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.

Quark Biotech Dazzles RNAi Therapeutics World with Expanding Pipeline, Adds to Evidence that Delivery Walls to Kidney Crumbling

Yesterday, the US-Israeli company Quark Biotech announced the filing of their now third RNAi Therapeutics IND. The latest IND candidate, DGFi, is the siRNA knockdown of p53 in the kidney for the treatment of kidney transplantation-associated ischemia-reperfusion injury. This program follows a similar systemic kidney-p53 oxidative stress RNAi program, Akli-5, for acute kidney injury, and a local RNAi program (RTP-801i) for age-related macular degeneration targeting the apoptosis-related gene RTP801/REDD1 that came out of Quark’s own gene discovery program.

This likely makes Quark Biotech, which specializes in the discovery of disease-associated genes that it then targets by in-licensed RNAi technology, the company with the most RNAi candidates in the clinic, unless, of course, Merck has early clinical programs that we haven’t heard about. This is quite remarkable given that very little is known about Quark’s RNAi science as judged by the literature and presence at leading RNAi conferences. My own patent search for Quark-related RNAi delivery technologies failed, although their IPO documents stated that they had been building an IP estate around RNAi Therapeutics, including proprietary delivery technologies [Note: the planned ~$80M IPO failed last year due to a difficult market; instead the company earlier this year raised around $27M from private Japanese investors].

So I can only speculate as to the systemic delivery technology employed. Given that unformulated and unmodified oligonucleotides have the propensity to end up being rapidly excreted by the kidney, it is well possible that some of these siRNAs get functionally taken up for gene silencing. In fact, the ground-breaking systemic siRNA delivery paper by Soutschek and colleagues from Alnylam employing cholesterol-conjugated siRNAs showed that the lipophilic siRNA conjugate was taken up reasonably well not only in the liver, but also jejunum, heart, adipose tissue, the lung, and kidney, albeit at quite high 50mg/kg dosages. Similarly, a recent publication by the Natarajan group from the City of Hope, CA, showed that subcutaneous administration of ~20mg/kg cholesterol-siRNA reduced gene expression in the kidney by about 50-80% with promising therapeutic effects in a mouse model for diabetic nephropathy. It is, however, possible that the apparently intravenous formulation is composed of a nanoparticle as suggested by the second name of the Akli-5 progam, I5NP (NP=nanoparticle?). In any case, the evidence is growing that the fact that siRNAs like to go to the kidney could be exploited for treating kidney-related disease by RNAi, slowly clearing yet another organ for RNAi.

Although I feel more comfortable judging an RNAi Therapeutics company with some scientific data at hand, Quark Biotech’s speed of entering the clinic while others are humbly optimizing their own candidates, particularly with regards to delivery, warrants some attention. In addition to the AMD program, the company has licensed a second RNAi program to the emerging RNAi superpower Pfizer, a program for COPD likely to be administered by inhalation. Overall, the Pfizer relationship has brought in over $25M of realized funding as of the filing of the IPO documents in March 2007. Another important relationship exists with Silence Therapeutics, although a report earlier this year suggested that there might be some frictions in that relationship. This would be consistent with Quark having subsequently licensed IP from Alnylam as well as Quark’s ambitions of developing proprietary RNAi trigger IP, whatever that is supposed to mean. I guess by providing a little more transparency, Quark Biotech might be able to attract more investor interest for a second IPO attempt. With so many clinical candidates and more coming up, such a cash infusion could be necessary soon.

In other news: The Pharmalot Blog posted yesterday that the approval rate of innovative medicines continues to be anemic. Only 5 new molecular entities were approved by the almighty FDA in the year through May. It’s time for RNAi to contribute to the development of more innovative drugs addressing unmet medical needs, and the regulatory agencies and society as a whole to understand that overdone conservatism and by killing the profitability of drug development aren’t helping in that regard.