It was with a healthy dose of suspicion that I went today to a presentation by Mike Varney from Genentech on their small molecule operations which is a new addition to the Genentech and which he was spear-heading. Of course, as the pioneer of biotech the first question to be addressed was why Genentech would go into small molecules at all if that was part of the reason why Big Pharma was ailing anyway?
Hearing about the challenges of RNAi delivery ad nauseum, you’d think that relative ease of delivery such as by oral bioavailability would be a major motivation, but this was not the case. In the business of treating serious, life-threatening disease with large unmet medical needs, it becomes less relevant if you can go home and take a pill twice a day, or whether you get an intravenous infusion every other week. No, the main rationale provided was that as Genentech scientists dive deep into the biology of disease pathways, they often find themselves with promising drug targets, but which cannot be reached by antibodies. Antibodies are great for targeting cell surface proteins, but useless for intracellular targets whereas small molecules can more easily achieve that feat. Target space is the keyword here, and according to Dr. Varney target space is very limited, so limited so that as a biotech reaches the size of a Genentech or Amgen it has to think about other drug classes while at the same time Big Pharma is expanding into biologics.
You can imagine how my mind was racing wishing to tell Genentech that it was right in front of their eyes and RNAi is what they were really looking for, a technology that may address virtually any gene and also circumvent the painful lead optimization process for small molecules Mike Varney was going through (and yes, I cannot believe that they have not thought about small RNAs already even if much of the thinking was done for them by mother Roche).
But that’s not really my main point tonight. As he was describing the diverse skills it took to bring the clinic and pointing out that part of the reason that current productivity in drug development is so dismal (the latest number is $1.4B spent for every new drug developed) and Genentech was so successful is that many companies think they can get away with by just concentrating on a small part of the skill pie. And this may be very true for the current RNAi Therapeutics space as well.
While the entry barrier for target discovery using RNAi is relatively low, developing an actual RNAi Therapeutics is much more complicated than that. Just considering the scientific aspects, the development of an RNAi Therapeutic requires among other things, precise knowledge of the disease biology, basic RNAi and microRNA biology, know-how in siRNA design and chemistry, assessing off-target risk and the interplay of the RNAi trigger and/or delivery vehicle with the immune system, RNAi pharmacology, and being able to safely deliver the RNAi cargo.
I get the impression that there are a number of programs/companies out there that do not take into account e.g. the off-target profile in their design of an RNAi trigger and instead select a published sequence or one that they find can simply knock down a gene and eventually take that into the clinic, or lack the know-how required to adequately assess innate immune responses. This could be avoided if smaller companies weren’t so afraid in collaborating with each other or larger companies, partly for fear that it may negatively affect how the investment community perceives their competitive scientific prowess and IP position. Right now, I can only see very few companies that have the financial wherewithal and scientific know-how to establish an integrated RNAi Therapeutics development platform that alone could shepherd RNAi Therapeutic candidates into the clinic. Alnylam, Merck, maybe Novartis, and probably soon Roche and Pfizer may have such capabilities, and these examples may not even cover all the bases just as Genentech is collaborating with both small and large.
Smaller companies, particularly those with a focus on delivery should probably seek help in deciding which RNAi trigger to use with their particular technology. Of course, having something to offer in return will help their negotiation position. As you know, I think Tekmira/Protiva have done that quite well and obtained up to 7 InterfeRx picks from Alnylam in exchange for liposomal siRNA delivery technology. In other instances where the technological payback may not be that obvious for the established company, it may still be a good investment to help with siRNA design as part of granting a technology license, as it should also increase the odds of successful clinical development and therefore potential for royalty income further downstream. Big Pharma most likely would not be interested in such top-to-bottom technology transfer arrangements, but it may be a consideration for some of the more established pure play RNAi Therapeutics companies.
Wednesday, April 30, 2008
Monday, April 28, 2008
Lipidoids Expand Chemical Space for Cationic Liposome Delivery of RNAi Therapeutics
[Important update, see end of entry]
Following a long series of presentations and publications involving Protiva, Tekmira, Alnylam, and Merck/Sirna, PEG-stabilized cationic liposomes known as SNALPs have to be considered one if not THE most advanced systemic RNAi delivery technology to date. While efficacy was very potent at single-digit mg/kg doses, the major drawback of the first studies on SNALP-siRNA delivery were slight elevations in liver enzymes, an indicator of toxicity (Zimmermann et al. study). It was therefore important to expand on those studies and search for formulations with even better knockdown efficacies and inherently less toxicity, thus pushing the therapeutic index well into predictably clinically safe ranges.
The recent announcements 0.1mg/kg IC50 knockdown efficiencies for SNALP-like formulations by both Protiva and Tekmira (due to their upcoming merger from now on referred to as Tekmira for simplicity) support the notion that the exploration of new chemistries should facilitate the development of SNALP RNAi for clinical use, and although only the surface has been scratched, a first IND with realistic chances at therapeutic success may not be very far away.
To exploit the chemical space available for SNALPs though requires the ability to generate new and diverse lipid chemistries as well as the ability to manufacture and formulate these chemistries to scale. The latter has been achieved by Tekmira’s spontaneous vesicle formation by ethanol dilution method allowing for the speedy manufacture of SNALP-siRNA formulations that can support late pre-clinical and clinical studies, while the long-awaited paper by Akinc and colleagues from the MIT (Langer/Anderson lab) and Alnylam Pharmaceuticals on so called lipidoids and that has now been published in Nature Biotechnology [Akinc et al. (2008): A combinatorial library of lipid-like materials for delivery of RNAi therapeutics.], will now faciliate the efficient exploration of novel, SNALP-compatible lipid chemistries.
