Thursday, August 29, 2013

Tekmira’s SNALP Technology Once Again Highlighted in High-Profile Medical Literature

It is a good sign to see RNAi Therapeutics appear in high-profile medical journals with increased regularity (see also Tekmira’s TKM-EBOLA in The Lancet and Arrowhead’s CALAA-01 in Nature).  This reflects the fact that RNAi has moved well past being a laboratory tool and is coming closer to first regulatory approvals.  The TTR amyloidosis program sponsored by Alnylam and critically enabled by Tekmira’s SNALP delivery technology is arguably spearheading this effort and results from the ALN-TTR01 and ALN-TTR02 studies were published last night in the New England Journal of Medicine (Coelhoet al.).

As most of you know, the top-line results from ALN-TTR01 in November 2011 was unambiguous proof of RNAi-mediated knockdown of a liver-expressed gene (~40% median peak knockdowns in the highest dose; SNALP Works!), with top-line results for ALN-TTR02 (knockdowns in the 90% range) in the summer of 2012 translating it from proof-of-concept for RNAi in Man to a medically highly relevant approach for a disease of high unmet need, TTR amyloidosis.   

The RNAi mechanism of action of the knockdown was confirmed both by showing no TTR knockdown with an unrelated siRNA (but same delivery) and by demonstrating cleavage sites by 5’ RACE as predicted by the RNAi trigger sequence.  Notably, the assay was performed on RNA harvested from simple blood draws (‘exosomes’).

In terms of adverse events, there was also little new in the publication: dose-related infusion reactions were the most significant adverse events and were readily managed by slowing the rate of infusion. Importantly, at doses up to and including 0.3mg/kg, the current dose in the later-stage studies with ALN-TTR02, no such infusion reactions have been observed. 


The most notable part in the publication was actually what was missing from it: nowhere throughout the main text nor in the countless pages of supplementary material was it mentioned that the critical delivery technology had been developed by Tekmira.  Based on the ongoing  arbitration over a milestone payment related to liver cancer drug candidate ALN-VSP02 which was triggered by Alnylam refusing to behave like an adult, you can rest assured that this was no innocuous omission and that Alnylam is intent on applying pressure on Tekmira wherever it can.   

10 comments:

Anonymous said...

Dirk, the press release I read did mention that Alnylam licenses delivery technology from Tekmira.
What bothers me is that the important advance of SNALP II was primarily an improvement of SNALP I by Alcana, a subsidiary of Alnylam. It is also my understanding that many of the scientists at Alcana were fired by Tekmira, after a merger, even though they were primarily responsible for the development of SNALP I. Please correct me if I am wrong.

Dirk Haussecker said...

The line at the end of the press release was pursuant to the settlement agreement. Alnylam wants to be seen acting according to the letter of the agreement while clearly violating the spirit thereof.

Experiencedmentor said...

Anonymous, If I'm not mistaken, you're basically asking the same questions that were settled by Alnylam paying up and giving back with no admission of guilt. ;)
I.e. The whole damned debate over ownership of MC3.
I LMAO at management's minimalization of Tekmira's role in their success.
Regards, Xman

Experiencedmentor said...

http://investor.tekmirapharm.com/releasedetail.cfm?ReleaseID=638462
Injunction against former Alcana employees.

Anonymous said...

Nothing is as it seems in these matters.. there's always 2 sides to every story.. What if the scientists referenced were Tekmira Staff.. Took the IP from Tekmira, started Alcana and was selling the acquired IP to Alnylam as their own products? Whether the scientists developed it or not isn't in dispute but it was done so while they were employed at Tekmira is the issue.

Anonymous said...

Dirk, look at this
http://jid.oxfordjournals.org/content/early/2013/08/29/infdis.jit465.abstract

Anonymous said...

Dirk,

Do you perhaps know if the TTR02 phase I premedication regimen posted on page 37 of 72 of the Coelho et al NEJM article supplementary file as summarized below is the same regimen for the TTR-02 phase II?

All subjects were premedicated prior to dosing with ALN-TTR02 or placebo in order to reduce the potential for an infusion reaction (IR). Premedication was as follows according to what was published in the trial protocol file of the NEJM article…

 Oral 8 mg dexamethasone administered the evening before dosing and 20 mg 30 to 60 minutes prior to start of infusion of ALN-TTR02 or placebo;
 Oral 500 mg paracetamol the evening before dosing and 30 to 60 minutes prior to the start of infusion of ALN-TTR02 or placebo;
* Oral H2 blocker (i.e., ranitidine 150 mg or famotidine 20 mg or equivalent other H2 blocker dose) the evening before dosing and 30 to 60 minutes prior to start of infusion of ALN-TTR02 or placebo;
 Oral H1 blocker, 10 mg cetirizine (hydroxyzine 25 mg or fexofenadine may be substituted if subject does not tolerate cetirizine) the evening before dosing and 30 to 60 minutes prior to start of infusion of ALN-TTR02 or placebo;

Then in the Methodology section on page 11 of 72 it is stated:

All subjects receive oral premedication with dexamethasone, paracetamol, and histamine receptor antagonists (H2 and H1 blockers) the night before (Day -1) and also in the morning (Day 0) 30-60 min prior to the dose of ALN-TTR02 or placebo.

Anonymous said...

Yes, the settlement between Aln. and Tek. was based on the ownership of the technology by Tek. As a share holder of both though, I am worried that Tek. does not have the scientists to advance its delivery technology in this rapidly evolving field. In an analogy with "Breaking Bad", it appears that Tek. fired Walter White, and kept Jessee.

Experiencedmentor said...

Politely and strongly disagree. Tekmira has freeze dried their product for long shelf-life, perfected their manufacturing, evolved their product, and is advancing their own sub-Q (described as far more potent by Dr. Murray).

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