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Re: Question about resultsI think it looks good. The experiment worked. It could have been unsafe due to dose accumulation or non-effective in further reducing dose. I think it means something like the hypothetical diagram above. With monthly doses (blue) there was a stepwise reduction in sAg. But before each new dose there was a little regrowth of sAg. With a biweekly protocol (red) there was no time for regrowth of sAg and each dose was working from a lower baseline. The overall depth of decline is greater. However, when they went back to dosing monthly at the end of the test period, there was some regrowth of sAg. So basically they feel the dosing needs to be every 2 weeks. To see how far that could push the sAg down they will do a new study and continue to dose 2 weekly in perpetuity. But they identify that a proportion of people have already effectively hit the lowest measurable value of sAg. So they will then hit them with IFN to see if absent of sAg inhibition, IFN or other agents (in due course) can create a seroconversion. It may be that this can happen as soon as sAg production and levels are near nothing. It may be that it requires it to be at low levels for a long time, in which case they would continue RNAi therapy. I don't think anyone knows. It would seem you have to get very low (as ARWR had no success with just log reductions as opposed to absolute values post reduction). But for how long? ALNY also released some preclinical data today on HBV. They have impressive durability after a single injection. However, the dose that they achieved 2 log at in an animal model (and we have now seen a lot of these cross companies), was 10mg/kg. That is higher than they have given for any sc therapy. The GalNAC platform is claimed to be safe at very high doses (and has been used reasonably high for the lipid MDCO program) but generally is administered in other programs at lower doses than the preclinical data. We also see big variations between unsuppressed animal models and real life. So there is a long way to go in seeing if ALNY's single trigger approach will work across all patients. All vendors, including ALNY, have claimed preclinical pan genotype efficacy but in the real world, eAg status, nuc history, sAg and HBV DNA levels, epigenetic modifications and a host of stuff we don't know has affected performance. ALNY's poster comments on some ways that resistance may develop and that has been generally claimed to be a deficiency of single trigger approaches. ALNY is also learning from its mistakes and appears to be making big strides in sc chemistry. So we will have to wait and see if this turns into a safe and effective competitor. It would be unwise to ignore them. ego |
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