Tuesday, July 29, 2014

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.

1 comment:

Marc Lemaitre said...

Dirk, are we speaking about the same trial?


By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.