Astex Pharmaceuticals and MD Anderson Announce Strategic Collaboration to Accelerate Clinical Evaluation of Therapies for Patients with Leukemia

Pleasanton, CA, and Houston, TX – September 8th, 2020. ­­– Astex Pharmaceuticals, Inc., a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan, and The University of Texas MD Anderson Cancer Center today announces a  strategic collaboration agreement aimed at accelerating the clinical evaluation of Astex’s pipeline of products for patients with certain types of leukemia, including myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML).  The collaboration will combine MD Anderson’s clinical trials infrastructure and expertise with Astex’s clinical pipeline products.

The initial focus will be on evaluating Astex’s oral decitabine and cedazuridine hypomethylating agent (INQOVI®) in combinations with other therapies. INQOVI recently was approved by the US FDA and by Health Canada for the treatment of intermediate- and high-risk MDS and CMML.

“MD Anderson is dedicated to providing the best treatment options to our patients, and there is tremendous interest in evaluating how a new generation of oral targeted therapies might work in combination to treat those with leukemia,” said Guillermo Garcia-Manero, M.D., Professor and Chief of Section of Myelodysplastic Syndromes, Department of Leukemia at MD Anderson. “This collaboration with Astex will allow us to expand those studies with the ultimate goal of providing patients with oral drug combinations that have the potential of improving clinical outcomes.”

Under the collaboration agreement, MD Anderson and Astex will design new clinical studies to be conducted at MD Anderson. Astex will provide funding, test compounds and other support. The collaboration will be overseen by a joint steering committee.

“MD Anderson has been a collaborator with Astex on multiple clinical studies for our pipeline products,” said Mohammad Azab, president & chief medical officer of Astex. “We are delighted to be entering into this new collaboration and look forward to continuing to advance this important area of clinical research.”

 

About INQOVI (See https://www.inqovi.com)

INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

 

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Myelosuppression: Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%.

Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.

Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors, and anti‑infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.

Embryo-Fetal Toxicity: INQOVI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise patients to use effective contraception during treatment with INQOVI and for 6 months (females) or 3 months (males) after last dose.

ADVERSE REACTIONS

Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

The most common adverse reactions (≥ 20%) were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (>50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased.

USE IN SPECIFIC POPULATIONS

Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for at least 2 weeks after the last dose.

Renal Impairment: No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min).

 

Please see the Full Prescribing Information at:

https://www.inqovi.com/pi

INQOVI is being commercialized by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc. in the U.S. and Canada respectively. Taiho and Astex are members of the Otsuka group of companies

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. The institution’s sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 51 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No.1 for cancer care in U.S. News & World Report’s “Best Hospitals” survey. It has ranked as one of the nation’s top two hospitals for cancer care since the survey began in 1990 and has ranked first 16 times in the last 19 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

About Astex Pharmaceuticals, Otsuka Pharmaceutical and Taiho Oncology

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.

Taiho Oncology, Inc., is a subsidiary of Taiho Pharmaceutical Co., Ltd. and an indirect subsidiary of Otsuka Holdings Co., Ltd. Taiho has established a world-class clinical development organization that works urgently to develop innovative cancer treatments and has built a commercial business in the U.S. Taiho has an oral oncology pipeline consisting of both novel antimetabolic agents and selectively targeted agents.

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

For more information about Otsuka Pharmaceutical, please visit: https://www.otsuka.co.jp/en/

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

Contact Details

Martin Buckland                                                                       Clayton R. Boldt, Ph.D.

Chief Corporate Officer                                                           Public Relations

Astex Pharmaceuticals, Inc.                                                    MD Anderson Cancer Center

4420 Rosewood Drive, Suite 200                                           Tel: +1-713-792-9518

Pleasanton 94588, CA, USA                                                    Email: crboldt@mdanderson.org

Tel: +1-925-560-2857

Email: info@astx.com

Astex Pharmaceuticals Announces That Tolinapant (ASTX660), a Novel Antagonist of Cellular and X-linked Inhibitors of Apoptosis Proteins, Has Been Granted Orphan Drug Designation for the Treatment of T-cell Lymphomas by the US FDA

Pleasanton, CA, August 31st, 2020. Astex Pharmaceuticals, Inc., a wholly owned subsidiary of Otsuka Pharmaceutical Co., Ltd., based in Tokyo, Japan, announces that the US Food & Drug Administration (FDA) has granted orphan drug designation for the company’s novel, orally administered non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), tolinapant (formerly known as ASTX660), for the treatment of T-cell lymphoma. Orphan drug designation is granted to drugs intended to treat a rare disease or condition.  In the US an orphan disease is defined as one affecting fewer than 200,000 people. The designation provides for seven years of marketing exclusivity in the US following product approval, as well as certain tax incentives and grants.

