Astex Pharmaceuticals announces U.S. Food and Drug Administration (FDA) acceptance for review of an NDA for the combination oral hypomethylating agent cedazuridine and decitabine (ASTX727 or oral C-DEC), for the treatment of MDS and CMML

  • NDA is supported by data from the phase 3 ASCERTAIN study of oral C-DEC in adults with intermediate- and high-risk myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia (CMML)
  • FDA designated the application for Priority Review
  • Potential for oral C-DEC to become first approved orally administered hypomethylating agent for MDS and CMML in the U.S.

Pleasanton, CA, February 11th, 2020. Astex Pharmaceuticals, Inc., a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Japan, today announced that the U.S. FDA has accepted for Priority Review its NDA for oral C-DEC (cedazuridine and decitabine) as a treatment for adults with previously untreated intermediate- and high-risk MDS including CMML. The NDA submission is based on data from the ASCERTAIN phase 3 study which evaluated the 5-day decitabine exposure equivalence of oral C-DEC and IV decitabine.

“We are very pleased that the FDA has accepted our NDA for Priority Review,” said Dr Mohammad Azab, MD, president & chief medical officer of Astex Pharmaceuticals, Inc.  “Subject to FDA review and regulatory approval, oral C-DEC 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 grateful to all the patients, investigators and other healthcare providers, and partner research and manufacturing organizations, who contributed to the clinical development program of oral C-DEC.”

The FDA grants Priority Review to applications for drugs that, if approved, would provide significant improvements in the safety and effectiveness of the treatment, diagnosis or prevention of serious conditions. The Priority Review designation means FDA’s goal is to take action on an NDA application within six months (compared to the ten months under standard review).

Oral C-DEC 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 oral C-DEC in the U.S. 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.

 About C-DEC (Cedazuridine 100 mg and Decitabine 35 mg) Fixed-Dose Combination

C-DEC 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, C-DEC 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

C-DEC 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 C-DEC had received orphan drug designation for the treatment of MDS and CMML from the U.S. 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 the Phase 3 ASCERTAIN Study

The study was designed as a randomized crossover study comparing oral C-DEC (cedazuridine 100 mg and  decitabine 35 mg fixed-dose combination tablet given once daily for 5 days on a 28-day cycle) to IV decitabine (20 mg/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 C-DEC from Cycle 3 onwards. The data from the ASCERTAIN study was presented at the American Society of Hematology (ASH) Meeting in Orlando, Florida in December 2019 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, on behalf of the study investigators.4  The data demonstrated that the ASCERTAIN study met the primary endpoint of total 5-Day decitabine Area-Under-The-Curve (AUC) equivalence of oral C-DEC and IV decitabine. 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 oral C-DEC and IV decitabine in the first 2 randomized cycles.  The most common adverse events of any grade >20% regardless of causality in patients in the first 2 randomized cycles who received oral C-DEC were thrombocytopenia (43.8%), neutropenia (35.4%), anemia (36.9%), and fatigue (23.8%).  The ASH presentation can be downloaded from the Astex website at https://astx.com/media-center/presentations-and-publications/ASTX727 ASCERTAIN Presentation – ASH – December 2019

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.  U.S. incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.5,6 The prevalence has been estimated to be from 60,000 to 170,000 in the U.S.7 MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.8  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,9 and CMML may transform into AML in 15% to 30% of patients.10 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 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 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/

Contact Details

Martin Buckland
Chief Corporate Officer
Astex Pharmaceuticals, Inc.
4420 Rosewood Drive, Suite 200
Pleasanton 94588, CA, USA
Tel: +1-925-560-2857
Email: info@astx.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, McCloskey J, Griffiths EA, et al. Pharmacokinetic exposure equivalence and preliminary efficacy and safety from a randomized cross over Phase 3 study (ASCERTAIN study) of an oral hypomethylating agent ASTX727 (cedazuridine/decitabine) compared to IV decitabine. Blood 2019; 134 (Supplement_1).
  5. Garcia-Manero G. Myelodysplastic syndromes: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90(9) 831-841.
  6. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: Incidence and survival in the United States. Cancer 2007;109(8):1536–1542.
  7. Cogle C. Incidence and burden of the myelodysplastic syndromes. Curr Hematol Malig Rep 2015; 10(3): 272-281.
  8. 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.
  9. 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 27 January 2020.
  10. About chronic myelomonocytic leukemia (CMML). Cancer Research UK Web site. https://www.cancerresearchuk.org/about-cancer/other-conditions/chronic-myelomonocytic-leukaemia-cmml/about . Accessed 27 January 2020.

