2011 promises to be a year of rich clinical data flow for RNAi Therapeutics. Results from clinical trials of ALN-VSP02, ALN-TTR01 (both Alnylam), Atu-027 (Silence Therapeutics), and TKM-PLK1 (Tekmira) in particular will be important in shaping the perception of RNAi Therapeutics as an investable drug modality. Following disappointment that Silence Therapeutics was not able to receive an attractive offer following the 'approach', the Company’s announcement this morning that it will provide an update, today at the Annual BIO CEO & Investor Conference, on the phase I trial of Atu-027 for solid cancers, fosters speculation that Silence Therapeutics rejected any bid as undervaluing it because of impending positive trial data and that the better game plan may be to raise capital at elevated prices following positive market reception of the trial data. Clearly, at this point Silence’s future depends to a large degree on Atu027 and the stakes are high.
This is an opportunity for me to urge the pure-play companies to treat retail investors fairly in upcoming financings. Believe it or not, with perhaps the exception of Alnylam, it is retail investors that keep these micro-cap companies alive. Financings of the type that Marina Biotech transacted last week are simply not acceptable: the underwriter and solicited large investors get hefty fees, discounts, and warrants which means that shares will be flipped for a quick profit and dumped onto retail investors which do not get the opportunity to participate on equal terms. In the end, these companies will have squandered the goodwill of their most important constituency as the deals will be perceived as a mutual back-scratching exercise to keep the biotech gravy train going while non-privileged investors lose their investments.
Despite its wide-spread practice, this does not have to be so. For example, in a recent financing by gene therapy company Oxford Biomedica, existing shareholders were given the opportunity to participate in the follow-on offering at the same (very steep) discount as the institutions. To be clear, this deal is still to be considered unfair in that the option to participate still did not allow retail investors to avoid substantial dilution while larger shareholders were given this opportunity and even could increase their stakes at the much reduced prices, on top of the obvious insider trading the week before the financing (but that’s a more general problem, I guess). So to the Tekmira’s, RXi’s and Rosetta’s of the world: if you have to issue shares, please consider your most loyal constituency and treat them fairly.
Early January update on ALN-VSP02
Since I would like to shift the focus of this blog towards the clinical developments in RNAi Therapeutics, a quick re-cap of the data presented by Alnylam a month ago which showed that the LNP-delivered ALN-VP02 achieved therapeutically relevant tissue levels and promoted RNAi-mediated target cleavage in the liver of cancer patients. This is similar to data published in Nature a year ago by Calando with their RNAi compound for solid cancer.
Certainly, the 5’ RACE assay used to determine the RNAi-mediated mechanism is (still) a non-quantitative technology and as such can only tell whether RNAi has occurred or not. However, in practice, this assay is not without its challenges even under standardized tissue culture conditions, so the fact that cleavage could be detected in a clinical setting where sampling issues were especially challenging is an important finding.
The other important piece of new data presented was on the drug accumulation in the liver where about half of the reported values well exceeded the 1ng/mg threshold that Alnylam reported to have 50% Factor VII knockdown efficacy by a log or so (Landesman et al. 2010). Although the dose responsiveness of siRNA accumulation in the liver was a bit shaky, possibly due to sampling challenges, the data also suggests that LNP delivery efficiency to rat and human liver may not differ by too much. It has to be said, however, that ALN-VSP02 is a first gen LNP formulation whereas the 1ng/mg threshold was established with a 2nd gen formulation. Moreover, the 50% threshold is always target gene specific and will differ between Factor VII and the ALN-VSP02-related VEGF.
In sum, the data supports that ALN-VSP02 may have a therapeutically meaningful impact in a subset of patients should maximally tolerated dosages of 1.25mg/kg or above be achieved and the genetics play out as hoped. We should not have to wait much longer for more clarity on the efficacy of ALN-VSP02 given that Alnylam has collected many more biopsies and should have conducted additional types of assays (e.g. RNA knockdown; mitotic spreads for spindle abnormalities expected from KSP knockdown etc) than were reported on.