Epigenetics has so far failed to live up to the hype. Although several cancer drugs have been approved that cause these types of changes in gene expression, they have not exactly revolutionised the field in the same way as, say, checkpoint inhibitors.
This has not put off one young UK company, Storm Therapeutics, which claims to have found a new path to tread: RNA epigenetics. As well as doubts about epigenetic drugs in general, though, Storm has other obstacles in its path, like a lack of patent protection and a larger US rival, Accent Therapeutics.
Accent was launched in May with a $40m series A round, dwarfing the £12m ($16m) that Storm raised in its series A two years ago. Storm topped this up with another £4m in January, but is still outgunned by its US counterpart.
Storm’s chief executive, Keith Blundy, is not fazed, telling EP Vantage that his company has been around for longer and is – as far as he knows – ahead in development. But, with both groups keeping quiet about their targets and progress so far, the race is hard to call.
Storm is planning another fund raising itself in the second half of the year, aiming for around £40m, Mr Blundy says, although the exact amount has not been finalised. “We’ll be looking to try to get one or two of the big US investors in in the next round,” he adds.
This should be enough for Storm to go into clinical trials, and the first data in humans should come in 2021 or 2022, according to the chief exec.
However, potential backers might want to wait until Storm has a firmer grip on intellectual property: Mr Blundy admits that his group has not yet filed a composition of matter patent for its lead project, but maintains that this is normal. “It’s still early to file – pharma companies don’t file until as late as they possibly can.”
This is one reason why Storm will not disclose the targets for its five ongoing programmes, which are yet to go into animal studies. Still, broad details are available: Storm’s candidates are all small molecules targeting enzymes that make modifications to RNA that then alter gene expression, with a focus on cancer.
And the company will say that, of the various enzyme families that make these RNA modifications, it is looking at two initially: the methyltransferases and TUTases.
Shoot the messenger
Inhibiting methylation is a familiar avenue for epigenetic drugs, but so far therapies have taken aim at enzymes that modify either DNA or histones, proteins that have a role in gene regulation. It is the targeting of RNA that is new, according to Mr Blundy.
Although RNA modifications have been known about for some time, he says, “it’s only now that people are beginning to unravel stories around those modifications and their effects on the biology of disease.” One such modification, catalysed by the METTL3 enzyme, was recently linked to acute myeloid leukaemia in a Nature paper by one of Storm’s founders, Dr Tony Kouzarides.
Mr Blundy will not say whether Storm is developing a candidate against METTL3, but agreed that "you might reasonably think we might have an interest in it”.
As well as Accent, Mr Blundy names two other groups that have a similar strategy to Storm in targeting RNA-modifying enzymes: Gotham Therapeutics and 278. Little information about either company is publicly available – neither even has a website.
Meanwhile, others are taking a slightly different approach by creating small molecules that bind directly to the RNA “and stop it doing whatever it should do. If it’s an mRNA perhaps you stop it being translated.” These companies include Skyhawk Therapeutics, Ribometrix, Arrakis Therapeutics and Expansion Therapeutics.
While Mr Blundy believes that the RNA epigenetic approach has been validated by the DNA and histone-targeting projects that have gone before it, marketed histone deacetylase inhibitors such as Merck & Co’s Zolinza and Spectrum/Onxeo’s Beleodaq have had a dismal commercial performance.
And one of epigenetics’ standard bearers, Epizyme, had a safety setback in April that led to a partial clinical hold of its lead project, tazemetostat. This raised concerns about its mechanism, inhibiting the methyltransferase EZH2, along with the epigenetics approach in general (Accelerated filing delay could be the least of Epizyme’s problems, April 24, 2018).
Accent, Storm’s closest rival in RNA epigenetics, has links with Epizyme – all of its leadership team previously worked for the older company. This experience, along with the company’s US investor base, could give it an edge over Storm.
Still, with big pharma groups like Roche and Glaxosmithkline pulling out of epigenetics deals in the past year, it is fair to say that the field has so far not lived up to the promise. Perhaps the real challenge for Storm is not staying ahead of Accent but proving that its approach really does have legs.