Plenge Lab
Date posted: October 9, 2015 | Author: | No Comments »

Categories: Drug Discovery

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It is not uncommon that I am asked the following question during public talks: “Does innovation happen in large pharmaceutical companies?” Sometimes, the question is just a critical comment, disguised as a question: “Large pharma does not innovate, they just conduct clinical trials and drive up the cost of drugs. Right?” Other times the questions are more thoughtful: “As an academic, I don’t see what happens in industry. Can you describe examples of innovation driven out of large pharma?

[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.]

At the risk of sounding defensive, here are some answers to the “pharma innovation” question. I know there are many more, and I invite readers to share their examples. Admittedly, the examples are biased towards examples at Merck, but that is just because I know these examples better.

First, the past couple of weeks have been particularly good for industry scientists. These recent examples provide objective evidence to answer the pharma innovation question.

(a) 2015 Nobel Prize in Physiology or Medicine. Former Merck scientist Dr. William Campbell was awarded the Nobel Prize for the discovery of an antiparasitic agent used to treat river blindness in places like Latin America, Africa and Yemen. The award was given jointly to Dr. Campbell, Dr. Satoshi Omura (a Japanese microbiologist), and Youyou Tu (for her work on an antimalarial agent). The history is one that points to academic-industry collaboration. Dr. Omura, at the Kitasato Institute in Japan, worked to isolate new strains of Streptomyces from soil samples, looking for new agents that could be used against harmful microorganisms. These samples were sent to Dr. Campbell, a parasitologist at Merck, who used them to find a new treatment for parasites in animals.

(b) Targeting non-coding RNA. While I am biased, I think this Nature study published by Merck scientists is very cool. As described in an accompanying News & Views: “A screen for compounds that block a bacterial biosynthetic pathway has uncovered an antibiotic lead that shuts off pathogen growth by targeting a molecular switch in a regulatory RNA structure.” That is, an unbiased phenotypic screen was performed on bacterial cultures. Approximately 57,000 small molecules were tested. After a “hit” was confirmed, target deconvolution via sequencing of resistance strains revealed something unexpected: resistant bacteria were found to harbor mutations in a non-coding stretch of the bacterial genome. The implications for drug discovery are substantial, as it serves as “a striking demonstration that structured regions in ncRNA may serve as targets for synthetic drugs.”

(c) Targeting the mRNA spliceosome. And yes, innovation happens at other large pharma companies, not just Merck! Scientists from Novartis recently published a study in Nature Chemical Biology that “demonstrates the feasibility of small molecule–mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.” The study, which focused on a rare genetic disease, spinal muscular atrophy (SMA), identified a small-molecule enhancer of mRNA splicing. The potent, orally active molecule acts “via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex”. A recent commentary in Chemical & Engineering News provides a useful perspective on therapeutic modulation of the mRNA-splicing machine.


Second, innovation happens in unexpected places within industry – not just at the level of fundamental biological discoveries.  I actually think this is a root cause of the misconception that innovation does not happen in pharma: many academic scientists think that fundamental biological discovery is the only way to innovate.

(a) Innovation in manufacturing. Buried among all the Tweets about drug pricing – which is a serious issue – was an overlooked interview in the Boston Business Journal. The topic of manufacturing might not seem very sexy, but it is critical for bringing therapies to patients. Continuous drug product manufacturing allows for much smaller manufacturing facilities, faster change over, and much lower cost. Jeff Leiden, CEO of Vertex, on biomanufacturing: “Because of the heavy regulatory environment, there’s actually been very little innovation historically in the manufacture in the biopharmaceutical and biotech areas, because once you nail down a manufacturing approach, you basically can’t change it without submitting it for a complete regulatory review. … That’s changing recently.” He goes on to describe a more nimble and efficient manufacturing system that “saves, literally, tens of millions of dollars over many years on the manufacturing process.” At the extreme, one could imagine a world where 3D printers manufacture clinical-grade small molecules for clinical trials on site, as described here by the Howard Hughes Medical Institute.  At Merck, our manufacturing division implemented an innovative enzyme biocatalysis-based process, which leverages a genetically engineered enzyme tailored to the desired chemical transformation, optimized for yield, time cycle and volumetric productivity. In addition, they applied Process Analytical Technology to establish a dynamic feed forward control of chemical crystallization to ensure quality. The process has been recognized externally with the U.S. EPA’s 2010 Presidential Green Chemistry Challenge Award, where it was highlighted as a new technology that clearly demonstrated a commitment to pursuing greener technologies that are scientifically and economically sound, while being less hazardous to human health and the environment.

