Thursday, June 27, 2013

Alnylam Reports Potential Advance in SNALP Safety

One concern with the use of any drug is that it ought to be eventually eliminated from the body.  This is a particular issue with nanoparticulate drugs for which efficacy have been the main design criterion.  To address biodegradability for Tekmira's SNALP delivery, a technology that routinely involves un-natural lipids which may not be easily biodegradable, Alnylam has just published on SNALP lipid-derivatives containing readily degradable ester bonds.   The results show that such SNALPs are rapidly eliminated from the body and indicate that their use can increase the therapeutic index.

In the paper, Maier and colleagues took the (once fiercely contested) MC3 lipid, which is part of the ALN-TTR02 formulation for which phase II results are imminent, and tested whether the incorporation of ester bonds at various positions in the lipid tail would retain knockdown efficacy.  The ester bond was chosen because it was predicted to maintain the MC3 lipid geometry and can be degraded by the ubiquitous esterases in the body.  Consistent with the idea that the apparent pKa of the head group is important for efficacy, positions were identified that left the pKa, and consequently knockdown activity in mice largely unchanged (ED50 of <0 .01mg="" kg="" o:p="">

To confirm the prediction that the resultant SNALP particles, economically formulated with microfluidics, were less stable than their parent particles, plasma and tissue elimination rates as well as the generation of turnover intermediates were tested.  Indeed, the new SNALP particles were much less stable.

What is more, at doses of more than 3mg/kg SNALP-siRNA there was a trend towards slight elevations with the MC3 SNALP, but not with a derivative.  The authors stopped short, however, to test concentrations at which much more toxicity can be seen.

The major downside of the study, however, was that in non-human primates, the new SNALPs had less activity than expected for MC3 SNALPs.  At 0.3mg/kg, the dose at which 80-90% knockdown was observed in the phase I study of ALN-TTR02, only a 70% TTR knockdown was achieved.  Nevertheless, it is likely that other biodegradable SNALPs optimized for primates will achieve MC3-type efficacy.    

I do not expect SNALP biodegradability to become an issue for the upcoming ALN-TTR02 phase II results.  The longer-term dosing experience with cancer RNAi Therapeutic ALN-VSP02, however, suggested that there could be spleen toxicity with extended dosing and at higher dose levels.  The last word from Alnylam on that issue had been that the spleen toxicity was due to on-target activity.   The paper by Maier et al., however, leads me to believe that both explanations are still on Alnylam’s table.   


Anonymous said...

Interesting paper. Did the authors mention whether MC3 was biodegradable?

Dirk Haussecker said...

No, they did not test it. Overall, it was strange that a lot of obvious direct comparisons with the parent MC3 SNALP were missing.

experiencedmentor said...

They probably didn't compare to the degradability of MC3 because they didn't want to fuel the next lawsuit. While reading your blog, I immediately began wondering whether "fruit of the poisoned tree" came into play. Can we be blamed if we no longer trust a cheating spouse?

Anonymous said...

This seems old news to me. Alnylam had reported data on reLNP last year before litigation was settled. I think it was Alcana who had developed reLNP. Wasn't Tekmira looking to licence some technology from Alcana? Could it be reLNP? What happened to Tekmira's plan to cross licence some technology from Alcana?

Dirk Haussecker said...

Yes, I also believe that Alcana played a large role in the invention of this, but if you look at the patent application, they are still missing (just Alnylam people):
I attribute this to the fact that this patent app had been filed pre-settlement.

Anonymous said...

Hi Dirk,

just have a look to this - already from 2011:



Unknown said...

Dirk ...

I might be mistaken, but you seemed to be in love with Tekmira the past couple years. After visiting your blog today, it seems that your flame for Tekmira has dissipated markedly ... an affinity for Arrowhead casts a shadow on Ol' Tekmira. Have u and Tekmira parted ways? ... or does she simply bore you these days?
Apologies in advance if I am mistaken.

Anonymous said...

Ill admit I've thought the same thing Dirk. Its of course a private matter for you.. but heck this is the Ill ask anyway as well.

No more love for TKMR ?

Having said that Im in huge arwr AND tkmr.

Dirk Haussecker said...

Tekmira vs Arrowhead.

Arrowhead has made much progress over the last year or so on developing scalable single-molecule, high-potency DPCs. In addition, they are building a HepB franchise that could set a new standard in the treatment of a significant disease affecting over 300M globally. I am also curious as to their next development program which they should announce in this half. These days, the right target/indication and predictive preclinical datasets can command large increases in market caps.

Pipeline progress with Tekmira on the other hand has been slow which has been my main frustration. Of course, this is the result of the protracted battle with Alnylam and them essentially hibernating R&D pending the outcome.

I certainly wish Tekmira and their shareholders well, and in my mind it still has one of the clinically most proven delivery tech and most beneficial risk/rewards overall, also in light of the Talon acquisition yesterday, but Arrowhead Research may be the most compelling opportunity among the publicly traded RNA Therapeutics companies, if not the pharmaceutical sector. The stars have aligned, all the shareholders need now are scientific results in line with expectations and some luck with the timing of their financings.

Anonymous said...

"These days, the right target/indication and predictive preclinical datasets can command large increases in market caps."
and exist in the northern hemisphere.

80 cured monkeys and HCV clinic starting this year, yet not a bump in the Benitec share price.

Anonymous said...

"I certainly wish Tekmira and their shareholders well..." Does that mean you are no longer a Tekmira shareholder?

NDx said...

80 cured monkeys (HCV) with Benitec's ONE SHOT CURE? Sounds impressive.
The SPP (shareholder private placement) discount expires on July 29th. This represents ~25% discount on purchases up to $10,000.

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