Bristol Sprycel Clears FDA As First Second-Line Leukemia Agent

Bristol-Myers Squibb will be required to submit follow-up data from ongoing clinical trials to convert the accelerated approval of Sprycel for chronic myeloid leukemia to full approval, FDA said after clearing dasatinib June 28.

FDA granted Sprycel accelerated approval for treatment of "adults with chronic accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy" including Novartis' Gleevec (imatinib).

Bristol is expected to submit 24-month follow-up data from the ongoing pivotal Phase II trials by late 2007 or early 2008, FDA said, noting the commitments mirror those of Gleevec when it received accelerated approval in 2001.

FDA has recently emphasized the value of using interim analyses from pivotal studies for accelerated approval of oncologics and using the final results of the same study to convert it to full approval, rather than relying on separate postmarketing commitments (¹ (Also see "Oncologic Accelerated Approval Best Based On Pivotal Trial Interim Analysis" - Pink Sheet, 26 Jun, 2006.), p. 16).

Sprycel also received full approval for treatment of adults with Philadelphia-chromosome positive acute lymphoblastic leukemia patients resistant to or intolerant of prior therapy including imatinib.

FDA noted that it has previously accepted complete hematologic response rates as a basis for full approval for treatment of acute leukemias.

In a June 28 release, Bristol said it expected to launch the multi-kinase inhibitor "within days" of approval.

Sprycel is the first agent approved for treatment of Gleevec failures. Currently, high-dose Gleevec is generally administered to such patients. While Gleevec failures represent only a small portion of the overall CML population, such patients account for a disproportionately large part of Gleevec's sales due to the higher dosing level.

During the recent American Society of Clinical Oncology annual meeting in Atlanta, Bristol presented data from an ongoing head-to-head trial of high dose Gleevec and Sprycel in Gleevec failures, which showed significantly higher response rates for dasatinib (² , p. 7).

At the ASCO meeting, Bristol consultant Neil Shah (University of California-Los Angeles) outlined the biologic rationale for Sprycel's efficacy in Gleevec failures. Dasatinib "is structurally unrelated to imatinib" and is approximately 325-fold more potent than imatinib, he explained. This makes it "very useful for those patients that are driven by too much BCR-ABL." CML growth is linked to BCR-ABL overexpression.

Another reason dasatinib is active in Gleevec-resistant patients is that it binds to both the inactive and active BCR-ABL conformations; imatinib only binds to the inactive conformation. "As a result of the fact that it binds to the active conformation as well, we think that is why it hits other kinases that imatinib doesn't hit," Shah said. He noted that in preclinical tests, dasatinib inhibited growth of 14 of 15 imatinib-resistant mutations.

³ Labeling for Sprycel states that "under the conditions of assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases...and multi-drug resistance gene overexpression."

The decision follows the recommendation of FDA's Oncologic Drugs Advisory Committee, which unanimously voted in favor of the oral multi-kinase inhibitor's safety and efficacy during a June 2 meeting. Panel members did say, however, that dasatinib could be more difficult to administer than Gleevec due to its safety profile, particularly its risk of pleural effusion.

In clinical trials, severe cases of pleural effusion were seen in 8% of patients. Labeling includes a precaution regarding fluid retention and advises that "patients who develop symptoms of pleural effusion such as dyspnea or dry cough should be evaluated by chest x-ray."

Other precautions include myelosuppression, bleeding related events, and QT prolongation. Other serious adverse events seen in clinical trials include pyrexia (9%), febrile neutropenia (7%), GI bleeding (6%), pneumonia (6%) and thrombocytopenia (5%).

Sprycel could face additional competition in the second-line CML market from Novartis' Gleevec follow-on Tasigna (nilotinib, formerly AMN-107); due to similar efficacy profiles, Novartis believes the compounds may ultimately be differentiated by their safety profile (⁴ (Also see "Safety May Decide Sprycel/Tesigna Battle For Gleevec Failures, Novartis Says" - Pink Sheet, 19 Jun, 2006.), p. 15).