“T-cell lymphoma remains a challenging disease area with poor prognosis and high unmet medical need,” said Mohammad Azab, MD, Astex Pharmaceuticals’ president and chief medical officer.  “Astex’s development of tolinapant is aimed at bringing a new therapeutic option for patients with this type of cancer. We are delighted that the FDA has granted the orphan drug designation which recognizes the continued need for development of new treatments for patients with rare diseases such as peripheral T-cell lymphoma and cutaneous T-cell lymphoma.”

ASTX660 is an investigational compound and is not currently approved in any country.

 

About Tolinapant (ASTX660)

Tolinapant is a novel, orally administered, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). Inhibitors of apoptosis proteins (IAPs) are frequently overexpressed in tumor cells and contribute to tumor cell survival and chemo-resistance. By inhibiting IAPs, tolinapant promotes cell death. Tolinapant also acts via a newly described immunomodulatory mechanism which works to enhance an anti-tumor immune response in T-cell lymphomas.  Tolinapant was designed using Astex’s fragment-based drug design technology.

Tolinapant is being evaluated in a phase 1/2 clinical study for the treatment  of advanced solid tumors and lymphomas (see https://www.clinicaltrials.gov NCT02503423)

 

About T-Cell Lymphomas

T-cell lymphomas are a rare and heterogeneous group of blood cancers arising from abnormal T-lymphocytes. Approximately 6-10% of non-Hodgkin’s lymphomas (NHL) are T-cell lymphomas.  The American Cancer Society estimates there will be 77,240 new cases of NHL diagnosed in the U.S. in 2020. Tumors of mature T-cell origin are usually referred to as peripheral T-cell lymphomas (PTCL).  The World Health Organization’s 2016 classification describes 29 discrete subtypes of peripheral T-cell lymphoma. T-cell lymphomas generally affect people aged 60 or older, and are more common in men than in women.  While some T-cell lymphomas follow an indolent course, many are aggressive and have poor prognosis.

  

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: https://www.astx.com

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

 

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

Astex Pharmaceuticals, Taiho Oncology, and Otsuka Pharmaceutical announce FDA and Health Canada approval of INQOVI® (decitabine and cedazuridine) tablets.

Astex Pharmaceuticals, Taiho Oncology, and Otsuka Pharmaceutical announce FDA and Health Canada approval of INQOVI® (decitabine and cedazuridine) tablets, oral hypomethylating agent (HMA) therapy for intermediate and high-risk MDS and CMML

  • INQOVI is the first orally administered hypomethylating agent approved by the FDA and Health Canada
  • INQOVI is a fixed-dose combination of the hypomethylating agent decitabine and the cytidine deaminase inhibitor cedazuridine, which prevents degradation of decitabine in the gastrointestinal tract and liver and enables its absorption via oral dosing
  • Approval is based on the ASCERTAIN phase 3 and other supporting studies that compared systemic exposure to decitabine from oral INQOVI with exposure from IV decitabine and assessed safety and efficacy of INQOVI
  • INQOVI delivers an option for intermediate and high-risk MDS and CMML patients to potentially reduce the number of office visits and to take their medication from the convenience and comfort of their homes

Pleasanton, CA, Princeton, NJ, and Tokyo, Japan, July 7, 2020. Astex Pharmaceuticals, Inc.; Taiho Oncology, Inc.; and Otsuka Pharmaceutical Co., Ltd. today announce that the U.S. Food and Drug Administration (FDA) and Health Canada have approved INQOVI® (decitabine and cedazuridine) tablets. The three companies are all part of the Otsuka group of companies.

INQOVI is the first and only orally administered hypomethylating agent for the treatment for adults with intermediate and high-risk myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia (CMML),1 two blood malignancies.

Approval was based on data from the ASCERTAIN phase 3 study and supporting phase 1 and 2 clinical studies.  The ASCERTAIN phase 3 study evaluated the five-day, decitabine exposure equivalence between oral INQOVI and intravenous decitabine. The safety and efficacy of INQOVI was also assessed in the clinical studies.

