Alnylam Pharmaceuticals Inc ALN-APP Call Transcript

The following is excerpted from the question-and-answer section of the transcript.

Question: Eliana Rachel Merle - UBS Investment Bank, Research Division - Analyst : Just in terms of the dose optimization, when you say that dose exploration in Part A is still continuing, you're already seeing some pretty deep knockdown in the CSF, can you just elaborate on what you're looking to optimize? And if you're looking at lower doses or higher doses, in the further Part A dose optimization and the latest thinking on sort of what the ideal degree of target knockdown of APP is? Pushkal P. Garg - Alnylam Pharmaceuticals, Inc. - Chief Medical Officer and Executive VP of Development & Medical Affairs Yes, Ellie. So I think, as I said, part of our obligation and what we want to do for any Phase I study, and certainly, as we're bringing in our first RNAi therapeutic in CNS, it's really to characterize the dose response curve. And so we're going to look at a range of doses to really fully characterize what that looks like. It will be important, as we said, to really understand pharmacokinetics, pharmacodynamics -- we're going to want to look at durability across a range of doses. And we're also going to want to get long-term safety data. So all of those things are enabled in Part A with the single dose and particularly in light of the data that we're seeing here today. So we'll continue Part A to do that. In terms of the next steps will then be to actually -- we can't say today exactly what doses we'll be taking into the subsequent studies. As I said, we are in the therapeutic range that we were hoping to get to, to explore these hypotheses in patients with Alzheimer's disease and with CAA. And we'll provide further details as the data mature and as we develop our plans further.

Question: Myles Robert Minter - William Blair & Company L.L.C., Research Division - Analyst : Congratulations certainly looks impressive data on the clinical side here. So congrats on that. Just got to get back to the chronic nonclinical tox here. Have you seen any signs of drug accumulation specifically relative to a GalNAc conjugate? I just know that you're putting a fatty acid conjugate here. So curious about drug accumulation. And then also, is the safety margin based on the no adverse effect levels or no observed adverse effect levels? Are they materially different for a C16 conjugate versus GalNAc, just given you've got so much history with the GalNAc conjugates here?

Question: Myles Robert Minter - William Blair & Company L.L.C., Research Division - Analyst : Just whether you're observing materially different safety margins based on no observed adverse effect levels between C16 and GalNAc because you know so much more about GalNAc.