Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT Amsterdam, Netherlands
Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, pyrimidine analogues; cytidine deaminase inhibitor
ATC code: L01BC58
Decitabine is a nucleoside metabolic inhibitor that is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA.
Cytidine deaminase (CDA) is an enzyme that is responsible for the degradation of cytidine nucleosides, including the cytidine analog decitabine. High levels of CDA in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability. Cedazuridine inhibits CDA. Oral administration of cedazuridine with decitabine increases the systemic exposure of decitabine via inhibition of first pass metabolism of decitabine in the gut and liver by CDA.
Inaqovi was evaluated in a Phase 3 (ASTX727-02-EU, NCT03306264) open-label, randomised, 2-cycle, 2-sequence crossover study that included adult patients with de novo or secondary AML as defined by World Health Organisation (WHO) criteria, who were not candidates for standard induction chemotherapy. A total of 89 patients were randomised 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 (n=44) or the reverse sequence (n=45). Both Inaqovi and intravenous 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. Two of the patients randomised did not receive any study treatment and fifteen were treated in Cycle 1 alone: 8 with Inaqovi, and 7 with intravenous decitabine.
The median treatment duration was 5 months (range 0 to 18 months).
Demographic and baseline disease characteristics are shown in Table 3.
Table 3. Demographic and disease baseline characteristics (Phase 3):
| Characteristic | Phase 3 Inaqovi (N=89) |
|---|---|
| Age (years) | |
| Median (min, max) | 78 (61, 92) |
| Gender (%) | |
| Male | 54 (60.7) |
| Female | 35 (39.3) |
| ECOG Performance Score (%) | |
| 0 | 36 (40.4) |
| 1 | 53 (59.6) |
| Disease Category (%) | |
| de novo AML | 57 (64.0) |
| Secondary AML | 32 (36.0) |
| MDS | 18 (20.2) |
| Other antecedent haematological disorder | 7 (7.9) |
| Therapy-related AML | 7 (7.9) |
| Prior HMA Therapy (%) | |
| Prior azacitidine | 2 (2.2) |
| Transfusion Dependencea (%) | |
| RBC transfusion dependence | 37 (41.6) |
| Platelet transfusion dependence | 14 (15.7) |
a Defined as documentation of ≥2 units of transfusion within 56 days of the first day of study treatment.
AML=acute myeloid leukaemia; ECOG=Eastern Cooperative Oncology Group; HMA=hypomethylating agent; MDS=myelodysplastic syndrome; RBC=red blood cell.
The primary outcome measure of the Phase 3 study was 5-day cumulative decitabine AUC between Inaqovi and intravenous decitabine. Inaqovi achieved AUC0-24h exposures equivalent to intravenous infusion of decitabine at 20 mg/m² (see section 5.2).
Secondary efficacy endpoints included complete response (CR) and the rate of conversion from transfusion dependence to transfusion independence. Descriptive summaries of efficacy are shown in Table 4.
Table 4. Efficacy results in patients with AML study ASTX727-02-EU AML (Phase 3):
| Efficacy endpoints | Inaqovi (N=89) |
|---|---|
| Complete response (%) [95% CI] | 21 [13.4, 31.3] |
| Median duration of CR* - months [95% CI] | 5.8 [3.3, NE] |
| Median time to CR – months [range] | 3.0 [1.8, 7.4] |
| Overall response† (%) [95% CI] | 32 [22.0, 42.2] |
* From start of CR until relapse or death
† OR included patients with a best response of CR, CRi, and PR
CI=confidence interval; CR=complete response; NE=not evaluable; OR=overall response; PR=partial response.
A patient was considered transfusion independent if the patient was both RBC and platelet transfusion free post-treatment for ≥56 consecutive days. Among a total of 41 patients (out of the 87 treated patients) who were dependent on either RBC and/or platelet transfusions at baseline, 14 (34%) became independent of RBC or platelet transfusions during any 56-day post-baseline period. Of the 46 patients who were independent of both RBC and platelet transfusions at baseline, 12 (26%) remained transfusion-independent during any 56-day post-baseline period.
The obligation to submit the results of studies with Inaqovi in one or more subsets of the paediatric population in AML has been deferred by the European Medicines Agency. See section 4.2 for information on paediatric use.
The pharmacokinetic (PK) parameters of decitabine and cedazuridine were studied following administration of Inaqovi at the recommended dose in patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML), and AML.
Decitabine AUC exposures equivalent to those achieved with intravenous infusion of decitabine at 20 mg/m² was achieved with the recommended dose of Inaqovi for 5 consecutive days. The geometric mean ratio (GMR) of 5-day total decitabine AUC0-24h between Inaqovi and intravenous decitabine was 99% for patients with MDS/CMML and 100% for patients with AML (90% confidence interval [CI] 93%, 106% and 91%, 109% for MDS/CMML and AML, respectively).
At steady state (achieved with the second dose), circulating plasma concentrations were typically 1.8 times and 1.1 times the Day 1 plasma concentrations for decitabine and cedazuridine, respectively.
In the MDS population (highest number of subjects available; data from AML were similar), decitabine mean (% coefficient of variation [CV]) AUC0-24h exposure at steady state was 189 (55%) ng×h/mL and Cmax was 145 (55%) ng/mL, respectively. Cedazuridine mean AUC0-24h exposure at steady state (Day 2) was 3290 (45%) ng×h/mL and Cmax was 349 (49%) ng/mL.
After oral administration of Inaqovi, the median time to peak concentration (tmax) at steady state was 3 hours (range: 0.5 to 7.9) for cedazuridine and 1 hour (range: 0.3 to 3) for decitabine. Co-administered with cedazuridine increased decitabine oral relative bioavailability to achieve systemic AUC exposures seen with intravenous decitabine. The bioavailability of cedazuridine was 20.7% (range: 12.7% to 25.6%).
