Such potency, however, came at the apparent expense of relatively frequent injection site reactions (23% of patients), with an additional skin reaction seen outside the area of injection. Moreover, there was a trend towards elevated liver enzymes, a marker of liver toxicity, including one that was adjudicated a serious adverse event (SAE; ~4x ULN deemed mild severity).
Friday, November 14, 2014
Injection Site Reactions and Liver Toxicity Emerge as Major Issues for GalNAc-siRNA Technology
Such potency, however, came at the apparent expense of relatively frequent injection site reactions (23% of patients), with an additional skin reaction seen outside the area of injection. Moreover, there was a trend towards elevated liver enzymes, a marker of liver toxicity, including one that was adjudicated a serious adverse event (SAE; ~4x ULN deemed mild severity).
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15 comments:
I know this post addresses ALNY TTR but how does the potency of GalNac siRNA compare to ARWR's DPC conjugation generally? Is ARWR precluded from GalNac formulation development?
As Regulus 101 uses a similar GalNac technology, can the adverse events be expected to be similar, or is this not a problem because of the limited doses of Rg 101 administered.
You got it right, RG-101 will not involve a demanding dosing schedule as ALN-TTRsc. Having said that, I expect that if AEs emerge for RG-101, it will be along the lines of ALN-TTRsc though milder in severity, and keep in mind, RG-101 is not a chronic therapy. My expectation is 2 doses max spaced 1 month apart.
Dirk, You've integrated disparate contradictory new knowledge into your analysis, once again. I'm impressed. In my humble opinion you now have a 25% rating vis a vis McCamant. You've done so well in this field I would be foolish to offer you advice, and so I'll only offer an old general adage that I have found to be true: The first million is the hardest to make. Best Wishes.
Considering Arcturus is getting comparable knock down at 0.3 mg/kg, has shown no DLTs up to 50 mg/kg, and is talking about once a month treatments v multiple injections with painful reactions on a weekly basis... I would expect that the TTR market is heading into a major shake up.
If the ALNY GalNac-sirna delivery is so adverse then the downstream effect for RGLS can't be great one would assume.
Yet it is RGLS which was able to raise the needed capital and fully enrol for its upcoming trials. Which kind of negates any concerns an investor would have because of the regulatory approval required to get to that point.
Which brings us back to the question of why does Benitec have such a stringent control on its trial? The upshot being only two patients have been dosed. The second conveniently on the eve of the annual meeting.
My conclusion; it is because of serious toxicity concerns from the FDA.
It's much more likely that the stringent protocol is about the irreversibility of the Benitec ddRNAi infusion. Off target effects being the risk. NHPs recieved excessive amounts of TT-034 without toxicity.
What is all this fuss about AE? All the AE were transient and returned to baseline level while the dosing continued. TTRsc continues to move into P3. It is not like TKMR-EBOLA which was halted by FDA. Issue with TTRsc is not AE or potency but clinical end points. There is a hotchpotch of a number of clinical end points to measure the clinical efficacy of TTRsc. This will make it more complicated to measure the clinical efficacy in FAC patients.
Second patient dosed, future patients much easier to source, toxicity issues are a feint and not a hint of FDA issue with toxicity. Fact is the protocol is rightly stringent, this is ddRNAi not siRNAi or antisense. In other words it is the real deal and NHP extensive toxicity testing points to safety not being an issue and efficacy hinted by 2nd cohort. How long can you afford to sit out the most promising and exciting RNAi platform that is soon to show validation. You liked RGLS 150% one day gain? Prepare for 150-300% when 3rd patient data flows and/or Calimune reports. Good luck all Benitec shorts or sideline sitters, you're going to need it. Keep sitting on TKMR and RGDO and kiss your cash goodbye.
"How long can you afford to sit out the most promising and exciting RNAi platform that is soon to show validation."
Until it is validated. Should be able to open their own lab when they do. Might even be able to challenge Voyager over patent rights.
DRNA news today sounds the death knell for BLT.
Maybe you can enlighten us and expand on this silly non-supported statement re:BLT. What's your reasoning and the facts that support it. Very sad effort on your part.
Attendance at their presentation on Wednesday will reveal all the warts I expect.
Should be good to see how far they have come in such a lengthy period of time and how far they still have to go before they can be validated.
As usual Dirk you are quick to ignore facts and jump to conclusions that suit your own personal (albeit distorted) agenda.
Ever consider the that AE profile seen might be related to the fact that this is a patient population with symptoms of advanced heart failure and related comorbidities?
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