RNAi Therapeutics More Relevant than Ever

If there ever was the impression that the pharmaceutical industry could afford not to pursue RNAi Therapeutics with urgency, this could not be further from the truth- at least not if you consider Roche a bellwether of the industry. Severin Schwan, who once served as the leader of the Roche Diagnostics division before becoming Roche's CEO, set the tone of this year’s Roche Investor Day by stating that the challenge the industry faces is to capitalize on our exponentially increasing understanding of the molecular basis of disease by being able to target more than the 100 out of the roughly 2,000,000 proteins in our bodies that mankind was able to develop in all its history.

This begs the question of where exactly the bottleneck lies. Is it true that small molecules and monoclonal antibodies alone will not be able to significantly expand on the 100 targets? If the answer is at least a partial ‘yes’, then the industry cannot afford to not invest in RNA(i) Therapeutics as the technology that virtually opens up the entire genome as drug targets.

The limitation in target space is quite obvious for monoclonal antibodies. While they have proven a great new class of therapeutics, they cannot address the majority of proteins that happen to reside inside cells. To be clear, there is a lot of innovation going on in monoclonal antibodies, including the development of ever more optimized and also ‘armed’ antibodies, but a lot of this has to do more with life-cycle management of existing MAbs than exploring new target space. Sure, with more insights into disease, new extracellularly accessible targets will emerge, but I do not see this alone sufficient to sustain the pipelines in the next 20 years. Of note, being in his early 40’s means that Dr. Schwan is one of the few CEOs that may actually be measured during his tenure against his long-term vision of drug development, rather than merely against his ability to squeeze short and mid-term value out of the current pipeline.

The limited target space of MAbs is actually also something that drove Genentech’s decision (now fully owned by Roche) to go against industry trends and adopt small molecules as a technology platform. By focusing on only a few select, but important cellular pathways rather than working superficially on many, a strategy that has really borne fruits, new attractive genetically defined targets have emerged that were not within the grasp of MAbs.

Certainly, there is room for novel exciting small molecule approaches for therapy, but their ability to expand on the druggable space is fundamentally limited by their cross-reactivity. To be fair, RNAi Therapeutics also have their off-target challenges, but I would submit that by off-targeting a random set of genes, which hopefully will teeter out in genomic noise, rather than structurally related, and functionally cross-talking GPCRs, kinases, phosphatases, proteases etc, there is less risk for confounding phenotypes, especially if you can weed out the most obvious unacceptable off-target profiles of RNAi Therapeutics early on with genomic profiling technologies.

So while safer and better MAbs, the exploitation of new major disease pathways also with small molecules, and the rapid growth of the emerging markets should drive the growth of Roche for the next 5-10 years, they are well aware that in order to substitute this growth they need new platform technologies, especially RNAi Therapeutics, and given the timelines, the time to invest is now, just as they invested into MAbs and PCR in the early 90’s when the precise commercial timelines of those technologies were still very much uncertain. And when it comes to developing a new platform, the quality of the science is paramount, and it is therefore not a coincidence that Roche has chosen Alnylam and Tekmira as its closest outside collaborators in that effort.

What is unique to Roche is that they have a very substantial foothold in (technology agnostic) diagnostics which allows them to lead the personalized medicine effort that aims to maximize the therapeutic benefit of a drug, thereby lowering clinical trial failure rates and justifying premium pricing in front of payers. If you had wondered what ever happened of the personalized medicine ‘hype’, it (not the hype) is already a reality. It seems that for virtually every drug in pre-clinical/early clinical research, Roche Pharma and Diagnostics are now collaborating to develop drug response markers and companion diagnostics. It is therefore only a matter of time until they come out on the other end of the drug approval process. Importantly, by seeking to understand the molecular basis of a ‘disease’ in a particular patient, this trend directly plays into the strength of RNAi Therapeutics as the key players in a disease do not care whether they are druggable or not. In fact, I find it ironic that there are actually some pharmaceutical companies, even some major biotechnology companies that use RNAi as a tool for target discovery that would limit their screening libraries to siRNAs that target only the so called druggable space. Not only are they missing out on a more complete understanding of a disease process in general which would also feed back positively on small molecule and MAb-based drug development, they will also miss out on many, if not most important targets. Once again, they risk being left behind by a company that sees the Big Picture and not only preaches innovation but actually lives it…Roche.