The review and approval of INQOVI was conducted under the ORBIS initiative from the FDA Oncology Center of Excellence (OCE) with simultaneous submission and regulatory review in the U.S., Canada, and Australia. The FDA also reviewed the NDA under Priority Review status. INQOVI is not currently approved in Australia. INQOVI was formerly named ASTX727, its experimental compound code.

“Intravenous or subcutaneous administered hypomethylating agents have been the cornerstone for the treatment of patients with MDS and CMML since the mid-2000s,” said 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, and Principal Investigator of the ASCERTAIN clinical study. “The FDA’s approval of INQOVI builds on the proven therapeutic utility of hypomethylating agents in these diseases and offers a new orally administered option that offers patients an alternative to five consecutive days of IV infusions every month during a treatment period that can extend to several months.”

“Until now, patients with intermediate and high-risk MDS and CMML have not had an approved, orally administered hypomethylating agent option for treatment of their disease,” said Mohammad Azab, MD, president and chief medical officer of Astex Pharmaceuticals, Inc. “The INQOVI clinical program was designed to deliver an oral alternative to IV decitabine based on comparative decitabine exposure data in the clinical trials, and to assess INQOVI’s safety and efficacy profile. As part of the ORBIS project initiative of FDA and Health Canada we were able to share and address information requests simultaneously with both agencies resulting in a more efficient review and completion of assessment in a timely manner. The outcome is expedited availability of this important oral alternative to patients in both countries” added Dr. Azab. “We greatly appreciate the FDA’s priority review and Health Canada’s review of the INQOVI NDA / NDS under Project ORBIS and the approval of a new therapeutic option for patients with these diseases.”

INQOVI is an orally administered, fixed-dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine,2 an inhibitor of cytidine deaminase.3 By inhibiting cytidine deaminase in the gut and the liver, INQOVI is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine (geometric mean ratio of the 5-day cumulative decitabine area-under-the-curve following 5 consecutive once daily doses of INQOVI compared to that of intravenous decitabine was 99% (90% CI: 93, 106).1 The phase 1 and phase 2 clinical study results have been published in Lancet Haematology4 and Blood,5 respectively. The phase 3 ASCERTAIN study data was presented at the American Society of Hematology (ASH) Meeting in Orlando, Florida, in December 2019 by Dr. Garcia-Manero.6

Astex’s parent company, Otsuka Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd. previously announced that, subject to regulatory approvals, commercialization of oral INQOVI in the U.S. and Canada will be conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc. respectively.

“Our partnership with Astex is a demonstration of the commitment that Taiho Oncology has to bringing new therapeutic options to patients with cancer,” said Tim Whitten, president and chief executive officer of Taiho Oncology, Inc. “The approval of INQOVI makes the possibility of at-home hypomethylating agent treatment of intermediate and high-risk MDS and CMML a reality, enabling patients to take their medication from the convenience and comfort of their home. This is especially significant during the COVID-19 pandemic, allowing patients to potentially reduce the number of office visits needed for current IV treatment administration. We look forward to working with all healthcare professionals to help deliver the first new oral HMA treatment alternative for patients with intermediate and high-risk MDS and CMML in nearly fifteen years.”

 

About INQOVI (See https://www.inqovi.com)

INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.1

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Myelosuppression: Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%.

Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.

Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors, and anti‑infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.

Embryo-Fetal Toxicity: INQOVI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise patients to use effective contraception during treatment with INQOVI and for 6 months (females) or 3 months (males) after last dose.

ADVERSE REACTIONS

Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

The most common adverse reactions (≥ 20%) were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (>50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased.

 

USE IN SPECIFIC POPULATIONS

Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for at least 2 weeks after the last dose.

Renal Impairment: No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min).

 

Please see the accompanying Full Prescribing Information. 
https://www.inqovi.com/pi

To view the FDA Press Release, please see the following link.
 https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-myelodysplastic-syndromes-mds-can-be-taken-home

 

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.7,8 The prevalence has been estimated to be from 60,000 to 170,000 in the U.S.9 MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.10 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,11 and CMML may transform into AML in 15% to 30% of patients.12 The hypomethylating agents decitabine and azacitidine are effective treatment modalities and are FDA-approved for the treatment of intermediate and high-risk MDS and CMML. These agents are administered by IV infusion, or by large-volume subcutaneous injections.

 

About Astex, Taiho, and Otsuka

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.

Taiho Oncology, Inc., is a subsidiary of Taiho Pharmaceutical Co., Ltd. and an indirect subsidiary of Otsuka Holdings Co., Ltd. Taiho has established a world-class clinical development organization that works urgently to develop innovative cancer treatments and has built a commercial business in the U.S.

