On October 14, 2020 Astex Pharmaceuticals, Inc., a member of the Otsuka group of companies, and Otsuka Pharmaceutical Co., Ltd., reported top-line results of the ASTRAL-2 and ASTRAL-3 clinical studies that evaluated the efficacy and safety of guadecitabine (SGI-110) in adults with previously treated AML (ASTRAL-2), and with previously treated MDS/CMML (ASTRAL-3), respectively (Press release, Astex Pharmaceuticals, OCT 14, 2020, View Source [SID1234568484]). Neither study met the primary endpoint of statistically significant (p <0.05) improvement in overall survival (OS) compared with the control arm of physicians’ choice of alternative therapy. Evaluation of the studies’ prospective subgroups and secondary endpoints is ongoing. Safety data were consistent with the expected safety profile of guadecitabine from prior studies. The full data will be presented at upcoming scientific meetings.

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"We are disappointed in the outcome of the ASTRAL-2 and ASTRAL-3 studies," said Mohammad Azab, Astex’s president and chief medical officer. "The ASTRAL series of studies were designed to deliver a new therapeutic option to patients with AML or MDS/CMML, and although guadecitabine is an active drug, the studies failed to demonstrate a statistically superior survival outcome compared to current therapeutic alternatives." Dr. Azab also added, "The ASTRAL studies generated for the medical community one of the largest bodies of clinical and genetic data from prospective randomized studies using hypomethylating agent (HMA) treatment. Guadecitabine was associated with improved outcomes in certain subgroups, but that needs to be validated by additional studies. We are extremely grateful to all the patients, physicians and other healthcare professionals, and collaborating research and manufacturing organizations who contributed to this global effort."

Guadecitabine is an investigational compound and is not currently approved in any country.

About Guadecitabine

Guadecitabine is a next-generation DNA hypomethylating agent.1,2 Guadecitabine was rationally designed to be resistant to degradation by cytidine deaminase, prolonging the exposure of tumor cells to the active metabolite, decitabine, thus ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells.3 Guadecitabine, through the action of decitabine, inhibits DNA methyl transferase (DNMT), with the potential to reverse aberrant DNA methylation, an epigenetic change characteristic of many cancer cells, and may restore the expression of silenced tumor suppressor genes and tumor-associated antigens.4 Through this re-expression of silenced genes, guadecitabine may have the potential to sensitize tumor cells to other anticancer agents,5,6,7 including immunotherapeutics,8 as well as re-sensitizing cancer cells previously resistant to chemotherapeutics.7

Guadecitabine was designed to be administered subcutaneously as a low-volume, stable formulation.

Astex and Otsuka announced in July 2018 that the global phase 3 ASTRAL-1 randomized study of guadecitabine in adults with previously untreated AML who were not eligible for intensive induction chemotherapy (View Source NCT02348489) failed to meet its co-primary endpoints.

Guadecitabine is also being evaluated in over twenty investigator-sponsored trials in other hematological malignancies and in solid tumors, both as a single agent and in combination with chemotherapy or immunotherapy.

About the ASTRAL-2 Study

The ASTRAL-2 study (View Source NCT02920008) evaluated the efficacy and safety of guadecitabine in adults with AML previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and who were refractory to initial induction (primary refractory) or in relapse after such initial induction with or without prior hematopoietic cell transplantation. The study randomized 302 patients from 98 investigator sites in 15 countries worldwide. The study randomized patients 1:1 to receive in 28-day cycles either guadecitabine, delivered subcutaneously for 10 days in Cycle 1 followed by 10 or 5 days in Cycle 2, and 5 days in Cycle 3 onwards, or physicians’ choice of (i) a high intensity regimen comprising intermediate or high dose cytarabine; mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida); (ii) a low intensity regimen comprising low dose cytarabine or azacitidine or decitabine; and (iii) Best Supportive Care only. In addition to the primary endpoint of OS, the study evaluated multiple secondary endpoints including event-free survival, long-term survival, number of days alive and out of the hospital, disease response, transfusion independence rate, complete response rate, composite complete response, hematopoietic cell transplant rate, duration of complete response, quality of life, incidence and severity of adverse events, and 30-day and 60-day all-cause mortality.

About the ASTRAL-3 Study

The ASTRAL-3 study (View Source NCT02907359) evaluated the efficacy and safety of guadecitabine in adults with MDS or CMML previously treated with a hypomethylating agent. The study randomized 417 patients from 91 investigator sites in 14 countries worldwide. The study randomized patients 2:1 to receive in 28-day cycles either guadecitabine delivered subcutaneously for 5 days, or physicians’ choice of (i) low dose cytarabine; (ii) a standard intensive chemotherapy (IC) 7+3 regimen of cytarabine and an anthracycline, or mitoxantrone; and (iii) Best Supportive Care only. In addition to the primary endpoint of OS, the study evaluated multiple secondary endpoints including transfusion independence, marrow complete response rate, survival rate, leukemia-free survival, number of days alive and out of the hospital, disease response, duration of response, number of transfusions, health-related quality of life, incidence and severity of adverse events, and 30-day and 60-day all-cause mortality.

About Acute Myeloid Leukemia

AML is the most common form of acute leukemia in adults.9 An estimated 19,940 new cases of AML are projected in the U.S. in 2020,10 and an estimate of 11,180 patients are projected to die from AML in the U.S. in 2020.10 Although 60 to 80 percent of AML patients less than 60 years of age may achieve a complete response with standard intensive induction chemotherapy,11 the outlook for previously treated patients, and for patients 60 years of age or more, particularly those with comorbidities, is significantly worse, and these patients are in need of effective, less toxic therapies.

About Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. U.S. incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.12,13 The prevalence has been estimated to be from 60,000 to 170,000 in the U.S.14 MDS may evolve into acute myeloid leukemia in one-third of patients.15 The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML.

CMML is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the U.S. is approximately 1,100 new cases per year,16 and CMML may transform into AML in 15% to 30% of patients.17

The hypomethylating agents decitabine, azacitidine, and oral decitabine and cedazuridine are FDA-approved for the treatment of intermediate and high-risk MDS and CMML.18,19,20 There is no approved therapy for patients who fail treatment with hypomethylating agents, and median survival following failure is less than six months.21