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.
Thursday, July 31, 2008
Wednesday, July 30, 2008
Comments Section of the RNAi Therapeutics Blog
I have been very impressed by the quality of the comments left below some of the blog entries. If somebody hasn't noticed them, I would highly encourage you to read them for interesting insights, fresh perspectives, and discussion.
I think this small forum here exemplifies that not only is drug development undergoing profound changes, from a sales-force and reformulation-driven model towards one of evidence-based medicine and innovation, but so is the practice of science and investment. Freely accessible scientific publications, realtime quotes and news, and online forums bringing together people with complementary backgrounds mean that everybody has now a chance to participate on a level playing field. Appropriately, RNAi Therapeutics has in the same way empowered the individual scientist to conceive novel drug candidates without the need for large-scale automation, and I would also hope that emerging economies that have thus far not participated in the development of innovative therapeutics will grasp the emerging field of RNAi Therapeutics as an opportunity to be at the cutting-edge of medicine.
Before I digress further, I just wanted to say that I will try and do my best to answer questions if directed to myself, but may not always be able to do so. A sincere “thank you” to all the contributors.
I think this small forum here exemplifies that not only is drug development undergoing profound changes, from a sales-force and reformulation-driven model towards one of evidence-based medicine and innovation, but so is the practice of science and investment. Freely accessible scientific publications, realtime quotes and news, and online forums bringing together people with complementary backgrounds mean that everybody has now a chance to participate on a level playing field. Appropriately, RNAi Therapeutics has in the same way empowered the individual scientist to conceive novel drug candidates without the need for large-scale automation, and I would also hope that emerging economies that have thus far not participated in the development of innovative therapeutics will grasp the emerging field of RNAi Therapeutics as an opportunity to be at the cutting-edge of medicine.
Before I digress further, I just wanted to say that I will try and do my best to answer questions if directed to myself, but may not always be able to do so. A sincere “thank you” to all the contributors.
Monday, July 28, 2008
RNAi Therapeutics delivery: not a zero-sum game
Shares of Tekmira briefly fell last week below 80c, a ~20% decline, following Roche’s purchase of fellow RNAi Therapeutics delivery company Mirus Bio. Initially, I did not draw a connection. If a reaction at all, then I would have expected the $125M price-tag to point out the value attached by the industry to promising RNAi delivery technologies in general, which “should have” resulted in a share price increase for Tekmira.
To my surprise, however, it then transpired that the Roche acquisition had been interpreted by some as a vote for DPC and against SNALP RNAi delivery, leading some to sell in a panic. This blog will briefly outline why, unlike is the case in the battle for core RNAi trigger IP, RNAi Therapeutics delivery is not a zero-sum game with room for more than just a handful of technology platforms.
As is becoming more evident by the day, RNAi Therapeutics offers the opportunity to address a very wide range of diseases. As all disease has a genetic element, regulating gene expression should always be able to modify or even correct a disease. To do this, however, one has to be able to knock down the desired genes in various different organs, tissues, and cell types. If there was a universal RNAi delivery technology, it would have to be able to physically contact every cell in the body, yet only knock down genes in the disease-related subset of cells.
Based on the limited publicly avaibable data, Mirus’ DPC technology actually promises to come close to that dream. It is very small in size (~20nm) and therefore satisfies at least one of the pre-requisites of achieving a broad biodistribution. Moreover, it has been shown to be capable of differentiating between the different cell types within an organ, in this case the liver, depending on which sugar had been added- all in the absence of apparent toxicity! It will clearly be exciting to learn more about the delivery profile of DPCs. Nevertheless, I doubt that DPC will necessarily be the delivery system of choice for every indication.
This is because the choice of a delivery system is not only determined by the ability to knock down a gene in a given cell, but also by factors such as overall maturity of the technology, safety as determined by the dose required to achieve such gene knockdown, the biodistribution and cell type-specific gene knockdown on a systemic level, as well as by cost, route of administration, and stability of the formulation.
