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.

Do Failed Biomarker Studies Spell Higher Costs for Bellwether Oligonucleotide Therapies?

Two of medicines most popular and accepted biomarkers, LDL-cholesterol for cardiovascular disease and blood-sugar levels for diabetes, have recently come under scrutiny after high-profile studies showed no benefit or even increased health risk despite the lowering of these biomarkers by drug treatment. Since some of oligonucleotide therapeutics’ most advanced early drug candidates are for metabolic diseases and aimed at lowering these two parameters for an accelerated path into the clinic, the issue deserves some further consideration.

The ENHANCE study used an imaging technique to look at changes in the thickness of plaque deposition in the carotid (large artery running through neck) in patients treated with a combination of a statin (Merck’s “Zocor”) and the dietary cholesterol uptake inhibitor ezetimibe (“Zetia” marketed by Merck and Schering-Plough) versus patients treated with the statin alone. After a year of delay in data reporting, the companies admitted that the combination, called Vytorin, did not lead to improvements in plaque thickness with even a trend towards adverse events, despite the fact that LDL-cholesterol was further decreased by the addition of ezetimibe. Combined with Pfizer’s infamous torcetrabip blunder that despite increasing the level of good cholesterol (HDL) the rate of death was actually increased, this shows that particularly with novel drug targets, biomarkers alone will not suffice and expensive outcome studies instead may be necessary to ensure clinical benefit. A similar lesson may be drawn from the results of a recent diabetes study that aimed to aggressively lower the gold standard biomarker in diabetes care, namely blood sugar levels as measured by glycylated hemoglobin.

It will therefore be interesting whether and how this will affect the view the FDA and other regulatory agencies take on drugs such as ISIS’ ApoB100 targeting antisense compound mipomersen or Alnylam’s PCSK9-targeting ALN-PCS01 siRNA. Although there is little doubt that e.g. in the case of mipomersen, similar to Zetia, there is a marked reduction in LDL-cholesterol in humans, because it is aimed at a novel target in LDL metabolism, the FDA may insist on having its therapeutic utility being proven in large outcome studies, except maybe for some patient populations with familial hypercholesterolemia.

These failed biomarker studies are only going to add to the increasingly conservative stance the FDA takes towards drug approval, at a time when drug approval rates are declining despite ballooning drug development expenses. These expenses are also driven in part by regulatory demands for large late-stage clinical registration studies. Clearly, this trend is not compatible with a drug industry from which we expect new medicines addressing unmet medical needs. This is compounded by popular calls for cheaper generic medicines which, while saving the healthcare system dollars in the short term, undermine long-term productivity and innovation. Drug development overall has become a money-losing game for most, and it is not fair pointing out the huge cash reserves of a few Big Pharma, which we know are about to diminish in the near future anyway, without taking into account the many enterprises that never see the light of profitability.

So what could be the solution? It is difficult to argue that savings should come at the detriment of patient safety. In the difficult act of juggling the demands for patient safety, ensuring innovation, drug access, and profitability for the companies, I see fostering innovation, leading to better medicines and more efficient development paths, as probably THE one solution that may satisfy all four demands.

The RNAi Therapeutics platform e.g. opens the prospect of shortening pre-clinical development times which should lead to faster drug approval times and therefore exponentially longer periods of sales exclusivities. Say conventional drug development takes 12 out of the 15 patent years, resulting in 3 years of sales exclusivity, while an RNAi Therapeutic may take on average 9 years to develop, i.e. doubling the time of sales exclusivity. One could therefore even argue that current trends actually amplify the competitive advantages of the RNAi Therapeutics platform. Nevertheless, in the end even RNAi Therapeutics will suffer when innovation fails to be protected, which is why the current temptation for prematurely approving or tolerating unlawful generics should be resisted and fundamental patents enforced. Given the importance of the US for worldwide drug development, I can only hope the candidates running for President understand all of this.