GlaxoSmithKline and Genmab gambled that by submitting a pivotal trial including both chronic lymphocytic leukemia patients refractory to two standard therapies and patients refractory to only one of them, fludarabine, but who also had bulky lymphadenopathy, they could garner a broader indication for Arzerra (ofatumumab), despite advice from FDA that the two groups could not be combined for one indication.

The sponsors lost.

"The applicant designed their clinical program to address the use of ofatumumab in the population of patients with CLL who had failed or who were intolerant to conventional therapies," Cross-Disciplinary Team Leader Joseph Gootenberg explained in a Sept. 21, 2009, memo. Genmab and FDA never, however, really saw eye to eye on who constituted that population.

Arzerra's ultimate approval was specifically for "double refractory" CLL patients (DR) who had previously been treated with fludarabine (Genzyme's Fludara and generics) and alemtuzumab (Ilex' Campath ), although the trial also enrolled "bulky fludarabine resistant" CLL patients (BFR). Efficacy results for those patients are excluded from labeling, though safety data is reported for the "total" patient population and for the DR patients.

As FDA told the sponsors at a pre-BLA meeting Sept. 29, 2008, "the BFR subgroup did not meet the regulatory standard for having unmet medical need as the protocol only required prior therapy with one drug," fludarabine, according to Gootenberg.

However, "patients with bulky lymphadenopathy can have a significant response to alemtuzumab," the primary clinical and safety reviewers, Steven Lemery and Jenny Zhang, maintained in a Sept. 14, 2009, joint review. "Approval of ofatumumab for the BFR group would imply a comparative effectiveness claim versus alemtuzumab (without comparison in a randomized clinical trial)."

Therefore, "the Office of Oncology Drug Products (OODP) determined that GSK will need to conduct a comparative study in order to support approval in a patient population (BFR) who were only required to be refractory to one drug," Lemery and Zhang stated.

FDA looked closely at prevailing medical practice to determine what were the conventional therapies that Arzerra patients needed to be refractory to in order to qualify for accelerated approval. Ofatumumab "should demonstrate efficacy in populations whose prognosis and response to treatment is representative of patients with CLL treated in the U.S.," FDA told Genmab, according to minutes of an Aug. 26, 2005, meeting. The geographic restriction ruled out cladribine, the minutes note, because "in the United States there is almost no use of cladribine as initial therapy for CLL and fludarabine has become the de facto standard of care."

The 2008 approval of a new alkylating agent, Cephalon's Treanda (bendamustine), for previously untreated CLL, did not affect FDA's sense of the appropriate agents for consideration in Arzerra's refractory CLL trials. Given the treatment experience of the Arzerra trial patients, "it is unlikely that an additional alkylating agent (bendamustine) would represent satisfactory alternative therapy," Lemery said.

During negotiations over the protocol for the pivotal study, Hx-CD20-406, FDA staff made no secret of their preference for keeping DR and BFR patient data separate.

The division also sought external advice on the design of study 406 from an expert consultant serving as a Special Government Employee, which it communicated to Genmab in an April 11, 2006, letter. The expert consultant advised that the DR population had an unmet medical need, and that the BFR population should be analyzed separately.

Genmab forged ahead with a protocol that did not adhere to FDA's advice - although the protocol was later amended to analyze the DR and BFR data separately. Genmab sought a Special Protocol Assessment for study 406, but FDA "did not agree to the SPA," Gootenberg reported. "After a second round of SPA review, GenMab initiated study Hx-CD20-406 without an SPA agreement."

As a result, when FDA determined not to count the BFR patients in the efficacy equation, the already small number of patients supporting was more than halved. Only 59 patients out of the 154 enrolled in study Hx-CD20-406 were double refractory and hence considered relevant to the efficacy discussion, a number that became one of the four major concerns about the BLA identified by the primary review team.

- Bridget Silverman ( ¹ b.silverman@elsevier.com )

GSK, Genmab Had Hoped For An Arzerra Indication With More Bulk

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