Rather than laboriously synthesizing and testing one lipid after the other on a hypothesis-driven basis, Akinc and colleagues developed a synthesis method that allowed them to generate libraries of cationic lipids with quite unusual and diverse characteristics to systematically evaluate them for siRNA delivery. A first library gave an indication of which chemistries worked better than others, and a second library was generated based on the characteristics of the best performing ones in the first set.
Initial tests were based on silencing reporter genes in tissue culture. It should be noted that for these high-throughput experiments, probably for speed and ease, simple siRNA-lipoplexes were used (siRNA-lipid mix), instead liposomally formulated siRNA as for later tests in vivo (siRNA captured inside liposomes), and this may be one limitation as it could have caused them to miss even more promising in vivo silencing chemistries. In any case, the best candidates were then taken forward into rodent and non-human primate studies, this time formulating the lipids together with cholesterol and PEG-lipid into cationic liposomes, essentially based on the same principles as SNALPs (stabilized liposomes containing diffusible PEG-lipids, the latter interestingly manufactured by Alnylam itself).
Overall, IC50s in the low mg/kg range were routinely observed for a number of liver targets. This was achieved without significant toxicities based on careful safety analysis, and only in some cases mild elevations, less than 2-fold, of liver enzymes were observed. Similarly, the absence of negative interference with endogenous microRNA pathways was reported last year. This is a good start and may not have employed the most efficacious siRNAs, but by optimizing the formulations further, e.g. by engineering additional fusogenic lipids and other properties into these particles, sub-mg/kg doses that would be desirable in the clinic should be achievable and still be compatible with the more scalable manufacturing technologies practiced by Tekmira (although 50nm particles and high encapsulation efficiencies were achieved, the extrusion-based method as employed in the present study may limit scale).
Beyond the liver, the lipidoid formulation showed some promise for the delivery of siRNAs to the lung as demonstrated in an RSV model. Interestingly, inhibition of RSV replication was enhanced by lipidoid-siRNAs (almost 3-log knockdown at 2mg/kg) over unformulated, naked siRNAs (1-log knockdown), in contrast to previous studies on which Alnylam’s ALN-RSV01 is based that showed somewhat less viral knockdown with naked siRNAs and that suggested no enhancement of siRNA delivery to the lung by formulation with other delivery chemistries. In addition, given the propensity of such nanoparticles to be taken up by phagocytic cells of the immune system and the largely unmodified siRNAs used for targeting RSV, follow-up studies need to look at any innate immune responses elicited by such lipidoid-siRNA combinations.
In summary, this study opens up a wide chemical space for the systematic evaluation of cationic liposome-mediated delivery of drugs, particularly siRNAs, but also microRNA antagonists (demonstrated in this study) and beyond. Following some of the recent breakthroughs and due to the triangular relationship between Alnylam, Tekmira, and the MIT, complementary in terms of both know-how and IP, progress of SNALP-siRNAs into the clinic may hopefully occur within the next few months and should be followed by next-generation chemistries.
[Update May 1, 2008: According to a report by RNAiNews , an Alnylam spokesperson indicated that the company had not given guidance on the specific liposome formulations to be used for their hypercholesterolemia and liver cancer clinical programs. This is in contrast to an earlier report by RNAiNews from last year’s Beyond Genome conference in San Francisco which indicated that Alnylam had chosen “choose lipidoids over SNALPs” for these indications (also discussed in a blog entry here). It therefore seems that Protiva/Tekmira's 0.1mg/kg IC50 liposomal nanoparticle formulations may be the current frontrunners in entering the clinic (see also a recent PR).
The sometimes imprecise use of the terms SNALPs and lipidoids may be partly to blame for the confusion. SNALP refers to a liposomal formulation technique, while lipidoids are a new class of lipids generated by combinatorial chemistry which can now be evaluated for liposomal drug delivery. As such, lipidoids could be used within the context of SNALPs, and both of these approaches are therefore complementary to each other.]
Following a long series of presentations and publications involving Protiva, Tekmira, Alnylam, and Merck/Sirna, PEG-stabilized cationic liposomes known as SNALPs have to be considered one if not THE most advanced systemic RNAi delivery technology to date. While efficacy was very potent at single-digit mg/kg doses, the major drawback of the first studies on SNALP-siRNA delivery were slight elevations in liver enzymes, an indicator of toxicity (Zimmermann et al. study). It was therefore important to expand on those studies and search for formulations with even better knockdown efficacies and inherently less toxicity, thus pushing the therapeutic index well into predictably clinically safe ranges.
The recent announcements 0.1mg/kg IC50 knockdown efficiencies for SNALP-like formulations by both Protiva and Tekmira (due to their upcoming merger from now on referred to as Tekmira for simplicity) support the notion that the exploration of new chemistries should facilitate the development of SNALP RNAi for clinical use, and although only the surface has been scratched, a first IND with realistic chances at therapeutic success may not be very far away.