Taiho has an oral oncology pipeline consisting of both novel antimetabolic agents and selectively targeted agents.

Otsuka Pharmaceutical 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: https://www.astx.com

For more information about Otsuka Pharmaceutical, please visit: https://www.otsuka.co.jp/en/

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

 

Contact Details:
Craig Heit
GCI Health
On behalf of Astex Pharmaceuticals, Inc. and Taiho Oncology, Inc.
Email: TaihoOncology@gcihealth.com
Tel: +1-212-798-9919

  

References

  1. INQOVI Prescribing Information. inqovi.com/pi
  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. 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.
  4. 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.
  5. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML [published online ahead of print, 2020 Apr 13]. Blood. 2020;blood.2019004143. doi:10.1182/blood.2019004143
  6. 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).
  7. Garcia-Manero G. Myelodysplastic syndromes: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90(9) 831-841.
  8. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: Incidence and survival in the United States. Cancer 2007;109(8):1536–1542.
  9. Cogle C. Incidence and burden of the myelodysplastic syndromes. Curr Hematol Malig Rep 2015; 10(3): 272-281.
  10. 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.
  11. 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 15 June 2020.
  12. About chronic myelomonocytic leukemia (CMML). Cancer Research UK Web site. https://www.cancerresearchuk.org/about-cancer/other-conditions/chronic-myelomonocytic-leukaemia-cmml/about. Accessed 15 June 2020.

 

CDEC-PM-US-0125

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: https://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.

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, CA, December 9th, 2019. 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: https://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. 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.

Taiho Oncology Announces Agreement with Otsuka to Commercialize Astex Pharmaceuticals’ Drug Candidates

PRINCETON, N.J., June 7, 2019 – Taiho Oncology, Inc. announces that it has assumed commercialization responsibility from Otsuka Pharmaceuticals Co., Ltd., (Otsuka) for the novel fixed-dose combination of cedazuridine and decitabine (ASTX727) and guadecitabine (SGI-110) in the U.S. and Canada, subject to regulatory approvals. Taiho Pharma Canada, Inc., will commercialize these compounds in Canada.

The two candidates are in late-stage clinical development by Astex Pharmaceuticals, a wholly owned subsidiary of Otsuka. Taiho Oncology is also part of the Otsuka group of companies.

“This commercialization agreement is highly significant for Taiho Oncology as it allows us to build on the long-term strategy of expanding our presence in North America,” said Taiho Oncology, Inc. Chief Executive Officer Timothy Whitten. “These investigational therapies have the potential to provide physicians and patients with much-needed treatment options for a range of hematologic malignancies. We look forward to working with Astex as we bring these compounds to market.”

On June 6, 2019, Astex Pharmaceuticals and Otsuka announced top-line results from the Phase III ASCERTAIN study evaluating ASTX727 vs. decitabine IV in adults with intermediate and high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). The trial met its primary endpoint of decitabine area-under-the-curve (AUC) equivalence of total 5-day dosing between orally administered ASTX727 and IV decitabine. The full data will be presented at an upcoming scientific meeting.

Astex has current studies with guadecitabine (SGI-110) in relapsed and refractory acute myeloid leukemia (R/R AML) and relapsed and refractory myelodysplastic syndromes (R/R MDS) and CMML.

About Taiho Oncology, Inc. (U.S.)
Taiho Oncology, Inc., a subsidiary of Taiho Pharmaceutical Co., Ltd. and an indirect subsidiary of Otsuka Holdings Co., Ltd., has established a world-class clinical development organization that works urgently to develop innovative cancer treatments and has built a commercial business in the U.S.

Taiho has an oral oncology pipeline consisting of both novel antimetabolic agents and selectively targeted agents. Advanced technology, dedicated researchers, and state of the art facilities are helping us to define the way the world treats cancer. It’s our work; it’s our passion; it’s our legacy.

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

For more information about Taiho Pharmaceutical Co., Ltd., please visit:

https://www.taiho.co.jp/en/.

About Astex Pharmaceuticals, and Otsuka Pharmaceutical
Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system. Astex is developing a proprietary pipeline of novel therapies and has multiple partnered products in development under collaborations with leading pharmaceutical companies. Astex became a wholly owned subsidiary of Otsuka in 2013.

Otsuka Pharmaceutical Co., Ltd., based in Tokyo, Japan, 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, visit: https://astx.com.

