Thursday, February 2, 2012

Alnylam Squares Off with Dicerna

Dicer-substrate RNAi triggers are often seen as a (probably cheaper) alternative to Tuschl siRNAs. Initially, based on a small sample size, it was even claimed that Dicer-substrates had superior potencies and prolonged durations of knockdown. Of course, Alnylam, considering Tuschl siRNAs to be its property, has recognized this and regards Dicer-substrates along with its corporate champion, Dicerna, a competitive threat. Although Alnylam has long claimed that Tuschl siRNAs are preferable over Dicer-substrates for various reasons, until now it has largely been Dicerna’s word against Alnylam’s word.

This has changed with a publication by Alnylam in the journal RNA which provides a comprehensive, and I believe fair comparison between the two structures (Foster et al 2012). Comparing large numbers of RNAi triggers both in vitro and in KC2-SNALP animal studies, the study shows that Tuschl siRNAs and Dicer-substrates are essentially equivalent in terms of potency and the duration of knockdown. However, when these structures are compared in terms of innate immune stimulation, Tuschl siRNAs had a very slight edge when unmodified sequences were tested. Of course, it is well recognized that chemical modifications are required and very effective at abrogating these immune responses. When these were applied, the potencies of Dicer-substrates were more likely to suffer than those of Tuschl siRNAs, and in a few cases innate immune stimulation was not entirely abrogated. The former can be explained by the additional requirement for the Dicer processing step which can be affected by chemical modification.

Overall, this means that it may take a little bit more effort to identify a suitable Dicer-substrate clinical development candidates, and there could be an increased risk in encountering unforeseen innate immune stimulations in humans. On the other hand, the study also suggests that for some genes it may be possible to find more potent RNAi triggers with Dicer-substrates, so that in an ideal world one would keep an open mind. I should also add that, not discussed in this paper, there are also other considerations which may favor one structure over the other.

Unfortunately, we are not living in an ideal RNAi Therapeutics world, but one in which patent trolls and IP freeloaders abound. The timing of the comparison study is particularly ironic since the freedom-to-operate of US-based Alnylam is very much in doubt, thus increasing the attractiveness of Dicerna's offering. This is because of the recent issuance of the Baulcombe patent in the US which has put essentially all the Tuschl siRNA structures, bar one, in a straitjacket. Until Baulcombe is sorted out, all buy-out and partnering efforts will be on hold, and if Merck gets exclusive rights to that patent...then Alnylam may well be toast.

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By Dirk Haussecker. All rights reserved.

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