Plenge Lab

A new sickle cell anemia gene therapy study published in the New England Journal of Medicine (see here, here) gives hope to patients and the concept of rapidly programmable therapeutics based on causal human biology. But how close are we really?

It takes approximately 5-7 years to advance from a therapeutic hypothesis to an early stage clinical trial, and an additional 4-7 years of late stage clinical studies to advance to regulatory approval. This is simply too long, too inefficient and too expensive.

But how can timelines be shortened?

In the current regulatory environment, it is difficult to compress late stage development timelines. This leaves the time between target selection (or “discovery”) and early clinical trials (ideally clinical proof-of-concept, or “PoC”) as an important time to gain efficiencies. Further, discovery to PoC is an important juncture for minimizing failure rates in late development and delivering value to patients in the real world (see here).

Here, I argue that rapidly programmable therapeutics based a molecular understanding of the causal disease process is key to compressing the discovery to PoC timeline.

Imagine a world where the molecular basis of disease is completely understood. For common diseases, germline genetics contributes approximately two-thirds of risk; for rare diseases, germline genetics contributes nearly 100% of risk.…

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Date posted: July 24, 2016 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics

Here are my thoughts on the Discussion Paper by Bernard H. Munos and John J. Orloff, “Disruptive Innovation and Transformation of the Drug Discovery and Development Enterprise” (download pdf here). This blog won’t make much sense if read out-of-context. Thus, I recommend reading the Discussion Paper itself, and using this blog as a companion guide at the completion of each section.

[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.]


In the near-term (10-years), I suspect that the pharma model of late development and commercialization will likely persist, as the cost and complexity of getting a drug approved is difficult by other mechanisms. Over time, however, new ways of performing late-stage trials will likely evolve. Drugs that are today in the early R&D pipeline will drive this evolution. If drugs look like they do today, dominated by small molecules and biologics with high probability of failure in Phase II/III, then the current model will likely continue with incremental improvements in efficiency. However, if new therapeutic modalities emerge (CRISPR, mRNA, microbiome, etc) and/or the probability of success in Phase II/III improves substantially, then the model of late development and commercialization will be forced to evolve, too.…

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Date posted: April 24, 2016 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

Inevitably when I post a blog on “human biology” I get a series of comments about the importance of non-human model organisms in drug discovery and development. My position is clear: pick targets based on causal human biology, and then use whatever means necessary to advance a drug discovery program to the clinic.

Very often, non-human model organisms are the “whatever means necessary” to understand mechanism of action. For example, while human genetic studies identified PCSK9 as an important regulator of LDL cholesterol, mouse studies were critical to understand that PCSK9 acts via binding to LDL receptor (LDLR) on the surface of cells (see here). As a consequence, therapeutic antibodies were designed to block circulating PCSK9 from the blood and increase LDLR-mediated removal of circulating LDL (and hopefully to protect from cardiovascular disease).

Moreover, non-human animal models are necessary to understand in vivo pharmacology and safety of therapeutic molecules before advancing into human clinical trials.

Beyond drug discovery, of course, studies from non-human animal models provide fundamental biological insights. Without studies of prokaryotic organisms, for example, we would not have powerful genome-editing tools such as CRISPR-Cas9. Without decades of work on mouse embryonic stem cells, we would not have human induced pluripotent stem cells (iPSCs).…

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Date posted: December 19, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

This week’s theme is genes to function for drug screens…with a macabre theme of zombies! As more genes are discovered through GWAS and large-scale sequencing in humans, there is a pressing need to understand function. There are at least two steps: (1) fine-mapping the most likely causal genes and causal variants; and (2) functional interrogation of causal genes and causal variants to move towards a better understanding of causal human biology for drug screens (“from genes to screens”).

Genome-editing represents one very powerful tool, and the latest article from the laboratory of Feng Zhang at the Broad Institute takes genome-editing to a new level (see Genetic Engineering & Biotechnology News commentary here).  They engineer the dead!

Genome-scale gene activation by an engineered CRISPR-Cas9 complex, Nature (December 2014).

Since its introduction in late 2012, the CRISPR-Cas9 gene-editing technology has revolutionized the ways scientists can apply to interrogate gene functions. Using a catalytically inactive Cas9 protein (dead Cas9, dCas9) tethered to an engineered single-guide RNA (sgRNA) molecule, the authors demonstrated the ability to conduct robust gain-of-function genetic screens through programmable, targeted gene activation.

Earlier this year, the laboratories of Stanley Qi, Jonathan Weissman and others \ reported the use of dCas9 conjugated with a transcriptional activator for gene activation (see Cell paper here).…

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