Dive Brief:
- The Food and Drug Administration has placed a clinical hold on recruitment into the U.S. trial of Epizyme, Inc.'s tazemetostat following reports of a child with advanced poorly differentiated chordoma, a rare bone cancer, developing a secondary T-cell lymphoma. Trial enrollment outside the U.S. has not been affected.
- The child, who had been treated for 15 months, showed a partial response to the drug. The treatment has been stopped in this case, and lymphoma treatment is under way.
- Epizyme's drug is EZH2 inhibitor, under development for genetically defined solid tumors and hematologic malignancies. Children already in the Phase 1 whose disease has not progressed will continue to get treatment. Analysts predict a New Drug Application around the end of 2018, based on an orphan drug indication.
Dive Insight:
Secondary cancers have long been known to be a risk of cancer therapies. The doses involved in this study of children are higher than those used in the adult patients, which Epizyme says is "an approach not uncommon to drug development in aggressive, difficult-to-treat pediatric cancers." However, this is the first case of secondary lymphoma seen in tazemetostat studies, which have included around 750 adult and pediatric patients so far.
The team at Epizyme is working to update its informed consent, investigator’s brochure and study protocols.
"We are working expeditiously with clinical trial investigators and regulatory authorities to initiate the appropriate steps to resume enrollment," CEO Robert Bazemore said in a statement.
Despite the stock fall, Jefferies analyst Michael Yee remains positive about the company. "While bad headline will have stock down, we predict it will bounce back like [Cellectis SA, Juno Therapeutics Inc.] and many others do when they just modify the protocol and trial brochures and get back up and running," he wrote in an investor note, adding that the hold won't affect the timeline for other areas of the drug's development, but cautioned the Epizyme's stock "could be in [the] penalty box for a few months."
He also contended that while the hold brings some safety and regulatory uncertainty, the risk/benefit ratio still holds up, as the drug is being tested in severe disease with unmet need. He suggested the drug may end up carrying a warning in its label, but that this shouldn't hamper its future.
Geoffrey Porges at Leerink is also optimistic.
"We don’t see this case as a major setback, and we expect the clinical program to resume enrollment in a matter of weeks once the study documents are updated," he wrote in a note. "The trials continue to enroll in Europe, and the company reiterated its 2018 first regulatory filing timeline."
Epizyme has had previous challenges in tazemetostat studies. In 2016, a Phase 2 trial of the agent in people with heavily pretreated non-Hodgkin lymphoma (NHL) showed early signs of efficacy, but a tumor response rate of 28% wasn't quite what investors had hoped, and its stock price fell.
The drug is also being assessed in combination with chemotherapy in first-line elderly patients with relapsed or refractory diffuse large B-cell lymphoma, as well as with Roche AG's Tecentriq (atezolizumab) in the same indication.
Tazemetostat will need a good safety and efficacy profile — not only to compete in a crowded oncology market, but also to face off against other companies working in the EZH2 arena.
Last month, Daiichi-Sankyo Co. began a Phase 1 trial in Japan with DS-3201, a dual EZH1/2 inhibitor in patients with malignant lymphoma and adult T-cell leukemia-lymphoma.
And in January 2018, Constellation Pharmaceuticals Inc. began a Phase 1b/2 study of CPI-1205, a small molecule EZH2 inhibitor, in combination with Bristol-Myers Squibb Co.'s Yervoy (ipilimumab) and other immunotherapies, in patients with melanoma and other cancers. The study is Constellation's second combo trial for CPI-1205, with an aim to overcome resistance mechanisms to existing cancer therapies.