Technologies of the Future

Dr. Richard Hargreaves, Vice President for Imaging and Dr. Alan Sachs, Vice President of RNA Therapeutics for Merck Research Laboratories talk to NGP about new breakaway technologies at Merck Research Laboratories.

Merck Research Laboratories (MRL) is focusing on harnessing new technologies in order to secure its future and continues to be one of the top pharmaceutical companies in the world. Dr. Richard Hargreaves and Dr. Alan Sachs head up two recently established departments that use the latest technologies to identify and validate new therapeutic targets and develop innovative therapies. As VP of Imaging, Hargreaves is currently leveraging imaging in all of the Merck therapeutic franchises, in particular, neurosciences, cardiovascular disease bone biology and oncology. His near term research focuses on using imaging to validate drug targets, assess drug candidates and evaluate the molecular mechanisms that are thought to produce therapeutic benefit.

Sachs, as VP of RNA Therapeutics and former head of Molecular Profiling/Rosetta Inpharmatics, is concentrating on both molecular profiling and RNA interference (RNAi) technology. By utilizing molecular technologies (e.g. DNA microarrays) the hope is to discover novel targets and biomarkers that predict drug activity and impact on disease in a clinical setting. RNAi is being used as a research tool to understand the complex networks that drive common diseases and to discover new targets and biomarkers, which are important for developing novel therapies. The ultimate goal of the department is to develop RNAi-based therapeutics to treat diseases in a new way.

Challenges
Most would concede that there are many obstacles up against the pharma industry, from patent expiries to increasing R&D costs. But for Hargreaves and Sachs, working with cutting-edge technologies may enable better and faster decision-making – which could be the key to success. Historically, phase II clinical trials have been the default stage for decision-making. MRL has established their biomarker departments and made strategic investments in imaging and molecular profiling technologies. These technologies and biomarker-based approaches have been integrated across franchises from the earliest stages of drug development in order in order to evaluate opportunities much earlier than in the traditional research paradigm. “The challenge is whether the biomarkers will deliver what we hope they will in terms of reducing the cost of drug discovery,” explains Hargreaves. “By decreasing the cycle time potential products will move through the pipeline faster so that we can get out medicines to patients in a more efficient way. We’ve taken our bets and we’re going to give it a go.” Sachs points to another area in need of an overhaul – choosing the right target. The failure rate in new chemical entities is high, and even if they are safe enough to be given to people many of them still don’t work and they don’t work because they are aiming at the wrong target. “Any hypothesis generated years ago could be incorrect, but you won’t know that until you get it into people and show that it doesn’t work,” remarks Sachs. “Years later a small molecule will be in phase II testing for efficacy and if it is the wrong target the drug could be perfectly safe but it’s just not going to work.”

Three breakaway technologies
New imaging technologies have the potential to revolutionize drug discovery. Imaging’s main potential is its use as a decision-making tool throughout the R&D pipeline. Imaging can be used to identify the best molecules, see them engage their targets and help move them from the lab to the clinic and from the first human to the patient dose faster. Imaging can also be used to facilitate rapid proof of principle (biology) and clinical concept testing. It can also provide metrics for dose-selection as well as identify the optimal patient populations in which to conduct our clinical trials, Imaging is currently used to support registration for oncology drugs and for some cardiovascular drugs; however, it is primarily used as a decision making tool. Apart from these specific areas “Imaging has not yet become a routine surrogate end-point for drug registration – it can certainly help support the registration of drugs but alone it is generally insufficient today,” explains Hargreaves.

Hargreaves goes on to say that using imaging, like any biomarker, involves taking a greater risk in decision making than with traditional clinical outcome studies, and that you have to be comfortable with this. “If you have a strategy and a philosophy that you are going to use biomarkers then you have to be prepared to make decisions on the information they give you,” emphasizes Hargreaves. “The investment only pays off if you execute on it on a portfolio basis and you are rigorous and disciplined about the fact that you will make decisions with it, otherwise you may as well not do it.”

In terms of technology advances in the future, Hargreaves believes that advances in fusion imaging such as PET/CT and PET/MR will play increasingly important roles in molecular imaging particularly in oncology and neuroscience.

Molecular profiling allows for a system wide view of what is happening in a disease state or how an organ or animal responds to a drug. It gives an insight into things that are happening that may have not been understood before, and as a result, the information received is much more powerful and informative. Merck are broadly using molecular profiling in all areas of discovery and development. As well as using the DNA-based, RNA-based, protein-based elements of molecular profiling separately, Merck also use informatics to stitch them together in order to come up with hypotheses regarding biomarkers and targets. Many new targets that are now small molecule programs are derived from the information that comes from molecular profiling. “Understanding how mRNAs or proteins interact with each other leads to hypotheses that targets, when inhibited or activated, will affect the disease. Then we show this in our animal models and begin making drugs against the successful targets,” summarizes Sachs.

RNA Therapeutics is a recently formed department at Merck, following the acquisition of Sirna Therapeutics in December 2006. RNAi targets specific messenger RNA, the intermediary between DNA and protein, for degradation. The discovery that RNA could be targeted for degradation by small RNAs within a cell was the basis for a Nobel Prize in 2006. Because cells have this natural mechanism, called RNA interference, if you introduce into the cell a very short piece of RNA (siRNA), it can find a match to its nucleotide sequence and degrade the matching mRNA. This is a potentially powerful way to treat disease because it’s a sequence-based molecular medicine.

