Harnessing the Power of RNAi Gene Silencing in Quest of a Cure for Chronic Hepatitis B, and the HBV KnockDown blog written by Dirk Haussecker, who believes it’s about time everyone got serious about a functional cure for hepatitis B.
Following cryptic remarks during a conference call earlier this year, Alnylam today officially announced its entry into the cure-HBV race. In impressive data presented at the ongoing TIDES meeting, the company showed that up to 0.5mg/kg SNALP-siRNA was able to knock down HBsAg by ~2 log (99% knockdown) in infected chimpanzees. The data had been generated by Merck from which Alnylam acquired the RNAi assets in January. The goal is now to apply some of the learnings generated with Merck’s research-grade SNALP LNP technology and come up with a new candidate based on Alnylam’s GalNAc delivery platform (IND to be filed end of 2015).
In addition to the impressive HBsAg knockdowns, 3-4log knockdowns of viral DNA in serum were seen in the 4 chimpanzees. In the most viremic chimp, the 4log lowering of viral load was able to normalize liver enzyme (ALT) levels that had been elevated by ~5x ULN. Intriguingly, in 2 chimps with normal ALTs at the time of treatment, liver enzymes started to increase after dosing had finished (ruling out SNALP LNP as the culprit) and in 1 case also well after viral DNA had started to recover following cessation of RNAi dosing.
Intriguingly, while viral DNA recovered in this short study involving the administration of 3 doses (for every chimp 0.125mg/kg, then 0.25mg/kg, then 0.5mg/kg) over a span of 40 days, there were indications of a desired immunological response similar to that seen withARC520 in the chimp study, most notably an elevation of interferon gamma accompanied by ~2x increases in ALT in 2 of the chimps.
With Tekmira, ISIS/GSK and now Alnylam (and possibly more to come) following on the heels of Arrowhead Research and ARC520, the competitive landscape is starting to look quite complex. How it will play out will likely depend on the degree of HBsAg knockdown required (in relative and absolute terms) and who will run the right combination studies with other HBV agents, especially immune boosters such as interferon and possibly RT inhibitors (note: Alnylam speculates that RT inhibitor co-treatment will be beneficial and thereby justified its use of a single RNAi trigger).
If a deep multi-log HBsAg knockdown were required, it would favor Tekmira’s candidate which will be based on a 3rd gen SNALP LNP which can be considered superior to what came out of Merck’s copy-cat efforts subject of today’s presentation. If lesser knockdowns were able to achieve comparable cure rates, then the power would shift to the subcutaneous versions by Alnylam and ISIS/GSK (esp. the likely GalNAc-based follow-up version).
For ARC520, especially at 2mg/kg and Tekmira probably just 6 months behind, the competition may prove too much, not least because in the 2-dose study in the chimpanzee, the HBsAg knockdown was less than a log (80%). Granted it was an extremely viremic chimp and one of the RNAi triggers was a mismatch, but still. If Arrowhead and/or Tekmira demonstrate increased cure rates in 2015, Arrowhead should waste no time and push a single-molecule DPC into development to potentially once again take the lead.
The big question is how far along the way to clinical translation is single-molecule DPC? Tomorrow may provide an answer.