To exploit the chemical space available for SNALPs though requires the ability to generate new and diverse lipid chemistries as well as the ability to manufacture and formulate these chemistries to scale. The latter has been achieved by Tekmira’s spontaneous vesicle formation by ethanol dilution method allowing for the speedy manufacture of SNALP-siRNA formulations that can support late pre-clinical and clinical studies, while the long-awaited paper by Akinc and colleagues from the MIT (Langer/Anderson lab) and Alnylam Pharmaceuticals on so called lipidoids and that has now been published in Nature Biotechnology [Akinc et al. (2008): A combinatorial library of lipid-like materials for delivery of RNAi therapeutics.], will now faciliate the efficient exploration of novel, SNALP-compatible lipid chemistries.
Rather than laboriously synthesizing and testing one lipid after the other on a hypothesis-driven basis, Akinc and colleagues developed a synthesis method that allowed them to generate libraries of cationic lipids with quite unusual and diverse characteristics to systematically evaluate them for siRNA delivery. A first library gave an indication of which chemistries worked better than others, and a second library was generated based on the characteristics of the best performing ones in the first set.
Initial tests were based on silencing reporter genes in tissue culture. It should be noted that for these high-throughput experiments, probably for speed and ease, simple siRNA-lipoplexes were used (siRNA-lipid mix), instead liposomally formulated siRNA as for later tests in vivo (siRNA captured inside liposomes), and this may be one limitation as it could have caused them to miss even more promising in vivo silencing chemistries. In any case, the best candidates were then taken forward into rodent and non-human primate studies, this time formulating the lipids together with cholesterol and PEG-lipid into cationic liposomes, essentially based on the same principles as SNALPs (stabilized liposomes containing diffusible PEG-lipids, the latter interestingly manufactured by Alnylam itself).
Overall, IC50s in the low mg/kg range were routinely observed for a number of liver targets. This was achieved without significant toxicities based on careful safety analysis, and only in some cases mild elevations, less than 2-fold, of liver enzymes were observed. Similarly, the absence of negative interference with endogenous microRNA pathways was reported last year. This is a good start and may not have employed the most efficacious siRNAs, but by optimizing the formulations further, e.g. by engineering additional fusogenic lipids and other properties into these particles, sub-mg/kg doses that would be desirable in the clinic should be achievable and still be compatible with the more scalable manufacturing technologies practiced by Tekmira (although 50nm particles and high encapsulation efficiencies were achieved, the extrusion-based method as employed in the present study may limit scale).
Beyond the liver, the lipidoid formulation showed some promise for the delivery of siRNAs to the lung as demonstrated in an RSV model. Interestingly, inhibition of RSV replication was enhanced by lipidoid-siRNAs (almost 3-log knockdown at 2mg/kg) over unformulated, naked siRNAs (1-log knockdown), in contrast to previous studies on which Alnylam’s ALN-RSV01 is based that showed somewhat less viral knockdown with naked siRNAs and that suggested no enhancement of siRNA delivery to the lung by formulation with other delivery chemistries. In addition, given the propensity of such nanoparticles to be taken up by phagocytic cells of the immune system and the largely unmodified siRNAs used for targeting RSV, follow-up studies need to look at any innate immune responses elicited by such lipidoid-siRNA combinations.
In summary, this study opens up a wide chemical space for the systematic evaluation of cationic liposome-mediated delivery of drugs, particularly siRNAs, but also microRNA antagonists (demonstrated in this study) and beyond. Following some of the recent breakthroughs and due to the triangular relationship between Alnylam, Tekmira, and the MIT, complementary in terms of both know-how and IP, progress of SNALP-siRNAs into the clinic may hopefully occur within the next few months and should be followed by next-generation chemistries.
[Update May 1, 2008: According to a report by RNAiNews , an Alnylam spokesperson indicated that the company had not given guidance on the specific liposome formulations to be used for their hypercholesterolemia and liver cancer clinical programs. This is in contrast to an earlier report by RNAiNews from last year’s Beyond Genome conference in San Francisco which indicated that Alnylam had chosen “choose lipidoids over SNALPs” for these indications (also discussed in a blog entry here). It therefore seems that Protiva/Tekmira's 0.1mg/kg IC50 liposomal nanoparticle formulations may be the current frontrunners in entering the clinic (see also a recent PR).
The sometimes imprecise use of the terms SNALPs and lipidoids may be partly to blame for the confusion. SNALP refers to a liposomal formulation technique, while lipidoids are a new class of lipids generated by combinatorial chemistry which can now be evaluated for liposomal drug delivery. As such, lipidoids could be used within the context of SNALPs, and both of these approaches are therefore complementary to each other.]
ENHANCE Ripple Effects Felt at ISIS Pharmaceuticals
The waves started by the ENHANCE tsunami have finally come to engulf ISIS Pharmaceutical’s stock this Friday as the FDA indicated that it wants to see costly and more time-consuming outcome studies for all but the most at-risk cardiovascular patient population in the approval of ISIS’ lead product mipomersen, an antisense compound directed against ApoB-100 in the liver. As I had discussed earlier in the wake of two high-profile studies that failed to correlate the responses of some of the most trusted biomarkers for diabetes and cardiovascular disease with disease outcome, most notably Merck/Schering-Plough’s ENHANCE study, this was almost to be expected.
