Pfizer and Quark Progress RNAi Therapeutic for Diabetic Macular Edema into Phase II

Quark Pharmaceuticals today announced that development partner Pfizer has initiated dosing of the first patient in a phase II trial of the RNAi Therapeutic candidate PF-4523655/RTP801i-14) for diabetic macular edema (DME). The start of the phase II trials is a vote of confidence in RNAi Therapeutics for eye diseases by a major pharmaceutical company with a considerable eye care franchise and growing ambitions in RNAi Therapeutics.

The 160-person safety and efficacy trial follows phase I/II studies conducted by Quark that showed the drug to be safe and well tolerated in patients with wet age-related macular degeneration (wet AMD). Similar to DME which affects about 10% of type I and II diabetics, wet AMD is caused by the growth of leaky blood vessels in the back of the eye leading to blurred vision, and in some cases blindness. For this reason, it is not uncommon that a given compound is being tested for both indications.

The reason that Pfizer has chosen DME instead of wet AMD as the indication for this trial may be related to the fact that the wet AMD RNAi Therapeutics space has become crowded with Opko Health and Sirna Therapeutics/Merck having wet AMD RNAi Therapeutics in phase III and II studies, respectively. Opko Health also has a phase II study for DME using the same compound. It may also be related to the recent controversy caused by a Nature paper that showed that dsRNA-triggered immune responses alone may be anti-angiogenic in a mouse model for wet AMD and that this may have led to mis-interpretations of data from related pre-clinical RNAi Therapeutics studies.

However, PF-4523655 is unlike Sirna’s and Opko’s compounds in that it is intended to prevent abnormal blood vessel growth and leakage in a VEGF-independent manner. It is also a 19bp blunt-ended compound and therefore unlikely to trigger non-specific TLR3 responses (21bp seems to be the cut-off where you have to take TLR3 signaling into account). I trust that the former Coley Pharmaceutical’s folks with their deep understanding of TLR biology and that are now running the RNAi Therapeutics show at Pfizer will have closely looked at the issue.

Quark received an undisclosed amount for the initiation of the trials, Silence Therapeutics which had originally licensed the AtuRNAi technology to Quark collected $1.9M, and Alnylam from which a technology license was subsequently obtained on Pfizer’s insistence another undisclosed amount. Clearly, with today's allowance of Silence Therapeutics’ 10/633630 patent in the US which specifically claims AtuRNAi molecules of 18 or 19 base-pairs the IP battles are about to begin, and will be addressed in a follow-up blog entry. In any case, it is an interesting coincidence that the initiation of the phase II studies and the patent allowance occurred on the same day.

Independent of all these patent issues, I look forward to the results of this compound which has the makings of a safe and differentiated RNAi Therapeutic for DME.

Silence Therapeutics Wins PR Prize in RNAi Therapeutics

Silence Therapeutics’ press release following the initiation of the Glover patent opposition hearings has to be counted as yet another example of the company’s series of misleading and factually flawed public statements.

Claiming that “the Glover patents was arguably Alnylam’s broadest patent” may be true in the sense that the patent claimed a lot, essentially double-stranded RNAs for gene silencing in mammals, but it is far from true, as Silence would want you to believe, that it represented Alnylam’s most important (RNAi trigger) patent. As Michael King from Rodman & Renshaw rightly noted in a report on the Xconomy blog, these are Tuschl II, followed by Crooke and Kreutzer-Limmer. Actually, when you would use the search function on my blog, yesterday may have been the first mention of the Glover patent. That’s how important I have considered this patent to be.

If I had been part in the early planning stages of Alnylam, a company that had been built around Tuschl II, Glover would have been a worry due to its early date and broad claims. But it is clear that Glover did not solve the non-specific interferon response issue that had critically impeded the broad application of RNAi in man, and claiming such based on studies in exceptional model systems such as oocytes and pre-implantation embryos may be overly ambitious. Still, a good patent to have control over and a weakening of Glover after the appeals have been heard, would only strengthen Tuschl II.

Another salient example of Silence’s overly zealous PR machine is the Quark issue. I’ve always found it amusing to come across Silence Therapeutics’ lengthy press releases that typically follow any pipeline and business development progress by their PR-wise much more conservative partner Quark Biotech, making it appear as if these achievements were almost entirely to the credit of Silence Therapeutics. Not surprisingly, according to a report in February this year by David P. Hamilton on the VentureBeat Blog, this appears to be a mis-representation and Quark is not very happy with this situation. I would not be surprised if Alnylam's COO Barry Greene, on his recent visit to Israel, had not visited Quark's operations there to see if the relationship between the two companies could be strengthened.

