My background in molecular profiling was around when the Human Genome Project sequence came out in 2000 and 2001, and living through that bubble. What you realize is that the essence of the excitement is correct, and the reduction to practice may make it less-than-anticipated, but it’s still real. The same thing will be true of the RNA therapeutics space. There is a lot of expectation and anticipation. The reality will be somewhere between that and zero. We’d like to think because of the experience we have in our company that we have a clear line of sight on what’s practical within a certain time frame.
This will settle down. The acquisition of Sirna by Merck really set this thing off. We’re three years past that. I think in two more years, you’ll see this settle down, much like in the genomics space. In genomics, many of the opportunities consolidated into a few big players. The same thing will happen here. But the big companies like Merck, Roche, Novartis and Pfizer, that have committed to do this, ultimately will be there. Because of the long-term potential of the modality, not the immediate potential, but the long-term potential. It’s huge.
All of the companies mentioned have ended their RNAi programs, including Alan Sachs' Merck. Alan was correct, It was a huge promise. A huge investment followed and a huge fall from grace has finally been completed. Among the Cargo Cults, Merck had the biggest RNAi airport.
Some investors still believe there is a pot of gold at the end of this rainbow. Here is why the CCS places the science into question.
The talking point among RNAi sympathizers is that monoclonal antibodies had likewise been left for dead back in the 90s. The difference however is that RNAi is a nucleic acid therapy like gene therapy. It is different than protein therapy. The diagrams and animations that depict the mechanism of action (MOA) of RNAi failed to depict the delivery of the small RNA pieces to the gene expressing cell targets. It offered a crisp clean MOA that had the same end result of monoclonal antibody therapy, a reduction in the amount of a specific protein. Without changing the highly simplified approach to biotech research, office bound PhDs ordered their white lab coat staff to run the same ELISAs and western blots to demonstrate knock-down. As a white lab coat staff member, I worked through a microcosm of what was to come back in 2002. My first blog post on RNAi was on May 10, 2006. After four years of thinking about RNAi, working with RNAi, watching others work with RNAi, and most importantly, watching the Cargo Cult leaders deal with the lack of efficacy in RNAi, I had come to the conclusion that this stuff is snake oil. That was several months before Merck bought SIRNA.
Since RNAi didn't work very well in the laboratory, it seemed preposterous that it would work in the clinic. The pharmaceutical industry relies heavily on pharmacy and much less on pharmacology. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. The former studies the effects of the drugs on biological systems, and the latter the effects of biological systems on the drugs. In broad terms, pharmacodynamics discusses the interactions of chemicals with biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion of chemicals from the biological systems. In contrast, pharmaceutical research is primarily concerned with preparation, dispensing, dosage, and the safe and effective use of medicines. Biotech and Big Pharma leaders put up the money to put RNAi through the latter forms of research. The lack of efficacy left RNAi companies scrambling to explain why RNAi wasn't panning out as a drug. Delivery of the little pieces of RNA to a cell that was actively translating the drug target became a hot topic. In other words, they needed to get a handle on the pharmacology. Delivery of the little pieces of RNA was the reason the leaders decision making had hit a snag.
Currently, delivery of little RNA pieces remains the missing link to the promise. It keeps the promise alive. If the pharmacology techniques were in place we could check on the likes of Alnylam and Tekmira. We should not take their word for the promise of SNALPs, Stable-Nucleic-Acid-Lipid-Particles. We should have a separate organization that works for the FDA and the NIH. This group of scientists would development methods ahead of time to test the claims of for profit organizations who can both profit and cause harm. Other possibilities with RNAi is that they can do no good or they can help what ails us. The important thing for scientists to work on is in the development of a science that will help evaluate claims.
In July of this year Merck ended their RNAi efforts after 5 years and $1.5 billion. They claimed that this was a difficult decision based not on science but on financial needs for the Merck corporation. As usual a learning opportunity was lost. As Feynman said;
In summary, the idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another.
It is our biased opinion here at the CCS that 2011 witnessed a most significant ending to biotechnology's biggest promise of the past decade. I didn't present any data that might have suggested that RNAi works. I left that up to the experts who still claim that RNAi works. As far as putting ones money where ones mouth is, the verdict is in. RNAi is not moving forward in the world of BigPharma.
Here at the CCS we began in 2006 with a strong opinion and we end in 2011 with the same opinion, backed by a huge failure of RNAi in biotechnology and BigPharma. Alan Sachs was right, the promise was huge. That is why the failure is also huge. Huge shifts in thinking are fun places to be in science. Not just in the beginning, like those who jumped on the RNAi bandwagon, but in the end like those who kept the story of N-Rays and cold fusion alive. We have much to learn in the psychology of Cargo Cults. It remains and area in the philosophy of science that is itself a mystery. How do these things happen and why are so many people successful leading failures? What RNAi has taught us is that, in fact, science corrects itself. How do we stray from the truth and how much work goes into correcting ourselves?
Don't believe in the hype of a trendy science story. Believe in the truth. As Alan Sachs would say, there is power in the long term potential of the modality.