On July 29, 2011, Merck announced that It was shutting down the San Francisco research laboratory that it had acquired as part of its $1.1 billion acquisition of therapeutic RNAi specialist company Sirna Therapeutics. This announcement was covered in a July 29, 2011 article in Xconomy, and in a news brief in the 4 August issue of Nature and a linked Nature news blog article.
According to the Xconomy article, the shutdown will include the loss of around 50 jobs. Around ten people are being offered transfers to other Merck facilities in nearby Palo Alto CA and on the East Coast.
As we discussed in the Roche article, Novartis had also decided to end its 5-year partnership with therapeutic RNAi specialty company Alnylam In September 2010. However, Novartis acquired technology and exclusive development rights for RNAi therapeutics against 31 targets for in-house use as the result of its partnership with Alnylam. Alnylam is entitled to receive milestone payments for any RNAi therapeutic products that Novartis develops based on these targets. Thus Novartis is still involved in RNAi therapeutics, despite the termination of the Alnylam partnership.
Moreover, according to the Nature news blog, Ian McConnell of Merck’s Scientific Affairs, R&D and Licensing and Partnerships said that Merck will continue to have over 100 scientists working on RNA-based therapeutics, and that it continues to invest significantly in the field. Closing the San Francisco lab represents an effort to trim the budget by eliminating the cost of maintaining a separate RNAi facility.
In our previous blog articles on Big Pharma RNAi therapeutics retrenchment, and in our October 2010 book -length report, RNAi Therapeutics: Second-Generation Candidates Build Momentum, we discussed the strategic issues that are involved in undertaking (or in retrenching from) R&D programs in RNAi therapeutics, and in investing in that area. The therapeutic RNAi (and microRNA) field represents an early-stage area of science and technology. The field may be technologically premature, as was the monoclonal antibody (MAb) drug field in the 1980s.
Big Pharma originally got into RNAi therapeutics in order to help fill weak pipelines, and with the hope of staking out a commanding position in the RNAi field once it became successful. However, with the short-term pressure at Big Pharma companies to cut expenses and programs, Big Pharmas have been losing the needed patience to continue with a technologically premature field like RNAi therapeutics.
In the June 2011 issue of Molecular Therapy, there is an editorial by Arthur Krieg, M.D. (former Chief Scientific Officer of the now-closed Pfizer Oligonucleotide Therapeutics Unit, and now Entrepreneur in Residence at Atlas Venture, Cambridge, MA), entitled “Is RNAi dead?” As discussed in the editorial, the move of Big Pharma away from RNAi, according to some observers, signals the death of the therapeutic RNAi platform. Dr. Krieg outlines an alternative view.
According to Dr. Krieg, Big Pharmas got into RNAi therapeutics with the hope of enabling the rapid development of targeted drugs without the long time lags and uncertainties of small molecule drugs and biologics. In theory, if a research team has a good target, it could rationally design a lead RNAi drug specific for the target and ready for human clinical trials within 15 months. And researchers would not have to worry about “undruggability” of targets. However, there have been several unforeseen hurdles to the development of RNAi drugs, the most formidable of which is the issue of drug delivery. Although certain high-profile publications suggested that the challenge of RNAi drug delivery could be easily overcome, this proved not to be the case in practice.
However, Dr. Krieg believes that the progress in RNAi delivery in recent years has been “nothing short of spectacular”. In 2008, the best RNAi delivery systems for a liver target might have an IC50 (i.e., the RNAi dose required for 50% inhibition of target expression) of 1–3 mg/kg, but in 2010/2011, the IC50 has been reduced to about 1% of this value, which is an improvement of two logs. Dr. Krieg also says that there have also been significant advances in reducing off-target and other undesired systemic effects of RNAi therapeutics in animal models in recent years.
Nevertheless, the advances in RNAi delivery and safety are moving too slowly for Big Pharma’s current short-term mindset. According to Dr. Krieg, if companies are not able to take an RNAi drug into clinical development this year, then the next time there is an R&D portfolio review, investments in “high-risk” technology platforms such as RNAi are likely to be cut. As we have discussed in this blog, and as is well-known to most of you, every Big Pharma company has been cutting R&D and shedding poorly productive and high-risk programs. The focus at many Big Pharmas is on fast, sure returns. High-risk or premature technologies that have not yet yielded any marketed drugs, such as RNAi (and for example, stem cells/regenerative medicine) is not likely to offer such returns.
Dr. Krieg also notes that in the case of another once-premature technology, monoclonal antibody (MAb) drugs, it took several waves of technology development to advance from repeated clinical failure to one of the most successful classes of drugs today. In our view, MAb technology is the classic case (in the life sciences, anyway) of how researchers and companies can take such a premature technology up the technology curve by developing enabling technologies. We discussed this case in our September 28, 2009 blog article, and its applicability to RNAi and stem cells in our July 13, 2009 blog article. As discussed in these articles, and as noted by Dr. Krieg, it was not Big Pharmas, but biotech companies “on the cutting edge” (together with academic labs) that advanced the therapeutic MAb field. Big Pharmas later bought into the MAb field, typically by large acquisitions. This is especially exemplified by the acquisition of MAb drug leader Genentech by Roche.
With respect to RNAi, as mentioned above, at least Merck and Novartis among the Big Pharmas are continuing with in-house RNAi therapeutics programs. And such biotechs as Alnylam, Silence Therapeutics, Quark Phamaceuticals, Dicerna, and Santaris have RNAi and/or microRNA-based drug candidates in clinical trials, often partnered with Big Pharma companies (such as Pfizer) that have cut or reduced their own RNAi drug programs. Therefore, there are companies that are working on advancing RNAi therapeutics up the technology curve. As Dr. Krieg says in his editorial, success in such programs will be expected to lead to Big Pharma reinvestment in RNAi/microRNA therapeutics, just as in the case of MAb drugs.