Summary Basis of Decision for Inqovi

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Inqovi is located below.

Recent Activity for Inqovi

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Inqovi

Date SBD issued: 2020-09-21

The following information relates to the new drug submission for Inqovi.

Decitabine and cedazuridine

Drug Identification Number (DIN):

  • DIN 02501600 - 35 mg decitabine and 100 mg cedazuridine, tablet, oral administration

Otsuka Pharmaceutical Co., Ltd.

New Drug Submission Control Number: 234610

On July 7, 2020, Health Canada issued a Notice of Compliance to Otsuka Pharmaceutical Co., Ltd. for the drug product Inqovi.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Inqovi (decitabine and cedazuridine) is favourable 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) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

1 What was approved?

Inqovi is a fixed-dose combination drug product that contains decitabine, a pyrimidine (cytidine) analogue, and a new molecular entity, cedazuridine, which is a cytidine deaminase inhibitor. It was authorized 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) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

Myelodysplastic syndrome is rare in children. The safety and efficacy of Inqovi have not been studied in patients younger than 18 years of age. Therefore, Inqovi is not indicated for the pediatric population.

Of the 208 patients treated with Inqovi, 75% were 65 years of age and older, whereas 36% were 75 years of age and older. No overall difference in effectiveness and safety of Inqovi was noted between patients 65 years of age and older and younger subjects.

Inqovi is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Inqovi was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Inqovi is presented as a fixed-dose combination oral tablet of decitabine and cedazuridine (35 mg decitabine and 100 mg cedazuridine). In addition to the two medicinal ingredients, the tablet contains colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, and magnesium stearate. The film coating material contains iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Inqovi Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Inqovi approved?

Health Canada considers that the benefit-harm-uncertainty profile of Inqovi is favourable 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) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

Myelodysplastic syndrome (MDS) constitutes a heterogeneous group of hematopoietic stem cell disorders characterized by ineffective, dysplastic hematopoiesis leading to cytopenias. Clinical presentation of MDS includes fatigue, infections, and bleeding. Transformation into acute myeloid leukemia (AML) may occur in 35% to 40% of patients with MDS. The main prognostic classification system for MDS is the International Prognostic Scoring System (IPSS), which was introduced in 1997 and revised in 2012 (IPSS-Revised, IPSS-R). Higher-risk MDS is classified as IPSS-R intermediate-risk (score >3.5), high-risk, and very high-risk MDS, all of which are associated with expected median survival of less than 3.5 years. Higher-risk MDS can be treated in the frontline setting with hypomethylating agents, azacitidine or decitabine.

Chronic myelomonocytic leukemia, previously classified as MDS, is a related hematopoietic disorder characterized by peripheral blood monocytosis. It is currently classified as myelodysplastic/myeloproliferative neoplasm. The treatment approach is similar to that for MDS.

Inqovi is an oral combination of two medicinal ingredients, decitabine (a pyrimidine [cytidine] analogue) and a new molecular entity, cedazuridine (a cytidine deaminase inhibitor). Decitabine for intravenous administration has already been authorized in Canada. Oral administration of cedazuridine with decitabine increases the oral bioavailability of decitabine. Inqovi is to be administered with water on an empty stomach, at approximately the same time each day.

The market authorization of Inqovi was based on evidence derived from two open-label, randomized, 2-cycle, 2-sequence crossover studies: one Phase II (ASTX727-01-B) and one Phase III study (ASTX727-02). The studies were conducted in adult patients with MDS (intermediate-1, intermediate-2, or high-risk IPSS groups), or chronic myelomonocytic leukemia, who were candidates for treatment with a hypomethylating agent. There were 80 patients in the Phase II study. The Phase III study included 133 patients.

Patients were randomized in a ratio of 1:1 to receive Inqovi in cycle 1, and intravenous decitabine (20 mg/m2) in cycle 2, or the reverse treatment sequence. Both Inqovi and intravenous decitabine were administered once daily for 5 days in 28-day cycles. Starting with cycle 3, all patients received Inqovi until disease progression, death, or unacceptable toxicity.

The studies aimed to establish equivalence between Inqovi (administered orally) and intravenous decitabine with respect to the primary pharmacokinetic endpoint, the 5-day cumulative decitabine exposure (area under the plasma concentration versus time curve, AUC). The secondary endpoints were overall response (complete response plus partial response) rate, duration of response, and rate of transfusion independence (no transfusions for at least a 56-day consecutive period) in transfusion dependent patients at baseline.

