Astex Pharmaceuticals Presents Topline Data from the ASCERTAIN Phase 3 Study of its Novel, Oral Hypomethylating Agent Cedazuridine and Decitabine (ASTX727) in MDS and CMML at the American Society of Hematology Meeting in Orlando, FL.

• The study achieved its primary objective of decitabine systemic exposure equivalence between oral ASTX727 and IV decitabine with an oral/IV ratio of approximately 99%
• Safety findings were consistent with those anticipated for IV administered decitabine; the most common Adverse Events were hematological.
• Astex plans to file a New Drug Application (NDA) with the US FDA before the end of 2019 

PLEASANTON, Calif.–(BUSINESS WIRE)–Astex Pharmaceuticals, Inc., a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan, today presented topline data from the ASCERTAIN phase 3 trial of the orally administered fixed dose combination of cedazuridine and decitabine (ASTX727) in adults with intermediate and high-risk myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia (CMML). The data were featured in an oral presentation given today at the American Society of Hematology (ASH) Meeting in Orlando, Florida by Dr Guillermo Garcia-Manero, MD, Professor and Chief of Section of Myelodysplastic Syndromes, Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas, on behalf of the study investigators.

The study was designed as a randomized crossover study comparing oral ASTX727 (100mg cedazuridine and 35mg decitabine fixed dose combination tablet given once daily for 5 days on a 28-day cycle) to IV decitabine (20mg/m² administered as a daily 1-hour IV infusion for 5 days on a 28 day cycle) in the first 2 cycles with patients continuing to receive oral ASTX727 from Cycle 3 onwards. The data presented demonstrated that the ASCERTAIN study met the primary endpoint of total 5-Day decitabine Area-Under-The-Curve (AUC) equivalence of oral ASTX727 and IV decitabine. The oral/IV decitabine 5-day AUC was 98.9% with a 90% Confidence Interval between 92.7% and 105.6%. Safety findings from the study were consistent with those anticipated with IV decitabine, with no significant differences in the incidence of most common adverse events between ASTX727 and IV decitabine in the first 2 randomized cycles. The most common adverse events (AEs) of any grade >20% regardless of causality in patients in the first 2 randomized cycles who received ASTX727 were thrombocytopenia (43.8%); neutropenia (35.4%); anemia (36.9%); and fatigue (23.8%). Preliminary clinical activity as of the data cutoff was also consistent with published data for IV decitabine. In evaluable patients, the Complete Response (CR) rate was 12%, with an overall response rate, including hematological improvement, of 64%.

“The ASCERTAIN phase 3 study data confirms the hypothesis that by inhibiting cytidine deaminase in the gut, systemic therapeutic concentrations of decitabine can be delivered orally to achieve decitabine systemic exposure equivalent to IV dosing,” said Dr Garcia-Manero. “The data support that ASTX727 could become an oral hypomethylating agent alternative to IV decitabine.”

“Based on the data from the ASTX727 clinical program, including the ASCERTAIN phase 3 study, Astex is moving ahead with plans to file a New Drug Application (NDA) with the US Food & Drug Administration (FDA),” said Dr Mohammad Azab, MD, President & Chief Medical Officer of Astex Pharmaceuticals, Inc. “Subject to regulatory review and approval, ASTX727 may offer a new option for patients with MDS and CMML that saves them the burden of 5-day IV infusions every month during their treatment period. We are extremely grateful to all the patients, caregivers, partner research and manufacturing organizations, as well as the healthcare professionals who contributed to the clinical development program of ASTX727.”

ASTX727 is an investigational compound and is not currently approved in any country.

Astex’s parent company, Otsuka Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd. previously announced that, subject to regulatory approvals, commercialization of ASTX727 in the US and Canada will be conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc. respectively. Astex, Otsuka and Taiho are all members of the Otsuka group of companies.

