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Imbruvica Gets FDA Nod in Mantle Cell Lymphoma

By Marie Powers

Staff Writer

The FDA gave drug developers a shot of good news Wednesday afternoon with the approval of Imbruvica (ibrutinib), the oral Bruton’s tyrosine kinase (BTK) inhibitor developed by Pharmacyclics Inc. and Johnson & Johnson, as a single agent to treat patients with mantle cell lymphoma (MCL) who received at least one prior therapy.

Approval in the initial indication came more than three months before the drug’s PDUFA date of Feb. 28, 2014.

BTK is a key signaling molecule of the B-cell receptor signaling complex that plays an important role in the survival of malignant B cells. Imbruvica blocks signals that stimulate malignant B cells to grow and divide uncontrollably.

The drug became the second to gain approval through the FDA’s breakthrough therapy designation, following by one week the approval of Genentech Inc.’s Gazyva (obinutuzumab), formerly GA101, in combination with chlorambucil to treat previously untreated chronic lymphocytic leukemia. (See BioWorld Today, Nov. 4, 2013.)

Pharmacyclics completed its new drug application (NDA) submission to the FDA in late June, along with an NDA for a separate indication in previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, which remains under review. The FDA accepted the applications in August. (See BioWorld Today, Aug. 30, 2013.)

The FDA approved Imbruvica under its accelerated approval program, granting the drug priority review and orphan drug designation. Approval, based on overall response rate, was predicated on the results of a multicenter, international, single-arm trial of 111 patients with previously treated MCL that showed a 65.8 percent overall response rate (95 percent CI: 56.2, 74.5); 17 percent of patients achieved a complete response and 49 percent achieved a partial response. The median duration of response was 17.5 months (95 percent CI: 15.8, not reached).

On a conference call to discuss the approval, Pharmacyclics officials said the label contained no black box warnings and no contraindications. Safety data during the drug’s pivotal trial showed the most common Grade 3 or 4 nonhematological adverse reactions (≥ 5 percent) included pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue and skin infections.

Five percent of patients had Grade 3 or higher bleeding events, and treatment-emergent Grade 3 or 4 cytopenias were reported in 41 percent of patients. Ten patients (9 percent) discontinued treatment due to adverse reactions in the trial. The drug’s prescribing information includes warnings of hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies and embryo-fetal toxicity.

The recommended dose in MCL is 560 mg (four 140 mg capsules) orally once daily.

In a first glance at Pharmacyclics following the approval, RBC Capital Markets analyst Michael Yee characterized the approval in MCL only as “a relative short time disappointment vs. Wall Street expectations for simultaneous approval in both indications with a broad label.” He added, however, that the FDA was “likely awaiting RESONATE-1 readout in [January] 2014 before rendering a final decision on CLL.”

Although Yee suggested Pharmacyclics’ shares (NASDAQ:PCYC) could dip, investors responded by sending the stock up by more than 4 percent Wednesday afternoon in brisk trading.

Imbruvica is the third drug approved in MCL, following Velcade (bortezomib, Millennium: The Takeda Oncology Co.) and Revlimid (lenalidomide, Celgene Corp.) on a supplemental NDA earlier this year.