Jubb et al., “COSMIC-3D provides structural perspectives on cancer genetics for drug discovery.” Nature Genetics 2018; DOI 10.1038/s41588-018-0214-9

Jubb, HC et al., “COSMIC-3D provides structural perspectives on cancer genetics for drug discovery.” Nature Genetics. 2018; DOI 10.1038/s41588-018-0214-9

Rathi et al., “Predicting ‘Hot’ and ‘Warm’ Spots for Fragment Binding.” J. Med. Chem., 2017, 60 (9), pp 4036-4046, DOI: 10.1021/acs.jmedchem.7b00366

Abstract

Computational fragment mapping methods aim to predict hotspots on protein surfaces where small fragments will bind. Such methods are popular for druggability assessment as well as structure-based design. However, to date researchers developing or using such tools have had no clear way of assessing the performance of these methods. Here, we introduce the first diverse, high quality validation set for computational fragment mapping. The set contains 52 diverse examples of fragment binding “hot” and “warm” spots from the Protein Data Bank (PDB). Additionally, we describe PLImap, a novel protocol for fragment mapping based on the Protein–Ligand Informatics force field (PLIff). We evaluate PLImap against the new fragment mapping test set, and compare its performance to that of simple shape-based algorithms and fragment docking using GOLD. PLImap is made publicly available from https://bitbucket.org/AstexUK/pli.

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Rathi et al., “Predicting ‘Hot’ and ‘Warm’ Spots for Fragment Binding.” J. Med. Chem., 2017, 60 (9), pp 4036-4046, DOI: 10.1021/acs.jmedchem.7b00366

2015_ESH-AML: Baseline biomarkers and DNA demethylation correlate w. clinical responses in SGI-110

Summary

Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase and results in prolonged in vivo exposure to its active moiety DAC. The differentiated pharmacokinetic profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. We reported previously results from the Phase 1 dose-escalation study in AML and MDS1 and the Phase 2 randomized dose-response study in r/r AML patients of SGI-110 given SC at 2 doses (60 and 90 mg/m2) in a 5-day regimen2 or at 60 mg/m2 in a 10-day regimen3. Here we report an overall assessment of the association between clinical responses, global DNA demethylation assessed by LINE1 assay and baseline expression of a panel of 7 genes (CDA, P15, P21, DNMT3B, DNMT3A, DNMT1 and CTCF) assessed by qRT-PCR.

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2015_ESH-AML: Baseline biomarkers and DNA demethylation correlate w. clinical responses in SGI-110

2015 EHA: Late response & OS long term follow up of randomized P2 Study of SGI-110 in elderly AML

Summary

  • We previously reported results from a multicenter study of guadecitabine randomized to a 5-day regimen at either 60 or 90 mg/m2 in 51 treatment naïve elderly AML patients not eligible for intensive chemotherapy
  • There were no significant differences in overall composite complete response (CRc: CR+CRp+CRi) or safety between the two doses; however 14 patients were still on treatment at the time of the prior analysis
  • We present here current results on these patients with a median follow-up of 24 months (20.2-33) during which 38 death events occurred in the 51 patients treated (75%)

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2015 EHA: Late response & OS long term follow up of randomized P2 Study of SGI-110 in elderly AML

2015 ASCO: Epigenome and Genome Alterations in Platinum Resistant Ovarian Cancer

Summary

Background : Epigenetic changes, particularly in DNA methylation, have been implicated in acquired resistance to platinum in ovarian cancer (OC). Methods: An ongoing phase I/II multi-institutional clinical trial uses the novel DNA methyltransferase (DNMT) inhibitor guadecitabine (SGI-110) to re-sensitize recurrent platinum resistant OC to carboplatin. Patients enrolled in this trial had recurrent platinum resistant OC and multiple lines of prior therapy. Tumor biopsies were collected at baseline and after two cycles of guadecitabine administered daily for 5 days in low dose (30mg/m2). The goal of the current study was to analyze and integrate global RNA expression and DNA methylation profiles of platinum resistant tumors and to measure genomic and epigenomic changes induced by guadecitabine in tumors. RNA and DNA were extracted from 48 and 57 baseline tumors and analyzed using next generation sequencing (RNA-seq) and Infinium Human Methylation450 (HM450) arrays, respectively. Differential gene expression and DNA methylation profiles were generated and used for Ingenuity Pathway Analysis (IPA) to identify the top altered pathways in response to guadecitabine. Results: Analysis of a limited number of paired samples before and after treatment (n=8) revealed significant changes in global gene expression profiles induced by SGI-110, with 960 altered genes representing immunopathway enrichment including: cytokine production in macrophages and T helper cells by IL-17A and IL-17F, granulocyte /agranulocyte adhesion and inflammation, IL-8 signaling, p38 MAPK signaling, cAMP-mediated signaling, and innate immunity. HM450 analysis showed a greater number of hypermethylated genes in baseline tumors compared to primary OC samples in The Cancer Genome Atlas (TCGA) and demethylation (decreased β-values relative to baseline) of a large number of loci (381 gene promoters) after guadecitabine treatment. IPA analysis of baseline tumor transcriptome and methylome demonstrated significant enrichment in a wide range of pathways associated with cancer, stem cells, inflammation and the immune system. Conclusions: These data suggest that treatment with a DNMT inhibitor induces a reactivation of immune responses in human OC. Correlations between methylation changes and expression profiles are being explored.

