Wednesday, June 6, 2012

ASCO for RNAi Therapeutics in Line with Expectations, but Curious Nevertheless (Part I- ALN-VSP02)


Alnylam and, finally, Silence Therapeutics have by now disclosed the latest results from the phase I studies of their RNAi Therapeutics candidates, ALN-VSP02 and Atu027, for solid cancers at this year's ASCO.  As the studies have thus more or less come to a conclusion, one has to say that, although clearly nothing spectacularly positive came out of them, these two candidates warrant further evaluation and their safety and pharmacokinetic profiles augur well for the other candidates based on the same SNALP and AtuPLEX delivery platforms.  

With most of the results known, I will therefore focus my discussions of the RNAi Therapeutics ASCO 2012 on the new insights and include some comments on recent corporate maneuvers of the companies involved.
  

ALN-VSP02 Provides First Insights into SNALP Repeat Dosing (and yes, SNALP technology belongs to Tekmira and AlCana is an instrument of Alnylam)

The extension study with ALN-VSP02 that was the subject of Alnylam's ASCO poster presentation included 7 patients with cancers involving the liver that had been rolled over from the main study (results presented a year ago here) and provided more insights into the long-term safety/tolerability of SNALP delivery technology.  It was good to see that even very sick patients could be given 1st generation SNALP formulations at dosages of 0.7mg/kg or more every other week for quite prolonged periods of time (up to 2 years).  As the phase I results with ALN-PCS02 indicate, such concentrations will allow for solid gene knockdowns in normal liver cells with some of the improved SNALP formulations. When I first got excited about SNALP delivery technology 6 years ago, one of the main risks that I saw was around repeat-dosing including antibody formation against the PEG component and other immune stimulations upon repeat dosing.  On that front at least, the ALN-VSP02 study, especially based on the PK data, was a clear pass. 

Certainly, there remains controversy around whether the precautionary transient pre-treatment with immunosuppressives (e.g. corticosteroids) that was applied here and may have aided in achieving these results is a realistic product feature of a RNAi Therapeutics.  As I have said before, personally I believe that for severe indications such as many cancers, this is mostly a minor practical inconvenience; it may, however, impede their adoption for less severe conditions in larger patient populations.

One new safety-related item worth mentioning is the reported effect of prolonged ALN-VSP02 administration on spleen size and Alnylam’s interpretation thereof.  As we know, the spleen is a non-essential organ in humans and the vast majority of us would not notice if we were without one.  Thus, the reduction in spleen size observed in this trial with prolonged treatment was not considered a severe adverse event or dose-limiting toxicity.  Spleen toxicity would not really be surprising for nanoparticle-formulated drugs such as ALN-VSP02 (and also phosphorothioate-based oligonucleotide therapeutics) as they are often observed in animal studies.  I therefore considered it possible that it could be a platform-based toxicity.  

Alnylam, however, put forward a more optimistic interpretation by claiming that it is more likely an on-target toxicity, meaning that knockdown of the proliferative gene KSP in the spleen was responsible for it.  Considering the biodistribution of SNALP and the recently highlighted data on SNALP and other LNP-mediated gene knockdown in immune cells that are enriched in lymphoid organs such as the spleen, this is certainly a plausible explanation as well and is further supported by the new monkey data presented at ASCO.  Adding to this confusion is the fact that ‘Alnylam’ has been developing 3rd generation SNALP technology to ameliorate spleen toxicity.  So if the spleen shrinkage was no general effect, why bother with 3rd generation?

Aside from these scientific developments, including a very nice complete response by RECIST in an endometrial cancer patient with multiple liver mets which had already started to respond during the main phase of the trial, my interest was equally piqued by the fact that the press release by Alnylam lacked any mention of the fact that ALN-VSP02 involves critical delivery technology by Tekmira and that key IP of a siRNA ingredient may also well belong to Tekmira, pending the outcome of an Interference proceeding in the US.  If you look for even more support for Tekmira’scontention that Alnylam has been aiming to marginalize the company, and as yet another of Alnylam's main rivals, Marina Biotech, looks like it is going out of business (my bet is that they will participate in some kind of consolidation to survive in another form), look no further.  The PR is only rivaled in silliness by the misleading one issued by Alnylam’s Canadian subsidiary, Alnylam Canada (AlCana), two weeks ago on the status of the Tekmira-Alnylam showdown in Canada (the misleading part being in quite obviously trying to suggest that the Canadian courts reversed all earlier decisions that went against AlCana, including handing over the allegedly stolen documents back to their rightful owners, Tekmira). 

But the real clincher of that PR was the following: despite of pointing out the elephant in the room, namely that the Canadian proceedings are part of a wider confrontation between Tekmira and Alnylam, Alnylam Canada hilariously and awkwardly at the same time failed to mention Alnylam at all- in the entire press release!  If they believed that this would make AlCana, a de facto academic lab financially supported and strategically instructed by Alnylam all along, any more independent of Alnylam, try again (note: a key element in the litigation is that Alnylam established an ‘independent’ company- AlCana- to gain insights into key Tekmira trade secrets and know-how thereby minimizing legal liability if caught).  More unintended humor was provided by stating that the Canadian case had been post-poned until resolution of the US case between the ‘corporate’ parties, implying that neither AlCana nor the courts consider AlCana to be a true, independent corporation.  Although I have not had the chance to read the primary court documents myself, the decision strongly suggests that the Canadian court took pity on the AlCana scientists and does not like to see them being thrown under the bus by their de facto employer, Alnylam.

In part 2, I will cover the latest data on Atu027 and share some thoughts on the confusing corporate strategies of that company.

4 comments:

Anonymous said...

Dirk,
As you indicated in your previous blog on the possibility of innate immune response as a potential mechanism for ALN-RSV. Do you know if Alnylam ever demonstrated the mode of action such as siRNA mediated cleavage in patient samples of either one of those two clinical trials? or what kind of dose were actually delivered to tumor?

Unknown said...

Correct me if I'm wrong: Alnylam was able to see 5' RACE product for one of the targets (VEGF) from the phase I VSP02 trial in 3 of 15 needle biopsy samples.

Anonymous said...

Great. Can you kindly locate the reference? Greatly appreciated.

Dirk Haussecker said...

Slides 19 and 20 of last year's ASCO presentation: http://www.alnylam.com/capella/wp-content/uploads/2011/06/ALN-VSP-PhI-ClinicalStudyResults-ASCO2011.pdf

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