Consider for example an RNAi Therapeutics against the kinesin spindle protein (KSP) that is being developed by Alnylam as a treatment for liver cancer. Although directly interfering with cell division by down-regulating KSP is seen as a very promising anti-cancer strategy, anti-KSP small molecule programs have indicated considerable dose-limiting toxicities that appear to be target specific. This, however, should not come as that much of a surprise since interfering with spindle function would be predicted to affect normally proliferating cells as well, particularly those of the hematopoietic system. Well, this dilemma is not new at all to the cancer field, and often the benefits outweigh the side-effects, but this example illustrates the value of a delivery technology such as SNALP-RNAi that can be tuned to deliver around 95% of the injected dose to the liver, including hepatic tumor tissue.
Certainly, Roche may elect DPC delivery over SNALP delivery (note: Roche has access to both) for some liver indications, but that type of competition has actually only decreased with Mirus Bio out of play. This is because all the other two dozen or so pharmaceutical companies equally interested in RNAi Therapeutics, will now have access to one less viable delivery technology. The incentive to gain access to the still fairly accessible RNAi delivery platforms with clinical potential has therefore never been greater. Roche, of course, enjoys the luxury of being able to choose between two technologies that, maybe in an effort to avoid the appearance of favoritism, it has valued essentially identically based on their $5M equity investment in Tekmira at $2.4 per share(Tekmira now has 51.6M shares outstanding).
Bottom line, due to the ever growing attraction of RNAi Therapeutics, any company, and that goes beyond Tekmira-SNALP, with clinically relevant RNAi delivery technology and a good IP package to protect it can rest assured that they own a very hot commodity.
RNAi Therapeutics portfolio update: With Roche’s validation of the value attributed to clinically relevant RNAi delivery technologies and with increased clinical visibility, I have slightly increased my position in Tekmira while paring back on the overweight ALNY position. In another attempt to capitalize on the idiosyncracies of the stock market, I have converted the RXi Pharmaceutical holdings back into CytRx shares (CytRx owns about 50% of RXi, but none of that is reflected in CytRx’s market cap) and added some more at the cost of largely cashing out of RNAi trigger competitor Silence Therapeutics (a token $1 investment is maintained to monitor stock performance).
Disclosure: Long Tekmira, Alnylam, Targeted Genetics, Oxford Biomedica.
To my surprise, however, it then transpired that the Roche acquisition had been interpreted by some as a vote for DPC and against SNALP RNAi delivery, leading some to sell in a panic. This blog will briefly outline why, unlike is the case in the battle for core RNAi trigger IP, RNAi Therapeutics delivery is not a zero-sum game with room for more than just a handful of technology platforms.
As is becoming more evident by the day, RNAi Therapeutics offers the opportunity to address a very wide range of diseases. As all disease has a genetic element, regulating gene expression should always be able to modify or even correct a disease. To do this, however, one has to be able to knock down the desired genes in various different organs, tissues, and cell types. If there was a universal RNAi delivery technology, it would have to be able to physically contact every cell in the body, yet only knock down genes in the disease-related subset of cells.
Based on the limited publicly avaibable data, Mirus’ DPC technology actually promises to come close to that dream. It is very small in size (~20nm) and therefore satisfies at least one of the pre-requisites of achieving a broad biodistribution. Moreover, it has been shown to be capable of differentiating between the different cell types within an organ, in this case the liver, depending on which sugar had been added- all in the absence of apparent toxicity! It will clearly be exciting to learn more about the delivery profile of DPCs. Nevertheless, I doubt that DPC will necessarily be the delivery system of choice for every indication.
This is because the choice of a delivery system is not only determined by the ability to knock down a gene in a given cell, but also by factors such as overall maturity of the technology, safety as determined by the dose required to achieve such gene knockdown, the biodistribution and cell type-specific gene knockdown on a systemic level, as well as by cost, route of administration, and stability of the formulation.
Consider for example an RNAi Therapeutics against the kinesin spindle protein (KSP) that is being developed by Alnylam as a treatment for liver cancer. Although directly interfering with cell division by down-regulating KSP is seen as a very promising anti-cancer strategy, anti-KSP small molecule programs have indicated considerable dose-limiting toxicities that appear to be target specific. This, however, should not come as that much of a surprise since interfering with spindle function would be predicted to affect normally proliferating cells as well, particularly those of the hematopoietic system. Well, this dilemma is not new at all to the cancer field, and often the benefits outweigh the side-effects, but this example illustrates the value of a delivery technology such as SNALP-RNAi that can be tuned to deliver around 95% of the injected dose to the liver, including hepatic tumor tissue.