A major activity at Merck is exploring how to use siRNA as a therapeutic modality. This involves research across the spectrum at MRL, from how to deliver the silencing siRNA into people safely all the way through to how to run a clinical study using siRNA as a therapeutic because that’s an entirely new area for medicine. “What drives my department is that RNA is a fundamental technology for our company,” says Sachs excitedly, “once we solve what we call the delivery problem, the ability to introduce RNAs safely into people who knows what good things will happen.”

Collaboration
External collaboration is extremely important at MRL and if it wasn’t for the acquisitions that they have been involved in they wouldn’t be where they are today in terms of their new technologies.

Merck acquired Rosetta Inpharmatics in July 2001. This acquisition provided not only a DNA microarray platform, but also all the informatics and data analysis competency that were built at Rosetta, in addition to the staff and notably Dr. Stephen Friend, who is currently executive vice president and franchise head of Oncology at Merck. This purchase has transformed Merck into a company that now relies very heavily on information derived from broad profiling in all aspects of its discovery and development platform. “Rosetta has allowed Merck to take advantage of these new technologies and integrate them so that as a group they provide a very defined view of what’s happening in a disease state that previously Merck didn’t have,” states Sachs.

In March 2004, Aton Pharma, an oncology company, was bought and Zolinza, the drug Merck acquired, reached the market by 2006, as a treatment for a rare skin disorder.

Sirna Therapeutics was acquired by Merck in December 2006 and was in many ways an outcome of the Rosetta acquisition because Rosetta was so successful in developing ways to look at disease in the molecular detail. “Partly because Rosetta started using RNA interference as an in vitro tool to probe cells that were growing in tissue culture – it became clear that the next logical step to use all that information was to interfere with RNA in the animal and in humans and use RNA as a therapeutic,” states Sachs.

Hargreaves believes that it is absolutely essential that Merck collaborates with those outside and continues its track record of acquisitions. “The amount of work we can do internally is just a drop in the ocean compared to what’s going on within academia, the biotech realm and government institutions all over the world,” stresses Hargreaves, “Collaboration where we can bring the best of Merck together with the best of external science is incredibly important to us.”

Transparency
Hargreaves is all for transparency in clinical trials and highlighted Merck's publicly available guidelines on publishing the results of its hypothesis testing studies. He believes that transparency has become a great driving factor to optimize drug discovery in terms of knowing that once you get to the clinic and studies in patients anyone and everyone can recognize what you are trying to achieve and know the mechanisms that you are using. “Once it’s in the public domain,” explains Hargreaves, “it’s not proprietary so we have to be even more efficient and more successful in our early stage work where we are identifying targets and finding the best molecules, because that’s where the interest is.” Hargreaves points to optimizing early decision making as a key factor in leading in R&D.

Sachs agrees that transparency is important – particularly in external collaboration, as the most effective collaborations are ones where there is complete confidential disclosure agreements; however, he sees that outside of these boundaries transparency is a more tricky issue. His issues are based around the difference of the first and second in class. Given that the average length of time before a first in class drug got its first competitor has gone from 8.2 years in the 1970s to 1.8 years in 1995 his concerns are obvious. “What’s interesting is the amount of time between the first entry into the market and the second entry – this is an indication of why the transparency issue is so complicated.” Sachs continues, “being first in class for a company like Merck and the leadership position and time gained has shrunk very significantly versus a decade or two ago.”

Future
Hargreaves predicts an increased use of biomarkers for the future of the pharma and biotech industries. By facilitating more informed and cost-effective drug discovery and development, biomarkers will help bring safe and effective products to patients faster. “This is the future for drug discovery and R&D,” says Hargreaves. “We can’t go back to the way we used to do development before where you didn’t make decisions before phase II – it’s prohibitive in cost – it’s so important to make decisions earlier and carry the risk associated with it.”

Sachs believes that there will be a much more personalized pharma of the future, with more information about which patient should be getting which drug, which in turn should increase the probability of success for compounds. By choosing the right patient, they will be more successfully launched drugs because their potency will be correct and they will be safer. “It’s all about choosing the right patient and the right target,” concludes Sachs.

Dr. Richard Hargreaves, PhD, is Vice President, Imaging and Proteomics, and acting Worldwide Head of Basic Research, Neuroscience, at Merck Research Laboratories.

Since joining Merck in 1988, Hargreaves has occupied positions of increasing seniority in research and in 1999 moved to the US to establish and lead a worldwide imaging research strategy. Since that time he has built a global multimodality Imaging group that supports decision-making in drug discovery and development across Merck's key therapeutic areas.

Previously he worked in Merck’s Neuroscience Research Center in Harlow, UK, where he led the discovery biology teams that contributed to the development of MAXALT (rizatriptan) for the treatment of migraine and EMEND (aprepitant) and IVEMEND (fosaprepitant), novel agents that advance the protective pharmacotherapy of acute and delayed chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting.

Dr. Alan Sachs, Vice President, RNA Therapeutics, Merck Research Laboratories (MRL), assumed leadership of Sirna Therapeutics and established the global MRL RNA Therapeutics Department in January 2007. Prior to this, Sachs assumed responsibility for the scientific leadership at Rosetta Inpharmatics LLC effective July 2002, responsibility for the Rosetta site effective March, 2004, and overall responsibility for the Department of Molecular Profiling in 2006. Sachs joined Merck & Co., Inc. as Director of Clinical Genomics for MRL in July 2001.

Prior to joining Merck, Sachs was Associate Professor of Molecular and Cell Biology while at the University of California at Berkeley, and a Whitehead Institute Fellow at the Whitehead Institute in Cambridge. Sachs is one of the leading figures in the field of mRNA translation and regulation, and has made landmark contributions, particularly to the understanding of the role of the poly(A) tail in translation and mRNA stability.