As measured by the AUC from time zero to 24 hours (AUC0-24), Inqovi achieved exposures equivalent to those observed with intravenous infusion of decitabine at a dose of 20 mg/m2. The ratio of the geometric mean of the 5-day total decitabine AUC0-24 between Inqovi and intravenous decitabine was 99% (90% confidence interval [CI]: 93%, 106%). The two-sided 90% CI was contained entirely within the prespecified bioequivalence range of 80% to 125%.

Efficacy was established based on the complete response rate (as there were no partial responses in both studies) and the rate of conversion from transfusion dependence to transfusion independence.

Overall, the responses seen in the Phase II and Phase III studies were comparable to those achieved with intravenous decitabine at a dose of 20 mg/m2 (a complete response rate of 16% in a historical single-arm trial).

In the Phase II study, the proportion of patients with complete response was 18% (14/80) (95% CI: 10%, 28%). The median duration of complete response was 8.7 months (range: 1.1 to 18.2 months) and the median time to complete response was 4.8 months (range: 1.7 to 10 months). Among the 41 patients who were dependent on red blood cell and/or platelet transfusions at baseline, 20 (49%) became independent of red blood cell and platelet transfusions during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both red blood cell and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day post-baseline period.

In the Phase III study, complete response was observed in 21% of patients (38/133) (95% CI: 15%, 29%). The median duration of complete response equaled 7.5 months (range: 1.6 to 17.5 months) and the median time to complete response was 4.3 months (range: 2.1 to 15.2 months). Of the 57 patients who were dependent on red blood cell and/or platelet transfusions at baseline, 30 (53%) became independent of red blood cell and platelet transfusions during any 56-day post-baseline period. Among the 76 patients who were independent of both red blood cell and platelet transfusions at baseline, 48 (63%) remained transfusion-independent during any 56-day post-baseline period.

The safety profile of Inqovi was evaluated based on pooled safety data from 208 patients (130 patients from the Phase III study and 78 patients from the Phase II study). The majority of patients received 80% or more of the planned doses of Inqovi for most of the treatment cycles. Among the patients treated with Inqovi, 61% received the drug for 6 months or longer and 24% received the drug for over 1 year.

All 208 (100%) patients experienced a treatment-emergent adverse event. In cycle 1, 106 (99%) out of 107 patients treated with Inqovi and 105 (99%) out of 106 patients treated with intravenous decitabine experienced a treatment-emergent adverse event. Overall, treatment-emergent adverse events appeared to be more common in patients treated with Inqovi compared to those receiving intravenous decitabine in the first cycle of therapy. This observation may have been due to imbalances in baseline patient demographics.

In patients treated with Inqovi, the most common treatment-emergent adverse events (occurring with a frequency of at least 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 increased transaminases.

Grade 3 or 4 laboratory abnormalities with a frequency of at least 50% were neutropenia, thrombocytopenia, and anemia. The grade 3 or 4 cytopenias were slightly more pronounced in patients treated with Inqovi during cycle 1 compared to patients treated with intravenous decitabine during cycle 1, with the exception of decreased platelet counts.

Sixty-eight percent of the Inqovi-treated patients experienced serious treatment-emergent adverse events. Among these, events that occurred in over 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%).

Treatment-emergent adverse events that resulted in death in 6% of patients included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

The most common treatment-emergent adverse events that led to dose delays or dose reduction of Inqovi were events related to cytopenias. Permanent treatment discontinuation due to a treatment-emergent adverse event was required for 5% of patients who received Inqovi. The most frequent treatment-emergent adverse events resulting in permanent discontinuation were febrile neutropenia (1%) and pneumonia (1%).

Overall, the safety profile of Inqovi observed in the pooled safety population is consistent with the known safety profile of intravenous decitabine. The risks of neutropenia and thrombocytopenia have been specifically addressed in a Serious Warnings and Precautions box in the Inqovi Product Monograph. Furthermore, based on findings from human and animal data and its mechanism of action, decitabine can cause fetal harm when administered to a pregnant woman. Therefore, the Serious Warnings and Precautions box warns of the potential for fetal harm associated with the use of Inqovi.

The Inqovi Product Monograph also lists the adverse reactions that have been identified during post-approval use of decitabine administered intravenously: differentiation syndrome, anaphylactic reactions and enterocolitis with fatal outcome, and interstitial lung disease.