Certainly, Roche may elect DPC delivery over SNALP delivery (note: Roche has access to both) for some liver indications, but that type of competition has actually only decreased with Mirus Bio out of play. This is because all the other two dozen or so pharmaceutical companies equally interested in RNAi Therapeutics, will now have access to one less viable delivery technology. The incentive to gain access to the still fairly accessible RNAi delivery platforms with clinical potential has therefore never been greater. Roche, of course, enjoys the luxury of being able to choose between two technologies that, maybe in an effort to avoid the appearance of favoritism, it has valued essentially identically based on their $5M equity investment in Tekmira at $2.4 per share(Tekmira now has 51.6M shares outstanding).
Bottom line, due to the ever growing attraction of RNAi Therapeutics, any company, and that goes beyond Tekmira-SNALP, with clinically relevant RNAi delivery technology and a good IP package to protect it can rest assured that they own a very hot commodity.
RNAi Therapeutics portfolio update: With Roche’s validation of the value attributed to clinically relevant RNAi delivery technologies and with increased clinical visibility, I have slightly increased my position in Tekmira while paring back on the overweight ALNY position. In another attempt to capitalize on the idiosyncracies of the stock market, I have converted the RXi Pharmaceutical holdings back into CytRx shares (CytRx owns about 50% of RXi, but none of that is reflected in CytRx’s market cap) and added some more at the cost of largely cashing out of RNAi trigger competitor Silence Therapeutics (a token $1 investment is maintained to monitor stock performance).
Disclosure: Long Tekmira, Alnylam, Targeted Genetics, Oxford Biomedica.
Tuesday, July 22, 2008
Roche Nabs Mirus Bio’s RNAi Therapeutics Delivery Technology
Roche again...before this week will have come to an end, Roche has drastically changed the RNAi Therapeutics playing field leaving many heads in the RNAi space spinning.
You may think it is because I live in an RNAi Therapeutics bubble, but the Roche-Genentech press release and conference call to me clearly shows that a major motivation for the proposed taking private of Genentech was to broaden their RNAi Therapeutics efforts by bringing in a company with deep immunology and personalized cancer know-how, as well as being able to leverage Genentech’s monoclonal antibody capabilities for targeted RNAi Therapeutics delivery.
To this they now add for $125M, a sum that makes related companies look very cheap in comparison, the privately held Madison, Wisconsin, nucleic acid delivery company Mirus Bio. The jewel of Mirus Bio is their Dynamic PolyConjugates (DPCs), small, flexible designer particles for the targeted systemic delivery of siRNAs. Although the technology is relatively young and data scarce, from the PNAS publication last year (reviewed here in the RNAi Therapeutics blog) and conference presentations, DPCs are very competitive with liposomal technologies for delivery to the liver. Also very attractive from a safety and efficacy point-of-view is their apparent ability to selectively target silencing either to hepatocytes or Kupffer cells in the liver, depending on whether glucose or galactose-derivatives were attached. Although I haven’t seen data beyond the liver, the small size and modularity suggests that with the appropriate pharmacology it could well have applications for a number of other tissue types and organs and nicely complement larger nanoparticle delivery technologies.
It’s unlikely to be a coincidence that Roche is making all these moves in such short order. What has started with an IP license from Alnylam for basic access to RNAi mechanism of action, within 2 days they have now added to that one of the most coveted delivery technologies and scientific depth. The rapid moves by Roche means that fellow Big Pharmas like Pfizer, which had a non-exclusive license to DPCs, and Merck which had probably also been very interested in DPCs, now risk falling behind on delivery while their core RNAi IP has either not been secured yet (Pfizer) or is at best uncertain (Sirna Therapeutics/Merck). From a strategic perspective, it will be interesting whether due to their close relationships there will be any sharing/coordination of DPC technology with Alnylam and Tekmira, and for which indications Roche will employ the two leading delivery technologies (DPCs and SNALPs) both of which it has now immediate access to.
