European Medicines Agency Commences Review of Oral Fixed-Dose Combination of Decitabine and Cedazuridine for the Treatment of Adults with Acute Myeloid Leukemia

PLEASANTON, Calif.--(BUSINESS WIRE)--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 leukemia (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)

ASTX727 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 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^11,12.

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 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 full Prescribing Information.

Commercialization of INQOVI in the U.S. and Canada is conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc., respectively.

OTHER APPROVALS

INQOVI^® is also 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 leukemia (AML)

AML is the most common form of acute leukemia 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 aging 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.

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

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2.	Benefits of AML Maintenance Therapy Extend to Quality of Life and Hospitalization. Oncologist. 2021;26 Suppl 1:S11-S12. doi:10.1002/onco.13653.
3.	Geissler K, Koristek Z, Bernal del Castillo T, et al. 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. HemaSphere, 2022;6:(S3):910-911.
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5.	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. doi.org/10.1182/blood.V122.21.2526.2526.
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; 57:2582-2588. doi:10.1021/jm401856k.
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. doi:10.1016/S2352-3026(19)30030-4.
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. doi:10.1182/blood.2019004143.
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. Blood. 2019; 134(Supplement_1): 846. doi.org/10.1182/blood-2019-122980.
10.	Savona M, McCloskey J, Griffiths E, et al. Current treatment options - hypomethylating agents: prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine. Leukemia Research, Volume 108, Supplement, 2021. doi.org/10.1016/j.leukres.2021.106681.47.
11.	INQOVI Prescribing Information (US).
12.	INQOVI Prescribing Information (Canada).
13.	INQOVI Prescribing Information (Australia).
14.	De Kouchkovsky I and Abdul-Hay M. 'Acute myeloid leukemia: a comprehensive review and 2016 update'. Blood Cancer J. 2016;6:e441. doi:10.1038/bcj.2016.50.