Wednesday, September 11, 2013

Alnylam Comments Suggest SubQ Tech Failed to Achieve Efficacy Goal

At today’s Morgan Stanley Healthcare Conference, the President and COO of Alnylam, Barry Greene, told the audience to assume that it took a dose of 5 to 10mg/kg of ALN-TTRsc to achieve the 80% knockdown that had been reported in July.  This suggests that ALN-TTRsc has failed to meet the stated goal of limiting the subcutaneous injection volume to 1ml or less as this is predicted to correspond to a dose of 2.5mg/kg.

If it holds up, this would have a number of important implications.  Firstly, it would affect the profile of ALN-TTRsc itself.  I don’t believe it to be necessarily terminal in a disease like the FAC form of TTR amyloidosis for which ALN-TTRsc is being developed.  Nevertheless, squeezing 2 or even 4ml into the subcutaneous space, or alternatively administering multiple 1ml shots in one sitting, could put some needle-phobic patients off, especially as TTR amyloidosis is set to become a competitive marketplace.

Secondly, such doses would not bode well for Alnylam’s GalNac delivery platform on which the company has pinned its future.  For example, one of the big draws of the hemophilia drug candidate ALN-AT3 which is about to enter clinical development was supposed to be its subcutaneous, instead of intravenous route of administration. However, as I speculated last week (Alnylam's GalNAcs as Cholesterol-siRNA 2.0), I believe ‘GalNac-siRNAs’ have advanced somewhat since ALN-TTRsc with the addition of lipophilic moieties such as cholesterol and the jury could therefore still be out regarding the capabilities of the GalNac delivery platform.


And finally, a weak potency of ALN-TTRsc would further increase the value of competing delivery technologies, especially SNALP (Tekmira) and the subcutaneous version of DPCs (Arrowhead Research). In fact, if the full results that are to be presented in about a week at the American Heart Failure Meeting confirm the 5-10mg/kg doses, it would explain why Alnylam chose not to have ALN-TTRsc compete with and potentially replace SNALP-based ALN-TTR02. Instead, the intravenous ALN-TTR02 will likely be applied to the earlier onset, more rapidly progressing form of TTR amyloidosis (FAP), whereas the subcutaneous ALN-TTRsc will be used for the more slowly progressing, later onset form of the disease (FAC).

10 comments:

Xman said...

Gee whiz.
Sounded like braggadocio all along to me. The sooner they mend fences with our tiny Tekmira, the better. We (Tekmira) aren't out to destroy them (Alnylam). The reverse cannot be said.

Xman said...

I still laugh when I remember J.M. declaring Tekmira's delivery as, "The Gold Standard."

Anonymous said...

sorry to disappoint but this is a non-issue
-neither buyside nor patients nor docs will care about this in setting of life-threatening diseases with no other good options
-thanks though

Anonymous said...

Your blog is totally distorted and gives a biased opinion. TTRsc replicates what they have found in NHP and so it is not a failure at all but it is a great success as it validates its GalNAc delivery platform. If you look at a slide from their presentation, they had achieved >80% knockdown of TTR in NHP at a dose of between 5 and 10mg/kg. So if they achieve the same kind of efficacy in human, then it can not be called a failure as your myopic view indicates. TTRsc never was their potent compound since it was their first drug in the clinic based on GalNAc delivery platform. They have substantially improved the potency of GalNAc since TTRsc. AT3 needs only 0.5mg/kg of weekly dosing to achieve 90% gene silencing in NHP. So it should achieve the same degree of efficacy in humans based on validation by TTRsc. Alnylam can always introduce a more potent version of TTRsc if there is a need for it in the future. But even a current version of TTRsc is potent enough to compete with what ISIS has in the market. Remember, ISIS TTRRx can knockdown only 70% of TTR with their current drug in the market, so Alnylam has nothing to worry about and TTRsc will continue its advancement through the clinic to your disappointment.

Xman said...

What you anonymous posters are saying is pure speculation. TTR02 is proven science in man.

You have no idea what sort of side effects or adverse reactions may occur in humans at the doses you mention.

The same can be speculated about Tekmira's SubQ under development.

Anonymous said...

XMAN,

TTR02 is not as great as you claim it to be. It has to be given with corticoid steroid and even with that they had an infusion reaction at 0.5 mg/kg so they had to limit the dose to 0.3 mg/kg. They were also forced to reduce the frequency of administration to make it efficacious. TTR02 has borderline potency at best and it is not proven until it gets FDA approval.

Anonymous said...

Xman said...

I still laugh when I remember J.M. declaring Tekmira's delivery as, "The Gold Standard."

Who is J.M.? Thanks.

Experiencedmentor said...

J.M. Is Maraganore, Alnylam CEO; a proven liar. Xman

Anonymous said...

"...it's hard for us to say very much about ongoing litigation other than we don't comment about ongoing litigation, but I think what we can say is we are as convinced as ever that the suit that was brought against us by Tekmira is completely without merit, is baseless and we will defend ourselves fully in that suit and we will be meritorious."

Anonymous said...

Was it "the gold standard" 3~5 years ago must be "the gold standard" at these days?

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