The 29% drop in the stock that day was caused by a discussion between ISIS and their partners at Genzyme with the FDA on the approval path for mipomersen. Instead of being able to gain accelerated approval by merely showing LDL-cholesterol lowering as a surrogate biomarker for a broader patient population, this will only be accepted for the small homozygous familial hypercholesterolemia (ho FH) population, and it was not clear from the conference call whether this would be a full or an accelerated approval. For all other indications, mipomersen now has to show tangible benefits with regards to cardiovascular events, which, although it would eventually increase the market value of the drug considerably, means longer and more expensive outcome trials before the real commercial value of mipomersen can be realized (in addition, ho FH will be delayed by at least one year, because the FDA requires 2 rodent carcinogenic studies, instead of the one they had planned for).
What can the RNAi Therapeutics space learn from this experience? One lesson is that it is very important to be clear early on with what the almighty FDA wants to see in approving a drug, something particularly relevant for novel technologies and novel drug targets such as will be the case with RNAi. It is probably not a coincidence that clarity has come now that Genzyme has joined the mipomersen effort, as it is probably THE company experienced with gaining regulatory approval for unique, high-margin drugs with small, but very well-defined patient populations, a category that a number of RNAi Therapeutics will fall into as part of the personalized medicine revolution.
Another lesson is that the fortunes of an entire technology platform may be subject to the woes of a single dominant development program. While the cardiovascular disease market is enormous and the potential rewards substantial, this is not without a reason and substantial investments have to be made before gaining approval. A number of RNAi Therapeutics companies such as Alnylam, Tekmira/Protiva, RXi, Mirus Bio, and Merck have all indicated an interest in targeting very promising liver targets for hypercholesterolemia by RNAi, and although it may limit the ultimate financial reward, a company like Alnylam that carries much of the hope for realizing the therapeutic promise of RNAi, may have to think twice about to what degree it wants to make itself dependent on a single development program such as ALN-PCS01.
Companies targeting ApoB by RNAi (probably including Tekmira/Protiva, RXi, and Merck) should benefit considerably by learning from ISIS’ pioneering ApoB experience, and actually should have a chance at gaining accelerated approval should ISIS be able to show that lowering LDL-cholesterol by targeting ApoB is associated with cardiovascular benefits. For companies like Alnylam though interested in other, previously untested targets, the decision may only confirm that, yes, outcome studies will be required.
I welcome the trend towards evidence-based medicine and addressing some of the problems associated with direct-to-consumerism, but again, the FDA and politicians should not blindly destroy the drug development industry by forgetting that at the same time there need to be clear rewards for innovative (patent protection!) and efficacious (reimbursement!) drugs. This way the pie could stay around the same size, and yet everybody including patients, payers, and the industry would be winners.
Also this week: In a catastrophic financing, Nastech raised just shy of $8M in a registered direct offering at a probably historically low $1.73 a share, and may raise another $3M at $2.17 a share. One has to wonder why this relatively small fund-raising round was done at all at these so unfavorable conditions- unfavorable at least for the present shareholders. In any case, this may be the best time to cut their losses and fully commit to developing RNAi Therapeutics while monetizing what is left over from TJT nasal delivery. Their experience in drug delivery and peptide technology in particular may position them to be a respectable player in peptide-facilitated RNAi delivery (direct conjugation of RNAi trigger to membrane-penetrating peptides and/or using peptides as ligands for targeted delivery). But there is one advice that I would give them: please do not waste any more of your shareholder money and your own credibility on senseless and blatant patent workaround efforts such as three-stranded siRNAs. As the 36% drop on Friday illustrates, investors are sophisticated enough to see through this and rather than claiming to own everything under the RNAi sun, or universe, it is more credible to specialize in an area of your expertise and be good at it. Develop clinically relevant delivery for example, and the market will more than generously reward you for it.
The 29% drop in the stock that day was caused by a discussion between ISIS and their partners at Genzyme with the FDA on the approval path for mipomersen. Instead of being able to gain accelerated approval by merely showing LDL-cholesterol lowering as a surrogate biomarker for a broader patient population, this will only be accepted for the small homozygous familial hypercholesterolemia (ho FH) population, and it was not clear from the conference call whether this would be a full or an accelerated approval. For all other indications, mipomersen now has to show tangible benefits with regards to cardiovascular events, which, although it would eventually increase the market value of the drug considerably, means longer and more expensive outcome trials before the real commercial value of mipomersen can be realized (in addition, ho FH will be delayed by at least one year, because the FDA requires 2 rodent carcinogenic studies, instead of the one they had planned for).
What can the RNAi Therapeutics space learn from this experience? One lesson is that it is very important to be clear early on with what the almighty FDA wants to see in approving a drug, something particularly relevant for novel technologies and novel drug targets such as will be the case with RNAi. It is probably not a coincidence that clarity has come now that Genzyme has joined the mipomersen effort, as it is probably THE company experienced with gaining regulatory approval for unique, high-margin drugs with small, but very well-defined patient populations, a category that a number of RNAi Therapeutics will fall into as part of the personalized medicine revolution.
Another lesson is that the fortunes of an entire technology platform may be subject to the woes of a single dominant development program. While the cardiovascular disease market is enormous and the potential rewards substantial, this is not without a reason and substantial investments have to be made before gaining approval. A number of RNAi Therapeutics companies such as Alnylam, Tekmira/Protiva, RXi, Mirus Bio, and Merck have all indicated an interest in targeting very promising liver targets for hypercholesterolemia by RNAi, and although it may limit the ultimate financial reward, a company like Alnylam that carries much of the hope for realizing the therapeutic promise of RNAi, may have to think twice about to what degree it wants to make itself dependent on a single development program such as ALN-PCS01.