Today's acquisition is yet another piece of evidence that Roche is building their future on RNAi Therapeutics in a big and bold way. It's also encouraging that this comes a year after the Alnylam platform licensing agreement and suggests that they must have been pleased with what they have seen since.
You may think it is because I live in an RNAi Therapeutics bubble, but the Roche-Genentech press release and conference call to me clearly shows that a major motivation for the proposed taking private of Genentech was to broaden their RNAi Therapeutics efforts by bringing in a company with deep immunology and personalized cancer know-how, as well as being able to leverage Genentech’s monoclonal antibody capabilities for targeted RNAi Therapeutics delivery.
To this they now add for $125M, a sum that makes related companies look very cheap in comparison, the privately held Madison, Wisconsin, nucleic acid delivery company Mirus Bio. The jewel of Mirus Bio is their Dynamic PolyConjugates (DPCs), small, flexible designer particles for the targeted systemic delivery of siRNAs. Although the technology is relatively young and data scarce, from the PNAS publication last year (reviewed here in the RNAi Therapeutics blog) and conference presentations, DPCs are very competitive with liposomal technologies for delivery to the liver. Also very attractive from a safety and efficacy point-of-view is their apparent ability to selectively target silencing either to hepatocytes or Kupffer cells in the liver, depending on whether glucose or galactose-derivatives were attached. Although I haven’t seen data beyond the liver, the small size and modularity suggests that with the appropriate pharmacology it could well have applications for a number of other tissue types and organs and nicely complement larger nanoparticle delivery technologies.
It’s unlikely to be a coincidence that Roche is making all these moves in such short order. What has started with an IP license from Alnylam for basic access to RNAi mechanism of action, within 2 days they have now added to that one of the most coveted delivery technologies and scientific depth. The rapid moves by Roche means that fellow Big Pharmas like Pfizer, which had a non-exclusive license to DPCs, and Merck which had probably also been very interested in DPCs, now risk falling behind on delivery while their core RNAi IP has either not been secured yet (Pfizer) or is at best uncertain (Sirna Therapeutics/Merck). From a strategic perspective, it will be interesting whether due to their close relationships there will be any sharing/coordination of DPC technology with Alnylam and Tekmira, and for which indications Roche will employ the two leading delivery technologies (DPCs and SNALPs) both of which it has now immediate access to.
Today's acquisition is yet another piece of evidence that Roche is building their future on RNAi Therapeutics in a big and bold way. It's also encouraging that this comes a year after the Alnylam platform licensing agreement and suggests that they must have been pleased with what they have seen since.
Monday, July 21, 2008
Speaking of the Devil: Genentech Receives Full Takeover Offer from Roche; Stands to Become Alnylam’s Partner
Just as I was speculating that Genentech may become Alnylam’s next major RNAi Therapeutics partner, Roche makes an offer to buy the rest of Genentech’s shares that it does not own already. I’m sure the pundits will be all over what this event will mean for drug development, so just a few notes on its relevance for RNAi Therapeutics.
From the press release and based on historical comments against the notion of mega-mergers with fellow Big Pharma and against entering generics, it is clear that Roche is very keen on leading the development of innovative medicines, particularly personalized medicine. What better candidate than Genentech with all its know-how in this arena as well as size to sufficiently impact Roche's top and bottom lines? Just to demonstrate that personalized medicine is more and more becoming a reality, Roche appropriately also announced today European approval for an interferon-ribavirin treatment regimen for hepatitis C based on individual viral titers and rapid viral response. Interestingly, Alnylam disclosed really for the first time in the Pharmaceutical Executive report its interest in hepatitis C which might be best addressed by SNALP delivery. And how much more personalized can hepatitis C treatment get than to sequence the virus in a given patient and then deliver the appropriate siRNA combination?
Reassuringly, the press release prominently mentions RNAi Therapeutics as a central component of the innovation engine of the combined company:
“The structure of the combined company will allow for a diversity of approaches in research and early development, while also strengthening cross fertilization between the companies, leading to enhanced overall innovation within the Group. Roche's recently adopted Disease Biology Area approach, which allows five diverse groups to manage their innovative portfolios, will be maintained and strengthened. This, together with recent moves into RNAi (Ribonucleic Acid interference) and delivery technologies, as well as licensing activities, continues to provide a stimulating
environment for the creation of medically differentiated medicines.”
