based on the published literature, with most prominently a recent Nature study demonstrating miR-122 antagonism in non-human primates, but also a nice transcriptomic study looking at changes in gene expression following miR-122 inhibition in mice. Santaris is using so-called LNA-“mixmers” which consist of a combination of interspersed DNA and LNA nucleotides and a phosphorothioate backbone and appear to act by sequestering the microRNA in the cytoplasm.

In mice, this LNA-antimiR-122 was quite a bit more potent than a competing technology developed originally by Alnylam and now owned by Regulus Therapeutics (‘antagomirs’) which were thought to induce the degradation of miR-122, possibly by RNase H. While these differences may also relate to the tissue concentrations and tightness of hybridization achieved by the various chemistries, my impression is that sequestration rather than RNaseH is the more promising approach to antagonizing microRNAs while for mRNA inhibition by antisense the opposite may be the case (e.g. morpholino versus gapmers). Moreover, the exact mechanism of action of the antagomir is still somewhat controversial, and I am curious to learn about the potency of antagomirs in vivo when formulated into SNALP-like particles.

A remarkable aspect of the LNA-antimiR-122 studies in non-human primates was the long duration of activity, up to 100 days after 3 loading doses of the antisense as judged by the lowering of plasma cholesterol. However, at this time point, the shift in the Northern blots which was taken to directly reflect microRNA sequestration, was not observed at this point. This could either mean that the Northern blot shift may represent an experimental artifact due to hybridization of antisense to miR-122 following sample preparation, and/or that the cholesterol lowering had persisted after LNA-antimiR-122 has ceased to sequester miR-122.

Of course, while the speedy technological progress is encouraging, there are a number of risks associated with this program. One is that it is unclear whether successfully inhibiting miR-122 in a chronic hepatitis C infection in man will have a meaningful effecgt on HCV burden. Compared to targets in RNAi Therapeutics trials, little is known about the actual role of miR-122 in HCV replication. Unlike in tissue culture liver cell lines which generally express less miR-122, miR-122 is a very abundant microRNA in the liver and may not be as rate limiting for HCV repliation in vivo. The argument, however, that this drug candidate lacks in vivo validation could be applied to a range of other HCV therapeutic programs, some of which have proven to be successful. The development of more convenient animal models for HCV infection over the next 5 years should change this and benefit not only the development of miR-122-based HCV therapeutics, but particularly RNAi-based HCV antivirals.

The Nature studies have also shown that anti-miR-122 may have limited utility for the treatment of hypercholesterolemia as its inhibition downregulated the “good cholesterol” even more than it did the “bad cholesterol”. On the other hand, given its abundance in the liver, it is likely that other indications for miR-122 antagonism will emerge and for which the Santaris phase I trial could be leveraged.

As far as the business strategy is concerned, maybe Santaris ought to solve the IP issues surrounding miR-122 for HCV once they initiate HCV-specific studies, as related IP fundamental to such an application has been exclusively licensed to Regulus and may thus limit the partnership value of this promising program.