The presentation can be downloaded from the Astex website at https://astx.com/media-center/presentations-and-publications/#toggle-id-2

About Cedazuridine and Decitabine Fixed-Dose Combination (ASTX727)

ASTX727 is a novel, orally administered fixed dose combination of cedazuridine, an inhibitor of cytidine deaminase,¹ with the anti-cancer DNA hypomethylating agent, decitabine.² By inhibiting cytidine deaminase in the gut and the liver, ASTX727 is designed to allow for oral delivery of the approved DNA hypomethylating agent, decitabine, at exposures which emulate exposures achieved with the approved intravenous form of decitabine administered over 5 days.³

ASTX727 has been evaluated in a phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study in patients with MDS and CMML (see https://www.clinicaltrials.gov NCT02103478) and a pivotal phase 3 study (ASCERTAIN) (see https://www.clinicaltrials.gov NCT03306264) conducted at investigator sites in the US and Canada and designed to confirm the results from the phase 1/2 study. The phase 3 study is now being extended to include patients with acute myeloid leukemia (AML) unsuitable to receive intensive induction chemotherapy.

In September 2019 Astex announced that ASTX727 had received orphan drug designation for the treatment of MDS and CMML from the US FDA.

The concept of using cedazuridine to block the action of cytidine deaminase is also being evaluated in a low dose formulation of cedazuridine and decitabine for the treatment of lower risk MDS (see https://www.clinicaltrials.gov NCT03502668).

About Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

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. US incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.^4,5 The prevalence has been estimated to be from 60,000 to 170,000 in the US.⁶ MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.⁷ 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 US is approximately 1,100 new cases per year,⁸ and CMML may transform into AML in 15% to 30% of patients.⁹ The hypomethylating agents decitabine and azacitidine are effective treatment modalities for hematologic cancers and are FDA-approved for the treatment of higher risk MDS and CMML. These agents are administered by IV infusion, or by large-volume subcutaneous injections.

About Astex Pharmaceuticals, Inc.

Astex Pharmaceuticals, Inc. is a leader in innovative drug discovery and development, committed to the fight against cancer. Astex is developing a proprietary pipeline of novel therapies and has multiple partnered products in development under collaborations with leading pharmaceutical companies. Astex is a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan.

Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: “Otsuka–people creating new products for better health worldwide.” Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and nutraceutical products for the maintenance of everyday health.

For more information about Astex Pharmaceuticals, Inc. please visit: http://www.astx.com

For more information about Otsuka Pharmaceutical, please visit: http://www.otsuka.com/en/

For more information about Taiho Pharmaceutical, please visit: https://www.taihooncology.com/

References

1. Ferraris D, Duvall B, Delahanty G, Mistry B, Alt, J, Rojas C, et al. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem 2014; 57:2582-2588.
2. Oganesian A, Redkar S, Taverna P, Choy G, Joshi-Hangal R, Azab M. Preclinical data in cynomolgus (cyn) monkeys of ASTX727, a novel oral hypomethylating agent (HMA) composed of low-dose oral decitabine combined with a novel cytidine deaminase inhibitor (CDAi) E7727 [ASH Abstract]. Blood 2013;122(21): Abstract 2526.
3. Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol [Internet]. 2019;6(4):e194-e203.
4. Garcia-Manero G. Myelodysplastic syndromes: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90(9) 831-841.
5. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: Incidence and survival in the United States. Cancer 2007;109(8):1536–1542.
6. Cogle C. Incidence and burden of the myelodysplastic syndromes. Curr Hematol Malig Rep 2015; 10(3): 272-281.
7. Shukron O, Vainstein V, Kündgen A, Germing U, Agur Z. Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database. Am J Hematol 2012;87:853–860.
8. What are the key statistics about chronic myelomonocytic leukemia? American Cancer Society Web site. https://www.cancer.org/cancer/chronic-myelomonocytic-leukemia/about/key-statistics.html. Accessed 08 April 2019.
9. About chronic myelomonocytic leukemia (CMML). Cancer Research UK Web site. https://www.cancerresearchuk.org/about-cancer/other-conditions/chronic-myelomonocytic-leukaemia-cmml/about. Accessed 08 April 2019.

Contacts

Martin Buckland

Chief Corporate Officer

Astex Pharmaceuticals, Inc.

4420 Rosewood Drive, Suite 200

Pleasanton 94588, CA, USA

Tel: +1-925-560-2857

Email: [email protected]