And on the “enhanced ability to innovate”, the press release goes:
“The transaction will over time significantly enhance cooperation and cross fertilization among all research hubs inside and outside of the combined company. Sharing of technologies (e.g. RNAi, novel protein architectures), assets (e.g. chemical libraries), intellectual property(e.g. antibody production), unique capabilities (e.g. exploratory development, modeling and simulation) and know-how of the combined research organization will strengthen the Group's ability to innovate.”
I wonder how much Genentech will be surprised by the offer. In this regard, it is also interesting to speculate whether Alnylam had been in negotiations with Genentech or not. If so, would an unsolicited takeover of Genentech by Roche mean that Alnylam has to forego platform license fees that it would have otherwise received if Genentech remained independent? On the other hand, could it be that Genentech’s moves into RNAi Therapeutics had long been co-ordinated with Roche’s efforts, relying on being able to access RNAi know-how and IP through Roche? I guess the answer will come whether the $89 a share offer will be recommended by Genentech management to shareholders or not. Given the close ties between the companies a Ventana-like takeover battle is difficult to imagine. The weak dollar may also aid Roche in increasing the price a little bit to satisfy all Genentech shareholders.
Today’s development promises to be a defining moment in the history of drug development. With the recent acquisitions of diagnostics company Ventana and now Genentech, Roche has now fully committed to embracing the future of personalized medicine. Based on comments by the new CEO Severin Schwan who has now more than amply demonstrated that he really means what he says, RNAi Therapeutics is to play a key part in this.
From the press release and based on historical comments against the notion of mega-mergers with fellow Big Pharma and against entering generics, it is clear that Roche is very keen on leading the development of innovative medicines, particularly personalized medicine. What better candidate than Genentech with all its know-how in this arena as well as size to sufficiently impact Roche's top and bottom lines? Just to demonstrate that personalized medicine is more and more becoming a reality, Roche appropriately also announced today European approval for an interferon-ribavirin treatment regimen for hepatitis C based on individual viral titers and rapid viral response. Interestingly, Alnylam disclosed really for the first time in the Pharmaceutical Executive report its interest in hepatitis C which might be best addressed by SNALP delivery. And how much more personalized can hepatitis C treatment get than to sequence the virus in a given patient and then deliver the appropriate siRNA combination?
Reassuringly, the press release prominently mentions RNAi Therapeutics as a central component of the innovation engine of the combined company:
“The structure of the combined company will allow for a diversity of approaches in research and early development, while also strengthening cross fertilization between the companies, leading to enhanced overall innovation within the Group. Roche's recently adopted Disease Biology Area approach, which allows five diverse groups to manage their innovative portfolios, will be maintained and strengthened. This, together with recent moves into RNAi (Ribonucleic Acid interference) and delivery technologies, as well as licensing activities, continues to provide a stimulating
environment for the creation of medically differentiated medicines.”
And on the “enhanced ability to innovate”, the press release goes:
“The transaction will over time significantly enhance cooperation and cross fertilization among all research hubs inside and outside of the combined company. Sharing of technologies (e.g. RNAi, novel protein architectures), assets (e.g. chemical libraries), intellectual property(e.g. antibody production), unique capabilities (e.g. exploratory development, modeling and simulation) and know-how of the combined research organization will strengthen the Group's ability to innovate.”
I wonder how much Genentech will be surprised by the offer. In this regard, it is also interesting to speculate whether Alnylam had been in negotiations with Genentech or not. If so, would an unsolicited takeover of Genentech by Roche mean that Alnylam has to forego platform license fees that it would have otherwise received if Genentech remained independent? On the other hand, could it be that Genentech’s moves into RNAi Therapeutics had long been co-ordinated with Roche’s efforts, relying on being able to access RNAi know-how and IP through Roche? I guess the answer will come whether the $89 a share offer will be recommended by Genentech management to shareholders or not. Given the close ties between the companies a Ventana-like takeover battle is difficult to imagine. The weak dollar may also aid Roche in increasing the price a little bit to satisfy all Genentech shareholders.
