Epizyme had hoped that a partial clinical hold on its lead candidate, tazemetostat, would be resolved quickly; three months on, however, the project’s prospects have gone from bad to worse.
This made the company one of two oncology groups, along with Clovis, that this week failed to shake off problems under which investors might by now have drawn a line. Epizyme’s triple whammy of bad news yesterday sent the stock down 24% and raised questions about when – and even if – tazemetostat can get back on track.
At present, the project’s sellside consensus sales forecasts of $914m by 2024 look unrealistic.
For one, Epizyme has discontinued tazemetostat’s development in diffuse large B-cell lymphoma (DLBCL), at least as a monotherapy and in combination with prednisone; combo trials with R-CHOP chemotherapy and Roche’s PD-L1 inhibitor Tecentriq are ongoing.
|Tazemetostat's remaining chances in DLBCL|
|Follicular lmphoma and DLBCL*||Tazemetostat + Tecentriq/Gazyva||I||NCT02220842||May 2019|
|DLBCL**||Tazemetostat + RCHOP||I/II||NCT02889523||Sep 2020|
|*Active, not recruiting; **Suspended. Source: Clinicaltrials.gov.|
And the company has delayed its filing for tazemetostat in its lead indication, epithelioid sarcoma, until the first half of next year, having previously hoped to submit the project to the FDA by the end of this year.
Still, an eventual approval is in doubt if Epizyme cannot resolve the safety concerns that led to April’s US clinical hold, which has now spread to include France and Germany (Accelerated filing delay could be the least of Epizyme’s problems, April 24, 2018).
That hold, prompted by a secondary lymphoma seen in a paediatric trial subject, looks no closer to being lifted, in spite of Leerink analysts’ assurances at the time that it should be sorted in a matter of weeks.
Epizyme now says it will finalise its response to regulators “in the weeks ahead”, but this vague timeline was evidently not enough to reassure investors.
Other indications remain in play, including follicular lymphoma and mesothelioma, despite disappointing Asco data in the latter; but no updates were given on these yesterday.
Clovis investors, meanwhile, might well have assumed that their company had drawn its own line under Xegafri, its now discontinued former lead asset.
Not so, as Clovis this week revealed a $20m charge to account for a settlement it was hoping to reach with the US SEC over a long-running investigation into the project’s controversial data package.
Back in 2015 Xegafri was in a race against Astrazeneca’s Tagrisso to reach the market for treating relapsed EGFR-positive lung cancer. But everything unravelled when independent review failed to back up investigator-reported pivotal trial remission rates, triggering the SEC investigation.
This came on top of hypoglycaemia emerging as a serious side effect – something Clovis had tried hard to play down. After a savaging at a US adcom, and communication from US and EU regulators that rejections were imminent, Clovis canned Xegafri (Clovis waves white flag on rociletinib but readies new attack, May 6, 2016).
The group was fortunate in that it could pivot to rucaparib, the drug now marketed as Rubraca. But there was further bad news this week about another asset, the VEGFR, PDGFR and FGFR inhibitor lucitanib, which Clovis hopes to combine with Rubraca in the Starfish study.
Lucitanib was being developed with Servier, but Clovis on Wednesday said the French firm would shortly hand back rights. Clovis is refusing to give up on lucitanib, touting the project’s potential in combination with checkpoint blockade and pointing to the success of a similarly acting drug, Eisai’s Lenvima, alongside Merck & Co’s Keytruda.
Still, Clovis’s stock fell 11% yesterday, partly over numbers suggested that Astra’s rival Parp inhibitor Lynparza was crushing Rubraca in the market.
It looks like Epizyme and Clovis alike now hope combinatorial approaches will get them out of trouble.