LONDON, UK, and PLEASANTON, CA, USA Otsuka Pharmaceutical Europe Ltd. (Otsuka) and Astex Pharmaceuticals, Inc. (Astex) today announce that the European Medicines Agency (EMA) has accepted the Marketing Authorisation Application (MAA) for the oral fixed-dose combination of decitabine and cedazuridine (ASTX727) for the initial treatment of adults with acute myeloid leukaemia (AML) who are not candidates for standard induction chemotherapy.

The current standard of care for AML is hospital-administered intravenous (IV) chemotherapy infusions or, for those patients not eligible for chemotherapy, parenterally administered hypomethylating agents, with treatment cycles typically extending for a week or more¹. Fatigue can significantly restrict daily activities and reduce health-related quality of life². If approved, oral decitabine and cedazuridine would be the first and only oral hypomethylating agent licensed in the European Economic Area (EEA) for the initial treatment of adults with AML who are ineligible for intensive chemotherapy, offering a potentially more convenient administration regimen.

The MAA is supported by results from the Phase 3 ASCERTAIN clinical trial investigating the pharmacokinetic (PK) exposure equivalence of the novel oral fixed-dose combination versus IV decitabine³.

The ASCERTAIN study met its primary endpoint, with the orally administered decitabine and cedazuridine fixed-dose combination showing exposure equivalence to a standard 5-day regimen of IV decitabine using a two-cycle cross-over study design. Safety findings for the fixed-dose combination of decitabine and cedazuridine were generally consistent with those anticipated for IV decitabine³.

In December 2021, the oral decitabine and cedazuridine fixed-dose combination was granted orphan drug designation by the European Commission which entitles companies to ten years of market exclusivity once the product is approved in the EU⁴. This status signifies that the oral decitabine and cedazuridine fixed-dose combination is considered to be a medicine that may potentially benefit those affected by this rare, life-threatening condition. In April 2022, the EMA agreed to a Paediatric Investigation Plan (PIP) in the EU for the oral decitabine and cedazuridine fixed-dose combination, representing an important milestone for the prospect of furthering clinical studies in children with AML. If granted, a paediatric extension would add a further two years of market exclusivity.

About decitabine and cedazuridine fixed-dose combination (ASTX727)

It is an orally administered, fixed dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine⁵, an inhibitor of cytidine deaminase⁶. By inhibiting cytidine deaminase in the gut and the liver, the fixed dose combination is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine administered over five days.

The oral decitabine and cedazuridine fixed-dose combination 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 myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) - the ASCERTAIN study. The ASCERTAIN study was expanded to include AML patients who were not candidates for standard induction chemotherapy. The Phase 1 and Phase 2 clinical study results have been published in Lancet Haematology⁷ and Blood⁸ respectively, and the Phase 3 results have been presented at the American Society of Hematology Annual Meeting in December 2019⁹, the International Congress on Myelodysplastic Syndromes in September 2021¹⁰, and the European Hematology Association Annual Congress in June 2022³.

Indications

Oral decitabine and cedazuridine fixed-dose combination is approved under the brand name INQOVI^® in the U.S. and Canada for the 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 anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts, and chronic myelomonocytic leukaemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups^11,12. INQOVI^® is approved in Australia for the treatment of adult patients with MDS intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups, and patients with CMML¹³.

About acute myeloid leukaemia (AML)

AML is the most common form of acute leukaemia in adults¹⁴. The median age at diagnosis is approximately 70 years¹. Within Europe, the incidence of AML is increasing; this may be attributed to the ageing population: AML incidence in Europe has risen from 3.48 in 1976 to 5.06 patients per 100,000 population in 2013¹. Across Europe and all age groups, AML is notably more common in males than it is in females¹. The outlook for patients diagnosed with AML has improved over time due to improved care and treatment, however between the years of 2000 and 2007, five-year survival for patients was just 17%¹.

About Otsuka

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 products, focusing on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs in several under-addressed diseases including tuberculosis, a significant global public health issue.

Otsuka Pharmaceutical in Europe employs over 500 people and focuses on psychiatric and neurologic disorders, infectious disease, nephrology, oncology, and digital medicines. Otsuka Pharmaceutical Europe Ltd. is a part of Otsuka Pharmaceutical Company, Ltd., a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan.

The Otsuka group of companies employed 47,000 people worldwide with consolidated sales of approximately €11.6 billion and a spend of €1.8 billion on research and development in 2021.

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

About Astex

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 commercialised in the U.S. and Canada by Taiho subsidiaries, and in the rest of the world by Otsuka subsidiaries.

References

1. Heuser M, Ofran Y, Boissel N, et al. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(6):697-712.
2. Benefits of AML Maintenance Therapy Extend to Quality of Life and Hospitalization. Oncologist. 2021;26 (Suppl 1):S11-S12.
3. Geissler K, Koristek Z, Bernal del Castillo T, et al. Pharmacokinetic exposure equivalence and preliminary efficacy and safety from a randomized crossover Phase 3 study of an oral hypomethylating agent, ASTX727 (DEC-C), compared to IV decitabine in AML patients. Poster presented at EHA Annual Meeting, Vienna, Austria June 9 - 12, 2022. Abstract P573.
4. Community Register of orphan medicinal products. European Commission (EC). Available from: https://ec.europa.eu/health/documents/community-register/html/reg_od_act.htm?sort=a [Last accessed July 2022].
5. Oganesian A, Redkar S, Taverna P, et al. Preclinical Data in Cynomolgus Monkeys of ASTX727, a novel oral hypomethylating agent (HMA) composed of low-dose oral decitabine combined with a novel Cytidine Deaminase Inhibitor (CDAi) E7727. Poster presented at ASH Annual Meeting, New Orleans, LA, December 7-10, 2013. Abstract 2526.
6. Ferraris D, Duvall B, Delahanty G, et al. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014; 57(6):2582-2588.
7. Savona MR, Odenike O, Amrein PC, 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. 2019;6(4):e194-e203.
8. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMM: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study. Blood. 2020; 136(6):674-683.
9. 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. Presented at 61^st American Sociaty of Hematology (ASH) Annual Meeting, Orlando, FL. Dec 7-10, 2019. Abstract 846.
10. Savona M, McCloskey J, Griffiths E, et al. Prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine. Poster presented at 16^th International Congress on Myelodysplastic Syndromes (MDS), virtual meeting, September 23-26, 2021. Abstract P48.
11. INQOVI Prescribing Information (US), July 2020.
12. INQOVI Product Monograph (Canada), July 2020.
13. INQOVI Prescribing Information (Australia), January 2021.
14. De Kouchkovsky I and Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J. 2016;6(7):e441.