Roche’s Oryzon farewell spells more bad news for epigenetics

Roche’s decision today to ditch Oryzon Genetics’ lead project, ORY-1001, is a puzzling U-turn over an asset to which the Swiss group had recently increased its commitment. Then again, while the official reason given is internal reprioritisation, underwhelming ORY-1001 data at Ash might have made Roche think twice.

Beyond the immediate effect on Oryzon, which is now left to face data readouts alone, Roche’s exit could have broader significance. Along with the rest of Oryzon’s pipeline ORY-1001 acts on epigenetic pathways – an approach that has largely failed to deliver on early promise.

Epigenetics can broadly be defined as the way in which molecular mechanisms can affect gene expression, and it has proved interesting for drug developers because of the way that such complex pathways can be triggered using small molecules.

However, Merck & Co’s Zolinza and Spectrum/Onxeo’s Beleodaq, the first two epigenetically acting drugs approved, have not impressed in the market. Shares in Epizyme, a US biotech focused on this approach, have drifted down over the past five years despite the group boasting Glaxosmithkline, Eisai and Roche as partners.

Shots on goal

Roche has made several efforts to get into epigenetics; in addition to deals with Oryzon and Epizyme it bought Tensha Therapeutics, a private player, for $115m up front a year ago.

Roche first gained rights to ORY-1001, which it designated RG6016, in 2014, and last year expanded the deal to commit to Oryzon for another 12 months. ORY-1001 targets lysine-specific demethylase 1 (LSD1), a histone-modifying enzyme thought to affect expression of genes involved in the onset and progression of certain diseases.

Hotly awaited data in acute myelogenous leukaemia (AML), presented at the Ash meeting in December, seemed to put a dampener on things, however. In what was primarily a safety trial serious adverse events potentially related to ORY-1001 were seen in two of 27 patients, including one death. Efficacy hints were limited to two partial remissions in 14 evaluable subjects.

At the time of the Ash abstract publication investors bid Oryzon stock up 30%, but news of Roche’s decision to pull the plug sent the shares down 23% today. Beyond AML Roche is still responsible for designing a trial of ORY-1001 in small-cell lung cancer, but no human data in this use have yet been generated.

Despite the Swiss group’s exit Oryzon seems committed to ORY-1001, though because development had until now been funded by Roche a new partner might be needed to take the financial strain. Oryzon also has a clinical programme in Alzheimer’s, Huntington’s and multiple sclerosis, with a second asset, ORY-2001.

However, this must be seen as risky, given both the CNS focus and ORY-2001’s novel mechanism – bispecific LSD1 and monoamine oxidase B inhibition. After generating safety data in volunteers in March Oryzon’s plan is to start efficacy studies with this unpartnered asset.

If Roche’s exit was indeed down to Epizyme or Tensha being preferred internally Oryzon investors might have some short-term cause for optimism. And since the Roche deal was heavily backend loaded they will note that the Swiss group’s sunk cost was relatively minor.

However, for an epigenetics-focused company like Oryzon the signs are not overwhelmingly positive. Beyond the takeout of Tensha, and Oncoethics by Merck & Co, the field is still awaiting a meaningful clinical success.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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