Pharma Focus Europe

Otsuka and Astex Secure European Commission Approval for INAQOVI® in the Treatment of Newly Diagnosed Acute Myeloid Leukemia in Adults

Wednesday, September 20, 2023

Otsuka Pharmaceutical Europe Ltd. (Otsuka) and Astex Pharmaceuticals, Inc. (Astex) have jointly announced that the European Commission (EC) has granted approval for INAQOVI® as a monotherapy for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for standard induction chemotherapy. The EC's approval extends to the European Economic Area (EEA), comprising EU member states, Iceland, Liechtenstein, and Norway. Notably, INAQOVI® is the first and only oral hypomethylating agent licensed for this patient population in the EEA.

The decision from the EC is founded on the results of the Phase 3 ASCERTAIN clinical trial, which assessed the pharmacokinetic exposure equivalence of the novel oral fixed-dose combination versus intravenous (IV) decitabine in AML patients. The ASCERTAIN study successfully met its primary endpoint, demonstrating that the orally administered decitabine and cedazuridine fixed-dose combination exhibited pharmacokinetic exposure equivalent 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 expected for IV decitabine.

Currently, treatment options for adults with AML include hospital-administered IV chemotherapy infusions or, for those ineligible for chemotherapy, regimens involving parenterally administered hypomethylating agents, typically lasting 5-7 days. Fatigue can significantly impact daily activities and a patient's quality of life. INAQOVI® may offer both patients and physicians an oral treatment option in this patient population.

On June 10, 2022, the European Medicines Agency (EMA) approved a Paediatric Investigation Plan for the oral decitabine and cedazuridine fixed-dose combination, marking an important milestone for advancing clinical studies in children with AML.

INAQOVI® is an orally administered, fixed-dose combination of the approved hypomethylating agent (HMA), decitabine (35 mg), along with cedazuridine (100 mg), an inhibitor of cytidine deaminase. By inhibiting cytidine deaminase in the gut and liver, the fixed-dose combination is designed to allow for oral daily administration of decitabine over 5 days in a given cycle to achieve comparable systemic exposure to IV decitabine administered with the same dosing regimen.

In the Phase 3 ASCERTAIN study, a total of 89 AML patients were randomized 1:1 to receive INAQOVI® (35 mg decitabine and 100 mg cedazuridine) orally in Cycle 1 and decitabine (20 mg/m2) intravenously in Cycle 2 or the reverse sequence. Both INAQOVI® and IV decitabine were administered once daily on Days 1 through 5 of the 28-day cycle. Starting with Cycle 3, all patients received INAQOVI® orally once daily on Days 1 through 5 of each 28-day cycle until disease progression, death, or unacceptable toxicity.

Primary endpoint results showed that patients receiving INAQOVI® achieved pharmacokinetic exposure equivalence of 99.64% to IV decitabine given at 20 mg/m2 for 5 days with a similar pharmacodynamic activity. Secondary findings showed a Median Overall Survival of 7.9 months and a Complete Response rate of 21.8% at 7.95 months median follow-up.

The most common adverse drug reaction (≥ 20%) was thrombocytopenia. The most common serious adverse reactions (≥ 20%) were febrile neutropenia and pneumonia. Permanent discontinuation occurred in 14% of patients while on treatment, with pneumonia being the most frequent adverse reaction resulting in permanent discontinuation (5%).

AML is the most common form of acute leukemia in adults. The median age at diagnosis is approximately 70 years. In Europe, the incidence of AML is increasing, potentially due to an aging population, with AML incidence rising from 3.48 in 1976 to 5.06 patients per 100,000 population in 2013. Across Europe and all age groups, AML is notably more common in males than in females. While outcomes for patients diagnosed with AML have improved over time due to improved care and treatment, between the years of 2000 and 2007, the 5-year survival rate for patients was just 17%.

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