And finally, whether it’s liposomes or lipoplexes, hey, we are also working with some kind of a fat globule and if Merck says they are safe then we want to be part of it. And who really cares and understands the difference anyway?

I understand that PR is a very important element of the business strategy particularly of a developmental-stage biotech, but it has to be handled with care and, in a financial world where free and fair reporting is lacking, if careless may cost you the credibility in the eyes of one of your most important constituencies- your investor.

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.

When Will Pfizer Finally Make its Big Move in RNAi Therapeutics?

This week, Pfizer crossed my RNAi Therapeutics radar twice again. One has to do with their much-anticipated biotechnology initiative, including an innovation center in the San Francisco Bay Area which, according to news reports, should have RNAi Therapeutics as one of its focus areas. As we all know, Big Pharma has come under pressure with upcoming patent expirations, declining drug approvals due to a conservative FDA and outdated pipelines, but actually has the cash to invest in much needed innovation. The other event was a recurring rumor about their interest in Silence Therapeutics which led to a rapid 25% increase in the shares of the UK/German RNAi Therapeutics outfit in a matter of only two trading days.

Just watching Pfizer’s actions in RNAi Therapeutics from a distance is quite curious. Initially, they appeared to be toying around with DNA-directed shRNAs, but then engaged in a triangular relationship for developing an RNAi Therapeutics for AMD with Quark and Silence based on Silence’ AtuRNAi-type of siRNAs and Quark’s identified target gene. Pfizer also appears to be scouting out RNAi delivery solutions with a deal earlier this year with Mirus Bio that was followed by a neat publication on hepatocyte-specific RNAi delivery in PNAS (see 24 July 2007 Blog: ”Mirus Scientists Publish Elegant Paper on Targeted siRNA Delivery to Hepatocytes”). Around the same time, I counted at least seven delegates from Pfizer at thie year’s leading RNAi Keystone conference who, I suspect, weren’t there just to satisfy their scientific curiosity.

It seems prudent for Pfizer to learn more about the potential for RNAi Therapeutics first-hand through smaller collaborations with groups that have demonstrated know-how in RNAi Therapeutics before committing more significant resources. On the other hand, if they really saw potential in the technology and given their balance sheet, it would appear that the longer they wait the costlier the licenses that Novartis, Roche, and others regard as a must for freedom-to-operate. Particularly with the recent Alnylam-Roche deal, the pressure among Big Pharma is only going to increase. With Merck’s chair now empty at Alnylam’s table, Silence up for sale, and the their biotech initiative taking shape, I wonder whether Pfizer is going to get serious and make their move soon.

Quark Biotech on Course to Submit 3 RNAi-based INDs in 2007

The speed with which Quark Biotech has been turning out clinical-stage siRNA drug development programs is quite remarkable. With one ongoing phase I study for age-related macular degeneration (AMD) and one submitted IND for acute kidney injury, the Fremont, California, based biotech company today announced plans to file a third IND in 2007 for an siRNA drug candidate, this time for preventing chemotherapy-induced hearing loss. More siRNA programs are already in the pipeline.

Quark Biotech is an interesting player in the RNAi Therapeutics field as it leverages genomic screening techniques to rapidly discover novel drug targets. Indeed, the discovery of RNAi in the era of the human genome could not have come at a better time. As RNAi can target virtually any gene, efforts like those of Quark Biotech will allow the genome-wide screen for drug candidates essentially based on their biological suitability and not limited by “druggability”. Further demonstrating the cross-fertilisation between genomics and RNAi, the inhibitor screens performed by Quark Biotech, Cenix BioScience, and a number of other commercial and academic groups, are largely based on RNAi itself. Thus, RNAi simultaneously functions both as a target validation tool and potential drug candidate and allows for such fast development time-lines.

Quark Biotech sees itself as part of a new type of triangular relationship in the RNAi space where its expertise and value-creative role is target discovery. It then licenses the rights to use RNAi against these targets from companies like Alnylam Pharmaceuticals and Silence Therapeutics, and partners with typically larger, deep-pocketed companies for clinical development and hopefully commercialisation of the drug. I, for one, will be watching very closely whether Quark Biotech’s aggressive development strategy will prove successful in the end.

More RNAi Therapeutics Deals by Alnylam and Silence Therapeutics

Silence Therapeutics and Alnylam Pharmaceuticals hardly let a week go past without announcing partnership news leveraging their IP position in the RNAi Therapeutics arena.

When Alnylam and the medical device company Medtronic announced their initial partnership in 2005, the plan was to evaluate Medtronic’s CNS drug delivery devices for use with RNAi Therapeutics (see July 22, 2007 Blog: “Looking Ahead: Alnylam-Medtronic Alliance Stop-Go Decision Expected Soon”), and a joint decision on whether to continue pursuing such drug-device combinations would then be made in 2007.