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

###

Contacts for U.S. Media

On behalf of Taiho Oncology:
Craig Heit
GCI Health
Taihooncology@gcihealth.com
646-946-6690

At Astex:
Martin Buckland
Chief Corporate Officer
Astex Pharmaceuticals, Inc.
info@astx.com
925-560-2857

PL-PM-US-0007 06/2019

British Company Behind Groundbreaking Breast Cancer Treatment

Astex welcomes positive, new data showing breast cancer drug, Kisqali® (ribociclib), cuts risk of death by up to a third when given with hormone therapy

Cambridge, UK, 7 June 2019. A new set of statistically significant overall survival (OS) data unveiled at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract# LBA1008), and published in The New England Journal of Medicine, are being heralded as a major breakthrough forpre- and perimenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancerpremenopausal women with advanced breast cancer.

Kisqali was discovered and developed by the Novartis Institutes for Biomedical Research (NIBR) under a research collaboration entered into with Astex in 2005.  Kisqali is a CDK4/6 inhibitor that slows the progression of cancer by inhibiting two proteins (CDK4 & CDK6) which, when over-activated, can enable cancer cells to grow and divide quickly.

Successful results from the phase III MONALEESA-7 clinical trial resulted in Kisqali receiving marketing approval in the US and EU in 2018 in combination with an endocrine-based therapy for pre- and perimenopausal women with (HR+/HER2-) locally advanced or metastatic breast cancer in combination with an aromatase inhibitor.

The UK’s National Institute for Health and Care Excellence (NICE) recommended Kisqali as a cost-effective treatment option for postmenopausal women within England and Wales with advanced breast cancer in November 2017. Advanced breast cancer in premenopausal women is the leading cause of cancer death in women 20-59 years old [1],[2].

Kisqali is the only CDK4/6 inhibitor to show superior overall survival in a clinical trial (alt. “v. placebo”) in advanced breast cancer (HR=0.712; p=0.00973)[3]. In its announcement at ASCO, Novartis noted that the new data from its MONALEESA-7 trial showed that after a median of 42 months follow-up, survival rate for women was 70.2% for women who received Kisqali combination therapy compared to 46.0% for women who received endocrine therapy alone. The breakthrough data has been widely reported in the world’s press.

Harren Jhoti Ph.D., President and CEO of Astex, UK, said, “It’s fantastic to see such a significant advance in cancer treatment. Ultimately as life science entrepreneurs, our goal is to improve lives through the discovery of new therapies. Kisqali was the first new cancer drug discovered and developed from our collaboration with Novartis to reach marketing approval and was a milestone for the company in 2017.  These new data are a real milestone for patients.”
The paper,Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer, was a published in The New England Journal of Medicinetoday and is available online.

See the discovery journey for Kisqali, here: https://astx.com/research-development/partnered-products-and-programs/kisqali-ribociclib-cdk46-inhibitor-oncology/

-ENDS-

About Astex Pharmaceuticals

Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system.  Astex is developing a proprietary pipeline of novel therapies and has a number of partnered products being developed under collaborations with leading pharmaceutical companies.  In October 2013 Astex became a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan.  Otsuka Pharmaceutical 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, please visit https://astx.com
For more information about Otsuka Pharmaceutical, please visit http://www.otsuka.co.jp/en/

References

[1] Benz CC. Impact of aging on the biology of breast cancer. Crit Rev Oncol Hematol. 2008;66:65-74.
[2] World Health Organization. Top cancer per country, estimated age-standardized mortality rates (World) in 2018, females, all ages. 2018. Available at http://gco.iarc.fr/today/home. Accessed May 2019
[3] Hurvitz S, Seock-Ah I, Yen-Shen L et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: Overall survival (OS) results. Presented at the 2019 ASCO Meeting, June 1, 2019, Abstract# LBA 1008.

CONTACT:

At the Company:
Jeremy Carmichael
VP Corporate Development
Head of Business Development
Tel: +44(0)1223 226289
Email: jeremy.carmichael@astx.com

For Media Enquiries:
Sue Charles / Ashley Tapp
Instinctif Partners
Tel: +44 (0)20 7866 7863
Email: astex@instinctif.com

 

Astex Pharmaceuticals Celebrates as Second New Cancer Drug Receives US Marketing Approval

Astex Pharmaceuticals Celebrates as Second New Cancer Drug Receives US Marketing Approval
  • Further Milestone from Janssen on NDA Approval by the US FDA of BALVERSA™ (erdafitinib) for the Treatment of Urothelial Cancer

