BGB-290: PARP1 and PARP2 Inhibitor with Unique Properties

BGB-290 is a highly potent and selective PARP inhibitor with favorable drug metabolism and pharmacokinetic properties. BGB-290 has shown favorable PARP1 and PARP2 selectivity in biochemical assays and has demonstrated improved specificity compared to other PARP inhibitors, such as olaparib, in cell line proliferation screens. EnhScientist 2anced selectivity could potentially translate into a better safety and tolerability profile over existing PARP inhibitors. We believe a favorable safety and tolerability profile could be particularly advantageous for the combined use of BGB-290 with immune checkpoint inhibitors or chemotherapeutic agents. We believe BGB-290 has the potential to be differentiated from other PARP inhibitors, including olaparib, the only PARP inhibitor currently approved by the FDA and the EMA, in terms of selectivity, DNA-trapping activity, oral bioavailability and brain penetration.

Potential advantages of BGB-290 include:

  • Brain penetration – BGB-290 has shown significant brain penetration in preclinical models. The brain/plasma ratio in mice after oral dosing of 10 mg/kg BGB-290 was approximately 18%, according to our data. We believe the only other PARP inhibitor currently in development that has shown significant brain penetration is veliparib, which appears to be significantly less potent compared to other PARP inhibitors and has minimal DNA-trapping activity.
  • Greater selectivity potentially leading to improved safety and tolerability – BGB-290 is a highly active and selective PARP1 and PARP2 inhibitor in biochemical and cellular assays. Based on the preliminary data reported by investigators in the ongoing dose-escalation phase of our clinical trial of BGB-290 the only drug-related adverse events that occurred in over 10% of patients are nausea (38%), fatigue (28%), vomiting (14%) and diarrhea (10%).
  • Strong DNA-trapping activity – BGB-290 also demonstrates potent DNA-trapping activity. PARP inhibitors are reported to trap PARP protein at damaged DNA sites, creating more cytotoxic DNA lesions. The potency of DNA-trapping for PARP inhibitors is shown to be better correlated with tumor cell growth-inhibition than inhibition of PARP enzyme activity. BGB-290 has demonstrated potent activity across multiple assays: DNA-trapping, enzymatic and cellular inhibition of PARP and tumor cell growth inhibition.
  • Good oral bioavailability and potent target inhibition – In preclinical animal models, BGB-290 shows good oral bioavailability. BGB-290 has demonstrated bioavailability of 71–76% in animal studies. In the ongoing dose-escalation phase of our clinical trial, we observed a linear and dose-dependent pharmacokinetic profile for BGB-290 with approximately two-fold accumulation at steady state. BGB-290 induced robust poly ADP ribose, or PAR, inhibition in PBMCs even at the first dose level and sustained PAR inhibition in PBMC was expected at a steady state dose of 10 mg BID or greater.

Mechanism of Action

Farmer H et al. Nature 2005;434:917–921 Bryant HE et al. Nature 2005;434:913–917 McCabe N et al. Cancer Res 2006;66:8109–8115

Farmer H et al. Nature 2005;434:917–921
Bryant HE et al. Nature 2005;434:913–917
McCabe N et al. Cancer Res 2006;66:8109–8115