About six months after Epizyme Inc. won FDA clearance of Tazverik (tazemetostat) for epithelial sarcoma (ES), the firm scored accelerated approval in the larger indication of relapsed or refractory (r/r) follicular lymphoma (FL).

Specifically, U.S. regulators cleared the methyltransferase inhibitor for adults whose tumors test positive for an EZH2 mutation who have received at least two prior systemic therapies and for those with no satisfactory alternative treatment options – language that “gives physicians a lot of flexibility to use their clinical judgement in how to best prescribe” the drug, CEO Robert Bazemore noted.

“We’ve had great collaborative discussions with the agency” to arrive at the label, he told BioWorld.

Jefferies analyst Michael Yee likes “the broad FL indication for both mutant (20% of total) and wild-type (80%) patients,” he wrote in a report. “For wild-type, some investors might perceive ‘no satisfactory’ alternative options to mean docs have to exhaust other approved drugs first,” such as phosphoinositide 3-kinase (PI3K) inhibitors, but the wording “leaves it open for oncologists to prescribe based on whatever the patient needs are.” He estimated “a $500 million to $1 billion long-term opportunity.”

The FDA also approved the cobas EZH2 Mutation Test, from Roche Holding AG, of Basel, Switzerland, as a companion diagnostic for Tazverik.

Cambridge, Mass.-based Epizyme gained priority review for orally administered Tazverik’s supplemental NDA, backed by phase II efficacy and safety data that rolled out during the 2019 annual meeting of the American Society of Hematology. Tazverik showed clinical benefit in terms of overall response rate and duration of response as assessed by investigators as well as an independent review committee. It proved generally well-tolerated, too, in FL patients with EZH2-activating mutations (n=45) and FL patients with wild-type EZH2 (n=54). Results from other experiments were disclosed during the recent annual meeting of the American Society of Clinical Oncology.

FL is the second most common form of lymphoma and accounts for 20% to 30% of all non-Hodgkin lymphoma cases. Although slow growing, FL is incurable. Many patients experience cycles of relapse and recurrence as therapies become less effective over time.

Robert Bazemore, CEO, Epizyme

During Epizyme’s earnings call in May, Bazemore said the firm was “very impressed with the launch so far” of Tazverik in rare ES. Revenues booked “based on two months of sales, our ability to execute being able to ship drug, and seeing the first prescriptions come in – in just the first week following approval – all have been great things,” he said. The firm’s chief strategy and business officer, Matthew Ros, said that “academic centers [are] really the place where the majority of prescriptions have been falling. When patients are diagnosed with this disease, they often go to a multidisciplinary treatment center or academic center,” of which about 60 exist in the U.S. “The utilization thus far has proportionally been in those centers as we would have expected that to occur,” he said. But the juicier prospects lie in FL, where “the overwhelming majority of patients, up to 80%, are actually observed in the community-based setting as compared to ES,” Ros said. “Our plan has always been to leverage the insights and the infrastructure from the ES grouping to then quickly expand to FL.”

PI3K inhibitors have shown admirable efficacy in FL but with less than optimal safety profiles, and market research shows that only about one-third of patients are prescribed drugs in the class, Bazemore pointed out. Zydelig (idelalisib) from Foster City, Calif.-based Gilead Sciences Inc., bears a black box warning for fatal or serious hepatic toxicity, severe diarrhea, colitis, pneumonitis and intestinal perforation. Grade 3 adverse events (AEs) with Leverkusen, Germany-based Bayer AG’s PI3K drug, Aliqopa (copanlisib), included hypertension (27%), hyperglycemia (33%), leukopenia (12%), infection (12%), neutropenia (10%), thrombocytopenia (7%), and grade 4 AEs were neutropenia (15%), leukopenia (15%) and hyperglycemia (6%). Zydelig chalked grade ≥3 AEs, too, including diarrhea (14%), pneumonia (16%), dyspnea (4%) and rash (3%).

Tazverik’s safety profile from clinical work, which included grade ≥3 rate of treatment‐emergent AEs of 17% and no grade 5 AEs, “stacks up very nicely to other approved therapies and could be a major driving force for uptake,” Wainwright analyst Andrew Fein wrote in a report. “Off-label usage of Tazverik in second-line, EZH-mutated FL suggests existing awareness,” he said.

Sounding more skeptical about Tazverik FL was SVB Leerink’s Andrew Berens. “Despite the company's high level of conviction, we remain on the sidelines given our concerns about the trajectory of the launch, which will require educating prescribers and identifying candidates for the drug,” he wrote in a May 5 report. The r/r FL setting has “traditionally been difficult commercially, something that may be magnified in the COVID-19 environment, as patients with indolent diseases may not readily seek medical care,” he said, and community-based treatment “could make clinician outreach more difficult amidst the pandemic.”

Bazemore doesn’t think so. “We’ve already had to adapt everything we’re doing commercially to be successful operating in a COVID-19 environment,” he said. Many contacts are made by virtual means. Although some centers likely will start opening up soon, allowing for face-to-face interactions, this will be “fairly slow going, so we can do it either way,” he told BioWorld. “Oncologists are looking for a new option that matches the unmet need that they see with this population,” he added. Challenges with launches of the kind cited by Berens have to do with “the products that have been offered, not the fact that [doctors are] hard to educate.” Community oncologists are particularly averse to dealing with AEs “that cause them to have to discontinue treatment, particularly if the drug is working,” he said – which means more upside with Tazverik, given its profile.

Epizyme is conducting a global, randomized, adaptive confirmatory trial to evaluate Tazverik paired with “R2” (Revlimid [lenalidomide, Celgene Corp.] plus rituximab), an approved chemo-free treatment regimen, for FL patients in the second-line or later setting. The trial is expected to enroll about 500 FL patients, stratified based on their EZH2 mutation status, and the safety run-in portion is underway. The company has made postmarketing commitments that include expanding its phase II trial cohort of FL patients with wild-type EZH2 who have been treated with at least one prior systemic treatment to enroll more patients, in order to support a potential label expansion in the second-line r/r setting down the road.

Pricing of Tazverik was established after the first approval, Bazemore said. The $15,500 per month cost is based on its value in ES and FL. “Because the two indications were so close together, we had to take both into account,” he said. Shares of Epizyme (NASDAQ:EPZM) closed June 18 at $20.46, up 94 cents.

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