Today’s development promises to be a defining moment in the history of drug development. With the recent acquisitions of diagnostics company Ventana and now Genentech, Roche has now fully committed to embracing the future of personalized medicine. Based on comments by the new CEO Severin Schwan who has now more than amply demonstrated that he really means what he says, RNAi Therapeutics is to play a key part in this.
Sunday, July 20, 2008
Genentech and RNAi Therapeutics- Part 1
A very enjoyable, yet detailed feature article by Walter Armstrong on the state and prospects of RNAi Therapeutics in the Pharmaceutical Executive this month, concludes with a somewhat bold prediction of mine: Genentech will partner with Alnylam to develop RNAi Therapeutics. I would like to use the next two blogs to expand on this speculation, explaining why such an alliance would not just make Alnylam shareholders happy (Part 1), but also the ways that Genentech’s participation in RNAi Therapeutics should benefit the entire sector (Part 2).
First off, all of this is conjecture and not based on inside information. I think it is fair to say that Alnylam is the bellwether of the RNAi sector. At the same time, however, Alnylam has made it no secret that it in turn is following the example of another biotech company- the iconic Genentech. For example, when Alnylam won the prestigious biotechnology James D. Watson Helix award for the mid-cap category in 2006, it was particularly proud to join Genentech as that year’s winner of the large cap category. References to Genentech’s business development strategy can also be heard at regular intervals in its conference calls and interviews like the one by Nature Biotech with Alnylam CEO John Maraganore in 2007 from which this excerpt is taken:
“JM: By that, I mean good old-fashioned, peer-reviewed, published research, appearing in top journals like Nature, Science and Cell. In this, we have a prominent role model: Genentech (S. San Francisco, CA, USA).When I was starting my career in biotech in the 1980s, Genentech wowed both academic and industrial scientists by blazing a trail in genetic engineering. Every week, it seemed, there
was a paper in one of those top journals describing an exciting new advance—Axel Ullrich making fusion receptors with cytoplasmic tails that helped us understand cell signaling, the cloning of tissue plasminogen activator—all of which were amazing feats at the time. Just as importantly,Genentech captured the imagination first of academic scientists, then of public-market investors and then of Hoffmann-
La Roche (Basel, Switzerland), all of whom profited handsomely on their decisions to place their trust and their capital in the hands of that company’s leaders.”
Also note the reference to Roche and Alnylam's deal with Roche announced 3 months thereafter. It was then also a statement by Roche made in the wake of Roche-Alnylam expressing their hopes that Alnylam may be their second Genentech (Roche is the majority owner of Genentech), that then confirmed that there may be more to Alnylam-Genentech than just the respect and admiration of an emerging company for the industry powerhouse. I’d like to think that at the time the statement was made, it was not merely hopes of making lots of money that where on Severin Schwan’s mind, now the CEO of Roche.
When as part of the Tekmira-Protiva reunion it was mentioned that out of the four technology evaluations by unnamed companies there was a Big Biotech, it was possible to start seeing the scientific dimensions take shape. Appropriately, in addition to Alnylam upping their stake, Roche joined by buying 4% of New Tekmira. As a reminder, one of the most promising therapeutic areas for SNALP RNAi delivery technology is oncology, and when it comes to Roche and cancer, we really mean Genentech and cancer.
Genentech not only pioneered recombinant protein therapeutics, but is also leading the pack in developing personalized cancer medicines. As I mentioned in an earlier blog, Genentech is now looking at small molecules as monoclonal antibodies cannot address the numerous targets it has discovered and accumulated considerable know-how in as part of their oncology efforts. These targets are downstream of the much more limited upstream components of cancer signaling pathways (downstream in general also means more specific/safer). This is particularly problematic when resistance mutations occur that render targeting the upstream ones futile. While RNAi Therapeutics had not been officially mentioned, I have to admit that I would be very surprised and quite frankly disappointed if Genentech did not resort to RNAi to harness its oncology target know-how by non-monoclonal means.
