ISIS today reported knockdown results from a phase I trial with its RNase H antisense compound ISIS-TTRRx against the transthyretin gene for the treatment of TTR amyloidosis. The results show that while high 81% knockdowns can be achieved, very large amounts of oligonucleotides (400mg weekly for 4 weeks) had to be given. When clinically more relevant doses were given (200mg as in mipomersen and the next lower dose from 400mg), a mean knockdown of 44% was achieved.
As you will remember (SNALP Works!), the RNAi Therapeutics candidate ALN-TTR01 last November showed a mean reduction of 41% of serum TTR from baseline following a single 1.0mg/kg infusion. In light of yesterday’s results with ALN-PCS02 where a supposedly less potent RNAi trigger was employed and a ~60% knockdown was achieved with 0.25mg/kg, it seems likely that the Tekmira SNALP-enabled ALN-TTR02 which is about to enter clinical development and which employs a formulation similar to PCS02 will show the type of 70-80% knockdown at 0.25mg/kg.
We have yet to learn more about the safety profile of ISIS-TTRRx which is being developed under an option agreement with GSK. ISIS stated in their press release that they were planning to enter pivotal studies with this compound soon. If it is with the 400mg dosage, they may be tempting fate. It might be interesting to try 300mg.
As you know, these days I’m strongly advocating RNAi Therapeutics as the technology is currently being sold at much below the worth of the science which has progressed steadily over the years despite the up and downs in public perceptions. Today’s results by ISIS show that the new darling in nucleic acid therapeutics can certainly knock down genes in the liver (and some other tissues). They also show, however, that even the initial SNALP formulations are already on par with it in terms of efficacy at the higher end of tolerability (not talking about other aspects such as absolute differences in dosage or route of administration).
Were you surprised by the teaming up of Alnylam and Arrowhead? Does Alnylam have any real interest in Arrowhead's proprietary delivery system or they only interested in the delivery systems Roche has developed?
ReplyDeleteI believe the agreement relates to DPC, not the Calando RONDEL tech. Am I surprised? Partly yes, because I had thought Alnylam had already claimed access to DPC. Partly no, because you can already see the battle fronts being formed in the space. The next couple of months should be interesting.
ReplyDeleteI think comparing the ISIS PS gap-mers to SNALP-mediated siRNA delivery is a bit like apples and oranges. You forgot to mention the fact that ISIS does not need to use a complicated delivery vehicle. What do you think the dose of siRNA would need to be to achieve ~ 50% silencing in man? Another interesting question is what would the dose be if ISIS used a nanoparticle delivery vehicle?
ReplyDelete"What do you think the dose of siRNA would need to be to achieve ~ 50% silencing in man?"
ReplyDeleteIt depends on the target and organ, but for SNALP-enabled PCS02 and TTR02 I expect it to be between 0.08-0.15mg/kg.
"Another interesting question is what would the dose be if ISIS used a nanoparticle delivery vehicle?"
PS gapmers probably won't benefit much from nanoparticle delivery formulations for gene silencing in liver because of their different pharmacokinetic mechanism.
But anyway, as long as you can master the nanoparticle, it can be a great tool to maintain market exclusivity.