A Risk Management Plan (RMP) for Inqovi was submitted by Otsuka Pharmaceutical Co., Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Inqovi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name, Inqovi, was accepted.

Based on non-clinical and clinical studies, Inqovi has been shown to have a favourable benefit-harm-uncertainty profile for the intended patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Inqovi Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Inqovi?

The New Drug Submission (NDS) for Inqovi was reviewed under Project Orbis. Project Orbis provides a framework for concurrent submission and review of oncology products as well as information sharing among regulators from multiple national jurisdictions. Health Canada, the United States Food and Drug Administration (FDA), and the Australian Therapeutic Goods Administration (TGA) participated in the review of the NDS for Inqovi. Although the review of the submission was collaborative, each jurisdiction made their regulatory decision independently. The Canadian regulatory decision on the review of Inqovi was based on a critical assessment of the data package submitted to Health Canada. The comments from multidisciplinary teams of foreign regulatory agencies were used as added references.

Submission Milestones: Inqovi

Submission MilestoneDate
Pre-submission meeting2018-11-15
Submission filed2019-12-31
Screening
Screening Deficiency Notice issued2020-01-22
Response filed2020-01-24
Screening Acceptance Letter issued2020-01-27
Review
Review of Risk Management Plan complete2020-06-10
Quality Evaluation complete2020-06-26
Biopharmaceutics Evaluation complete2020-07-06
Clinical/Medical Evaluation complete2020-07-06
Labelling Review complete, including Look-alike Sound-alike brand name assessment2020-07-06
Notice of Compliance issued by Director General, Therapeutic Products Directorate2020-07-07

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Inqovi?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Inqovi. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Inqovi is an oral combination of two medicinal ingredients, decitabine, a pyrimidine (cytidine) analogue, and a new molecular entity, cedazuridine, which is a cytidine deaminase inhibitor. Decitabine for intravenous administration has already been authorized in Canada.

Decitabine is a nucleoside metabolic inhibitor that is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into deoxyribonucleic acid (DNA) and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis.

The new molecular entity, cedazuridine, inhibits cytidine deaminase, an enzyme responsible for the degradation of cytidine nucleosides, including the cytidine analog decitabine. High levels of cytidine deaminase in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability. Oral administration of cedazuridine with decitabine increases the oral bioavailability of decitabine via inhibition of first pass metabolism of decitabine in the gut and liver by cytidine deaminase.

Cedazuridine is primarily metabolized by conversion to cedazuridine epimer in the gastrointestinal tract prior to absorption. The sum of cedazuridine, its epimer and the metabolite M266/1 accounted for 99% of drug-related material in circulation.

The predominant elimination pathway of cedazuridine is renal, as the parent drug and its epimer. Following intravenous administration of 14C-cedazuridine, 80.9% of the total radioactivity was recovered in the urine and 0.6% was recovered in the feces. After a single oral dose of 100 mg radiolabelled cedazuridine, 45.7% (17.1% as unchanged cedazuridine) of the administered dose was recovered in urine and 51.2% (mostly unabsorbed drug, 27.3% unchanged) was recovered in the feces.

Following administration of Inqovi, decitabine exposure on day 1 was 40% less compared to that after administration of the intravenous decitabine. Steady-state exposures for both cedazuridine and decitabine were reached on day 2 of dosing with Inqovi. The recommended dosage of Inqovi for five consecutive days achieved decitabine exposures (area under the plasma concentration versus time curve, AUC) equivalent to those achieved with intravenous infusion of decitabine at a dose of 20 mg/m2.

In patients administered the recommended five consecutive daily doses of Inqovi, the mean of maximal reduction from baseline of the long interspersed nucleotide elements-1 (LINE-1) demethylation was observed at day 8, with less than complete recovery of LINE-1 methylation to baseline at the end of the treatment cycle.

According to an exposure-safety analysis of selected adverse events in patients enrolled in the Phase II (ASTX727-01-B) and Phase III (ASTX727-02) studies (described in the Clinical efficacy section), increases in decitabine exposure are associated with increased risks of neutropenia and thrombocytopenia.

A dedicated study to evaluate the QT prolongation potential of Inqovi has not been conducted.

A population pharmacokinetic analysis indicated that mild hepatic impairment did not have a clinically meaningful effect on the pharmacokinetics of decitabine or cedazuridine following oral administration of Inqovi. The effects of moderate and severe hepatic impairment on the pharmacokinetics of decitabine and cedazuridine are unknown.