Companies targeting ApoB by RNAi (probably including Tekmira/Protiva, RXi, and Merck) should benefit considerably by learning from ISIS’ pioneering ApoB experience, and actually should have a chance at gaining accelerated approval should ISIS be able to show that lowering LDL-cholesterol by targeting ApoB is associated with cardiovascular benefits. For companies like Alnylam though interested in other, previously untested targets, the decision may only confirm that, yes, outcome studies will be required.
I welcome the trend towards evidence-based medicine and addressing some of the problems associated with direct-to-consumerism, but again, the FDA and politicians should not blindly destroy the drug development industry by forgetting that at the same time there need to be clear rewards for innovative (patent protection!) and efficacious (reimbursement!) drugs. This way the pie could stay around the same size, and yet everybody including patients, payers, and the industry would be winners.
Also this week: In a catastrophic financing, Nastech raised just shy of $8M in a registered direct offering at a probably historically low $1.73 a share, and may raise another $3M at $2.17 a share. One has to wonder why this relatively small fund-raising round was done at all at these so unfavorable conditions- unfavorable at least for the present shareholders. In any case, this may be the best time to cut their losses and fully commit to developing RNAi Therapeutics while monetizing what is left over from TJT nasal delivery. Their experience in drug delivery and peptide technology in particular may position them to be a respectable player in peptide-facilitated RNAi delivery (direct conjugation of RNAi trigger to membrane-penetrating peptides and/or using peptides as ligands for targeted delivery). But there is one advice that I would give them: please do not waste any more of your shareholder money and your own credibility on senseless and blatant patent workaround efforts such as three-stranded siRNAs. As the 36% drop on Friday illustrates, investors are sophisticated enough to see through this and rather than claiming to own everything under the RNAi sun, or universe, it is more credible to specialize in an area of your expertise and be good at it. Develop clinically relevant delivery for example, and the market will more than generously reward you for it.
Sunday, April 27, 2008
Small RNAs with First Clinical Impact
Small RNAs are about to make their clinical debut. This week, Asuragen, a leading microRNA diagnostics and therapeutics company, announced that it is about to launch the first microRNA-based diagnostic test for the differentiation between chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). PDAC is the most prevalent pancreatic cancer type and known for its late clinical presentation and poor prognosis. Because chronic pancreatitis that has a roughly comparable incidence and presents with often similar symptoms such as abdominal pain, digestive problems, and biliary obstruction resulting in mis-diagnosis rates of up to 25%, diagnostics that help to differentiate between them are invaluable for ensuring optimal treatment.
The test will be made available on May 2, 2008, from Asuragen’s own CLIA-certified test laboratory. It is a PCR-based test of apparently a single microRNA that is specific for pancreatic cancer cells and was originally identified as part of a collaboration between Asuragen and a clinical group from a hospital in Bochum, Germany [Szafranska et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26:4442-52 (2007)].
Other tests by Asuragen, but also notably Rosetta Genomics and Exiqon in the field, are about to enter the market in the coming months. Like the present one, they are PCR-based diagnostics of one or a few microRNAs. Despite the 25% mis-diagnosis rate, it seems that the need to obtain biopsies from the pancreas is not trivial and may therefore limit the use of this particular test. Tests which may diagnose a cancer based on microRNAs isolated from blood samples, and are currently under development, should have wider applicability, although this may be at a rather late stage of cancer.
Asuragen is a private company and it has been therefore more difficult for me to follow their progress. The fact that they beat the publicly held Rosetta Genomics and Exiqon in bringing the first microRNA diagnostic to market is likely based on their heritage of having been spun-out from the RNA research reagents company Ambion (now an Applied Biosystems subsidiary), therefore giving them prime access to very relevant technologies and know-how. The fact that they operate a CLIA-certified laboratory, of course, may be another significant efficiency giving them an advantage over its competitors. Ultimately, however, it would appear that the commercial success will depend on their ability to make the test widely available through larger diagnostics distribution partners. Alternatively, microRNA diagnostics that are tied to certain drugs, such as Rosetta’s squamous versus non-squamous non-small cell lung cancer (NSCLC) Dx that ensures that Genentech’s Avastin is not used for squamous NSCLC, could benefit from the marketing reach of large therapeutics partners.
At any rate, the fact small RNAs are about to have a real clinical impact less than a decade after their widespread occurrence in biology was first recognized, is to be celebrated and indicates that their small size and stability, and their biological involvement in disease makes them a very promising class for molecular diagnostics.
The test will be made available on May 2, 2008, from Asuragen’s own CLIA-certified test laboratory. It is a PCR-based test of apparently a single microRNA that is specific for pancreatic cancer cells and was originally identified as part of a collaboration between Asuragen and a clinical group from a hospital in Bochum, Germany [Szafranska et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26:4442-52 (2007)].
Other tests by Asuragen, but also notably Rosetta Genomics and Exiqon in the field, are about to enter the market in the coming months. Like the present one, they are PCR-based diagnostics of one or a few microRNAs. Despite the 25% mis-diagnosis rate, it seems that the need to obtain biopsies from the pancreas is not trivial and may therefore limit the use of this particular test. Tests which may diagnose a cancer based on microRNAs isolated from blood samples, and are currently under development, should have wider applicability, although this may be at a rather late stage of cancer.