Yesterday, the companies announced that the progress to date, particularly in their pre-clinical program for Huntington’s disease, warranted a continuation of their partnership. Simultaneously, the original terms of the agreement were amended as a 50:50 relationship in the US, while Medtronic will be solely responsible for development and commercialisation in Europe. It is not clear, however, whether Medtronic will make a $1-8M equity investment in Alnylam as under the original agreement. If not, the new deal structure might reflect the greater flexibility gained by Alnylam through their strong financial position, especially in the wake of the Roche alliance 2 weeks ago.

Such details should become available during next week’s Q2 conference call. Meanwhile, the decision to pursue this alliance further speaks to the promise of RNAi Therapeutics for the treatment of neurodegenerative diseases.

In a similar development, Silence Therapeutics announced a deepening of their existing partnership with Quark Biotech. Quark Biotech, which only very recently dropped their ambitious plans to go public, has two ongoing clinical programs with siRNAs licensed from Silence. In the new agreement, Quark obtains non-exclusive rights to develop RNAi Therapeutics for three gene targets using Silence Therapeutics’ AtuRNAi platform. Details of the deal were not available, but it does not appear to involve a significant upfront cash payment to Silence. Although the deal sizes by Silence Therapeutics pale in comparison to those of Alnylam, at least some of their partners appear to be convinced that Silence’s AtuRNAi technology is sufficiently distinct from Tuschl’s siRNAs to be worth paying money for. It could also mean, however, that some are unwilling or unable to meet the terms that Alnylam can ask for now.

RNAi Therapeutics Companies

There are a few dozen companies now, small and large alike, that have started developing drugs based on RNAi. While most of them are in the pre-clinical stages, in 2004 Acuity Pharmaceuticals (soon to be known as Opko) was the first to start phase I trials for age-related macular degeneration (AMD). Since then 5 more programs have entered the clinic: 2 additional ones for AMD (Sirna Therapeutics, acquired by Merck in 2006 for the handsome sum of $1.1 billion; and Quark Biotech), and one each in RSV (Alnylam Pharmaceuticals), diabetic macular edema (Acuity), and acute kidney injury (Quark Biotech).

Due to reasons discussed in the previous post, almost all of these programs are Direct RNAi programs, i.e. the siRNA is administered close to the diseased site. All except for Acuity's program are also with siRNAs that have been chemically modified (to enhance stability etc), and it remains to be seen whether Acuity's strategy to plunge into the clinic first was a wise one. Sirna Therapeutics soon followed suit, but I think took the right decision to invest time to carefully think about how to position their potential product in the more and more crowded AMD market. Sirna Therapeutics was also the first public company based on RNAi. Formerly known as Ribozyme Pharmaceuticals, they leveraged their experience with RNAs to build an operation that had all the tools to to build a decent IP portfolio and quickly enter the clinic. This IP portfolio is mostly based on chemistry and targeting many genes one by one such that it could claim exclusivity for targeting those genes with RNAi. It remains to be seen, however, how this brute force approach will hold up in the patent courts. Also, ISIS pharmaceuticals may contest some of their chemistry claims. However, the strategy has paid off extremely well at least for those that engineered it with Merck's takeover of the company last year for about 50x the price it had been valued before it committed to RNAi. SR Pharma, known as of today as "Silence Therapeutics", of the UK, looks as if it was seting itself up for a similar sale with an almost 8-fold price appreciation since last year.

The brightest star in the sky of RNAi Therapeutics by far, however, is Alnylam Pharmaceuticals. This is the company whose scientific founders were seminal in the development of RNAi and microRNAs, particularly in humans. Consequently, the company sits on an unparalled exclusive IP portfolio that gives them freedom to operate and pursue highly lucrative deals with Big Pharma and Biotech. These deals should help it through the development phase and have brought in already well over $100M. All this is managed by a seasoned team, led by CEO John Maraganore, that has considerable experience in developing succesful biotech companies (many of them hail from Biogen). It is also the company mentioned by the Karolinska Institute in their explanation for the 2006 Nobel Prize Award to Fire and Mello, as having demonstrated the therapeutic potential of RNAi through ground-breaking studies. These studies represent important de-risking events that continue to attract academic and indrustrial collaborators and important investments, including the RNAi Therapeutics field as a whole.

Other notable companies involved in RNAi Therapeutics include Benitec, a pure-play Australian company that uses DNA-based RNAi vectors to tackle a range of viral diseases, Nastech Pharmaceuticals (not a pure-play; focuses on siRNA delivery and Dicer-substrate technology), and large pharmaceuticals such as Merck, Novartis, GSK, and Pfizer, and probably many more knocking on the doors of Alnylam and co.