Cambridge, UK, 12 April 2019. Astex Pharmaceuticals (Astex), a pharmaceutical company dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, announced today that it has received a milestone payment from Janssen Pharmaceutica N.V. (Janssen). This follows the United States Food and Drug Administration’s (FDA) accelerated review and approval of a Janssen New Drug Application (NDA) for BALVERSA™ (erdafitinib) for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC) which has susceptible fibroblast growth factor receptor (FGFR)3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

BALVERSA™ (erdafitinib) is a once-daily, oral pan-FGFR inhibitor that was discovered by Astex and Janssen as part of a 2008 exclusive worldwide collaboration and licence agreement to identify novel, small molecule inhibitors of FGFR kinase, including for the treatment of cancer. Under the ongoing collaboration, Janssen is responsible for the clinical development and commercialisation of all products, including erdafitinib. Astex is eligible to receive further milestone payments on additional regulatory filings and approvals in the US and Europe and for additional indications, as well as tiered double-digit royalty payments on annual sales of erdafitinib.

BALVERSA™ (erdafitinib) received Breakthrough Therapy Designation from the FDA for the treatment of patients with metastatic urothelial cancer in March 2018 and Janssen announced submission of an NDA seeking its approval to the US FDA in September 2018. Urothelial cancer, particularly of the bladder, is the sixth most common type of cancer in the USA.

Before entering into its exclusive worldwide collaboration and licence agreement with Janssen, Astex performed pioneering work on FGFR with the Cancer Research UK Drug Discovery Group at the Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, UK, underlining the quality of UK science and strengths in academic-biotech collaboration.

Harren Jhoti Ph.D., President and CEO of Astex, UK, said, “‘We are delighted with the approval of BALVERSA™ and congratulate our valued colleagues at Janssen for their determination and excellent work in the discovery and development of this new medicine. We also congratulate our academic collaborators at Newcastle University for their contribution to our pioneering early collaboration on FGFR that aided in its discovery. Astex continues to strive to discover new medicines for cancer patients and is very proud that BALVERSA™ is the second of our Pharma-partnered products to have been approved in the last two years.’

-ENDS

About Astex Pharmaceuticals

Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system. Astex is developing a proprietary pipeline of novel therapies and has a number of partnered products being developed under collaborations with leading pharmaceutical companies. In October 2013 Astex became a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan. Otsuka Pharmaceutical 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, please visit https://astx.com

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

BALVERSA is a trademark of Janssen Biotech, Inc.

Contact

At the Company:
Jeremy Carmichael
VP Corporate Development
Head of Business Development

Tel: +44(0)1223 226289
Email: jeremy.carmichael@astx.com

For Media Enquiries:
Sue Charles / Ashley Tapp
Instinctif Partners

Tel: +44 (0)20 7866 7863
Email: astex@instinctif.com

Astex Pharmaceuticals and Otsuka announce results of the phase 3 ASTRAL-1 study of guadecitabine (SGI-110) in treatment-naïve AML patients ineligible to receive intense induction chemotherapy

Astex Pharmaceuticals and Otsuka announce results of the phase 3 ASTRAL-1 study of guadecitabine (SGI-110) in treatment-naïve AML patients ineligible to receive intense induction chemotherapy

  • Guadecitabine did not meet the co-primary endpoints of complete response (CR) rate or overall survival (OS) in the ASTRAL-1 study
  • Astex continues to focus on completing the phase 3 ASTRAL-2 and ASTRAL-3 studies evaluating the efficacy and safety of guadecitabine in relapsed and refractory acute myeloid leukemia (R/R AML) and relapsed and refractory myelodysplastic syndromes (R/R MDS) and chronic myelomonocytic leukemia (CMML)

Pleasanton, CA and Tokyo, Japan, July 30th, 2018. Astex Pharmaceuticals, a member of the Otsuka group of companies, and Otsuka Pharmaceutical Co. Ltd., announce top-line results from the ASTRAL-1 study evaluating the efficacy and safety of guadecitabine (SGI-110) in adults with previously untreated AML who are not eligible for intensive induction chemotherapy. The study did not meet its co-primary endpoints: complete response (CR) rate (p>0.04), and overall survival (OS) (p>0.01) as per the protocol analysis plan, compared with the control arm of physician’s choice of azacitidine, decitabine, or low dose cytarabine. Evaluation of the study’s secondary endpoints and safety data is ongoing. The full data will be presented at an upcoming scientific meeting.

The company continues to focus on completing the ongoing global phase 3 ASTRAL-2 and ASTRAL-3 studies evaluating guadecitabine in the treatment of relapsed and refractory AML and relapsed and refractory MDS and CMML.

