December 2013 Edition Vol.7, Issue 11

Lessons Learned from the First FDA-Approved Breakthrough Therapies

Lessons Learned from the First FDA-Approved Breakthrough Therapies

By Cory Blaiss, PhD

In 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA), mandating the introduction of the Breakthrough Therapy status.1 During the year and a half since the FDASIA was signed into law, there has been much excitement and conversation about this new program for Breakthrough Therapies, but the question has remained: Will the Breakthrough Designation translate into a shortened development time, even with the already available expedited development programs offered by the FDA?

In November 2013, Gazyva® (obinutuzumab, Roche/Genentech) and Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) became the first FDA approved oncology agents with Breakthrough Therapy status. Gazyva was approved in combination with chlorambucil in patients with chronic lymphocytic leukemia (CLL); Imbruvica was approved as monotherapy in patients with mantle cell lymphoma (MCL). These approvals provide an opportunity to examine the development histories of Gazyva and Imbruvica to address the question of whether and to what degree the Breakthrough Therapy designation can accelerate time to market.

Gazyva Time to Market

Gazyva, a humanized and glycoengineered CD20-targeted monoclonal antibody, has a mechanism of action similar to Rituxan® (rituximab, Roche/Genentech), the current standard of care for CLL patients. The Phase I GAUGIN trial of Gazyva was initiated in September 2007, and based on Phase I results, the Phase III CLL11 study was initiated in December 2009. The trial enrolled untreated CLL patients into one of three arms: 1) chlorambucil alone, 2) Rituxan plus chlorambucil, or 3) Gazyva plus chlorambucil. The trial was designed with two stages of analysis.

Results from the Stage 1 analysis showed clear and robust activity for Gazyva in combination with chlorambucil compared with chlorambucil alone, with improvements in complete response (CR) rate, overall response rate (ORR) and high rate of minimal residual disease negativity. The primary endpoint, progression-free survival (PFS), was significantly improved from a median of 10.9 months in patients who received chlorambucil alone to 23.0 months in patients who received Gazyva plus chlorambucil (HR 0.14, P<0.0001).2

Based on this analysis, a regulatory filing for Gazyva in CLL was submitted in April 2013, and Breakthrough Therapy designation was announced in May 2013. The FDA accepted the application for Priority Review in July 2013 and a PDUFA date was set for December 20, 2013. With a review that lasted only slightly more than six months from submission and four months from application acceptance, a decision was announced before the PDUFA date, and on November 1, 2013, Gazyva was FDA approved for use in combination with chlorambucil in treatment-naïve CLL patients.

From the time of the Phase I trial initiation to the FDA approval date, Gazyva’s time to market was 6.2 years (see Figure 1), not a spectacular showing for the first oncology drug approved with a Breakthrough Therapy designation. However, because the Breakthrough Therapy designation was not available during the early development of Gazyva, the agent did not receive the status until after regulatory submission to the FDA.

The FDA’s recent draft guidance outlines its expectations that companies will request Breakthrough Therapy status earlier in the development process, optimally “no later than the end-of-Phase II meetings”.3 Therefore, using Gazyva as a case study for time to market has limitations, since it did not receive Breakthrough Therapy designation early enough to take advantage of the increased FDA interactions.

The FDA did reach a decision on Gazyva more than a month and a half earlier than the scheduled PDUFA date, and it is certainly possible that the agent’s Breakthrough status could have contributed to this increased speed of review. However, the FDA has been trending toward shorter review times in general. For example, the approvals of Nexavar® (sorafenib, Bayer/Onyx), which received Priority Review for differentiated thyroid cancer, and Xofigo® (radium-223 dichloride, Bayer/Algeta), which received Priority Review for castration-resistant prostate cancer (CRPC), were both announced about one month earlier than expected. In addition, Xtandi® (enzalutamide, Medivation/Astellas), which received Priority Review for CRPC, was approved almost three months earlier than its PDUFA date. Therefore, it is unclear whether Gazyva’s faster-than-expected review time was related to its Breakthrough Therapy status or whether Roche simply reaped the rewards of the FDA’s recent focus on improving review times for all submissions.

Imbruvica Time to Market

In contrast to Gazyva, Imbruvica received the Breakthrough Therapy designation earlier in its clinical development process. Imbruvica is an inhibitor of Bruton’s tyrosine kinase (Btk), a protein that is part of the B-cell receptor signaling pathway involved in cell proliferation and survival in multiple B-cell malignancies.

In February 2009, a Phase I trial was initiated to evaluate the safety and tumor response of Imbruvica in patients with recurrent B-cell lymphoma, including CLL and B-cell non-Hodgkin’s lymphoma (NHL). Initial data from this dose escalation trial were first presented in 2009 at ASH showing that Imbruvica was well-tolerated,4 and subsequently several Phase II trials of Imbruvica, both as monotherapy and in combination with other agents, were initiated in patients with B-cell malignancies.

A Phase I/II trial initiated in May 2010 evaluated Imbruvica monotherapy in patients with CLL or small lymphocytic leukemia (SLL), and data showed strong clinical activity in treatment-naïve patients, relapsed/refractory patients, and high-risk patients (defined as having short response to initial therapy or a deletion of the short arm of chromosome 17 [del17p]), with overall response rates of 71%, 67% and 50%, respectively.5 A separate Phase II trial initiated in February 2011 evaluated Imbruvica monotherapy in relapsed/refractory mantle cell lymphoma (MCL) patients, and it again showed striking clinical activity in this heavily pre-treated patient population ― the median PFS observed in these patients was 13.9 months, with a 68% response rate.6

In February 2013, Imbruvica monotherapy was granted Breakthrough Therapy status for MCL, and in April 2013, a Breakthrough Therapy designation followed for treatment of CLL or SLL patients with the del17p mutation. Based on Phase II data in MCL and CLL/SLL patients, Pharmacyclics and Johnson & Johnson submitted a regulatory application covering both relapsed/refractory MCL and CLL/SLL in late June 2013, and the FDA set a PDUFA date for February 2014. Although the regulatory application for CLL/SLL is still under review, the FDA’s decision on the use of Imbruvica in MCL patients came early. On November 13, 2013, Imbruvica was FDA approved for use in MCL patients who have received at least one prior treatment.

For Imbruvica, the time from Phase I trial initiation to FDA approval was approximately 4.75 years, setting a very promising benchmark for time to market. However, is Imbruvica’s impressive time to market a result of the benefits of the Breakthrough Therapy designation, or could it have been possible even without Breakthrough Therapy status? Could the FDA’s other programs available to expedite drug development, such as the accelerated approval program, have been sufficient to achieve such a fast time to market?

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