Panel discussion on OLIGONUCLEOTIDES

Nearly four decades ago when I was a student, I read an article about scientists employed by pharmaceutical companies to travel the globe collecting plant and soil samples. Thousands of samples were collected and taken back to company labs to be screened for compounds with medicinal properties. The next blockbuster drug could be waiting to be discovered in a vial full of soil taken from the rainforest floor. The whole process seemed so romantic and exciting to my teenage brain. My adult brain sees that process for what it is, an expensive and inefficient way to discover new drugs.

Oligonucleotide based therapeutics (oligos) are attractive to drug developers because they offer an efficient and rational way to design drugs. Oligos also have well understood mechanisms of action. Most of these drugs derive their therapeutic properties from the regulation of gene expression. Some oligo drugs incorporate features that impart immunostimulatory properties, which is why oligos can be potent vaccine adjuvants. Oligos are produced using well established solid phase synthesis methodologies that can be applied to multiple oligo sequences.

The potential of oligos was clear for many years, but few realized how long it would take to develop oligos into a viable drug platform. The first approved oligo drug was fomivirsen in 1998. Only two other oligos would be approved by regulators over the following seventeen years. Pegaptanib sodium was approved in 2004, and mipomersen was approved in 2013. All three oligos were small volume drugs with limited commercial success. During that same seventeen year period, numerous oligos were part of late-stage clinical trials that failed to produce the desired end points. Professionals working in the field often felt as if they were on a rollercoaster as they anticipated clinical successes only to witness clinical failures.