“We are disappointed in the outcome of the ASTRAL-1 study,” said Mohammad Azab, Astex’s president and chief medical officer. “The study used very strict criteria of ineligibility to receive intensive chemotherapy based on age (over 75 years) or poor performance status (ECOG PS of 2 or 3) or comorbidities, which made it a difficult population to show superior benefit of guadecitabine.” Dr. Azab also added, “ASTRAL-1 is the largest global prospective study ever conducted in this specific patient population with low intensity therapy, with 815 patients randomized, of whom about 90% were treated with hypomethylating agents or HMAs (guadecitabine, azacitidine, or decitabine). The large body of clinical and genetic data will still provide the medical community with very valuable insights into the role of several prognostic clinical and genetic markers that may influence outcome with HMA treatment. We are extremely grateful to all the patients, physicians and other healthcare professionals, and partner research and manufacturing organizations who contributed to this global effort. We are now looking forward to the completion of the ASTRAL-2 and ASTRAL-3 studies currently actively recruiting in two different indications.”

About Guadecitabine (formerly SGI-110)

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 that results in silencing of critical genes. This action 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 is currently being studied in two additional phase 3 studies:

  • ASTRAL-2: A randomized, open-label study in leukemia patients with relapsed or refractory acute myeloid leukemia (AML) following intensive chemotherapy. See www.clinicaltrials.gov NCT02920008.
  • ASTRAL-3: A randomized, open-label study in myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) after failure of treatment with azacitidine, decitabine, or both. See www.clinicaltrials.gov NCT02907359.

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

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

About the ASTRAL-1 Study

The ASTRAL-1 study evaluated the efficacy and safety of guadecitabine (formerly SGI-110) in adults with previously untreated AML who are not eligible for intensive induction chemotherapy (see www.clinicaltrials.gov NCT02348489). The study is the largest global prospective study ever conducted in this specific patient population, with 815 patients randomized from 163 investigator sites in 24 countries worldwide. The study compared guadecitabine, delivered subcutaneously (SC) 60mg/m2/day for 5 days, with physicians’ choice of azacitidine IV or SC 75 mg/m2/day for 7 days, decitabine IV 20 mg/m2/day for 5 days, or low dose cytarabine SC 20 mg bid for 10 days, all administered in 28-day cycles. In addition to the co-primary endpoints of OS and CR, the study evaluated multiple secondary endpoints including progression-free survival; composite CR or CRc (CR + CRi + CRp); overnight stays in hospital; red cell / platelet transfusions; QOL (EQ-5D-5L); duration of response and safety.

About Acute Myeloid Leukemia

AML is the most common form of acute leukemia in adults.9 There were an estimated 21,380 new cases of AML diagnosed in the US in 2017,10 and an estimate of 10,590 patients were projected to have died from AML in the US in 2017.11 Although 60 to 80 percent of AML patients less than 60 years of age may achieve a complete response (CR) with standard intensive induction chemotherapy,12 the outlook for patients 60 years of age or more is significantly worse, with response rates less than 50 percent, cure rates following transplant remaining at less than 10 percent and a median survival of less than one year.12,13,14 These figures have not significantly improved during the last three decades. These patients have few therapeutic options available.15,16 Effective, less toxic therapies are needed for the treatment of AML, particularly for elderly patients where comorbidities and other consequences of aging may often render them ineligible to receive intensive induction chemotherapy, thus denying them a potentially curative transplant.14

About Astex Pharmaceuticals and Otsuka Pharmaceutical

Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system. Astex is developing a proprietary pipeline of novel therapies and has multiple partnered products being developed under collaborations with leading pharmaceutical companies. In October 2013 Astex became a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan.

Otsuka Pharmaceutical 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, please visit https://astx.com