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2015 ASCO: Epigenome and Genome Alterations in Platinum Resistant Ovarian Cancer

2015: AACR First Results of a 10-Day Regimen of SGI-110 in Previously Untreated Elderly AML

Summary

  • Elderly and unfit individuals with AML are often ineligible to receive intensive chemotherapy
  • Hypomethylating agents (HMA) such as decitabine and azacitidine have shown efficacy and acceptable safety in these patients
  • SGI-110 (guadecitabine) is a next generation HMA given as a small volume subcutaneous (SC) administration
  • We previously presented Phase 2 data of SGI-110 using the standard 5-day regimen which showed good good clinical activity in these patients
  • We present here , the preliminary results (minimum follow up of 3 months) of a 10-day regimen of SGI-110 in treatment naïve (TN) AML patients who are ineligible for intensive chemotherapy (IC)

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2015: AACR First Results of a 10-Day Regimen of SGI-110 in Previously Untreated Elderly AML

2015: AACR PD and PK Results of SGI-110 in Patients with HCC after Progression on Sorafenib

Summary

  • Hepatocellular Carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer death worldwide (1)
  • Sorafenib treatment improves survival in advanced disease, but no therapy has demonstrated significant activity after progression on sorafenib (2)
  • SGI-110, a dinucleotide of decitabine and deoxyguanosine (Fig 1), affords increased in vivo exposure of decitabine by protecting it from deamination due to slow release upon SQ injection
  • In Phase 1 AML/MDS studies, SGI-110 provides longer exposure and more potent hypomethylation compared to decitabine (3)
  •  Preclinical studies demonstrated:
    • In vitro, SGI-110 induced significant hypomethylation of tumor suppressor genes RASSF1A, SOCS1 and DAB2IP in human HCC cell lines HuH7 an HepG2 and resulted in a potent reduction in colony formation at low nanomolar concentrations of SGI-110 (4)
    • SGI-110 efficiently sensitizes HCC cells and xenografts to oxaliplatin by inhibiting distinct signaling pathways, allowing for high antitumor activity without systemic toxicity (Kuang et al., AACR 2015, Abst 2533)
    • Numerous epigenetic alterations accumulate during hepatocarcinogenesis, leading to activation of oncogenes or loss of tumor suppressor genes in HCC. Specifically, increased methylation of genes implicated in HCC tumorigenesis has been associated with pathogenesis and poor outcome
  • In this study, we evaluated therapeutic and biologic effects of SGI-110, a hypomethylating agent (HMA)in patients with HCC. PK and PD results of this open-label, phase 2 study in patients with HCC are presented here

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2015: AACR PD and PK Results of SGI-110 in Patients with HCC after Progression on Sorafenib

2015 AACR Novel Combination Therapy of SGI-110 and BMN-673 for BRCA-Proficient Ovarian Cancer

Summary

  • Ovarian cancer (OC) is initially chemoresponsive but the majority of patients relapse after first line platinum-, taxane-based chemotherapy.
  • Recurrence has been shown to be associated with increased DNA damage response (DDR) mediated by poly-(ADP)-ribose polymerase 1/2 (PARP1/2), which can be therapeutically targeted by PARP inhibitors (PARPi). Although PARPi are indicated for platinum-responsive, BRCA-mutated OC, most OC patients have BRCA-proficient disease.
  • Based on our previous studies supporting a role for DNA methylation in chemoresistant OC, mediated by the enzyme DNA methyltransferase 1 (DNMT1), and reports on a functional role for DNMT1 in DNA double strand break repair mediated by BRCA1/2, we hypothesize that combining the DNMTi SGI-110 and the PARPi talazoparib (BMN673) will impair BRCA-mediated DDR, resulting in cytotoxicity. CONCLUSION: Combination SGI-110 + talazoparib treatment significantly reduced cancer cell colony formation. Regardless of BRCA and platinum sensitivity status, co-administration of SGI-110 and talazoparib reduced cell survival, albeit %survival was dependent on drug dose and cancer cell line.

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2015 AACR Novel Combination Therapy of SGI-110 and BMN-673 for BRCA-Proficient Ovarian Cancer