Epizyme Has Aggressive Plans For Accelerated Approval For Tazemetostat

Biotech is developing its EZH2 inhibitor in multi-arm Phase II studies in various forms of non-Hodgkin lymphoma as well as genetically defined solid tumors.

A year after losing its big pharma partner, epigenetic cancer therapy-focused Epizyme Inc. used its quarterly earnings call March 9 to outline a four-step strategy for becoming a commercial company, expanding the potential uses for lead candidate tazemetostat (EPZ-6438, aka taz) and bringing at least three novel proprietary cancer candidates into clinical development by 2020.

Central to this strategy is a plan to seek expedited approval of tazemetostat based on findings from Phase II studies in various forms of non-Hodgkin lymphoma (NHL) and in rare genetically defined solid tumors. CEO Robert Bazemore, who joined the Cambridge, Mass.-based biotech last September after departing the chief operating officer's role at Synageva BioPharma Corp., outlined a plan by which Epizyme will seek approval for varying indications based on data from individual arms of the two Phase II studies.

In an interview prior to the investor call, Bazemore said tazemetostat could present a "platform-within-a-product opportunity." Epizyme regained almost all rights to the EZH2 inhibitor last year by paying Eisai Co. Ltd., its partner since 2011, $40m up front to largely unravel the collaboration around tazemetostat [See Deal]. Eisai retains Japanese rights to the compound, and is responsible for 100% of the development costs in that market.

"Prior to last year, all of our programs were partnered with somebody – taz with Eisai, and Eisai was driving the clinical development of taz," the exec said. "The rest of our pipeline was partnered with Celgene Corp., and through renegotiating with Celgene, we now own the worldwide rights to our platform with the exception of the three targets that we're pursuing with them." [See Deal]

Bazemore said his company wants to accelerate development of tazemetostat because it can afford to give the compound its full focus. With $320m in cash on hand after netting $130m in a January follow-on public offering, he says Epizyme has financial runway through 2017. [See Deal]

"In terms of creating value for the company, we'd like to find a way to get the product to market as quickly as possible," Bazemore explained. "When Eisai owned this program, it was one of a number of programs that they were executing across their portfolio in many therapeutic areas."

The firm hopes to quicken its path to market by roughly doubling the number of trial sites and including US patients and sites for the first time; Eisai's vision was to develop the drug entirely in Europe.

The CEO added that the unmet medical need for some of the cancer indications being studied, such as malignant rhabdoid tumor (MRT) and synovial sarcoma, add to the urgency of getting to market quickly.

"When you think about the NHL population, we're studying in a third-line setting so by the time patients get to third-line, there aren't really any consistently effective options for treating these patients," Bazemore said. "And the relapse rate tends to be quite high."

"For genetically defined solid tumors, there really is no standard of care, there's nothing that works in these patients. And typically the first treatment approach is surgery, but beyond that there isn't anything that is consistently effective," he continued. The company is targeting INI-deficient tumors, which Bazemore noted have. "a very low survival rate without anything to treat them."

The Phase II studies have been designed so that each of their multiple arms is powered to demonstrate efficacy, Bazemore said. In the NHL study, arms are investigating diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Epizyme does not expect to be able to file for approval based on Phase II data in all the indications being studied, but it hopes it will get there in several, he added.

"For example, the malignant rhabdoid tumors – this is a fairly rare tumor type, we're talking about thousands of patients globally who have this particular type of tumor," Bazemore said. "There isn't a standard of care to treat these patients, so if we generate a robust clinical response in the Phase II program, we would want to immediately go to FDA and discuss with them an expedited path to get the product to market."

"FDA could ask us continue to study and just enroll more patients so that the cohort is bigger and then file," he added. "In some of the arms, we anticipate there may be a follow-on study that would be needed where you have a control arm, but in many of the genetically defined solid tumors, if there's nothing that consistently works effectively, it would be hard to imagine the next step would be to design and execute a comparative study."

Planning Ahead

Epizyme wants to be a commercial company by 2020, and is committed to developing tazemetostat, a histone methyltransferase inhibitor, over a variety of cancer indications, both as monotherapy and in combination regimens, including potentially with immune checkpoint inhibitors, Bazemore said.

Beyond tazemetostat, the company is also working preclinically on five novel proprietary targets and has a goal of bringing three new cancer programs into clinical development by 2020, as it develops and establishes its leadership in the space of epigenetics and chromatin remodeling.

"These transformative activities address our intent to grow in the short-, mid- and long-term, so we're not just focused on the year 2020," Bazemore explained. "We're looking at creating sustainable value for the company over the long term."

For the goal of investigating tazemetostat's potential in combination therapy, Epizyme has conducted preclinical studies with several other cancer therapy types to search for synergistic activity. Based on those studies, it will study tazemetostat in tandem with R-CHOP, the front-line standard of care in NHL, for front-line therapy. "Obviously, we don't want to be in the third-line setting only," Bazemore noted.

Other preclinical tests have indicated synergy with various types of cancer immunotherapies, and Epizyme is seeking a partnership with a company in immuno-oncology space that can add its expertise in that arena to Epizyme's epigenetic therapy know-how. Ideally, such a partner would run and fund the combination study, Bazemore said. Having a partner take the lead is necessary in part because Epizyme is undertaking a new Phase II study of tazemetostat monotherapy in BAP1 loss-of-function mesothelioma in the third quarter of 2016, he added.

The company has been working on the strategy for some time, "so we actually began talking with interested companies late last year in the fourth quarter," Bazemore said. "There's been a tremendous amount of interest to talk with us about collaborating and doing a combination study like this. We are fairly far down the path of discussing this with potential partners and we hope to be able to announce an agreement by the end of the first half of the year."

In a March 9 note rating Epizyme's shares "outperform," WedBush Securities analyst David Nierengarten called the company's strategy more aggressive than he expected. He also expressed solid optimism for tazemetostat as a combo regimen partner with immune checkpoint inhibitors.

"We find the proposed immunotherapy study to be particularly promising, as reports from investigators suggest that EZH2 inhibition could sensitize tumors to checkpoint inhibition by enhancing exposure of tumor antigens to the immune system," he wrote. "We have long viewed tazemetostat as well suited for a combination approach, due to its unique mechanism of action, favorable safety profile and preclinical data showing synergistic activity with other NHL therapies."