Translational Bytes
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New Drug Rounds: Translational Biomarkers

New Drug Rounds: Translational Biomarkers

A main goal of translational science is to understand the pathology of human disease and find treatments that have a relevant mechanism of action. In some cases, disease mechanisms may be well-understood, as for inherited disorders that map to a well-characterized genetic defect. In some cases, it may take decades of research to isolate disease subtypes or pin down a disease’s primary drivers. The in silico, in vitro, or in vivo tools to interrogate the genome, characterize functional consequences of certain molecular defects, and screen for active drugs have improved over time, leading to many novel drug approvals in recent years. The recent FDA approvals for ivacaftor1 and pembrolizumab2 represent two success stories that have ensued from advances in molecular pathology.

Ivacaftor, approved in 2012, initially carried an indication for the treatment of patients with a specific mutation in the gene that encodes the cystic fibrosis transmembrane conductance regulator. This mutation was targeted on the basis of changes in protein function observed when cells were treated with ivacaftor. In vitro responses were also studied in experiments of less prevalent mutations, which led to additional clinical trials in patients with mutations that were found to be amenable to treatment. As the clinical database grew, the conditions for use also grew incrementally. Based on extensive clinical evidence that accrued by May 2017, the FDA approved an expansion of the ivacaftor indication to include patients bearing those mutations that had been linked to an in vitro response. Clinical data were not available for some of these mutations, marking a shift in the approach to identifying candidates for ivacaftor treatment.

Along similar lines, pembrolizumab was initially approved in 2014 for metastatic melanoma, before additional clinical trials supported the FDA decision to expand its use to other tumor types. Data pointing to a high degree of immune cell infiltration, somatic mutation burden, and neo-antigens in tumors with mismatch repair deficiency or microsatellite instability, coupled with a durable anti-PD-1 response in a patient with colorectal cancer whose tumor had such features, prompted investigation of pembrolizumab in tumors where mismatch repair biomarkers were identified. Indeed, responses were observed across numerous tumor types sharing this feature. In May 2017, the FDA approved pembrolizumab, under the accelerated approval pathway, for the treatment of refractory metastatic cancers that exhibit microsatellite instability or mismatch repair deficiency without regard to the tumor’s tissue of origin. This approval marks the first “tissue-agnostic” cancer drug product.

“Targeted” therapies, such as ivacaftor and pembrolizumab, are predicated upon a solid mechanistic understanding of the disease and extensive biomarker evaluation. The path to a predictive biomarker can be built on accumulating biological evidence and finding a drug that has a relevant mechanism, often sifting through a proverbial haystack of biomarkers in order to identify responders. In a recent issue of CTS, Ipe and colleagues reviewed the various modalities that may be used to understand the functional consequences of genomic variations – a critical first step in finding a mechanism of disease that can open the door for development of targeted therapies. However, as McShane suggests in her recent commentary, it is far too easy to generate unreliable results in the field of biomarker development; following good scientific practices is essential to generate reproducible results that support biomarker testing in conjunction with a given treatment. Nevertheless, success is possible.  Together, these approvals signal the importance of translating mechanistic information into new therapeutics for the treatment of patients in need.


  1. FDA press release for ivacaftor:
  2. FDA press release for pembrolizumab:

Disclaimer: This publication reflects the views of the author and should not be construed to represent FDA’s views or policies. 

Categories: CTS

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