Over the next six weeks Seattle Genetics intends to negotiate with FDA over its plans for confirmatory trials to support accelerated approval of Adcetris (brentuximab vedotin) – which the company hopes to accomplish using studies already planned as further development of the antibody-drug conjugate.

Seattle Genetics has a program of label expansion trials and will consult with the agency, in advance of its Aug. 30 user fee deadline, as to which of these are acceptable as confirmatory, CEO Clay Siegall said on a July 15 conference call. “We feel that we have a number of pathways that we could go down as part of our label expansion,” he explained.

FDA's Oncologic Drugs Advisory Committee July 14 voted unanimously (10 to 0) in favor of accelerated approval of brentuximab for relapsed or refractory Hodgkin’s lymphoma following an autologous stem cell transplant, and for relapsed or refractory systemic anaplastic large cell lymphoma.

Advisory Committee Votes

10-0 in favor of accelerated approval for relapsed or refractory Hodgkin's lymphoma following autologous stem cell transplant
10-0 in favor of accelerated approval for relapsed or refractory systemic anaplastic large cell lymphoma

Office of Oncology Drug Products Director Richard Pazdur, however, made clear that approval by the PDUFA date is contingent on a plan for confirmation.

Accelerated approval is contingent on an agreement between FDA and the sponsor on post-approval trials that will be conducted to confirm the benefit and safety of the drug in question. Best practices for confirmatory trials were the subject of a February ODAC meeting about accelerated approval (Also see "Adcetris Review Gives ODAC Chance To Apply Principles On Accelerated Approval" - Pink Sheet, 12 July, 2011.).

At the Adcetris review, Pazdur said FDA wants a discussion with the company on a “comprehensive drug development program – exactly where they’re going, what trials they plan on doing and what trials they plan on designating as confirmatory trials.”

Many Options In The Development Program

Pazdur noted that post-approval trials involving another indication can serve as a means to both confirm a drug’s benefit and safety, allowing conversion from accelerated to regular approval, and to expand its use.

That flexibility can get the company where it wants to go, Siegall indicated.

The firm is already enrolling Phase I trials in front-line Hodgkin’s and ALCL to examine how to best combine brentuximab with multi-agent chemotherapy, and results from those trials are to be used to design Phase III trials in those patient populations.

The firm also plans to evaluate the ADC in other CD30-positive malignancies, such as cutaneous T-cell lymphoma and other types of non-Hodgkin’s lymphoma.

But the company missed out on the near-term opportunity for a confirmatory trial.

But Some Not For Confirmation

Seattle Genetics has a randomized placebo-controlled Phase III trial it began enrolling a year ago. AETHERA has a planned enrollment of 322 patients with high risk of residual Hodgkin’s lymphoma following an autologous stem cell transplant. The primary endpoint is progression-free survival.

Seattle Genetics discussed the trial design with FDA before initiating it, but did not incorporate all of the agency’s suggestions.

That has come back to haunt the company, as FDA is critical of the target patient population. The trial includes both participants with no residual disease and those with active disease, making a risk/benefit calculation difficult, according to FDA.

“My fear is that it’s going to be uninterpretable,” Pazdur told the panel.

Committee Chairman Wyndham Wilson, National Cancer Institute, suggested that assessing the results would be like comparing apples and oranges. You will “be looking at its ability to cure people who are in CR [complete remission] and then you’re basically going to have a trial of people who have active disease getting the drug or not getting the drug.”

William Kelly, Thomas Jefferson University, pointed out that “the heterogeneous population they have is inadequate. With the numbers you’re going to get, you really don’t see an outcome.”

The firm plans to discuss modifications to AETHERA to make it confirmatory, Siegall said. “If that doesn’t work,” he added, “we really value AETHERA for getting efficacy data and safety data.”

But, he insisted, “We’re capturing a ton of data, so there’s a lot of different ways we can talk about this and think about patient populations, and we discussed stratification with them. There might be different ways that we could make this study fit their needs.”

The company also faced concern from an analyst that it attempted to gain regular approval after being advised by FDA at a pre-BLA meeting to submit for accelerated approval. Though Siegall maintained the company is in the same spot it would have been, Banc of America Securities-Merrill Lynch Research analyst Rachel McMinn saw a "massive disconnect" with FDA and implied that the company had missed out on planning for confirmatory trials for an accelerated approval by focusing on regular approval.

By Cathy Dombrowski

Seattle Genetics Hoping Adcetris Label Expansion Trials Can Be Confirmatory

More from Archive

More from Pink Sheet