(b) Advances in drug metabolism and pharmacokinetics (DMPK). I recently gave a talk at the Broad Institute titled “Genetics and drug discovery: the future is now” (see slides here). David Altshuler, formerly from the Broad and now at Vertex, also gave a talk about the experience of genetics and drug discovery at Vertex. Both David and I set up our talks by describing how the cause of drug failures have changed over the past 30 years (see slide #4). In the 1980-90’s, clinical failures occurred because of problems with drug metabolism and pharmacokinetics (DMPK). Thanks to innovation by the pharmaceutical industry, many of these challenges have been solved, and the industry is much better at predicting DMPK in humans.

(c) Advances in clinical trial design. There are a number of innovative trial designs that have emerged from collaborations between academics and industry. This video and graphic from Memorial Sloan Kettering Cancer Center describes a novel trial design termed “basket trial”. A recent Ebola vaccine study used a “ring vaccination” design. As described in a review article in the British Medical Journal: “rings are randomised 1:1 to (a) immediate vaccination of eligible adults with single dose vaccination or (b) vaccination delayed by 21 days. Vaccine efficacy against disease is assessed in participants over equivalent periods from the day of randomisation.” The application of mobile technology in the setting of clinical trials will certainly be an area to watch in the near future.


Finally, innovation knows no boundaries. Great ideas can come from anywhere, as illustrated by the 2015 Nobel Prize in Physiology or Medicine. In fact, what is exciting about the biomedical ecosystem today is that there is an enormous amount of cross-fertilization among academics, government, small biotech (see Geroge Church and pig cloning here), large pharma, and others. The story of a cure for hepatitis C virus (HCV) provides one example of this ecosystem in action (see Nature Reviews Microbiology article here for a much more detailed description).

The journey for an HCV cure has taken place across the biomedical ecosystem over multiple decades. Scientists at Chiron Corporation (e.g., Michael Houghton, who won the Lasker Award in 2000) and the Center for Disease Control first characterized the virus in the 1980’s. A vast effort ensued to define key biological mechanisms of the viral life cycle, which led to three key therapeutic targets: NS3, NS5A and NS5B. Scientists at Merck were the first to show that nonstructural protein 3 (NS3) is a serine protease, and that NS5B is an RNA-dependent RNA polymerase. However, knowledge of biology alone is insufficient to advance a drug discovery program; practical tools are required. One of the most enabling contributions in the development of practical tools came from the academic labs of Ralf Bartenschlager and Charles Rice: the invention of the replicon assay. Without this assay, a drug discovery program couldn’t advance at any pace in any institution.

There are many who contributed to the discovery of therapeutic molecules against NS3, NS5A and NS5B, including John McCauley, a Merck chemist who just this week received the Gordon E. Moore award from the Society of the Chemical Industry for his part in the invention of NS3 protease inhibitors. The invention of safe, efficacious molecules took Dr. McCauley and hundreds of scientists over a decade, guided by replicon assays and enabled by crystallography. For NS5B inhibitors, a major breakthrough came from the labs of Bristol-Myers Squibb (BMS), where the only hit across the industry in an high-throughput screen turned out to be an impurity present in a compound in their collection…how easily could that have been missed without smart, creative – and innovative – industry scientists!


Thus, I hope these examples provide at least a partial answer to the “pharma innovation” question. I know there are many, many more.


BTW – the photograph used in this blog comes from an innovative Merck scientist, Dr. Iain Martin. If you like what you see, please visit his website (




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