On your marks

How the slowly-progressing epigenetics field is moving away from cancer

With less fanfare than the first two waves, a quiet rise in activity is driving a revival of interest in epigenetics, despite little progress in solving the fundamental challenges that have dogged the field from the start.

Although a host of new chromatin-regulators have been identified over the last five years, few of the targets have been touched by drug developers. Instead, preclinical innovation has been springboarding off positive clinical data by devising workarounds to selectively hit validated targets and explore uses for them beyond cancer (see "New Epigenetic Targets").

And while companies may be missing opportunities by not jumping on the new targets, preclinical progress in the field has clearly been sufficient to sustain enthusiasm among investors, who have been steadily backing new opportunities created out of the earlier waves.

In the last five years, at least 12 epigenetic companies have been formed, raising more than $428.5 million between them. Of those, nine are going after epigenetic targets already in the clinic, including HDACs and BET bromodomain proteins. Two have not disclosed targets and one is working on diagnostics based on epigenetic profiles (see "New Epigenetic Companies").

Approval of the first pan-HDAC inhibitor in 2006 launched the initial era of epigenetics; since then seven more pan-HDAC inhibitors have been approved and at least 30 more are in clinical development, along with the first isoform-selective versions, which should have less widespread effects across the genome.

The second epigenetics surge kicked off five years ago when BET bromodomain inhibitors were shown to have exceptional clinical efficacy in NUT midline carcinoma -- a rare genetic disease caused by rearrangement of the NUT gene that often results in generation of BRD-NUT fusion proteins. At least 11 BET inhibitors are now in the clinic for various cancers.

The advent of HDACs, and then BET bromodomain proteins, was met with broad enthusiasm, but the idea that regulating the agents that regulate gene expression could make major inroads into treating cancer proved harder than anticipated to realize.

In 2013, a collection of epigenetic experts at BioCentury’s SciBX Summit on Innovation in Drug Discovery & Development highlighted three key challenges for the field: determining which patients will respond to an epigenetic modulator, developing therapeutics selective for individual proteins within a family, and creating the tools that will help compile the mechanistic and biological information needed to solve the other two problems.

Those problems have

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