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.
Showing posts with label chronic RNAi. Show all posts
Showing posts with label chronic RNAi. Show all posts
Monday, July 21, 2008
Monday, May 12, 2008
Alternate Use of Two SiRNAs for Chronic RNAi Therapeutics
First, I wanted to write about the pros and cons of developing RNAi Therapeutics as antivirals, or the use of dual-acting siRNA agents, but then decided to sacrifice what remains of my credibility and propose a somewhat unorthodox method to manage off-targeting in RNAi Therapeutics for chronic medication.
As discussed before, both bioinformatics and gene profiling technologies can be applied in the selection of candidate siRNAs with the least likely adverse off-targeting effects. Bioinformatics may avoid sequence elements that occur at high frequencies in mRNAs or in a particular unwanted genes, while microarray profiling may experimentally pick out those genes which are downregulated at least on the RNA level which, despite some caveats, is still a pretty good predictor of off-targeting (note that potentially even more predictive protein mass-spec techniques may also be applied soon for off-targeting). In that manner, it is possible for Merck, for example, to screen out those siRNAs which off-target numerous genes or those genes that you would rather leave untouched. Finally, chemical siRNA modifications may allow for the general reduction in the number off-target interactions.
Still, with all of this in hand, off-target risk remains. Due to the redundancy of the genetic code, it should be generally easier to translate into humans off-target phenotypes from preclinical models for protein-targeting drugs than for RNA knockdown therapeutics. That means, a given drug is more likely to still interact with the same homologous protein in different species because the overall function and therefore usually shape of a protein is more conserved than the underlying mRNA sequence, while even a slight nucleic acid change at even a single position may decide whether an mRNA is an off-target for an siRNA or not at all. So what may be true for off-targeting even in a non-human primate may look quite different in man.
Off-targeting should be a concern particularly for chronic applications of RNAi Therapeutics. A 50% reduction in an important gene due to an siRNA for hypercholesterolemia for example may eventually manifest itself as an off-target toxicity following prolonged drug use. While this is true for essentially any class of drugs, RNAi Therapeutics may have an advantage. Because siRNAs as a class are quite homogenous in terms of pharmacological properties, how about entering two siRNAs targeting the same gene into the clinic, as a single drug development program, but whereby the siRNAs are given alternately?
This would be somewhat similar to how siRNA cocktails are considered for cancer and antiviral RNAi, but with a different rationale, or the idea behind Dharmacon’s smartpools. Just change the siRNA and leave the rest the same, including the delivery formulation. Similar to food where it’s better to consume a varied diet than constantly eat a single healthy dish, that way the siRNA would be changed before an off-target had the chance to manifest itself without having to take a drug holiday. That way, the fact that, unlike protein-targeting therapeutics, two siRNAs even for the same target have completely different off-target spectra, could be turned into an advantage.
I’m not sure how well this would go down with the increasingly defensive FDA, but maybe they could make a start and be more open-minded when it comes to new technologies.
PS: Another advantage of RNA knockdown therapeutics versus protein therapeutics is that it’s much easier to measure changes in RNA and protein abundance (RNA therapeutics) than determine drug-host interactions and their potential consequences, which in the case of RNA therapeutics, as a class, should be quite predictable while they should differ much more widely in the case of say small molecules.
As discussed before, both bioinformatics and gene profiling technologies can be applied in the selection of candidate siRNAs with the least likely adverse off-targeting effects. Bioinformatics may avoid sequence elements that occur at high frequencies in mRNAs or in a particular unwanted genes, while microarray profiling may experimentally pick out those genes which are downregulated at least on the RNA level which, despite some caveats, is still a pretty good predictor of off-targeting (note that potentially even more predictive protein mass-spec techniques may also be applied soon for off-targeting). In that manner, it is possible for Merck, for example, to screen out those siRNAs which off-target numerous genes or those genes that you would rather leave untouched. Finally, chemical siRNA modifications may allow for the general reduction in the number off-target interactions.
Still, with all of this in hand, off-target risk remains. Due to the redundancy of the genetic code, it should be generally easier to translate into humans off-target phenotypes from preclinical models for protein-targeting drugs than for RNA knockdown therapeutics. That means, a given drug is more likely to still interact with the same homologous protein in different species because the overall function and therefore usually shape of a protein is more conserved than the underlying mRNA sequence, while even a slight nucleic acid change at even a single position may decide whether an mRNA is an off-target for an siRNA or not at all. So what may be true for off-targeting even in a non-human primate may look quite different in man.
Off-targeting should be a concern particularly for chronic applications of RNAi Therapeutics. A 50% reduction in an important gene due to an siRNA for hypercholesterolemia for example may eventually manifest itself as an off-target toxicity following prolonged drug use. While this is true for essentially any class of drugs, RNAi Therapeutics may have an advantage. Because siRNAs as a class are quite homogenous in terms of pharmacological properties, how about entering two siRNAs targeting the same gene into the clinic, as a single drug development program, but whereby the siRNAs are given alternately?
This would be somewhat similar to how siRNA cocktails are considered for cancer and antiviral RNAi, but with a different rationale, or the idea behind Dharmacon’s smartpools. Just change the siRNA and leave the rest the same, including the delivery formulation. Similar to food where it’s better to consume a varied diet than constantly eat a single healthy dish, that way the siRNA would be changed before an off-target had the chance to manifest itself without having to take a drug holiday. That way, the fact that, unlike protein-targeting therapeutics, two siRNAs even for the same target have completely different off-target spectra, could be turned into an advantage.
I’m not sure how well this would go down with the increasingly defensive FDA, but maybe they could make a start and be more open-minded when it comes to new technologies.
PS: Another advantage of RNA knockdown therapeutics versus protein therapeutics is that it’s much easier to measure changes in RNA and protein abundance (RNA therapeutics) than determine drug-host interactions and their potential consequences, which in the case of RNA therapeutics, as a class, should be quite predictable while they should differ much more widely in the case of say small molecules.
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