Summary

• Relapsed/refractory AML (r/r AML) is often drug-resistant with high mortality
• Hypomethylating agents (HMAs) such as decitabine and azacitidine have shown some clinical activity in r/r AML
• SGI-110 is next generation hypomethylating agent (HMA) given as a small volume subcutaneous (SC) administration
• We previously presented phase 2 data of SGI-110 in heavily pretreated r/r AML using a standard 5-day regimen Q 28 days showing an overall Complete Remission (CR+CRp+CRi) rate of 16% (Kantarjian et al, ASH, 2013)
• Here we present the first phase 2 results of SGI-110 given SC in a 10-day regimen Q 28 days

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2014 ASCO: First results of a Phase 2 study using a 10-day SC regimen of the HMA SGI-110 for r/r AML

Summary

• In the past 20 years there has been little change in the 1‐, 3‐, and 5‐ year survival rates for patients with
  ovarian cancer
• 5‐year survival is ~25% for patients diagnosed with advanced stage disease
• Recurrence is common and patients develop resistance to chemotherapy
• Platinum resistant ovarian cancer is uniformly fatal and epigenetic changes have been implicated in the development of platinum resistance
• Previous experience with decitabine, a hypomethylating agent, in combination with carboplatin demonstrated activity in recurrent platinum resistant ovarian cancer patients (Matei et al. Cancer Research 2012)
• SGI‐110 is a dinucleotide of decitabine and deoxyguanosine, affords increased in vivo exposure of decitabine by protecting it from deamination due to slow release upon SQ injection
• In Phase 1 studies, SGI‐110 provides longer exposure and more potent hypomethylation compared to decitabine. Combining SGI‐110 with carboplatin in this population may improve upon the encouraging preliminary results

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2014 AACR: Clinical epigenetic resensitization of platinum-resistant recurrent ovarian cancer

Summary

• Patients with advanced stage ovarian cancer (OC) have a 5-year survival rate of less than 25%. The most common treatment strategy comprises debulking surgery followed by platinum-based chemotherapy. Patients commonly respond to first-line chemotherapy, but >70% relapse, developing platinum-resistance.
• There is evidence that the acquisition of platinum resistance is associated with the epigenetic silencing of specific genes by DNA methylation.
• SGI110 is a novel second generation DNA hypomethylating agent, which is  currently in a Phase II clinical trial in combination with carboplatin, in platinumresistant recurrent ovarian cancer patients (NCT01696032).
• SGI110 is a dinucleotide of decitabine and deoxyguanosine, which is resistant to modification by cytidine deaminase: a common pathway of decitabine metabolism and deactivation.
• Here we demonstrate that SGI110 reverses the cisplatin-resistance of the A2780 OC model, by abrogating the epigenetic silencing of MLH1. We demonstrate SGI110 activity in a panel of OC cell lines. We suggest that epigenetic silencing of ZIC1 is a mechanism of cisplatin resistance in the OAW28 and Ovcar8 cells and demonstrate that it is reversed by SGI110.

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2014 AACR: SGI-110 DNA HMA SGI-110 reverses Platinum resistance of ovarian cancer models

2013 ASH: Determinants of Demethylation and Clinical Response in AML patients treated with SGI-110

2013 Cell Symposia: Cancer Epigenomics. Anti-tumour Activity of SGI-110, a Novel Hypomethylating