Mechanism of Action
Pamiparib (BGB-290) is an investigational small molecule inhibitor of PARP1 and PARP2. Pamiparib is being evaluated as a monotherapy in pivotal clinical trials in China in recurrent platinum-sensitive and BRCA1/2 mutated ovarian cancers. It is currently in global clinical development as a monotherapy, and in combination with other agents, including BeiGene’s investigational anti-PD1 antibody, tislelizumab (BGB-A317), for a variety of solid tumor malignancies.
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The Role of PARP
Poly ADP ribose polymerase (PARP) family members PARP1 and PARP2 are involved in DNA replication and transcriptional regulation, and play essential roles in cell survival in response to DNA damage. PARP1 and PARP2 can bind to the site of damaged DNA and modulate a variety of proteins in DNA repair processes. Inhibition of PARPs prevents the repair of common single-strand DNA breaks which leads to formation of double-strand breaks during DNA replication. Double-strand DNA breaks in normal cells are repaired by homologous recombination, and normal cells are relatively tolerant of PARP inhibition.
PARP Combination Therapies
PARP proteins are key factors in DNA repair pathways, in particular, base-excision-repair, which is critical for the repair of DNA lesions caused by some chemotherapeutic agents and by radiation. PARP inhibitors are hypothesized to potentiate cytotoxicity of DNA-alkylating agents such as platinum compounds, temozolomide and ionizing radiation and can potentially be used in combination with these agents in treating various cancers. PARP inhibitors are also considered potential combination partners with immune checkpoint inhibitors, in part due to the mutational burden that tumor cells acquire as a result of the blockade of DNA repair by PARP inhibitors.
In Combination with Tislelizumab
Tislelizumab (BGB-A317) is a humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is the first drug candidate produced from BeiGene’s immuno-oncology biologic programs. In a multi-center, Phase 1b trial, BeiGene is evaluating pamiparib combined with tislelizumab for a variety of solid tumor malignancies.