Plenge Lab
Date posted: April 13, 2018 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics

[Disclaimer: I am an employee of Celgene. The views reported here are my own.]

Drug research and development (R&D) is a slow, arduous process. As readers of this blog know, it takes >10 years and upwards of $2.5 billion dollars to bring new therapies to patients in need. An aspiration of the biopharmaceutical ecosystem is to shorten cycle times and increase probability of success, thereby dramatically improving the efficiency of R&D.

One potential solution is to use human genetics to pick targets, understand molecular mechanism, select pharmacodynamics biomarkers, and identify patients most likely to respond to treatment (see Science Translational Medicine article here). While intuitively appealing and supported by retrospective analyses (here), it is not yet routinely implemented in most R&D organizations (although see Amgen blog here; Regeneron study below). Indeed, human genetics often represents an inconvenient path to a new therapeutic, as it takes substantial effort to understand the molecular mechanism responsible for genetic risk and many such targets are difficult to drug.

But what if…

…it were possible to go from gene variant to therapeutic hypothesis instantly via in silico analysis;

…it were possible to select an “off-the shelf” therapeutic molecule that recapitulates a human genetic mutation, and take this molecule into humans almost immediately, with limited pre-clinical testing;

…it were possible to select pharmacodynamics (PD) biomarkers that capture underlying human physiology, and to measure those PD biomarkers in a small, human proof-of-mechanism clinical trial;

…it were possible to model the magnitude of effect of a therapeutic intervention relative to existing standard-of-care, and thereby to estimate the commercial market of an as-yet-to-be-approved drug?…

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Date posted: March 9, 2017 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Precision Medicine

Yesterday I participated in the National Academy workshop, “Enabling Precision Medicine: The Role of Genetics in Clinical Drug Development” (link here).  There were a number of great talks from leaders across academics, industry and government (agenda here).

I was struck, however, by a consistent theme: most think that “precision medicine” will improve delivery of approved therapies or those that are currently being developed, whether or not the therapies were developed originally with precision medicine explicitly in mind.  Many assume that the observation that ~90% medicines are effective in only 30% to 50% is the result of biological differences in people across populations (see recent Forbes blog here).  This hypothesis is very appealing, as there are many unique features to each of us.

An alternative explanation is that most medicines developed without precision medicine from the beginning only work in ~30% patients because the medicines don’t target the biological pathways that make each of us unique.

I believe the most likely application is in the discovery and development of new therapies.  That is, I believe that the greatest impact will come when precision medicine strategies are incorporated into the very beginning of drug discovery, and will only rarely have an impact on therapies that were not developed with precision medicine in mind from the start.…

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