Asuragen is a private company and it has been therefore more difficult for me to follow their progress. The fact that they beat the publicly held Rosetta Genomics and Exiqon in bringing the first microRNA diagnostic to market is likely based on their heritage of having been spun-out from the RNA research reagents company Ambion (now an Applied Biosystems subsidiary), therefore giving them prime access to very relevant technologies and know-how. The fact that they operate a CLIA-certified laboratory, of course, may be another significant efficiency giving them an advantage over its competitors. Ultimately, however, it would appear that the commercial success will depend on their ability to make the test widely available through larger diagnostics distribution partners. Alternatively, microRNA diagnostics that are tied to certain drugs, such as Rosetta’s squamous versus non-squamous non-small cell lung cancer (NSCLC) Dx that ensures that Genentech’s Avastin is not used for squamous NSCLC, could benefit from the marketing reach of large therapeutics partners.
At any rate, the fact small RNAs are about to have a real clinical impact less than a decade after their widespread occurrence in biology was first recognized, is to be celebrated and indicates that their small size and stability, and their biological involvement in disease makes them a very promising class for molecular diagnostics.
Friday, April 25, 2008
The Business of RNAi Therapeutics
I’m often asked about explaining RNAi and its potential as a therapeutic modality and investment in more layman terms. I hope my review, The Business of RNAi Therapeutics, that came out today in Human Gene Therapy will be able to address at least some of these questions. Although originally written with the scientist in mind asking him/herself about what the development of RNAi Therapeutics may mean as an investment or business opportunity, the science should be pretty digestible and accessible to the scientifically minded lay public. Here’s the abstract, the rest is freely accessible on the Human Gene Therapy website:
Business for RNAi Therapeutics has never been better. The confluence of the genome revolution, a pharmaceutical industry greatly challenged by generic competition and starved for innovation, and pre-existing nucleic acid drug development know-how that can now be directly applied to RNAi Therapeutics, means that RNAi, less than 10 years after its discovery in worms, has every chance of becoming the next major drug development platform for improving healthcare and generating profits at multiple levels. From the perspective of a molecular biologist interested in both basic and applied aspects of RNAi and related investments, I would like to first put RNAi into the context of the drug development enterprise and then discuss various strategies for translating the science of RNAi into commercially viable drugs as well as some of the risks the industry faces. While the discussion will focus on RNAi Therapeutics and the major US and European markets, it should be kept in mind that RNAi is a global effort and holds further commercial promise in agriculture, the research reagent and services markets, and the related area of microRNA-based therapeutics and diagnostics. Read on…here
Business for RNAi Therapeutics has never been better. The confluence of the genome revolution, a pharmaceutical industry greatly challenged by generic competition and starved for innovation, and pre-existing nucleic acid drug development know-how that can now be directly applied to RNAi Therapeutics, means that RNAi, less than 10 years after its discovery in worms, has every chance of becoming the next major drug development platform for improving healthcare and generating profits at multiple levels. From the perspective of a molecular biologist interested in both basic and applied aspects of RNAi and related investments, I would like to first put RNAi into the context of the drug development enterprise and then discuss various strategies for translating the science of RNAi into commercially viable drugs as well as some of the risks the industry faces. While the discussion will focus on RNAi Therapeutics and the major US and European markets, it should be kept in mind that RNAi is a global effort and holds further commercial promise in agriculture, the research reagent and services markets, and the related area of microRNA-based therapeutics and diagnostics. Read on…here
Sunday, April 20, 2008
Lost in Translation? Financial Express Report Says Multiple Merck RNAi Therapeutics Candidates in Clinical Development
[Update 23 April, 2008: added "multiple" to the title to emphasize potential clinical candidates in addition to the widely known wet AMD RNAi trial by Merck/Allergan]
This week I escaped from the lab to step into the warm and sunny California spring weather to see what was going on at Stanford’s Biotechnology job fair on the lawn of the Medical School. The first booth that I encountered was that by Sirna Therapeutics, the RNAi Therapeutics subsidiary of Merck. Strangely enough, when I started asking what kind of jobs they were offering, they suggested me to sign a non-disclosure agreement before saying anything more. Go figure, how do you intend to recruit the right people if you can’t properly tell them what jobs you are trying to fill?
I think this is somewhat symptomatic of Merck’s secretive attitude towards their RNAi Therapeutics development efforts. Following the Sirna acquisition, essentially nothing specifically has been disclosed about the stage of their development programs, one for wet AMD already in the clinic and others that were were close to IND filings as of before the Sirna takeover.
A February 7 interview of the Financial Express of India with Sirna Therapeutics’ Bharatt Chowrira, responsible for Merck’s Asian licensing and collaboration activities ex-Japan, could shed astounding light on Merck’s recent RNAi Therapeutics activities and have significant repercussions for the competitive landscape of RNAi Therapeutics.
Not only is it notable that while the interview was predicated on Merck’s general collaboration activities in India, most of Dr. Chowrira’s comments were geared towards RNAi Therapeutics, even more tantalizing, intended or not, was the following section:
“''We are serious about the R&D relationships in Asia in areas such as contract research and clincical trials and will be embracing partnerships,'' he said adding that Merck is building a virtual laboratory by mounting best scientific programs and there is more of external research conducted by partners. The company is searching for partners with a true collaboration mindset and the ability to deliver compounds against novel targets.
