Yesterday, Tekmira Pharmaceuticals presented the long-anticipated RNAi candidate for the treatment of HBV infection at the Annual Oligonucleotide Therapeutics Society conference (click here for the corresponding slide deck). Accordingly, it was shown that TKM-HBV mediated solid knockdown of all HBV viral RNAs and proteins. This included data in the challenging (and costly) mouse model carrying humanized livers (comprised of a mixture of mouse and human liver cells) competent of supporting the full HBV viral life-cycle.
In these mouse models, repeat doses of 0.3mg/kg resulted in ~90% reductions of both the critical HBV surface antigen (HBsAg) and viral DNA. This may be an underestimate of the true potency of TKM-HBV as suggested by data targeting the human apoB gene in this model. These suggested (although not proved) that it is much more difficult to achieve potent knockdowns of genes expressed in the human liver cells as compared to genes expressed in the neighbouring mouse cells of the same liver: around 10x the amount of RNAi trigger was required to achieve comparable knockdowns for the human ApoB gene relative to the mouse ApoB gene.
Based on these results, I expect an approx. ~85% knockdown of HBsAg in single-dose studies at doses that I conservatively expect to be very well tolerated (~0.2mg/kg). As indicated by the recent clinical results with ALN-TTR02 and chimpanzee studies by Alnylam/Merck, both of which involved Tekmira's SNALP LNP delivery technology, these knockdown numbers are likely to improve with more prolonged repeat administration.
In case that Tekmira is able to safely dose escalate to higher dosages, say 0.5mg/kg, significantly more potent knockdowns can be expected. One ought to, however, keep in mind that such higher doses are not necessarily supported by the clinical history of SNALP LNP which indicates that innate immune stimulations could become an issue around 0.3mg/kg. On the other hand, the otherwise conservative Tekmira management has been surprisingly optimistic as to 3rd gen SNALP LNP-enabled TKM-HBV being devoid of innate immunostimulatory activity.
Comparison with Arrowhead's ARC520
The results support the notion that Tekmira's HBV candidate will be more potent than Arrowhead's competing HBV candidate, ARC520. However, there are many uncertainties in making such a prediction, most importantly the dose levels found to be safe and well tolerated in the clinical studies. To wit, ARC520 is still dose-escalating and so far has exhibited a very good safety profile meaning that 90% (1log)-type knockdowns are well within reach, especially with repeat dosing.
Beyond potency, it should be noted that TKM-HBV comprises of 3 different RNAi triggers, both to cover the vast majority of viral sequence variation and to minimize the potential of breeding drug resistance. To my surprise, such resistance mutations were observed in a woodchuck model that Tekmira conducted together with HBV powerhouse Bristol Myers Squibbs.
Oh, BMS? You can bet that should RNAi Therapeutics be able to meaningfully increase HBV cure rates from the low bar set by current standard of care (~15% with ill-tolerated immune stimulants), not only will BMS, but also the likes of Gilead be very interested to swoop in to pick up one or both of these compounds and/or companies.
An IND filing for TKM-HBV is on track for year-end 2014 with first drug administrations in early 2015.
Disclosure: I am long both TKMR and ARWR.
Thank you Dirk, much appreciated.
ReplyDeleteWhat do you think of the cccDNA reduction of 50% at day 42 (terminal analysis)? This would seem quite encouraging re functional cure hypothesis!
What about the impressive reduction of eAg? Could this open some therapeutic angles in eAg+ patients?
Great use of the chimeric model, well done.
ReplyDeleteHowever, I do not really understand your/their claim that it may underestimate the potency in humans.
I guess there are a lot of possible differences between murine and human hepatocytes; the amount of particles you get in, the amount of particles that gets out of the endosome and the ease of triggering the RNAi pathway.
But in my opinion this would more likely OVERestimate the potency, given that "it is much more difficult to achieve potent knockdowns of genes expressed in the human liver cells"
Or are you saying that the murine hepatocytes 'consume' such a big part of the dose that in a situation with only human cells, the available dose would be higher?
I could live with that explanation, but I consider it highly speculative as the ApoB data does not proof anything.
Can you clarify your thoughts on this?
BR, Erik
cccDNA:I do not understand how much continued hepatocyte replication there is in this model. Normally, liver cells turn over quite slowly, but this may be accelerated in this model. It is likely through the turnover of liver cells that cccDNA is lost.
ReplyDeleteunder/overestimate: there is a thought that the human hepatocytes may not be as accessible to drug delivery (PK/biodistribution issue). I have not seen this before, but the data would support that. Benitec supporters, please chime in.
I think the main problem in the TKM-HBV data is that the required doses (mg/kg) were similar in both mouse models even though it is just the Chimeric mouse model that is supposed to underestimate the potency.
ReplyDeleteFeel that ALNY has gained lately partly because people view their HBV data as the most encouraging. Ironically, of course, is that ANLYs data are enabled by TKMRs second gen LNP delivery, and there won't be any pre clinical data on the ANLY program for at least a year! They seem to think that they can 1up the LNP data, however. Is it possible that the UsiRNA trigger could be that much less potent than the siRNA trigger used in the sirna studies (or the one used in ARC-520) or is potency always just a question re delivery?
I just can't get my head around the fact that 3rd gen has been described as ~10-30x more potent than 2gen, but the HBV results seem almost inferior regarding potency, certainly not more potent by even 4x!
Hi Everyone,
ReplyDeleteCertainly Tekmira is well positioned to answer detailed technical questions about the in vivo chimeric studies. However, if any of you would like the phoenix bio publication history, please contact me via LinkedIn or email me and I'll email the publication history. Easier for all my bright science friends to answer their own Q's with pier reviewed publications.