Based on the population pharmacokinetic analysis, mild or moderate renal impairment increased cedazuridine exposures, measured as the AUC from time zero to 24 hours (AUC0-24), by 1.2-fold and 1.4-fold, respectively. Decitabine 5-day cumulative exposures were increased by 1.4-fold and 1.8-fold, respectively. Increases in decitabine exposure in patients with moderate renal impairment were associated with increased toxicity. Accordingly, frequent monitoring for adverse reactions is recommended in patients with moderate renal impairment. The effects of severe renal impairment or end-stage renal disease on the pharmacokinetics of decitabine and cedazuridine are unknown.

According to the population pharmacokinetic analysis, decitabine and cedazuridine exposures were affected by body weight, age, and gender, following oral Inqovi administration. Decitabine 5-day cumulative exposures increased by 1.3-fold in patients with lower baseline body weight (<70 kg) and decreased by 24.1% in patients with higher baseline body weight (>93 kg). Cedazuridine AUC0-24 decreased by 21.3% in patients with higher baseline body weight (>93 kg). The 5-day cumulative exposures for decitabine were 1.4-fold greater and the AUC0-24 for cedazuridine was 1.2-fold greater in patients aged above 75 years. Cedazuridine AUC0-24 and decitabine 5-day cumulative exposures were 1.2-fold and 1.6-fold greater in female patients.

About 42% of subjects treated with Inqovi had taken gastric pH modifying drugs at some point during the clinical studies. Gastric pH modifying drugs, including proton pump inhibitors, can potentially affect the rate of conversion of cedazuridine into its much less active epimer. Based on the population pharmacokinetic analysis, no effect on cedazuridine or decitabine pharmacokinetics was shown with proton pump inhibitors administered after 4 hours of Inqovi administration.

Drug-drug interaction studies were not conducted with decitabine or cedazuridine. Given that cedazuridine is a cytidine deaminase inhibitor, concomitant administration of Inqovi and drugs metabolized by this enzyme may result in increased systemic exposure with potential for increased toxicity of these drugs. Therefore, coadministration of Inqovi with drugs metabolized by cytidine deaminase should be avoided.

For further details, please refer to the Inqovi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The evidence to support authorization of Inqovi stems from two open-label, randomized, 2-cycle, 2-sequence crossover studies: one Phase II (ASTX727-01-B) and one Phase III study (ASTX727-02).

The studies were conducted in adult patients with myelodysplastic syndrome (MDS) (International Prognostic Scoring System [IPSS] intermediate-1, intermediate-2, or high-risk level), or chronic myelomonocytic leukemia, who were candidates for treatment with a hypomethylating agent. Other eligibility criteria included the Eastern Cooperative Oncology Group performance status score of 0 to 2. There were 80 patients in the Phase II study. The Phase III study included 133 patients.

Patients were randomized in a ratio of 1:1 to receive Inqovi in cycle 1 and intravenous decitabine (20 mg/m2) in cycle 2, or the reverse treatment sequence. Randomization was stratified by IPSS risk level in the Phase II study, whereas no stratification was performed in the Phase III study. Both Inqovi and intravenous decitabine were administered once daily for 5 days in 28-day cycles. Starting with cycle 3, all patients received Inqovi until disease progression, death, or unacceptable toxicity. In the Phase II study, the median follow-up time of patients was 24 months (range: 12 to 28.8 months) and the median treatment duration was 6.6 months (range: <0.1 to 28 months). Twelve (15%) of the 80 patients went on to stem cell transplantation following treatment with Inqovi. The Phase III study had a median follow-up time of 12.6 months (range: 9.3 to 20.5 months) and a median treatment duration of 8.2 months (range: 0.2 to 19.7 months). Twenty-seven (20%) of the 133 patients went on to stem cell transplantation following Inqovi treatment.

The studies aimed to establish equivalence between Inqovi (administered orally) and intravenous decitabine with respect to the primary pharmacokinetic endpoint, the 5-day cumulative decitabine exposure (AUC). The secondary endpoints were overall response (complete response plus partial response) rate, duration of response, and rate of transfusion independence (no transfusions for at least a 56-day consecutive period) in transfusion dependent patients at baseline.

As measured by the AUC from time zero to 24 hours (AUC0-24), Inqovi achieved decitabine exposures equivalent to those observed with intravenous infusion of decitabine at a dose of 20 mg/m2. The ratio of the geometric mean of the 5-day total decitabine AUC0-24 between Inqovi and intravenous decitabine was 99% (90% confidence interval [CI]: 93%, 106%). The two-sided 90% CI was contained entirely within the prespecified bioequivalence range of 80% to 125%.

