On Monday, Alnylam revealed an update on their lead ALN-TTR02 drug candidate for the treatment of the FAP form of TTR amyloidosis. Given that this could be the first commercially meaningful RNAi Therapeutics to hit the market, a lot of attention is being paid to its progress in the clinic. Success and failure of this program are expected to have widespread repercussions for the RNAi, if not Oligonucleotide Therapeutics field.
Importantly, the data from the phase II open-label extension study provided strong evidence that the underlying SNALP LNP delivery technology, licensed from Tekmira Pharmaceuticals, is safe and well tolerated with 19 of the 27 patients involved having now received ALN-TTR02 once every 3 weeks for at least 6 months. After 282 doses administered, no drug-related serious adverse events were seen with infusion-related issues as expected the main source of adverse events. Notwithstanding the 8 mild flushing events and infusion reactions, there have been no drop-outs in the study so far.
On the efficacy side, ALN-TTR02 continued to produce robust sustained 80-90% knockdowns with a trend towards increased knockdown efficacy with prolonged dosing. This knockdown certainly puts ALN-TTR02 ahead of the competitor antisense drug from ISIS and GSK (ISIS-TTRRx) which is expected to be in the 70% range, but is probably ahead in terms of patient enrolment in their pivotal study.
The results presented at the ANA conference had been widely anticipated because it was the first time that Alnylam revealed measures of therapeutic efficacy beyond the gene knockdown. Accordingly, at the 6-month time-point patients treated with ALN-TTR02 exhibited less neurological declines as would have been expected from the Natural History of the disease. Unfortunately, in the absence of hard biomarker evidence indicating improved neurological and, for a subset of patients, cardiac functions, the apparent improvement in the well-being of the patients (mNIS+7) could easily be attributed to the open-label nature and the relatively early time-point of the study.
Therefore, despite of the fact that shares in Alnylam increased 20% on the results and the provider of the delivery technology, Tekmira, barely budged on the news, the most important take-home from the results was that SNALP LNP delivery technology and indeed extended robust RNAi has a remarkably good safety profile.
Importantly, the data from the phase II open-label extension study provided strong evidence that the underlying SNALP LNP delivery technology, licensed from Tekmira Pharmaceuticals, is safe and well tolerated with 19 of the 27 patients involved having now received ALN-TTR02 once every 3 weeks for at least 6 months. After 282 doses administered, no drug-related serious adverse events were seen with infusion-related issues as expected the main source of adverse events. Notwithstanding the 8 mild flushing events and infusion reactions, there have been no drop-outs in the study so far.
On the efficacy side, ALN-TTR02 continued to produce robust sustained 80-90% knockdowns with a trend towards increased knockdown efficacy with prolonged dosing. This knockdown certainly puts ALN-TTR02 ahead of the competitor antisense drug from ISIS and GSK (ISIS-TTRRx) which is expected to be in the 70% range, but is probably ahead in terms of patient enrolment in their pivotal study.
The results presented at the ANA conference had been widely anticipated because it was the first time that Alnylam revealed measures of therapeutic efficacy beyond the gene knockdown. Accordingly, at the 6-month time-point patients treated with ALN-TTR02 exhibited less neurological declines as would have been expected from the Natural History of the disease. Unfortunately, in the absence of hard biomarker evidence indicating improved neurological and, for a subset of patients, cardiac functions, the apparent improvement in the well-being of the patients (mNIS+7) could easily be attributed to the open-label nature and the relatively early time-point of the study.
Therefore, despite of the fact that shares in Alnylam increased 20% on the results and the provider of the delivery technology, Tekmira, barely budged on the news, the most important take-home from the results was that SNALP LNP delivery technology and indeed extended robust RNAi has a remarkably good safety profile.
I believe if you check ISIS data that they do approach 80% knockdown as well. Their shot to be given once a week and sq. And that with without excessive volume, no IV's, and no premedication required.
ReplyDeleteHi Dirk,
ReplyDeleteAny comment on the TKM-HBV data package?
The only thing I'm a bit concerned over is the level of knockdown vs. mg/kg of the Tx. Per the presentation they needed 1mg/kg to achieve ~1Log knockdown in the chimeric mouse model. They did indeed disclaim that the Chimeric mouse model might understate potency (slide 20), fine. What I find concerning is that per the press release a similar amount i.e. 1mg/kg was required for a 1-2log KD in the Hydrodynamic mouse model as well:
"A rapid 1 log reduction in serum HBsAg was achieved with a single 1 mg/kg dose of TKM-HBV in the chronically infected humanized mouse model, which mimics human hepatitis B infection. 1-2 log viral reductions from similar single-dose LNP treatments in two other true-infection animal models have also been demonstrated."
This seems to undermine the argument re. potency and the Chimeric model?!
As LNP is usually used in max 0.5mg/kg quantities and this was supposed to be way more potent than the 2gen Sirna/ALNY tech, which reached multi-log (2.5log?) KD with only ~0.23mg/kg, this seems a bit strange... What do you think?
Also, notice that they did not clarify the specific different mg/kg used in the hydrodynamic model which would have allowed for a more direct comparison between ARWRs respective model(!) Is this a bit strange?
Furthermore, why only show KD for 0.3mg/kg (coincidentally the MTD in the EBOV trials and max amount of 3rd gen LNP safely administered anywhere to date)and 1 mg/kg? Surely they would have tested many, many different mg/kg configurations and their respective KD potency? The two numbers seem a bit arbitrary, e.g on which we can give safely and one that achieved the result(?) we wanted... Why not just show the KD for every single tried and tested dose of kg/mg; surely they started at 0.0something mg/kg?
... As it stands now, from my point of view, what they essentially presented yesterday is that TKM-HBV works well, at a dose that is 100% higher than the MTD dose of 3rd gen LNP Tx known today. This makes the program significantly more risky than I would've wanted.
ReplyDeleteOr am I missing something?
No volume in TKMR and the Maxim note was completely generic and uninformative; the world is waiting for your analysis of the TKM-HBV data,Dirk, at least every TKMR and RNAi investor:)
ReplyDeleteDude! This is getting ridiculous! First talking about TKM-HBV as the main value driver, crown jewel of the pipeline etc. (not just you, and no disrespect meant) and now, after the much waited pre-clin. data are out, nobody talks about it or comments on the data. Still just mongering about EBOLA.
ReplyDeleteThe press release was almost cryptic when one considers that it is their main asset.
As the previous poster pointed out, the dosing seems a bit strange compared to known dosing of second gen and third gen in EBOV. Could this have to do with the usiRNA trigger? Although ARWR seems to get to lower doses using it than with the ALNY HBV trigger in ARC-520.
So, get your trades aligned and write a piece on the data, please. Cannot stand the EBOLA news anymore!