Clinical Pipeline

Phase 1	Phase 2	Phase 3

Guadecitabine (SGI-110)

DNMT inhibitor (Relapsed/Refractory MDS or CMML)

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Ownership: Astex

Mechanism of Action: DNA methyltransferase (DNMT) inhibition

Indication: Relapsed/Refractory Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukaemia (CMML)

How this therapy can help

Guadecitabine was rationally designed to prolong the exposure of tumor cells to the active metabolite, decitabine, ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells.

As a next generation DNA-hypomethylating agent, guadecitabine targets and reverses aberrant DNA hypermethylation, an epigenetic change characteristic of many cancer cells, restoring the expression of silenced tumor suppressor genes and cancer testis antigens. Guadecitabine-mediated demethylation of DNA upregulates tumor-associated antigens, and may sensitize tumor cells to other anticancer agents, including immunotherapeutics, as well as resensitizing resistant cancer cells to chemotherapeutics.

Clinical studies

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Astex is conducting ASTRAL-3 (Relapsed/Refractory MDS or CMML): 408-patient multicenter, randomized, open-label study in Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) after failure of prior azacitidine, decitabine, or both.

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LDAC – low-dose cytarabine; IC (7+3) – intensive chemotherapy (cytarabine/anthracycline); BSC – best supportive care

For more information on clinical studies and status visit: www.clinicaltrials.gov or email: ASTRAL-3@astx.com.

Previous clinical studies

The ASTRAL-3 clinical studies are based on data from a completed 400-patient Phase 1/2 study of guadecitabine in patients with AML or MDS (www.clinicaltrials.gov).

Other active clinical programs

Astex also has an active program evaluating the combination of guadecitabine with checkpoint inhibitors in the treatment of both hematological malignancies and solid tumors, and as a single agent and in combination with chemotherapy for the treatment of solid tumors. These include studies investigating combination with carboplatin in the treatment of platinum-resistant ovarian cancer; in hepatocellular (liver) cancer following failure of Nexavar^® (sorafenib), and in combination with irinotecan in the treatment of colorectal cancer.

Clinical Pipeline