Oral Decitabine and Cedazuridine (ASTX727) Granted Orphan Drug Designation (ODD) by the European Commission for the Treatment of Acute Myeloid Leukemia (AML)

PLEASANTON, Calif.--(BUSINESS WIRE)-- Astex Pharmaceuticals, Inc. (“Astex”) announces today that the European Commission (EC) has granted orphan-drug designation (ODD) to the oral fixed dose combination of decitabine and cedazuridine (ASTX727) for the treatment of Acute Myeloid Leukemia (AML)¹.

ODD is granted by the EC to medicinal products intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating and which affects fewer than five in 10,000 people in the European Union (EU)². The EC incentivises companies to develop medicines that provide significant benefit to those affected by rare conditions. ODD-granted therapies, such as ASTX727, entitle companies to 10 years of market exclusivity once the product is approved, among other benefits². The ODD initiative plays a key role in facilitating and encouraging the development of these important medicines to potentially improve the lives of the 30 million people in the EU suffering from a rare disease².

“The granting of ODD is a key and important step in the journey toward finding a new treatment option for patients with AML,” said Andy Hodge, CEO of Otsuka Pharmaceutical Europe Ltd., Astex’s commercialization partner in Europe. “We will continue to collaborate with all key stakeholders, including the EC, to make this treatment available to patients in need.”

Harold Keer MD, PhD, Chief Medical Officer of Astex Pharmaceuticals, Inc. said “AML continues to be a challenging disease area with high rates of relapse and low rates of five-year survival. The disease has a higher incidence rate in people aged over 60 years, which presents an important challenge as the population ages. The granting of ODD signifies that ASTX727 is considered to be a medicine that may potentially benefit those affected by this rare life-threatening condition.”

ASTX727 is not approved for any indication in Europe and is not approved in any country for the treatment of AML.

About ASTX727

ASTX727 is an orally administered, fixed-dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine, an inhibitor of cytidine deaminase (CDA)^{3, 4}. By inhibiting CDA in the gut and the liver, ASTX727 is designed to allow for oral delivery of decitabine over five days in a given cycle⁵. The phase 1 and phase 2 clinical study results have been published in Lancet Haematology and Blood, respectively^{5, 6}.

ASTX727, under the brand name INQOVI^®, is approved in the U.S. and in Canada as follows:

U.S. and Canada Indications

INQOVI (decitabine and cedazuridine) tablets, for oral use, is approved 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 groups⁷.

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, 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

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

In Europe, ASTX727 is currently being evaluated within the ASCERTAIN phase 3 trial (EudraCT Number: 2018-003395-12) for the treatment of Acute Myeloid Leukemia (AML)⁸.

About Acute Myeloid Leukemia (AML)

AML is the most common form of acute leukemia in adults⁹. The median age at diagnosis is 70 years¹⁰. Within Europe, there is an increase in incidence of AML; 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 people in 2013¹⁰. Across Europe and all age groups, AML is notably more common in males than it is in females¹⁰. 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 over 65 years-old was 17%¹⁰. After two courses of intensive induction therapy, 10 to 20% of younger and 50% of older AML patients do not achieve complete response (CR). While those that do obtain CR, 50-70% of these patients will relapse. Following relapse, prognosis for the patients is poor and treatment is challenging, with few therapeutic options available¹⁰.

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 tumours and hematological malignancies. In October 2013 Astex became a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan.

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 Europe employs approximately 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 €11.7 billion and a spend of €1.8 billion on research and development in 2020.

For further information on Otsuka Pharmaceutical Europe Ltd., please visit www.otsuka-europe.com.

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

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

References

1. 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 December 2021].
2. Orphan Drug Designation. European Medicines Agency (EMA). Available from: https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designation-overview [Last accessed December 2021].
3. Oganesian A, Redkar S, Taverna P, et al. 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]. 2013; 122(21): Abstract 2526.
4. 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;57:2582-8.
5. 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:e194-e203.
6. Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136:674-683.
7. INQOVI Prescribing Information. Available from: https://inqovi.com/pi [Last accessed December 2021].
8. EU Clinical Trials Register. Study of ASTX727 vs IV Decitabine in MDS, CMML, and AML. Available from: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003395-12 [Last accessed December 2021].
9. De Kouchkovsky I and Abdul-Hay M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update’. Blood Cancer J. 2016;6:e441.
10. 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;31:697-712.

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