FDA Grants BSI-201 Fast Track Designation for Metastatic Triple-Negative Breast Cancer

French pharmaceutical giant Sanofi-aventis and its wholly-owned subsidiary, BiPar Sciences, announced today that the clinical development program in metastatic triple-negative breast cancer (mTNBC) for the investigational PARP1 inhibitor, BSI-201, progresses as planned with the Phase III study meeting expectations on patient accrual and trial site coverage in the United States. Study investigators have enrolled 214 of the target number of 420 patients.Poly(ADP-ribose) polymerases (PARPs), defined as a family of cell signaling enzymes present in eukaryotes, is involved in poly(ADP-ribosylation) of DNA-binding proteins. PARP-1, the best studied of these enzymes, is involved in the cellular response to DNA damage so that in the event of irreparable DNA damage overactivation of PARP-1 leads to necrotic cell death. Inhibitors of PARP-1 activity in combination with DNA-binding antitumor drugs may constitute a suitable strategy in cancer chemotherapy. [1]BSI-201 is the first of a new class of agents that inhibit cancer cells’ DNA-repair mechanisms. BSI-201 inhibits the nuclear enzyme PARP1, which is involved in multiple cellular processes, including DNA repair. The drug candidate entered a Phase III clinical trial in the United States in July 2009 and is being evaluated in combination with chemotherapy in patients with mTNBC, a condition defined by tumors lacking expression of estrogen, progesterone receptors and without overexpression of HER2. BSI-201 is a novel investigational targeted therapy that inhibits poly (ADP-ribose) polymerase (PARP1), an enzyme involved in DNA damage repair. [2]The decision to commence with the Phase III study in July was based on the encouraging Phase II study results presented at ASCO on May 31, 2009. In the Phase II clinical trial, women with mTNBC who were randomly assigned to receive gemcitabine and carboplatin (GC) in combination with the investigational agent BSI-201 or GC alone. Updated Phase II data ? including overall survival ? were presented on December 11, 2009, at a poster session at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS). [3]The addition of BSI-201 to GC improved median overall survival from 7.7 months to 12.2 months. (HR=0.5, p=0.005). BSI-201 did not add to the frequency or severity of adverse events associated with chemotherapy. This is not a final analysis of the Phase II data, but rather an updated analysis of overall survival. Median survival has not yet been reached in the BSI-201 arm, therefore the data cut-off period for the Phase II trial from September to November.?The updated analysis from the Phase II program, including data on overall survival, are consistent with the positive results presented earlier this year at ASCO,? [4] declared Marc Cluzel, Executive Vice President, R&D, sanofi-aventis. ?We are very encouraged by the fast recruitment of patients in Phase III trial. We hope the findings will lead to emerging strategy that may help women with metastatic triple negative breast cancer.?The U.S. Food and Drug Administration (FDA) granted Fast Track designation to BSI-201 for mTNBC. As described by the FDA, the Fast Track process is designed to expedite the review of drugs being developed for serious diseases with the potential to address an unmet medical need.For more information[1] Cepedaa V, Fuertesa MA, Castillac J, Alonsoa C, et al. Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors in CancerChemotherapy. Recent Patents on Anti-Cancer Drug Discovery, 2006, 1, 39-53[2] The Science of PARP[3] O’Shaughnessy J, Osborne C, Pippen J, Patt D, Rocha C, Ossovskaya V, et al. Final Results of a Randomized Phase II Study Demonstrating Efficacy and Safety of BSI-201, a Poly (ADP-Ribose) Polymerase (PARP) Inhibitor, in Combination with Gemcitabine/Carboplatin (G/C) in Metastatic Triple Negative Breast Cancer (TNBC) SABCS Poster Session 3: Tumor Biology: Novel/Emerging Therapeutic Targets (5:30 PM-7:30 PM Date/Time: Friday, December 11, 2009 5:30 PM[4] O’Shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 27:18s, 2009 (suppl; abstr 3)For more about clinical trials– A Phase 3, Multi-Center Study of Gemcitabine/Carboplatin, With or Without BSI-201, in Patients With ER-, PR-, and Her2-Negative Metastatic Breast Cancer- Evaluation of Paclitaxel (Taxol, NSC #673089), Carboplatin (Paraplatin, NSC #241240), and BSI-201 (NSC #746045, IND #71,677) in the Treatment of Advanced, Persistent, or Recurrent Uterine Carcinosarcoma.