On the research front, the company is working towards providing personalized medicine. It has screened over six lakh RNAi, out of which two to three are in clinical trials and 10-20 are candidates for in pre-clinical trials. For starters, RNA interference (RNAi) is a mechanism that inhibits gene expression at the stage of translation or by hindering the transcription of specific genes. RNAi targets include RNA from virus [DH: HCV?] and play a role in regulating development and genome maintenance [DH: cancer?].”
It is known that Allergan is responsible for the development of one Sirna Therapeutics-derived product candidate, but is it really true that Merck has another one or two RNAi Therapeutics programs in the clinic (and 10-20! in pre-clinical studies)? Unlike development-stage biotechs for which making scientific progress public is an essential element in attracting investor interest, Big Pharma often likes to be secretive about their research programs, particularly in areas that here highly competitive.
If true, this would cast events in the past several months going back to Merck’s acquisition of Sirna in a completely different light. Much has been made of the $1.1billion price-tag, particularly as the impression was growing that Merck’s efforts to moving RNAi into the clinic were stalling. However, this equation would change dramatically from a discounted cash flow perspective if they were actually conducting RNAi Therapeutics trials right now in India. As such, Merck could gain valuable early insights into the safety and efficacy of SNALP-RNAi in man, for example by targeting ApoB or PCSK9 and measuring protein levels in the blood early on in phase I. That information could then either be used to progress these drug candidates further or to optimize the formulations. In addition to the competitive advantage, the secretive nature of these studies would also spare them the public humiliation that any failure would bring with it.
As the involvement of Tekmira, Protiva, Roche, Merck, Alnylam, and four as yet undisclosed Big Pharma/biotech companies document, the interest and potential competition for gene targets that can be addressed by SNALP-RNAi could be considerable. Could therefore say a conflict between Merck and Alnylam or one of Alnylam’s partners (e.g. Novartis) for the same gene targets have contributed to the break-up of Alnylam and Merck in the fall of last year? Did the court injunction forbidding Merck to further develop SNALP-based programs force them into the Protiva settlement, because otherwise it would have imperiled their clinical development activities? Does the possibility that Merck may have more than one additional RNAi clinical trial on top of wet AMD ongoing mean that the initial experience was positive so that they could rapidly expand the technology towards targeting multiple genes as is the promise of RNAi?
Maybe everything here is a misunderstanding and the truth was lost in translation, but in any case such a scenario certainly makes for an interesting exercise in game theory.
This week I escaped from the lab to step into the warm and sunny California spring weather to see what was going on at Stanford’s Biotechnology job fair on the lawn of the Medical School. The first booth that I encountered was that by Sirna Therapeutics, the RNAi Therapeutics subsidiary of Merck. Strangely enough, when I started asking what kind of jobs they were offering, they suggested me to sign a non-disclosure agreement before saying anything more. Go figure, how do you intend to recruit the right people if you can’t properly tell them what jobs you are trying to fill?
I think this is somewhat symptomatic of Merck’s secretive attitude towards their RNAi Therapeutics development efforts. Following the Sirna acquisition, essentially nothing specifically has been disclosed about the stage of their development programs, one for wet AMD already in the clinic and others that were were close to IND filings as of before the Sirna takeover.
A February 7 interview of the Financial Express of India with Sirna Therapeutics’ Bharatt Chowrira, responsible for Merck’s Asian licensing and collaboration activities ex-Japan, could shed astounding light on Merck’s recent RNAi Therapeutics activities and have significant repercussions for the competitive landscape of RNAi Therapeutics.
Not only is it notable that while the interview was predicated on Merck’s general collaboration activities in India, most of Dr. Chowrira’s comments were geared towards RNAi Therapeutics, even more tantalizing, intended or not, was the following section:
“''We are serious about the R&D relationships in Asia in areas such as contract research and clincical trials and will be embracing partnerships,'' he said adding that Merck is building a virtual laboratory by mounting best scientific programs and there is more of external research conducted by partners. The company is searching for partners with a true collaboration mindset and the ability to deliver compounds against novel targets.
On the research front, the company is working towards providing personalized medicine. It has screened over six lakh RNAi, out of which two to three are in clinical trials and 10-20 are candidates for in pre-clinical trials. For starters, RNA interference (RNAi) is a mechanism that inhibits gene expression at the stage of translation or by hindering the transcription of specific genes. RNAi targets include RNA from virus [DH: HCV?] and play a role in regulating development and genome maintenance [DH: cancer?].”
It is known that Allergan is responsible for the development of one Sirna Therapeutics-derived product candidate, but is it really true that Merck has another one or two RNAi Therapeutics programs in the clinic (and 10-20! in pre-clinical studies)? Unlike development-stage biotechs for which making scientific progress public is an essential element in attracting investor interest, Big Pharma often likes to be secretive about their research programs, particularly in areas that here highly competitive.
If true, this would cast events in the past several months going back to Merck’s acquisition of Sirna in a completely different light. Much has been made of the $1.1billion price-tag, particularly as the impression was growing that Merck’s efforts to moving RNAi into the clinic were stalling. However, this equation would change dramatically from a discounted cash flow perspective if they were actually conducting RNAi Therapeutics trials right now in India. As such, Merck could gain valuable early insights into the safety and efficacy of SNALP-RNAi in man, for example by targeting ApoB or PCSK9 and measuring protein levels in the blood early on in phase I. That information could then either be used to progress these drug candidates further or to optimize the formulations. In addition to the competitive advantage, the secretive nature of these studies would also spare them the public humiliation that any failure would bring with it.