RNAi-related microRNAs should also be of great interest to Genentech as they could be developed as companion diagnostics for personalized cancer drug treatment, and possibly as therapeutic targets themselves to which Alnylam could provide access via Regulus.
Building on publicly disclosed RNAi screening know-how, the following job advertisement by Genentech earlier this year suggests that its RNAi Therapeutics plans are rapidly materializing:
“Responsibilities: We are seeking a highly motivated Research Associate or Senior Research Associate to conduct a range of research activities to enable delivery of an exciting new class of therapeutics based on RNA interference (RNAi). As a key member of our research team, this scientist will use a variety of methods (molecular biology, cell biology and biochemistry) to: (a) develop technologies to effectively deliver RNA-based drugs for a variety of therapeutic indications and (b) discover and elucidate the mechanisms of delivery and gene silencing.”
Whether an alliance is announced this year or not, the above circumstantial evidence and the secretive Genentech conference participants suggest to me that srtl RNAi Therapeutics will not only be validated as the innovation outlet for Big Pharma, but even biotech.
To be continued…
First off, all of this is conjecture and not based on inside information. I think it is fair to say that Alnylam is the bellwether of the RNAi sector. At the same time, however, Alnylam has made it no secret that it in turn is following the example of another biotech company- the iconic Genentech. For example, when Alnylam won the prestigious biotechnology James D. Watson Helix award for the mid-cap category in 2006, it was particularly proud to join Genentech as that year’s winner of the large cap category. References to Genentech’s business development strategy can also be heard at regular intervals in its conference calls and interviews like the one by Nature Biotech with Alnylam CEO John Maraganore in 2007 from which this excerpt is taken:
“JM: By that, I mean good old-fashioned, peer-reviewed, published research, appearing in top journals like Nature, Science and Cell. In this, we have a prominent role model: Genentech (S. San Francisco, CA, USA).When I was starting my career in biotech in the 1980s, Genentech wowed both academic and industrial scientists by blazing a trail in genetic engineering. Every week, it seemed, there
was a paper in one of those top journals describing an exciting new advance—Axel Ullrich making fusion receptors with cytoplasmic tails that helped us understand cell signaling, the cloning of tissue plasminogen activator—all of which were amazing feats at the time. Just as importantly,Genentech captured the imagination first of academic scientists, then of public-market investors and then of Hoffmann-
La Roche (Basel, Switzerland), all of whom profited handsomely on their decisions to place their trust and their capital in the hands of that company’s leaders.”
Also note the reference to Roche and Alnylam's deal with Roche announced 3 months thereafter. It was then also a statement by Roche made in the wake of Roche-Alnylam expressing their hopes that Alnylam may be their second Genentech (Roche is the majority owner of Genentech), that then confirmed that there may be more to Alnylam-Genentech than just the respect and admiration of an emerging company for the industry powerhouse. I’d like to think that at the time the statement was made, it was not merely hopes of making lots of money that where on Severin Schwan’s mind, now the CEO of Roche.
When as part of the Tekmira-Protiva reunion it was mentioned that out of the four technology evaluations by unnamed companies there was a Big Biotech, it was possible to start seeing the scientific dimensions take shape. Appropriately, in addition to Alnylam upping their stake, Roche joined by buying 4% of New Tekmira. As a reminder, one of the most promising therapeutic areas for SNALP RNAi delivery technology is oncology, and when it comes to Roche and cancer, we really mean Genentech and cancer.
Genentech not only pioneered recombinant protein therapeutics, but is also leading the pack in developing personalized cancer medicines. As I mentioned in an earlier blog, Genentech is now looking at small molecules as monoclonal antibodies cannot address the numerous targets it has discovered and accumulated considerable know-how in as part of their oncology efforts. These targets are downstream of the much more limited upstream components of cancer signaling pathways (downstream in general also means more specific/safer). This is particularly problematic when resistance mutations occur that render targeting the upstream ones futile. While RNAi Therapeutics had not been officially mentioned, I have to admit that I would be very surprised and quite frankly disappointed if Genentech did not resort to RNAi to harness its oncology target know-how by non-monoclonal means.
