Monday, November 21, 2011

SNALP Works!

The long wait is finally over: Systemic RNAi delivery has been proven in Man. No 'ifs' or 'buts'. Alnylam just announced that Tekmira’s SNALP-enabled ALN-TTR01 reduced target transthyretin (TTR) protein levels in ATTR patients in a dose-dependent manner- without causing an elevation of liver enzymes or serious adverse event (SAE).

Following preliminary evidence in Tekmira’s TKM-ApoB study, this is the long-awaited moment where there is no doubt that successful systemic RNAi delivery has been achieved. With already about half a dozen SNALP-based programs in or very close to the clinic, this result de-risks a major segment of the RNAi Therapeutics pipeline and should stimulate further investments in SNALP-enabled RNAi Therapeutics development as well as provide a boost of confidence to the entire sector.

Today's presentation at the FAP meeting in Kumamoto can be found here. For a more detailed background on ALN-TTR01 for ATTR, please read yesterday’s blog entry.

In the phase I study (single-dose, dose-escalating), 5 patients received 1mg/kg, the highest planned dose. At this dose, there was a mean reduction of 41% in serum TTR levels from baseline. Despite the small patient numbers and natural TTR variability, this was stat significant at p=0.02 relative to placebo. While this level of knockdown may not seem dramatic and may or may not be useful for eventually achieving a therapeutic effect in ATTR patients, it is important to keep in mind that the other liver-targeted SNALP programs employ formulations that should be at least 10x more potent than the one used in TTR01 and probably also slightly better tolerated. As such, this was a stringent test for the safety and tolerability of SNALP technology and bodes well for the commercial potential of particularly the liver-targeted SNALP pipeline following TTR01, including TTR02 for which an IND is expected by year end.

The time course of TTR protein suppression in one patient provided a picture-book example of bona fide RNAi knockdown in Man. Consistent with the now extensive experience with SNALP in pre-clinical animal models, including non-human primates, this patient exhibited a rapid onset of knockdown (63% reduction at 48 hours) which became a peak knockdown of 81% a week after drug administration with 50% suppression still being observable 4 weeks after this single dose. There is no doubt that this was an RNAi-mediated response.

Preclinical repeat dosing studies have shown that in order to maintain the same level of gene suppression, one can reduce the amount of drug given at subsequent doses. This also means that perhaps giving patients two or three loading doses of 1mg/kg within a week or so may allow one to achieve the 70-80% knockdown with ALN-TTR01 not just in select patients.

Importantly, the safety profile seems to exceed even my own expectations. Unless Alnylam will reveal major immune stimulations in the upcoming conference call (at 8.30am Eastern Time; note added in proof 11/23: none were revealed), the only mild-to-moderate adverse reactions seemed to be infusion reactions that were experienced by 3 out of the 23 TTR01-treated subjects and which was well controlled by simply slowing the infusion rate. As the same was seen in the SNALP-enabled ALN-VSP02 study, it seems that this risk factor is indeed well manageable. What is more, even at the high dose of 1mg/kg, there were no signs of liver toxicity as evidenced by increases in liver function tests. As SNALP-RNAi for ATTR will be a chronic treatment, this should be the major safety focus in the future.

Whatever Alnylam decides to do with ALN-TTR01 (I expect it to remain on the shelf as a viable alternative pending TTR02 results), today represents a milestone in the history of RNAi Therapeutics and I do believe that we have seen the bottom in RNAi Therapeutics. Credit belongs to Alnylam for pushing ahead with the SNALP clinical studies. Alnylam has a truly gifted, and in many ways inspirational drug development team, but it is probably also this talent that has made them blind to what they are actually entitled to. My sympathies are therefore with Tekmira today as it has developed (and owns) the delivery technology that is turning out to be quite literally the savior of RNAi Therapeutics: SNALP. Clinical results eventually follow strong science.

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Barry said...

Thank you for all of the info you provide that enhances our opportunity to make good RNAI investment decisions!

Happy Thanksgiving to you and yours! God Bless!


Anonymous said...


I don't know if you had a chance to hear the podcast of a Barry Greene, Alnylam COO, interview on the Burrill Report. Link:
Greene indicated the focus of Alnylam's pipeline in the future will be delivery through the liver, presumably with LNP, for any targets that can be reached through that process. Any thoughts? Impacts for Tekmira in the future?

Dirk Haussecker said...

I noted the same and was surprised, given their own delivery activities that go beyond the liver. There are many ways to interpret this. If this becomes the new message, it would make for a good speculative blog topic.

Anonymous said...

Interesting!!! "Delivery through" is the interesting term. I wonder Greene meant to say that, it almost means liver is a processing plant and converting the complex for effective delivery to other target sites??? Is that what he meant?

Nick said...

Thanks for posting this Dirk. Can you please clarify; when you say, "There is no doubt that this was an RNAi-mediated response," is this based on the timeframe and degree of TTR knockdown? Or, in addition to this, the lack of liver toxicity as a means to verify that the knockdown is not due to inflammation (I am particularly curious about this because, based solely on some of the cell culture work, a negative control siRNA was used, but for the clinical trial I don't see a control siRNA explicitly stated as being the "placebo")? Or, did I miss somewhere in the FAP presentation that some 5' or 3' RACE analysis like the RONDEL study by Davis et al. (Nature, 2010) paper was done?

Dirk Haussecker said...

It is the time-course of the knockdown that is very typical of a bona fide RNAi knockdown induced by SNALP in the liver. A TTR knockdown by some funny inflammatory pathway (which I have not seen yet that this is an issue for the TTR gene) would a) be much more transient; b) more shallow.

You will NEVER see a control siRNA as a control. There are both scientific and ethical reasons for that. It would also be odd to expect that RNAi Rx should have such controls, but not demand this of small molecules, monoclonal antibodies, or essentially any type of drug. They all have numerous off-target effects if one only bothered to look at them. Many small molecules e.g. are selected largely based on target affinity, with off-target binding being only an after-thought. RNAi Rx by comparison is much more thoughtful about this (well, the 'good' companies at least). RNAi Rx also has the advantage that you can test for most off-targets pre-clinically simply by performing gene expression analysis.

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