As the involvement of Tekmira, Protiva, Roche, Merck, Alnylam, and four as yet undisclosed Big Pharma/biotech companies document, the interest and potential competition for gene targets that can be addressed by SNALP-RNAi could be considerable. Could therefore say a conflict between Merck and Alnylam or one of Alnylam’s partners (e.g. Novartis) for the same gene targets have contributed to the break-up of Alnylam and Merck in the fall of last year? Did the court injunction forbidding Merck to further develop SNALP-based programs force them into the Protiva settlement, because otherwise it would have imperiled their clinical development activities? Does the possibility that Merck may have more than one additional RNAi clinical trial on top of wet AMD ongoing mean that the initial experience was positive so that they could rapidly expand the technology towards targeting multiple genes as is the promise of RNAi?
Maybe everything here is a misunderstanding and the truth was lost in translation, but in any case such a scenario certainly makes for an interesting exercise in game theory.
Thursday, April 17, 2008
Regulus Deal Makes GSK Clear Force in MicroRNA Therapeutics
Only months after closing a similar agreement for the development of antiviral microRNA therapeutics with LNA company Santaris (Santaris PR), GSK today agreed to a co-development partnership with the Alnylam-ISIS microRNA therapeutics joint venture Regulus Therapeutics in the inflammatory disease area (Regulus PR).
In both deals, GSK has the option to select up to 4 microRNA therapeutics candidates developed by Santaris or Regulus in the respective disease areas for comparable financial terms that gives the microRNA therapeutics companies important and largely undilutive upfront cash, development milestones, and royalties (for exact terms, please refer to the Santaris and Reguls PRs).
It is also a vote of confidence by Big Pharma that it sees microRNA therapeutics as a significant new emerging treatment modality. While the antiviral programs with Santaris should be based on the straight-forward targeting of either viral or host microRNAs directly implicated in viral infection, the anti-inflammatory programs with Regulus may be based on more complex microRNA pathway biology.
Interestingly, in both cases the emphasis is on microRNAs as targets for antisense antagonists and much of the discussion in today’s conference call on Regulus’ general microRNA therapeutics activities centered on such antagonist approaches, although I previously was under the impression that microRNA agonist approaches would also fall within the scope of Regulus.
Actually, when I woke up this morning and saw the headlines, I thought that the GSK-Regulus alliance would relate to a mystery surrounding microRNA-122 in HCV replication that is currently being developed by both Santaris and Regulus. Since miR-122 is by far the most advanced antiviral microRNA therapeutics candidate program, it is no stretch of the imagination that GSK will exercise their rights to Santaris’ HCV program that, in collaboration with the Sarnow lab, was subject to a recent high-profile publication in Nature. The issue here is that the Sarnow patents for targeting miR-122 in HCV from Stanford were exclusively licensed to Alnylam (now part of Regulus IP) and GSK-Santaris would therefore ultimately need access to this important patent. A Regulus-Santaris collaboration, however, is complicated by the fact that this program pits ISIS’ against Santaris’ LNA antisense chemistries. It is hoped that miR-122 will eventually aid in synergizing microRNA therapeutics efforts rather than leading to a Merck-like situation where GSK would end up in mutually exclusive collaborations. This issue probably should be addressed early on before it may cause harm down the line.
In both deals, GSK has the option to select up to 4 microRNA therapeutics candidates developed by Santaris or Regulus in the respective disease areas for comparable financial terms that gives the microRNA therapeutics companies important and largely undilutive upfront cash, development milestones, and royalties (for exact terms, please refer to the Santaris and Reguls PRs).
It is also a vote of confidence by Big Pharma that it sees microRNA therapeutics as a significant new emerging treatment modality. While the antiviral programs with Santaris should be based on the straight-forward targeting of either viral or host microRNAs directly implicated in viral infection, the anti-inflammatory programs with Regulus may be based on more complex microRNA pathway biology.
Interestingly, in both cases the emphasis is on microRNAs as targets for antisense antagonists and much of the discussion in today’s conference call on Regulus’ general microRNA therapeutics activities centered on such antagonist approaches, although I previously was under the impression that microRNA agonist approaches would also fall within the scope of Regulus.
Actually, when I woke up this morning and saw the headlines, I thought that the GSK-Regulus alliance would relate to a mystery surrounding microRNA-122 in HCV replication that is currently being developed by both Santaris and Regulus. Since miR-122 is by far the most advanced antiviral microRNA therapeutics candidate program, it is no stretch of the imagination that GSK will exercise their rights to Santaris’ HCV program that, in collaboration with the Sarnow lab, was subject to a recent high-profile publication in Nature. The issue here is that the Sarnow patents for targeting miR-122 in HCV from Stanford were exclusively licensed to Alnylam (now part of Regulus IP) and GSK-Santaris would therefore ultimately need access to this important patent. A Regulus-Santaris collaboration, however, is complicated by the fact that this program pits ISIS’ against Santaris’ LNA antisense chemistries. It is hoped that miR-122 will eventually aid in synergizing microRNA therapeutics efforts rather than leading to a Merck-like situation where GSK would end up in mutually exclusive collaborations. This issue probably should be addressed early on before it may cause harm down the line.
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