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

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. Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol 2017; 18(10): 1317-26.
  2. Roboz GJ, Kantarjian HM, Yee KWL, et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer 2018; 124(2): 325-34.
  3. Issa JJ, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol 2015; 16(9): 1099-110.
  4. Griffiths EA, Choy G, Redkar S, Taverna P, Azab M, Karpf AR. SGI-110: DNA Methyltransferase Inhibitor Oncolytic. Drugs Future 2013; 38(8): 535-43.
  5. Kuang Y, El-Khoueiry A, Taverna P, Ljungman M, Neamati N. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin. Mol Oncol 2015; 9(9): 1799-814.
  6. Srivastava P, Paluch BE, Matsuzaki J, et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res 2014; 38(11): 1332-41.
  7. Fang F, Munck J, Tang J, et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res 2014; 20(24): 6504-16.
  8. Lindblad KE, Goswami M, Hourigan CS, Oetjen KA. Immunological effects of hypomethylating agents. Expert Review of Hematology 2017; 10(8): 745-52.
  9. De Kouchkovsky I, Abdul-Hay M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update’. Blood Cancer J. 2016; 6(7):e441.
  10. Society AC. Key Statistics for Acute Myeloid Leukemia 2018 [Available from: https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html.
  11. SEER. Cancer Stat Facts: Leukemia – Acute Myeloid Leukemia (AML) 2018 [Available from: https://seer.cancer.gov/statfacts/html/amyl.html.
  12. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424-47.
  13. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011; 29(5):487-94.
  14. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016; 127(1):53-61.
  15. Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015; 94(7):1127-38.
  16. Wang R, Zeidan AM, Halene S, Xu X, Davidoff AJ, Huntington SF, et al. Health Care Use by Older Adults With Acute Myeloid Leukemia at the End of Life. J Clin Oncol. 2017; 35(30):3417-24.

Astex’s Harren Jhoti Made Fellow of the Royal Society

Astex Pharmaceuticals (“Astex”), a pharmaceutical company dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, announced today that Harren Jhoti Ph.D., co-founder of Astex and President and CEO of Astex Pharmaceuticals (UK) has been elected a Fellow of the Royal Society in recognition of his outstanding contribution to drug discovery research and science in general.

Election to the Fellowship of the Royal Society is the highest accolade in UK science and recognises individuals for their scientific excellence and substantial contributions to research endeavours. At Astex Dr. Jhoti pioneered the development of fragment-based drug discovery, an approach now widely used in pharmaceutical and academic drug discovery centres worldwide.

Astex is one of the UK’s leading biotech companies, employing some 130 staff at its research headquarters in Cambridge UK and over 200 worldwide, and has been highly successful in translating research into new medicines. Notably this includes Kisqali®, a drug co-discovered by Astex under a partnership with Novartis that received marketing approval in the USA and in Europe as a treatment for metastatic breast cancer in 2017.

Dr. Jhoti commented, “I’m delighted and humbled to have been made a Fellow of the Royal Society.  I would like to thank all my scientific colleagues, past and present, who have supported me in my research career. This Fellowship is also a reflection of the excellence of science at Astex created by its many highly talented researchers.”

-ENDS-

Notes to Editors

About Astex Pharmaceuticals

Harren Jhoti co-founded Astex in 1999 and was Chief Scientific Officer until November 2007 when he was appointed Chief Executive Officer.  He was elected a Fellow of the Royal Society in 2018, the Royal Society of Biology in 2017, the Royal Society of Chemistry in 2016, and of the Academy of Medical Sciences in 2015.  In January 2018 he was honoured with a Lifetime Achievement Award from the UK BioIndustry Association (BIA).  He received the Prous Institute-Overton and Meyer Award for New Technologies in Drug Discovery from the European Federation for Medicinal Chemistry in 2012 and was also named by the Royal Society of Chemistry as “Chemistry World Entrepreneur of the Year” for 2007.

He has published widely including in leading journals such as Nature and Science, and has also been featured in TIME magazine after being named by the World Economic Forum a Technology Pioneer in 2005.  He has served on the board of the BIA, the UK BioIndustry Association and currently consults for life science venture capital firms. Before founding Astex in 1999, he was head of Structural Biology and Bioinformatics at GlaxoWellcome in the United Kingdom (1991-1999). Prior to Glaxo, Dr. Jhoti was a post-doctoral scientist at Oxford University. He received a B.Sc. (Hons) in Biochemistry in 1985 and a Ph.D. in Protein Crystallography from the University of London in 1989.

More information on the Royal Society can be found here: https://royalsociety.org/

About Astex Pharmaceuticals

Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system.  Astex is developing a proprietary pipeline of novel therapies and has a number of partnered products being developed under collaborations with leading pharmaceutical companies.  Astex is a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan; 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, please visit https://astx.com

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

At the Company

Jeremy Carmichael
VP Corporate Development
Head of Business Development
Astex Pharmaceuticals
436 Cambridge Science Park
Milton Road, Cambridge
CB4 0QA, UK

Tel: +44(0)1223 226289
Mobile: +44 (0)7786 738066
Email: jeremy.carmichael@astx.com