Efficacy was established based on the complete response rate (as there were no partial responses in both studies) and the rate of conversion from transfusion dependence to transfusion independence.

In the Phase II study, the proportion of patients with complete response was 18% (14/80) (95% CI: 10%, 28%). The median duration of complete response was 8.7 months (range: 1.1 to 18.2 months) and the median time to complete response was 4.8 months (range: 1.7 to 10 months). Among the 41 patients who were dependent on red blood cell and/or platelet transfusions at baseline, 20 (49%) became independent of red blood cell and platelet transfusions during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both red blood cell and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day post-baseline period.

In the Phase III study, complete response was observed in 21% of patients (38/133) (95% CI: 15%, 29%). The median duration of complete response equaled 7.5 months (range: 1.6 to 17.5 months) and the median time to complete response was 4.3 months (range: 2.1 to 15.2 months). Of the 57 patients who were dependent on red blood cell and/or platelet transfusions at baseline, 30 (53%) became independent of red blood cell and platelet transfusions during any 56-day post-baseline period. Among the 76 patients who were independent of both red blood cell and platelet transfusions at baseline, 48 (63%) remained transfusion-independent during any 56-day post-baseline period.

Overall, the responses seen in the Phase II and Phase III studies were comparable to those achieved with intravenous decitabine at a dose of 20 mg/m2 (a complete response rate of 16% in a historical single-arm trial).

Indication

The New Drug Submission for Inqovi was filed by the sponsor with the following indication:

  • Inqovi is indicated for treatment of adult patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System (IPSS) groups.

The French-American-British classification subtype of a myelodysplastic syndrome with refractory anemia with excess blasts in transformation is currently categorized according to the newer World Health Organization classification as acute myeloid leukemia. Therefore, it was excluded from the initially proposed indication. Accordingly, Health Canada approved the following indication:

  • Inqovi (decitabine and cedazuridine) is indicated for 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 (IPSS) groups.

For more information, refer to the Inqovi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Inqovi was evaluated based on pooled safety data from 208 patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. The pooled patient population included 130 patients from one Phase III study (ASTX727-02) and 78 patients from one Phase II study (ASTX727-01-B). Both studies are described in the Clinical Efficacy section.

The majority of patients received 80% or more of the planned doses of Inqovi for most of the treatment cycles. Among the patients treated with Inqovi, 61% received the drug for 6 months or longer and 24% received the drug for over 1 year.

All 208 (100%) patients experienced a treatment-emergent adverse event. In cycle 1, 106 (99%) out of 107 patients treated with Inqovi and 105 (99%) out of 106 patients treated with intravenous decitabine experienced a treatment-emergent adverse event.

Overall, treatment-emergent adverse events appeared to be more common in patients treated with Inqovi compared to those receiving intravenous decitabine in the first cycle of therapy. This observation may have been due to imbalances in the baseline patient demographics.

The most common treatment-emergent adverse events (occurring with a frequency of at least 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 increased transaminases.

Two cases of grade 2 acute febrile neutrophilic dermatosis (also known as Sweet's syndrome) were reported (one patient in each trial).

Three patients (1%) in the pooled patient population experienced increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values that were over three times the upper limits of normal (ULN), combined with an increased total bilirubin values of two or more times the ULN and an increased alkaline phosphatase value of lower than two times the ULN. The review of all of the potential Hy's law cases ruled out drug-induced liver injury based on plausible alternative causes.

Grade 3 or 4 laboratory abnormalities with a frequency of at least 50% were neutropenia, thrombocytopenia, and anemia. The grade 3 or 4 cytopenias were slightly more pronounced in patients treated with Inqovi during cycle 1 compared to patients treated with intravenous decitabine during cycle 1, with the exception of decreased platelet counts.

Sixty-eight percent of the Inqovi-treated patients experienced serious treatment-emergent adverse events. Among these, events that occurred in over 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%).

Treatment-emergent adverse events that resulted in death in 6% of patients included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

The most common treatment-emergent adverse events that led to dose delays or dose reduction of Inqovi were events related to cytopenias.

Treatment-emergent adverse events leading to dose delays occurred in 86 (41%) patients, including seven (7%) patients treated with Inqovi and nine (8%) patients treated with intravenous decitabine during cycle 1.