In a crossover food effect study conducted in 16 patients, administration of the medicinal product with a high-fat, high-calorie meal reduced the overall decitabine exposure (AUC) by approximately 40% and Cmax by 54%. Cedazuridine time to maximum concentration (tmax) was slightly delayed but its systemic exposure was not significantly affected by the meal.
Decitabine is approximately 5% bound to human plasma proteins in vitro. The geometric mean (CV%) of apparent volume of distribution at steady state is 417 L (54%).
Cedazuridine is approximately 35% bound to human plasma proteins in vitro. The geometric mean (CV%) of apparent volume of distribution for cedazuridine is 296 L (51%).
Decitabine is metabolised primarily via deamination by cytidine deaminases and also physiochemical degradation at physiological conditions.
The primary metabolic pathway for cedazuridine is conversion to its epimer by physiochemical conversion in GI tract preabsorption.
Following a single oral dose of Inaqovi, the mean (CV%) terminal elimination half-life (t1/2) of decitabine was 1.2 (23%) hours. The apparent oral clearance (CL/F) was 197 L/h at steady state. The main pathway of elimination for decitabine is metabolic/degradation. Metabolites and degradation products are excreted mainly renally.
Following a single oral dose of Inaqovi, the mean (CV%) t1/2 of cedazuridine was 6.3 (18%) hours. The mean (CV%) apparent oral clearance (CL/F) was 25.6 (159%) L/h at steady state.
The two major elimination pathways of cedazuridine are renal elimination as parent drug and conversion to its epimer (which is then renally excreted). Following a single oral dose of 100 mg radiolabeled cedazuridine, 46% (17.1% unchanged) of the administered dose was recovered in urine and 51% was recovered in the faeces.
An approximately dose-proportional increase in peak concentrations (Cmax) and AUC over the dosing interval was observed for decitabine over a dose range from 20 mg to 40 mg in combination with 100 mg cedazuridine.
Exposure for cedazuridine over the dose range evaluated from 40 mg to 100 mg once daily were dose proportional.
Age, sex, body weight, and body surface area did not have a clinically relevant effect on the PK parameters of decitabine or cedazuridine after dosing with Inaqovi.
The PK of decitabine and cedazuridine have not been formally studied in patients with impaired renal function. Patients with normal renal function (N=65) as well as mild (N=129) and moderate (N=103) renal impairment were included in the clinical studies. Renal impairment increases the exposure of cedazuridine (as renal elimination of parent drug is a major elimination pathway) and potentially also increases the exposure of decitabine (due to inhibition of decitabine metabolism caused by increased cedazuridine exposure). Decitabine is mainly metabolised and not excreted renally as unchanged drug. Only three patients with severe renal impairment and no patient with end stage renal disease were included in the studies. See also sections 4.2 and 4.4.
The PK of decitabine and cedazuridine have not been formally studied in patients with hepatic impairment. Very few patients with impaired liver function were included in the clinical studies. Large effects of hepatic impairment on decitabine or cedazuridine exposure are not expected as cedazuridine is not hepatically metabolised and decitabine is metabolised by cytidine deaminase, which is present in several tissues.
Carcinogenicity studies with decitabine, cedazuridine, or their combination have not been conducted.
Decitabine was mutagenic in in vitro and in vivo studies. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies.
Cedazuridine was mutagenic in the reverse bacterial mutation assay (Ames assay) and was genotoxic in the in vitro chromosomal aberration study using human lymphocytes. Cedazuridine was negative for the genotoxicity assessment in three in vivo studies including the mouse micronucleus, Comet assay, and the Pig-A assay.
Fertility and repeat-dose toxicity studies in animals showed adverse outcomes on reproductive function and fertility.
In male mice given intraperitoneal injections of 0.15, 0.3, or 0.45 mg/m² decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, testes weights were reduced, abnormal histology was observed, and significant decreases in sperm number were found at doses ≥0.3 mg/m². In females mated to males dosed with ≥0.3 mg/m² decitabine, pregnancy rate was reduced, and preimplantation loss was significantly increased.
Decitabine was administered orally to male rats at 0.75, 2.5, or 7.5 mg/kg/day in cycles of 5-days-on/23-days-off for a total of 90 days. Low testes and epididymis weights, abnormal histology, and reduced sperm number were observed at doses ≥ 0.75 mg/kg (approximately ≥3 times the exposure in patients at the recommended clinical dose based on AUC).
Cedazuridine was administered orally to male and female mice at 100, 300, or 1,000 mg/kg/day in cycles of 7-days-on/21-days-off for a total of 91 days. Adverse reactions including abnormal histology in the testes, epididymis, and ovaries, as well as reduced sperm numbers were observed at the 1,000 mg/kg dose (approximately 108 times the exposure in patients at the recommended clinical dose). These findings showed evidence of reversibility following 3 weeks off-dose.
Evidence from the literature indicates that decitabine has carcinogenic potential. The available data from in vitro and in vivo studies provide sufficient evidence that decitabine has genotoxic potential. Data from the literature also indicate that decitabine has adverse effects on all aspects of the reproductive cycle, including fertility, embryo-foetal development and post-natal development. Multi-cycle repeat-dose toxicity studies in rats and rabbits indicated that the primary toxicity was myelosuppression, including effects on bone marrow, which was reversible on cessation of treatment. Gastrointestinal toxicity was also observed and in males, testicular atrophy that did not reverse over the scheduled recovery periods.
Decitabine administration to neonatal/juvenile rats showed a comparable general toxicity profile as in older rats. Neurobehavioural development and reproductive capacity were unaffected when neonatal/juvenile rats were treated at dose levels inducing myelosuppression.
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