BioMarin Provides Program Update for Talazoparib in Metastatic Breast Cancer

ABRAZO Phase 2 Study Meets Protocol-Specified Criteria to Expand Enrollment
 EMBRACA Phase 3 Study Enrollment Completion Targeted 1H 2016

SAN RAFAEL, CA, USA I July 20, 2015 I BioMarin Pharmaceutical Inc. (BMRN) today announced an update on the ABRAZO Phase 2 study of its poly ADP-ribose polymerase (PARP) inhibitor, talazoparib (formerly referred to as BMN 673) for the treatment of patients with deleterious germline BRCA 1 or BRCA 2 mutations and locally advanced and/or metastatic breast cancer.

The company announced that the ABRAZO Phase 2 trial has met the study's protocol-specified threshold for documented tumor reduction (using the RECIST response rate criteria) in order to warrant expanding enrollment in the study from 70 to 140 patients. The ABRAZO study includes two cohorts of patients with BRCA mutated metastatic breast cancer. The first cohort consists of patients who have initially responded to a platinum-containing regimen then progressed, while the second cohort consists of patients who have received more than two prior chemotherapy regimens for metastatic disease. The protocol-specified expansion criteria requires that a minimum of five responses per cohort, of up to 35 patients, be observed in order to expand the study. The minimum of 5 responses was seen prior to full enrollment in each cohort.

The ABRAZO study is the first study treating BRCA breast cancer patients with a PARP inhibitor monotherapy that has demonstrated activity in patients who are in a salvage setting defined as having failed at least two prior chemotherapy regimens for metastatic disease. In addition, this is the first reported data showing tumor reduction from a PARP inhibitor in BRCA breast cancer patients previously treated with a platinum regimen. The trial, now targeting enrollment of a total of 140 patients, is expected to be fully enrolled in the first quarter of 2016 with results expected by year end 2016. These interim results of the ABRAZO study are planned to be presented at an upcoming medical meeting in 2016.

"We are pleased to have met our protocol-specified criteria in the ABRAZO Phase 2 trial allowing us to expand enrollment and complete the study," said Hank Fuchs, M.D., Chief Medical Officer at BioMarin. "If successful, single agent efficacy in a salvage setting potentially could support registration, adoption and use by patients who have exhausted therapeutic options. We also are thrilled to have seen anti-tumor activity in patients previously treated with platinum regimens. This is an unprecedented finding in BRCA metastatic breast cancer, which may provide a further treatment option for these patients."

The company also updated guidance for completion of enrollment of the pivotal EMBRACA study, which the company now estimates to be in the first half of 2016. EMBRACA is a Phase 3, open-label, 2:1 randomized trial to compare the safety and efficacy of oral PARP inhibitor talazoparib versus protocol-specific physician's choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations. Prior guidance had been for enrollment of 430 patients by year end 2015. Since study initiation, a newly completed review of published data suggests that the median progression-free survival (PFS) is lower than originally estimated for the control arm in this patient population, and that fewer than the originally estimated 430 patients may need to be enrolled in order to achieve the targeted hazard ratio.

ABRAZO Trial Design

This is a Phase 2, 2-Stage, 2-Cohort Study of oral PARP inhibitor talazoparib (BMN 673) in patients with locally advanced and/or metastatic breast cancer with germline BRCA mutations.

The purpose of this study is to evaluate the safety and efficacy of talazoparib (BMN 673) in patients with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Subjects will be assigned to either Cohort 1 or 2 based on prior chemotherapy for metastatic disease:

Cohort 1) Subjects who have previously responded (PR or CR) to a platinum-containing regimen for metastatic disease with disease progression > 8 weeks following the last dose of platinum

Cohort 2) Subjects who have received more than two prior chemotherapy regimens for metastatic disease and no prior platinum therapy for metastatic disease

EMBRACA Trial Design

This is a Phase 3, open-label, 2:1 randomized trial to compare the safety and efficacy of oral PARP inhibitor talazoparib (BMN 673) versus protocol-specific physician's choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations.

The primary objective of the study is to compare progression-free survival (PFS) of subjects treated with talazoparib (BMN 673) as a monotherapy relative to those treated with protocol-specific physician's choice. The secondary objectives are to evaluate objective response rate (ORR) and overall survival (OS). Exploratory objectives are to evaluate duration of response (DOR) and health-related quality of life.

About Hereditary Breast Cancer with BRCA Mutation

BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer. A woman's risk of developing breast and/or ovarian cancer is greatly increased if she inherits a deleterious (harmful) BRCA1 or BRCA2 mutation. Men with these mutations also have an increased risk of breast cancer. Both men and women who have harmful BRCA1 or BRCA2 mutations may be at increased risk of other cancers.

Source: National Cancer Institute at the National Institutes of Health http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

About BioMarin

BioMarin develops and commercializes innovative biopharmaceuticals for serious diseases and medical conditions. The company's product portfolio comprises five approved products and multiple clinical and pre-clinical product candidates. Approved products include Vimizim(R) (elosulfase alfa) for MPS IVA, a product wholly developed and commercialized by BioMarin; Naglazyme(R) (galsulfase) for MPS VI, a product wholly developed and commercialized by BioMarin; Aldurazyme(R) (laronidase) for MPS I, a product which BioMarin developed through a 50/50 joint venture with Genzyme Corporation; Kuvan(R) (sapropterin dihydrochloride) Powder for Oral Solution and Tablets, for phenylketonuria (PKU), developed in partnership with Merck Serono, a division of Merck KGaA of Darmstadt, Germany and Firdapse(R) (amifampridine), which has been approved by the European Commission for the treatment of Lambert Eaton Myasthenic Syndrome (LEMS). Product candidates include drisapersen, an exon skipping oligonucleotide, for which a marketing application has been submitted to FDA and EMA for the treatment of patients with Duchenne muscular dystrophy (DMD) with mutations in the dystrophin gene that are amenable to treatment with exon 51 skipping, pegvaliase (formerly referred to as BMN 165 or PEG PAL), PEGylated recombinant phenylalanine ammonia lyase, which is currently in Phase 3 clinical development for the treatment of PKU, talazoparib (formerly referred to as BMN 673), a poly ADP-ribose polymerase (PARP) inhibitor, which is currently in Phase 3 clinical development for the treatment of germline BRCA breast cancer, reveglucosidase alfa (formerly referred to as BMN 701), a novel fusion protein of insulin-like growth factor 2 and acid alpha glucosidase (IGF2-GAA), which is currently in Phase 3 clinical development for the treatment of Pompe disease, vosoritide (formerly referred to as BMN 111), a modified C-natriuretic peptide, which is currently in Phase 2 clinical development for the treatment of achondroplasia, BMN 044, BMN 045 and BMN 053, exon skipping oligonucleotides, which are currently in Phase 2 clinical development for the treatment of Duchenne muscular dystrophy (exons 44, 45 and 53), cerliponase alfa (formerly referred to as BMN 190), a recombinant human tripeptidyl peptidase-1 (rhTPP1) for the treatment of CLN2 disease, a form of Batten disease, which is currently in Phase 1, BMN 270, an AAV-factor VIII vector, for the treatment of hemophilia A and BMN 250, a novel fusion of alpha-N-acetyglucosaminidase (NAGLU) with a peptide derived from insulin-like growth factor 2 (IGF2), for the treatment of MPS IIIB.

SOURCE: BioMarin

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