Roche/Genentech Inc.’s Gazyva (obinutuzumab) is the first approval through FDA’s new “breakthrough” therapy program, but the leukemia drug, which by all accounts certainly deserves the designation, might not be the best test of the new program’s ability to speed reviews of important and innovative new drugs.

Gazyva, once known as GA101, was approved Nov. 1 for use in combination with chlorambucil chemotherapy for patients with previously untreated chronic lymphocytic leukemia. It will be available within approximately two weeks at a cost of $41,300 for a set six-month course of treatment. A similar course of treatment with Rituxan (rituximab), the drug Gazyva is designed to succeed, is $34,400.

Genentech filed the obinutuzumab BLA in April and anticipated a Dec. 22 approval under the new eight-month priority review clock. With a review time of six months plus a week, it does show that the breakthrough program may have shaved a couple months off the total.

But six months is not an unusual review time for FDA, and especially not for a promising cancer drug. The Office of Hematology and Oncology Products has often set internal goals to complete reviews for such products within four months, and Gazyva certainly fills that bill ([A#14130710003]).

Most of the fastest product approvals – like Novartis AG’s Gleevec (imatinib) in 2.4 months, Sanofi’s Jevtana (cabazitaxel) in 2.6 months and Medivation Inc./Astellas Pharma Inc.’s Xtandi (enzalutamide) in 3.3 months – came out of the oncology office Also see "CDER Approvals In January Came Early And Often" - Pink Sheet, 1 February, 2012.. Clearing a biologic in six months, given the more difficult manufacturing requirements, is a more impressive feat, but it is also a normal performance for FDA.

Still, OHOP Director Richard Pazdur touted the approval as a harbinger of things to come. “The approval reflects the promise of the breakthrough therapy designation program, allowing us to work collaboratively with companies to expedite the development, review and availability of important new drugs,” he said in the agency’s announcement of the approval.

Deutsche Bank analyst Robyn Karnauskas saw the approval as a positive for other pending breakthrough approvals. While the approval was expected, it came earlier than the PDUFA date, and “in our opinion, this early approval could be seen positively for other breakthrough therapies under review,” she said in a Nov. 1 note to investors.

Late Designation = Missed Opportunities

Gazyva, however, is not a true test of the program’s impact. Because the designation wasn’t available during GA101 development, Genentech requested it at the time of the BLA submission, so the company missed out on the program’s opportunities for accelerating drug development ([A#2013500123]).

At that time Genentech already had initial results from a registrational Phase III trial, though breakthrough designations ordinarily require only early evidence in human testing that the product shows potential to be a dramatic improvement over available therapies for serious or life-threatening diseases.

Genentech may have missed out on the bounty of “all-hands-on-deck” attention from FDA managers that drugs granted the designation appear to be receiving, but company execs say there was a pleasantly noticeable difference in the time between BLA filing and first contact from the agency that continued throughout the review Also see "A “Breakthrough” Reality Check: Sponsors Seek FDA Flexibility On Manufacturing, Diagnostics" - Pink Sheet, 8 July, 2013..

One concern about the breakthrough program has been that while the clinical timeframe can be accelerated, the manufacturing side could be the rate-limiting factor. FDA officials have assured industry that they will work with sponsors to accelerate the CMC process as well ([A#00130708011]).

The summary review memo for Gazyva, signed by Division Director Ann Farrell Oct. 25, shows that “due to the need to expedite the review and approval of this BLA, the agency worked with the applicant to develop a plan for launch.” Though the documents are heavily redacted, it is clear that from early in the review period, Genentech and the CMC review team worked out an agreement to enable commercial launch prior to the PDUFA date.

Strong Standing For Approval

Genentech plans to release final data from the CLL11 trial showing Gazyva’s superiority to the aging anti-CD20 antibody Rituxan at the American Society of Hematology annual meeting in December.

The trial was cut short in September after a pre-planned interim analysis showed the study, in elderly patients with chronic lymphocytic leukemia, had met its progression-free survival endpoint well ahead of the anticipated 2014 completion date ([A#06130901016]).

Median PFS for the Gazyva/chlorambucil arm was 23.0 months, while for chlorambucil alone PFS was 11.1 months at a median observation time of 14.2 months.

Data supporting the April BLA were reported at the American Society of Clinical Oncology annual meeting in June. Stage 1 of CLL11 enrolled 589 real-world CLL patients with at least three serious comorbidities, such as heart failure or diabetes. It not only demonstrated that the fragile population could safely benefit from the addition of anti-CD20 therapy to chemo, it demonstrated an 86% reduction in the risk of death in the obinutuzumab arm and a still statistically significant 68% reduction for Rituxan ([A#00130610015]).

Gazyva labeling contains a boxed warning with two of the same cautions carried by Rituxan, regarding the potential for reactivation of hepatitis B virus and for progressive multifocal leukoencephalopathy. FDA’s announcement notes those dangers are known risks with other anti-CD20 antibodies and “rare cases were identified in participants on other trials of Gazyva.”

The agency did not see the need for a Risk Evaluation and Mitigation Strategy and did not attach any post-marketing requirements to the approval.

Other possible serious side effects are infusion reactions, tumor lysis syndrome, infections, thrombocytopenia, neutropenia and anemia.

Roche’s Gazyva Clears FDA, But First Breakthrough Approval Breaks No Speed Barriers

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