Dose reductions due to treatment-emergent adverse events were required for 39 (19%) patients. Treatment-emergent adverse events leading to dose reductions during all cycles were neutropenia (12%), anemia (3%), and thrombocytopenia (3%). The median number of dose-reduced cycles in patients was 2 (range: 1 to 10 cycles).

Permanent treatment discontinuation due to a treatment-emergent adverse event was required for 5% of patients who received Inqovi. The most frequent treatment-emergent adverse events resulting in permanent discontinuation of Inqovi were febrile neutropenia (1%) and pneumonia (1%).

Overall, the safety profile of Inqovi observed in the pooled safety population is consistent with the known safety profile of intravenous decitabine.

The risks of neutropenia and thrombocytopenia, and the potential for fetal harm associated with the use of Inqovi have been included in a Serious Warnings and Precautions box in the Inqovi Product Monograph. In addition, the Inqovi Product Monograph specifies recommendations for close monitoring of patients receiving Inqovi.

The Inqovi Product Monograph also lists the adverse reactions that have been identified during post-approval use of decitabine administered intravenously: differentiation syndrome, anaphylactic reactions and enterocolitis with fatal outcome, and interstitial lung disease.

For more information, refer to the Inqovi Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Inqovi is an oral combination of two medicinal ingredients, decitabine (a pyrimidine [cytidine] analogue) and a new molecular entity, cedazuridine (a cytidine deaminase inhibitor). Decitabine for intravenous administration has already been authorized in Canada.

The new molecular entity, cedazuridine, inhibits cytidine deaminase. This enzyme is responsible for the degradation of cytidine nucleosides, including the cytidine analog decitabine. High levels of cytidine deaminase in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability. Oral administration of cedazuridine with decitabine increases the oral bioavailability of decitabine.

In vitro studies support the proposed mechanism of action of cedazuridine. Cedazuridine increased the half-life of gemcitabine (known to be metabolized by cytidine deaminase) from less than 36 minutes to over 66 hours. Cedazuridine was a potent inhibitor of human cytidine deaminase with a half-maximal inhibition (IC50) value of 281 nM. In vivo, oral cedazuridine increased the antitumour activity of oral decitabine, as demonstrated by an increased lifespan in the KG-1 and L1201 disseminated leukemia mouse models.

In safety pharmacology studies, action potential parameters were unaffected in isolated papillary muscles of guinea pigs by treatment with up to 100 µM of cedazuridine. Cedazuridine showed negligible inhibition of the human ether à-go-go related gene (hERG) potassium channel current (IC50 estimated at >300 µM). In vivo, cardiovascular and respiratory parameters were unaffected by cedazuridine treatment in telemetry-instrumented cynomolgus monkeys. Since cedazuridine does not have a strong tendency to distribute into tissues, the central nervous system has not been assessed in safety pharmacology studies.

Radiolabelled cedazuridine was highly distributed into the gastrointestinal tract in mice. Mean in vitro protein binding of cedazuridine in mouse, monkey, and human plasma ranged between 29.8% and 37.6%. Unchanged cedazuridine was the most abundant component in plasma, across animal models and in humans. The primary metabolite of cedazuridine was its epimer. After oral administration in mice and monkeys, cedazuridine was primarily excreted in feces as unabsorbed drug.

In repeat-dose toxicity studies, the toxicity and toxicokinetic profiles of cedazuridine and its primary metabolite, cedazuridine epimer, were characterized in mice, rhesus monkeys, and cynomolgus monkeys. Based on these non-clinical data, the following organs were identified as potential toxicity targets of cedazuridine in humans: bone marrow, gastrointestinal tract, spleen, lymphoid tissues (thymus, spleen, mesenteric lymph nodes), and testes.

No reproductive or developmental toxicity studies were conducted with cedazuridine.

Cedazuridine was genotoxic in the Ames test and in a chromosome aberration assay in human lymphocytes.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Inqovi Product Monograph. In view of the intended use of Inqovi, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

Appropriate warnings and precautionary measures are in place in the Inqovi Product Monograph to address the identified safety concerns.

For more information, refer to the Inqovi Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Inqovi has demonstrated that the drug substances and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable, when the drug product is stored at room temperature (15ºC to 30ºC).

In view of the intended use of Inqovi, and considering the genotoxic potential of this combination product, the proposed limits of drug-related impurities are considered acceptable.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (i.e., excipients, described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipient lactose monohydrate is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.

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