RNAi-related microRNAs should also be of great interest to Genentech as they could be developed as companion diagnostics for personalized cancer drug treatment, and possibly as therapeutic targets themselves to which Alnylam could provide access via Regulus.
Building on publicly disclosed RNAi screening know-how, the following job advertisement by Genentech earlier this year suggests that its RNAi Therapeutics plans are rapidly materializing:
“Responsibilities: We are seeking a highly motivated Research Associate or Senior Research Associate to conduct a range of research activities to enable delivery of an exciting new class of therapeutics based on RNA interference (RNAi). As a key member of our research team, this scientist will use a variety of methods (molecular biology, cell biology and biochemistry) to: (a) develop technologies to effectively deliver RNA-based drugs for a variety of therapeutic indications and (b) discover and elucidate the mechanisms of delivery and gene silencing.”
Whether an alliance is announced this year or not, the above circumstantial evidence and the secretive Genentech conference participants suggest to me that srtl RNAi Therapeutics will not only be validated as the innovation outlet for Big Pharma, but even biotech.
To be continued…
Tuesday, July 15, 2008
Journal Club: Structural Basis for Double-Stranded RNA Recognition by TLR3 and Activation
The recent Nature paper by Ambati and colleagues raised some concerns about whether non-specific inflammatory responses due to activation of TLR3 by double-stranded RNAs, the inducers of RNAi, would represent a significant, if not insurmountable obstacle towards the development of RNAi Therapeutics. While the short answer was no, since most in the field had already recognized the need to screen against the capacity of RNAi triggers to induce immune responses, determining the rules activating TLR3 and similar molecular patterns should facilitate the more efficient design of safe and potent RNAi triggers. Recent papers on TLR3 structural biology should do just that.
In an April edition in the journal Science, Liu and colleagues from the NIH report on the structure of mouse TLR3 with its double-stranded RNA substrate (note that mouse and human TLR3 are very similar). The structure suggests that a 40-50 base-pair double-strand RNA is optimal for binding by TLR3 thereby inducing TLR3 dimerization and downstream signaling. The fact that one of the dsRNA binding patches contains a number of pH-sensitive histidines further suggest why TLR3 signaling is most robust following uptake into endosome which provides for an acidic compartment. Overall, the structure supports previous observations that dsRNAs longer than what is typically used for siRNAs are better inducers of TLR3; however it does not explain well how smaller siRNAs may also induce such signaling.
An explanation for this is provided by structure-based mutagenesis studies by Pirher and colleagues from the University of Ljublijana (Slovenia). In this paper, they identify two dsRNA-binding patches within a TLR3 monomer and also find and explain why B-type helices, as typically found in DNA, only bind to one of the two binding patches and therefore fail to induce, and even competitively inhibit TLR3. This is in contrast to dsRNAs that typically assume A-type helical formation and bind both patches. With this the authors come up with a model to explain how TLR3 dimers bind to shorter double-stranded RNAs by assuming alternative conformations with ddimerization on the shorter dsRNAs being less efficient.
These findings immediately suggest various ways to avoid TLR3 signaling. The simplest would be to stay below 21 nucleotides, and it is well known that 20 nucleotide siRNAs are equally potent inducers of RNAi. Unlike the somewhat disgruntled 1st commentator following my previous blog would like to suggest, 15-21 nucleotide siRNAs as covered by one version of Kreutzer-Limmer in Europe are therefore therapeutically highly relevant. Generally, keeping it short is the probably easiest way to avoid non-specific immune responses. Next to sequence length, limited modifications of the siRNA at sites where they interact with TLR3 as shown by the structure should abolish any TLR3 activation and possibly serve to antagonize TLR3, similar to what has been found for 2’o-methylation and TLR7. Likewise, changing the helical shape at one end which may also have the added benefit in encouraging asymmetric RiSC loading may be a third strategy of circumventing TLR3 activation.
It is clear from reading the papers that much of the motivation for performing these is related to RNAi Therapeutics. These are findings that are not just theoretical in nature, but very much of practical relevance. The speed with which this progress has been achieved illustrates the vigor and the many tools brought to bear by the scientific community on making RNAi Therapeutics become a reality.
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