Thursday, December 13, 2007

Breaking News: Alnylam Reports on the Safety of Inhaled ALN-RSV01

The eyes of the RNAi Therapeutics world are on Alnylam as they are approaching critical clinical milestones for their lead development program ALN-RSV01 for the treatment of respiratory syncytial virus infection.

Before initiating phase II studies in naturally infected adults, the company seeks to gather more information first on the pharmacodynamics of RSV-01 in an experimental infection model where the siRNA is administered by nasal administration (top-line data expected early 2008; company reported patient enrollement complete now), and second from the safety of an inhaled version of RSV-01, the eventual route of administration, in healthy adult volunteers. Results from the latter phase I trial were just reported at the 18th Annual Drug Delivery to the Lungs meeting in Edinburgh, Scotland.

This study included 109 subjects, 71 of whom received siRNA either in a single dose (0.1mg/kg to 3mg/kg) or multiple doses (0.01mg/kg to 0.6mg/kg once daily for 3 days). The safety data were encouraging as there were no serious adverse events reported. Nevertheless, the press release mentioned a “mild to moderate flu-like adverse event” at the higher dose group in the single-dose arm. While this is pure speculation, this reminds me of the fact that RSV-01 is an unmodified siRNA and should therefore be more prone to elicit cytokine responses, an area Alnylam by the way is taking quite seriously as they actively seek to recruit scientists working in the field of immunostimulatory nucleic acids, which by the way may be accelerated by the recent acquisition of Coley by Pfizer. Indeed, I would not be surprised if part of the remarkable antiviral efficacy of RSV-01 is based on the siRNA acting as an isiRNA, the term with which Gunther Hartmann from Bonn describes small interfering RNAs with immunostimulatory properties.

In order to find the best therapeutic window, Alnylam has also been working on comparing the pre-clinical efficacy of single-dose versus multiple dose RSV-01. Gratifyingly, for the same amount of total siRNA administered, multiple dose administration was significantly more potent. This means that a good strategy of increasing antiviral efficacy while at the same time decreasing the risk of eliciting flu-like effects may be to choose multiple dose administration for the phase II studies of naturally infected patients.

Another interesting point mentioned in the press release is that siRNA delivery as evidenced by siRNA plasma levels was remarkably efficient compared to some pre-clinical data. Well, I guess had they not observed siRNA in the plasma, then the press release would have stated that avoiding systemic exposure was an additional safety feature of RSV01. This is how the phase I nasal data were interpreted. In any case, this is reminiscent of recent data for systemic siRNA administration to the liver where the efficacy and duration of RNA silencing in non-human primates was above expectation based on small animal experience and may have in fact contributed to the side-effects observed at the higher doses. But before actual plasma levels are reported, it is premature to speculate whether systemic siRNA administration by inhalation should be considered for other indications.

Overall, while the results indicate that the development of RSV-01 is not without risk, Alnylam continues to demonstrate that by conducting a wide-ranging scientific program supporting the compound, it will allow them to choose the most promising development path. The apparently efficient delivery efficacy via nebulizer makes me quite bullish about the antiviral efficacy of ALN-RSV01 so that safety should be the focus of future studies.

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By Dirk Haussecker. All rights reserved.

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