Regulatory Decision Summary for ONUREG

Efficacy of ONUREG was determined by the QUAZAR study and safety of ONUREG was determined by the QUAZAR study and three other supportive clinical studies.

Review of the non-clinical studies identified the bone marrow, liver, kidneys, intestines, and lymphoid tissues (spleen, lymph nodes) as the main target organs of toxicity for azacitidine. Azacitidine administered to rodents resulted in an increased incidence of tumours in various tissues and organs. Azacitidine also presents a significant risk to the embryo, fetus, and male and female reproductive organs.

The pivotal Phase 3 QUAZAR study was an international, multicenter, placebo-controlled, with a double-blind, randomized, parallel-group design in subjects with de novo AML or AML secondary to prior diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukaemia (CMML). The primary end-point of the study was overall survival (OS) and the key secondary end-point was remission-free survival (RFS). After randomization, no crossover between the treatment arms was permitted.

The study showed a statistically significant reduction in the risk of death favouring patients treated with ONUREG (HR of 0.69 [95% CI: 0.55, 0.86], stratified log-rank test p-value = 0.0009). The median OS was 24.7 months for the azacitidine group and 14.8 months for the placebo group. All the sensitivity analysis performed by the sponsor confirmed the robustness of the OS finding favouring the ONUREG arm and most of the subgroup analysis were supportive of the findings made with the whole population.

The key secondary end-point, RFS, was also favouring the ONUREG arm. RFS was significantly improved with ONUREG versus placebo (stratified log-rank test p-value = 0.0001). The median RFS was 10.2 months for ONUREG and 4.8 months for the placebo group. The hazard ratio was 0.65 (95% CI: 0.52, 0.81), indicating a 35% reduction in risk of relapse or death for the ONUREG group.

Other secondary end-points such as median time to relapse and median time to treatment discontinuation were also favourable for the ONUREG group. The median time to relapse was 10.2 months in the ONUREG group and 4.9 months in the placebo group. The median time to treatment discontinuation for any reason was 11.4 months in the ONUREG group and 6.1 months in the placebo group.

The most frequently reported treatment emergent adverse event (TEAE) preferred terms (> 25% in the ONUREG group) were nausea, vomiting, diarrhea, neutropenia, constipation, thrombocytopenia, and fatigue.

TEAE leading to death were reported for 9 subjects in the ONUREG group and 4 in the placebo group. TEAE leading to death in the ONUREG group include sepsis, cerebral hemorrhage, cardiogenic shock, multiple organ dysfunction syndrome, suicide, and pneumonia aspiration. None were considered treatment related.

Treatment-related Grade 3 or 4 TEAE preferred terms for which the incidence differed by > 2% between treatment groups were neutropenia, thrombocytopenia, leukopenia, diarrhea, vomiting, and pneumonia. Treatment-related serious TEAE preferred terms reported for more than 1 subject in either treatment group were pneumonia, febrile neutropenia, sepsis, neutropenia, and gastritis.

The incidence of TEAEs leading to dose reduction and dose interruption were reported for 15.7% and 43.2% of subjects in the ONUREG group vs 2.6% and 17.2% of subjects in the placebo group. Among TEAEs leading to dose reduction in the ONUREG group were neutropenia, diarrhea thrombocytopenia, nausea and pneumonia. The most frequently reported TEAEs leading to dose interruption in the ONUREG group were neutropenia, thrombocytopenia, nausea, diarrhea, vomiting and upper/lower respiratory tract infection.

TEAEs leading to treatment discontinuation in the ONUREG arm (and experienced by more than 1 subject) were nausea, diarrhea, vomiting, abdominal pain upper, and fatigue.

Risk mitigation to address the uncertainties regarding pregnant women, patients with severe renal and severe hepatic impairment and patient with an unstable angina, significant cardiac arrhythmia, or New York Heart Association class 3 or 4 congestive heart failure were added to the proposed product monograph (PM) for ONUREG.

A contraindication for patients with advanced malignant hepatic tumors was also added to the PM of ONUREG to be consistent with the PM of the commercially available IV formulation of azacitidine (VIDAZA). Otherwise, the safety profile derived from the QUAZAR study was consistent with the safety profile reported for VIDAZA. Most of the TEAEs related to the treatment with ONUREG can be mitigated by dose modification/interruption or best supportive care (such as antibiotics, anti-emetics etc.).

The QUAZAR study has demonstrated a gain in OS favouring the ONUREG group vs the placebo group. Secondary end-points also favoured the ONUREG group vs the placebo group. The safety profile of ONUREG is consistent with the commercially available formulation of azacitidine. Overall, the benefit-harm-uncertainty profile is favourable for ONUREG for the recommended indication. A Notice of Compliance (NOC) was issued.