Astex Announces That the Phase 3 ASCERTAIN - Acute Myeloid Leukemia (AML) Clinical Study of Oral Hypomethylating Agent Decitabine and Cedazuridine Fixed-Dose Combination (ASTX727 or DEC-C) Met the Trial’s Primary Endpoint

PLEASANTON, Calif.--(BUSINESS WIRE)-- Astex Pharmaceuticals, Inc. announces today top-line results from the ASCERTAIN phase 3 study evaluating oral decitabine and cedazuridine fixed-dose combination (ASTX727 or DEC-C) tablets versus IV decitabine in adults with AML who are not candidates to receive standard induction chemotherapy.

The study met its primary endpoint of decitabine exposure equivalence of 5-day dosing between orally administered ASTX727 and intravenous (IV) decitabine as per the protocol analysis plan with a high degree of confidence. Safety observations were similar to those observed with IV decitabine.

The full data will be presented on June 10 as part of EHA2022. Astex plans to file a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) and similar applications in other countries where IV decitabine is indicated for the treatment of AML.

“We are delighted with the outcome of the ASCERTAIN - AML trial, and the demonstration that the fixed-dose oral combination of decitabine and cedazuridine provides exposure equivalence to IV decitabine in the AML population,” said Harold Keer, MD, PhD, chief medical officer of Astex Pharmaceuticals, Inc. “Subject to regulatory review and approvals, ASTX727 could bring a new treatment option to patients with AML who are not candidates to receive standard induction chemotherapy. The ASCERTAIN - AML study was conducted during the height of the COVID-19 pandemic, and this experience helped to highlight the potential advantage of an orally administered therapy. We are extremely grateful to all the patients, caregivers, partner research and manufacturing organizations, as well as the healthcare professionals who contributed to this effort.”

“Parenterally administered hypomethylating agents have been a cornerstone of the treatment of AML patients who are not candidates to receive standard induction chemotherapy for over 10 years,” said Professor Klaus Geissler MD, principal investigator of the ASCERTAIN – AML phase 3 study and head of the Fifth Medical Department, Clinic Hietzing Hospital, Vienna, Austria. “Oral ASTX727 may deliver a treatment alternative for patients with AML which potentially reduces the number of office visits and offers an option for patients to take their medication from the convenience and comfort of their homes.”

Based on the data from the ASCERTAIN clinical program, the oral decitabine and cedazuridine fixed-dose combination is also being investigated in combination with other agents in hematological malignancies. The first of these studies is investigating the all-oral combination of decitabine and cedazuridine with venetoclax for the treatment of AML.

Oral decitabine and cedazuridine fixed-dose combination is approved as INQOVI^® in the U.S. and Canada for the treatment of intermediate and high-risk myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML) and is the only approved oral hypomethylating agent that has demonstrated equivalent exposure to its IV form.

Commercialization of INQOVI in the U.S. and Canada for the above indication is conducted by Taiho Oncology, Inc., and by Taiho Pharma Canada, Inc., respectively. Astex, Otsuka and Taiho are all members of the Otsuka group of companies.

ABOUT THE ASCERTAIN – AML CLINICAL STUDY¹

The ASCERTAIN – AML clinical trial was designed as a randomized crossover study comparing oral decitabine (35mg) and cedazuridine (100mg) 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 infusion for 5 days on a 28-day cycle, in the first 2 cycles in AML patients who were unfit to receive intensive chemotherapy. Patients continued to receive oral decitabine and cedazuridine from cycle 3 onwards. The primary endpoint for the study was total 5-day decitabine area-under-the-curve (AUC) equivalence of oral decitabine and cedazuridine and IV decitabine. See: https://www.clinicaltrials.gov/ct2/show/NCT03306264

ABOUT DECITABINE AND CEDAZURIDINE FIXED-DOSE COMBINATION (ASTX727)

ASTX727 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, ASTX727 is designed to allow for oral delivery of decitabine over 5 days in a given cycle to achieve comparable systemic exposure to IV decitabine administered over 5 days.

ASTX727 has been evaluated in a phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study, and a phase 3 exposure equivalence study in patients with MDS and CMML. The phase 1 and phase 2 clinical study results have been published in Lancet Haematology⁴ and Blood,⁵ respectively, and the phase 3 results have been presented at the American Society of Hematology Annual Meeting in December 2019⁶ and the International Congress on Myelodysplastic Syndromes in September 2021.⁷

Astex is also expanding the evaluation of decitabine - cedazuridine combinations through a program of investigator-sponsored trials.

ASTX727 is an investigational compound and is not currently approved in any country other than the U.S., Canada, and Australia.

The EHA abstract can be downloaded from the EHA website at: https://library.ehaweb.org/eha/2022/eha2022-congress/357436.

Learn more about INQOVI at https://www.inqovi.com

INDICATIONS

In the U.S., INQOVI (decitabine and cedazuridine) 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.⁸

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%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

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 (55%), constipation (44%), hemorrhage (43%), myalgia (42%), mucositis (41%), arthralgia (40%), nausea (40%), dyspnea (38%), diarrhea (37%), rash (33%), dizziness (33%), febrile neutropenia (33%), edema (30%), headache (30%), cough (28%), decreased appetite (24%), upper respiratory tract infection (23%), pneumonia (21%), and transaminase increased (21%). The most common Grade 3 or 4 laboratory abnormalities (>50%) were leukocytes decreased (81%), platelet count decreased (76%), neutrophil count decreased (71%), and hemoglobin decreased (55%).

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 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.

ABOUT ACUTE MYELOID LEUKEMIA (AML)

AML is the most common form of acute leukemia in adults.⁹ An estimated 20,050 new cases of AML are projected to be diagnosed in the U.S. in 2022¹⁰ and an estimated 11,540 patients are projected to die from AML in the US in 2022.^10. 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,¹¹ 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.^11-13. These figures have not significantly improved during the last three decades. These patients have few therapeutic options available.^14-15. 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 remission induction chemotherapy, thus denying them a potentially curative transplant.¹³

ABOUT ASTEX PHARMACEUTICALS AND OTSUKA PHARMACEUTICAL

Astex Pharmaceuticals, Inc. is committed to the fight against cancer. Astex is developing a proprietary pipeline of novel therapies for the treatment of solid tumors and hematological malignancies. Astex is a member of the Otsuka group of companies. The group also includes Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Taiho Oncology, Inc. Subject to regulatory approvals, Astex’s products will be commercialized in the U.S. and Canada by Taiho subsidiaries, and in the rest of the world by Otsuka subsidiaries.

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://www.astx.com

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

Astex, the Astex logo, Otsuka, and INQOVI are registered trademarks of Otsuka Holdings Co., Ltd. or its subsidiaries.

References

1. Geissler K, Koristek Z, Castillo T, et al. Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross Over Phase 3 Study of an Oral Hypomethylating Agent DEC-C Compared to IV Decitabine in AML Patients. 2022; HemaSphere 2022; 6:S3. Abstract P573.
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 2526]. Blood 2013;122(21):2526.
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6. Garcia-Manero G, McCloskey J, Griffiths EA, et al. Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Crossover Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine. Blood. 2019; 134(Supplement_1): 846. doi.org/10.1182/blood-2019-122980.
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8. INQOVI Prescribing Information. www.inqovi.com/pi
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14. 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):1127-1138. doi:10.1007/s00277-015-2351-x.
15. Wang R, Zeidan AM, Halene S, 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. doi:10.1200/JCO.2017.72.7149.

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