There has been some unhappiness among certain Big Pharma companies about their adventures in RNAi Therapeutics. Roche, Pfizer, and Abbott Labs were among the publicized companies that discontinued RNAi Therapeutics platform development efforts not too long ago. Unsurprisingly, you could hear criticism from these companies about alleged immaturity of the technology and having been misled by the RNAi Therapeutics industry. Some of that backlash can now be felt in the peer-reviewed literature. Two recent papers by Abbott and Pfizer allow us to gain further insight into the causes of this unhappiness based on their actual practical experiences with the technology.
Pfizer: If it’s not ‘naked’ or involves invasive routes of administrations, we aren't interested
Pfizer, famous for its track-record of turning life-style drugs into blockbusters, apparently made the decision to pursue phosphorothioate LNA antisense over RNAi Therapeutics. As could be deduced from comments by then Pfizer oligonucleotide therapeutics chief Art Krieg that the need for intravenous administration makes a number of RNAi delivery technologies much less attractive, this was partly driven by concerns about patient convenience. Somewhat related and as could be seen from Pfizer’s conference abstracts, Pfizer also abhorred the complexity of some RNAi formulations. Consequently, instead of having therapeutic efficacy drive their research, Pfizer tried to make RNAi conform to their commercial principles (convenience and simplicity) meaning that they asked RNAi do what it is not suited to.
This type of scientifically conflicted approach was also exhibited in a paper by Pfizer published this month in Molecular Therapy (Moschos et al.: Uptake, Efficacy, and Systemic Distribution of Naked, Inhaled Short Interfering RNA (siRNA) and Locked Nucleic Acid (LNA) Antisense). The researchers set out to test the utility of unformulated siRNAs or LNA antisense for knocking down genes in the lung following intratracheal administration. To their disappointment, they were not able to observe target gene knockdown in the lung by either RNAi or LNA phosphorothioate antisense. This, of course, is in contrast to Alnylam’s studies that claimed that unformulated, unmodified siRNAs were an effective way to knock down genes in the respiratory epithelium and therefore fight respiratory syncytial viral (RSV) infection via RNAi gene knockdown.
Another surprising (this time for real) observation from these studies was that quite a bit of the unformulated oligonucleotides apparently made it into the systemic circulation following intratracheal administration, and as would be expected from the pharmacology of unformulated siRNAs and phophorothiote antisense, they were then either rapidly excreted into urine (siRNAs) or in the case of phosphorothioate antisense accumulated in various tissues, essentially identical to their biodistributions following intravenous or subcutaneous administrations.
For antisense therapeutics, inhalation may therefore be an interesting new route of administration for systemic therapy (e.g. knocking down ApoB in the liver). No more needles and injection site reactions.
In summary, Pfizer came out disappointed on RNAi Therapeutics as it approached it in one of the worst possible ways. Whether this ‘naked’ oligonucleotide thinking is really a choice or also reflects lack of know-how and technology access, only Pfizer really knows. As could be seen from the author affiliations in the paper, a number of scientists lost their jobs over this strange approach towards developing RNAi Therapeutics.
Abbott: Even the much-touted ‘SNALP’ cannot satisfy our cancer needs
The next technology to receive a scolding from Big Pharma, in this case the siRNA Therapeutics group from Abbott Labs, was…SNALP. The Li et al. paper published online in Gene Therapy at the end of September investigated the use of SNALP for knocking down genes in solid tumors. For this, they used their mouse cancer model where either a beta-gal or luciferase reporter gene in cancer cells was suppressed by the tetracycline repressor, tetR. Knockdown of tetR causes the derepression of the reporter genes which can be used as a marker of RNAi activity. They used SNALP because they had, in their own hands, previously identified it to be the most effective delivery system using this model system (Lin et al. 2011).
To summarize the results, Abbott found that SNALP-mediated gene knockdown was most effective in cells close to the vasculature. Cells in areas further removed did not exhibit knockdown sufficiently potent to cause the de-repression of the reporter gene. This in fact is in line with what is known from the pharmacology of similar liposomal particles and is relevant for the development of ALN-VSP02 and TKM-PLK1, two SNALP-delivered RNAi Therapeutics in clinical development for solid cancer: higher vascularized tumors will likely respond better, and the target gene should allow for strategies where a tumor can be killed from the vasculature outside in. It’s also not like all small molecules or antibodies would homogenously distribute within a tumor.
Overall, the Abbott scientists did not seem all too pleased as the following concluding remarks of that paper show: ‘Although, in a general sense, the impact of tumor vasculature on nanoparticle-mediated delivery is not surprising, it is enlightening that the delivery efficiency of SNALP, the perceived current state of art in siRNA delivery, is still severely limited by tumor vascularity.’
Not surprising, but enlightening...Apparently, Abbott people have also lost their jobs over RNAi Therapeutics, so some of the bitterness is understandable. On the other hand, when I look at the Big Pharma RNAi literature and conference abstracts, perhaps with the exception of Merck, I see little problem solving or innovation. Instead, it is dominated by passive technology evaluations, often using home-made brews rather than the original stuff, or pretty mundane process development studies which, in the absence of viable delivery technologies, seems like putting the cart before the horse. It is even possible that having these internal RNAi groups has been harmful for allowing the technology to get a fair evaluation in Big Pharma as such groups may cause the companies to become too much inward-looking, protective of one’s own people, instead of tapping into what is already out there. Without owning a leading delivery technology themselves, the best strategy may be for Big Pharma to just license product candidates instead of trying to build their own RNAi Therapeutics platforms in-house.