Genentech Inc.’s Gazyva (obinutuzumab), formerly known as GA101, became the first therapy approved through the FDA’s breakthrough therapy designation, indicated in combination with chlorambucil to treat previously untreated chronic lymphocytic leukemia (CLL).

Approval was widely expected after Genentech, a unit of the Roche Group, reported in July that Gazyva beat Rituxan (rituximab, Biogen Idec Inc. and Roche AG) in a Phase III study in previously untreated CLL, becoming the first compound to show improvement over Rituxan head to head. (See BioWorld Today, July 25, 2013.)

Gazyva is a glyco-engineered, Type II, humanized anti-CD20 monoclonal antibody designed to selectively target the CD20 protein on malignant B cells. By modifying specific sugar molecules, the antibody essentially functions as an immunotherapeutic. In preclinical studies, the drug showed evidence of binding to CD20 and inducing direct cell death.

Gazyva’s clinical development program, managed by Roche, was crafted specifically to assess superiority to Rituxan in CLL and non-Hodgkin’s lymphoma (NHL). The multicenter, open-label, randomized three-arm CLL11 study investigated the efficacy and safety of Gazyva vs. Rituxan, both in combination with chlorambucil, compared to chlorambucil alone in 781 previously untreated people with CLL and co-existing medical conditions.

The trial showed that patients who received Gazyva/chlorambucil had significantly reduced risk of disease progression or death (HR = 0. 16; p < 0.0001) and lived twice as long without disease progression compared to chlorambucil alone (median PFS 23.0 months vs. 11.1 months).

Gazyva also showed a good safety profile. The most common Grade 3/4 adverse events for those who took Gazyva in combination with chlorambucil – an oral – compared to chlorambucil alone were infusion-related reactions during the first infusion (21 percent vs. 0 percent), low platelet count (thrombocytopenia, 11 percent vs. 3 percent) and low count of certain types of white blood cells (neutropenia, 34 percent vs. 16 percent), though Genentech said the finding did not result in an increased rate of infections in the Gazyva arm.

Gazyva represents a distinct differentiation in treatment for the CLL population, which is generally older and less tolerant of aggressive chemotherapy regimens, said Emmy Wang, spokeswoman at South San Francisco-based Genentech. The median age of participants in the CLL11 study was 73.

The drug’s approval, which came nearly two months before a Dec. 20 PDUFA date, and label are based on the Stage 1 data, Wang added.

Final data from Stage 2 of the CLL11 trial, which investigated the direct comparison between Gazyva and Rituxan, will be presented next month at the American Society of Hematology’s (ASH) annual meeting, Wang added. Stage 2 enrolled an additional 192 patients to enable final direct comparison. Biogen plans to disclose data from the head-to-head study Nov. 7 after the ASH abstracts are released.

“Gazyva was developed not as a modified Rituxan,” Wang emphasized. “It’s a completely different molecule. It’s great the data have shown superiority over Rituxan, and we look forward to having that data out there at ASH.”

Gazyva remains in multiple head-to-head Phase III studies compared to Rituxan in indolent NHL and diffuse large B-cell lymphoma and compared to chemotherapy alone in refractory CLL. Those programs are expected to report data beginning in 2015, Wang said.

Although Genentech declined to comment on projected revenues for the drug, Deutsche Bank analyst Robyn Karnauskas suggested peak revenues of $1 billion in 2017. The drug’s early approval also was a positive indication for other breakthrough therapies under review, she suggested, citing hepatitis C candidate sofosbuvir from Gilead Sciences Inc. and CLL drug ibrutinib, an oral Bruton’s tyrosine kinase inhibitor from Pharmacyclics Inc. and Johnson & Johnson. (See BioWorld Today, Oct. 31 , 2013, and Aug. 30, 2013.)

Approval of Gazyva likely marked the end of an era for the blockbuster Rituxan franchise, which earned $303 million for Weston, Mass-based Biogen in the third quarter ending Sept. 30. (See BioWorld Today, Oct. 29, 2013.)

However, Biogen still stands to benefit from Gazyva through a complex arrangement with Genentech, amended several times. In 2010, the two companies tweaked a longstanding CD20 deal following Genentech’s acquisition by Roche, which gained GA101 through its $180 million buyout of Glycart AG in 2005. (See BioWorld Today, Nov. 3, 2008.)

Under their original deal, Biogen paid $31.5 million up front and agreed to share in the development costs of GA101. The amended agreement increased Biogen’s share in U.S. losses and profits by 5 percent, to 35 percent, and provided for a $10 million “catch-up” payment to Genentech for GA101 costs incurred prior to the amended agreement. Biogen collaborated in the drug’s U.S. development and, assuming Gazyva hits certain sales milestones, the amended deal calls for Biogen’s share of U.S. Rituxan profits to decrease from 40 percent to as little as 30 percent while picking up 35 percent to 39 percent of the Gazyva profits. (See BioWorld Today, June 18, 2009, and Oct. 25, 2010.)

Priced at $41,300 for a six-month course of treatment, Gazyva will be available in the U.S. within approximately two weeks, according to Wang. Genentech plans to offer assistance programs for qualified patients through Genentech Access Solutions.

In Europe, the marketing authorization application for GA101 remains under review by the European Medicines Agency, she added.

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