Washington Editor

A lot is on the line Thursday when the FDA's Oncologic Drugs Advisory Committee (ODAC) reviews Seattle Genetics Inc.'s Adcetris as a treatment for relapsed or refractory Hodgkin lymphoma and for relapsed or refractory systemic anaplastic large cell lymphoma (ALCL).

If approved by the FDA, Adcetris could be the first new Hodgkin's treatment since 1977 and the first treatment for ALK1 negative ALCL.

The agency is asking the committee to consider full or accelerated approval for both indications.

Because Adcetris is one of the first cancer drugs seeking accelerated approval since ODAC weighed in earlier this year on the evidence needed to support such approval, Thursday's meeting also could serve as a bit of a litmus test.

At a February meeting, the committee told the FDA that randomized, controlled trials should be the standard for accelerated approval, noting that the bar should not be lowered to move drugs to market faster through single-arm trials.

However, ODAC didn't rule out single-arm trials, saying they should be the exception – but only for drugs used in rare diseases and that demonstrate a high level of activity or a pronounced treatment effect.

Seattle Genetics' Adcetris (brentiuximab vedotin) has both going for it.

Besides meeting unmet needs in both indications, it proved highly effective in the single-arm Phase II trials being used to support accelerated approval of its two biologic license applications (BLA), which were submitted a few weeks after the committee's February meeting. (See BioWorld Today, March 1, 2011.)

In the Hodgkin's trial, 94 percent of the 102 subjects had reductions in tumor volume and 75 percent had objective responses, including 32 percent who achieved complete remission.

The Bothell, Wash.-based company reported similar results for its Phase II ALCL trial, with 97 percent of the 58 patients experiencing reductions in tumor volume and 53 percent complete remission.

The FDA confirmed the Adcetris results in its briefing documents for Thursday's meeting, but it is asking ODAC to comment on the level of evidence presented for the efficacy results.

FDA's Discomfort: Single-Arm Trials

Seattle Genetics conducted one single-arm Phase II trial for each BLA.

The company has started Phase III trials in Hodgkin lymphoma patients after autologous stem cell transplant (ASCT) and is conducting an additional Phase II study for relapsed patients and a Phase I study for Hodgkin lymphoma front-line treatment.

While the agency raised no serious concerns about Adcetris in the run-up to the meeting, it "reiterated its discomfort with single-arm trials," Baird Equity Research analyst Christopher Raymond said.

If, as expected by most analysts, ODAC supports accelerated approval for Adcetris, single-arm trials for many cancer drugs, such as Onyx Pharmaceuticals Inc.'s carfilzombib, still would be a risky strategy, Raymond added.

ODAC has exhibited a trend of increasing caution in cancer drug applications in recent years.

In 2009, the committee voted against accelerated approval for Genzyme Corp.'s Clolar (clofarabine) and Vion Pharmaceuticals Inc.'s Onrigin (laromustine) because the applications were based on single-arm, uncontrolled Phase II trials.

Since then, biotechs have tended to go the full nine yards with large, randomized Phase III trials. For instance, Sunesis Pharmaceuticals Inc. opted not to attempt accelerated approval for its first-in-class quinolone derivative, vosaroxin, despite good results in two separate Phase II studies in acute myeloid leukemia. It began Phase III trials instead. (See BioWorld Today, Dec. 22, 2010.)

One exception was Celgene Corp.'s Istodax (romidepsin), which received accelerated approval last month as a treatment for peripheral T-cell lymphoma, based on two small single-arm Phase II trials. Istodax had already been approved to treat cutaneous T-cell lymphoma. (See BioWorld Today, June 20, 2011.)

"It is clear that the bar for trials in first- and second-line disease will be set higher and that safety will be a larger issue," said J.P. Morgan analyst Cory Kasimov.

In addition to the evidence questions Thursday, the FDA will ask ODAC to consider the acceptability of Seattle Genetics' confirmatory trial design for the Hodgkin's BLA. A confirmatory trial is needed to move a drug from accelerated approval to full approval.

The agency also will ask the committee whether accelerated approval should be granted for the ALCL BLA without an ongoing confirmatory trial.

In the briefing documents, the FDA emphasized that the Hodgkin's trial evaluated only patients who had previously received an autologous stem cell transplant.

That could lead to a more restrictive label than the broader relapse/refractory label that has been widely anticipated, according to Kasimov.

Should it get accelerated approval by its Aug. 30 PDUFA date, Seattle Genetics is in a strong position to launch its lead antibody-drug conjugate (ADC), which was developed through a partnership with Millennium, of Cambridge, Mass., a unit of Takeda Pharmaceuticals Co. Ltd.

In exchange for global rights outside North America, Millennium paid half the development costs and gave Seattle Genetics $60 million up front with more than $230 million in milestones, Seattle Genetics Chief Operating Officer Eric Dobmeier told BioWorld Today. The company also stands to get royalties from the mid-teens to mid-20s on Millennium's sales.

The European Medicines Agency accepted Millennium's filing of marketing authorization applications for Adcetris for both indications last month, and Dobmeier expects European approval next year.

Seattle Genetics has three other ADCs in Phase I, two of which are being developed in collaboration with Astellas Pharma Inc., and 11 others being developed by partners. (See BioWorld Today, March 23, 2011.)

Adcetris is "sort of the tip of the iceberg using this technology," Dobmeier said.