Quark’s Failure in Kidney Study Heralds End of Naked RNAi Triggers

Quark Pharmaceuticals today announced that RNAi Therapeutic candidate QPI-1002 has failed in a fairly large phase II kidney transplant study to meet its primary efficacy end-point.   For those interested, it was a pre-defined threshold of reducing the risk of having to go on dialysis after receiving a kidney transplant (30% pre-defined, 15% achieved with no p-value provided).  Following failures with similar 'naked' RNAi candidates by Quark and others (e.g. Opko/Acuity wet AMD candidate and Alnylam’s ALN-RSV01), this probably puts a nail in the coffin of a naïve, but convenient approach to RNAi delivery taken by quite a few in the early days of RNAi Therapeutics. 

QPI-1002 is a blunt-end 19 base-pair AtuRNAi targeting p53, thereby aiming to protect struggling kidney cells trying to take hold in their new host from dying.   It carries simple alternate 2’-o-methyls on both strands and is given by intravenous infusion reconstituted in saline.  While it is well established that unformulated/naked oligonucleotides without special modifications or delivery formulations to make them ‘drug-like’ will concentrate in proximal tubule cells of the kidney, the declared target cell for QPI-1002, it is still a mystery how the RNAi trigger is supposed to cross into the cytoplasm of those cells. 

Of course, a drug may fail for reasons other than target engagement, which couldn't be determined in this study, but I believe Quark in private would also side with the view that this most likely had to do a failure to deliver. This is because Quark itself has been adding chemistry to their more recent molecules to turn them into more credible self-delivering RNAi triggers.  And even if it wasn’t due to a failure to deliver, there is now little reason to pursue it any more.

RIP naked RNAi, RNAi Therapeutics has moved on.