Plenge Lab

nj7360-361a-i1.0

The primary purpose of this blog is to recruit clinical scientists into our new Translational Medicine department at Merck (job postings at the end). However, I hope that the content goes beyond a marketing trick and provides substance as to why translational medicine is crucial in drug discovery and development. Moreover, I have embedded recent examples of translational medicine in action, so read on!

[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]

There is a strong need to recruit clinical scientists into an ecosystem to develop innovative therapies that make a genuine difference in patients. This ecosystem requires those willing to toil away at fundamental biological problems; those committed to converting biological observations into testable therapeutic hypotheses in humans; and those who develop therapies and gain approval from regulatory agencies throughout the world.   The first step is largely done in academic settings, and the other two steps largely done in the biopharmaceutical industry…although I am sure there are many who would disagree with this gross generalization!

The term “Translational Medicine” has been broadly used to describe the second step, thereby bridging the Valley of Death between the first and third steps. In the accompanying slide deck (see here) and content below, I describe translational medicine in more detail, with a focus on: fundamental challenges in drug development; guiding principles for translational medicine; examples that highlight these principles; and future technologies that will likely transform the industry.

First, here is what I see as two fundamental challenges facing drug development: (1) the high cost of drug development, and (2) the lack of innovation that prevents the development of breakthrough therapies that have a genuine impact on patient care. I won’t go into details on these issues, as much has been written already.  Suffice it to say that high cost is largely driven by failures in late stage development (Phase II/III), and that most failures are due to lack of efficacy. Innovation in this context refers to the ability to find therapies that genuinely differentiate in the real world and that substantially impact patient care. While this need has always existed, economic forces are creating an environment where therapies without unambiguous promotable advantages will not survive in the marketplace (e.g., payers will not pay for them).  To address these challenges, many companies have set up Translational Medicine departments (for example, see YouTube video about Novartis’ Translational Medicine group here).

At Merck, our Translational Medicine department has three guiding principles: (1) pick the right targets, (2) develop the right biomarkers to measure target modulation, and (3) test therapeutic hypotheses as safely, quickly and efficiently as possible. Although simple in concept, we believe that disciplined adherence to these principles will address both challenges (high attrition, low innovation). Below I provide examples.  [Note that there is a very important step that is missing – developing the right therapeutic molecule. I have not called out this step as it falls outside of the direct mandate of our Translational Medicine department. Within Merck, as with many companies, this step is performed in close collaboration with functional colleagues in Biologics, Vaccines, Chemistry, Pharmacology, and Therapeutic Areas, amongst others.]

Targets should be selected based on causal human biology. I have written about the role of human genetics extensively in this blog series, so I will not comment further. Here, I want to emphasize that there are many non-genetic approaches to find targets with causal human biology (see slide #10 of deck). An important role of our Translational Medicine Department is to conduct experimental medicine studies to provide causal human biology support for new targets. For example, our Department is uniquely positioned to perform deep ‘omic profiling of patients treated with approved therapies or molecules in our clinical trials.

Biomarkers should be developed that measure target modulation in humans. If a target is selected based on causal human biology, then it should be possible to formulate specific hypotheses about the consequences of target modulation in humans. This knowledge should allow for the development of robust biomarkers that can be measured in clinical trials to assess proof-of-mechanism. An example is measuring A-beta levels in the CSF of non-human primates and human subjects treated with drugs for Alzheimer’s disease (see slides #12-14 of deck and Journal of Neuroscience article here).

Therapeutic hypotheses should be tested in clinical proof-of-concept (PoC) studies as safely and efficiently as possible. The ultimate test of causal human biology is to take a molecule into the clinic to see if it works. By linking basic science with clinical trials, translational medicine scientists have the opportunity to creatively design studies that test PoC. An example is polysomnography sleep studies in human subjects treated with orexin antagonists to develop drugs for insomnia (slides #18-20). Further, there has been renewed interest in small PoC studies in subsets of patients with predefined molecular profiles – a.k.a., precision medicine. Mark Fishman (Novartis Institutes for BioMedical Research) wrote in a Science Translational Medicine article about “the strategy of performing exploratory first-in-human clinical studies on mechanistically homogeneous populations (often small groups of patients with rare diseases) as a routine entrance to full-registration clinical trials.” The launch of a new neurodegeneration company, Denali (see here), was based, in part, on the principle that the world has new tools to test therapeutic hypotheses in predefined patient subsets.

What I find incredibly exciting is that there are new technologies that will enable each of these three guiding principles. For example, the cost of genome sequencing is decreasing to the point where very large sequenced-based genetic studies will be performed in extremely large patient populations to find new targets (slides #7-9). A recent Nature Genetics paper (here) by Richard Gibbs, Eric Boerwinkle, and colleagues on loss-of-function mutations in chronic disease provides a glimpse into this future. Novel single cell, nanoparticle and sequencing technologies are creating new ways to monitor target modulation in humans (slide #15). The explosion of digital medicine is allowing for innovative models of monitoring patients in clinical trials (slide #21; see also recent Nature Biotechnology articles by Daphne Zohar and colleagues here, and another by Sachin Jain, John Brownstein and colleagues here). In short, what an amazing time for translational medicine!

Two additional points about the biopharma ecosystem in translational medicine: (1) There has been very interesting commentary on “conflicts of interest” between patient care and industry from Lisa Rosenbaum in a recent NEJM series (see here, here), with an Editorial by Jeff Drazen (here).  The commentaries underscore the need for stronger partnerships within the biopharma ecosystem, including responsible relationships between academics and industry.  (2) Given the flow of capital into the biotech sector, talent recruitment is very competitive across the biopharma ecosystem. At the Convergence Forum 2015 (tweet hashtag #cvforum15), this was a major theme. As further corroborating evidence, over 150 well-funded biotechs have been founded over the last 5 years, resulting in the creation and recruitment of new roles: 150 CEOs, 150 CMO’s, 150 CSOs, 150 Heads of Regulatory, etc. Thus, this is a unique time for those clinical scientists in academics who are interested in making the switch to industry, and it is a reminder that the ecosystem of biopharmaceutical research is thriving.

Lastly, here are the links for those interested in applying to a translational pharmacology (tPharm) job at Merck.  The postings include positions in neuroscience, cardiometabolic disease, infectious disease, inflammation, and general clinical pharmacology.  We are looking for talented physician-scientists and experienced clinical pharmacologists who are passionate, curious and dedicated to making a difference in patients.  Potential applicants must be highly collaborative, as our scientists work closely with the broader discovery, pre-clinical and late stage development teams at Merck (slide #4).  In addition, our scientists work as part of our Translational Medicine team that includes geneticists, genomicists and molecular biologists; discovery and clinical imaging scientists; translational biomarker scientists; and clinical operations specialists (see slide #5).  Please come join our team!

 

 

Cardiometabolic (Principal Scientist and Senior Principal Scientist)

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003913&lang=en&sns_id=mailto

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003914&lang=en&sns_id=mailto

 

Neuroscience (Principal Scientist and Senior Principal Scientist)

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003907&lang=en&sns_id=mailto

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003908&lang=en&sns_id=mailto

 

Infectious disease / inflammation (Principal Scientist and Senior Principal Scientist)

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003909&lang=en&sns_id=mailto

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003910&lang=en&sns_id=mailto

 

General clinical pharmacology (Principal Scientist and Senior Principal Scientist)

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003911&lang=en&sns_id=mailto

https://merck.taleo.net/careersection/merck_external_career_section/jobdetail.ftl?job=CLI003912&lang=en&sns_id=mailto

 

 

 

Leave a Reply