Health Canada Issues Notice of Compliance with Conditions (NOC/c) for IDHIFA™ The First Oral Targeted Therapy for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia and an IDH2 Mutation
Conditional approval validates IDHIFA™ as the first and only oral, targeted inhibitor of IDH21
Relapsed or refractory acute myeloid leukemia is a debilitating disease with a significant unmet medical need2
TORONTO, Feb. 11, 2019 /CNW/ - Celgene Inc. today announced Health Canada has issued a Notice of Compliance with conditions (NOC/c) for IDHIFA (enasidenib) for the treatment of adult patients with relapsed or refractory (R/R) Acute Myeloid Leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. Treatment with IDHIFA should be initiated following confirmation of IDH2 mutation through a validated test.1 IDHIFA, an oral targeted inhibitor of the IDH2 enzyme, is the first and only Health Canada-approved therapy for patients with R/R AML and an IDH2 mutation, which represents between 8 and 19 per cent of AML patients.3
"AML is a complex and heterogeneous disease, making it difficult to treat. Treatment is especially challenging in patients with relapsed or treatment refractory disease. Until now in Canada, we did not have a therapy that specifically targets the metabolic abnormalities unique to AML patients with an IDH2 mutation," said hematologist Dr. Andre Schuh from the University Health Network in Toronto. "Our goal as leukemia physicians is to provide efficacious and minimally-toxic therapies that target the unique molecular features of a patient's AML. Having an option that specifically targets IDH2-mutated AML is a step forward in this direction."
The Impact on Acute Myeloid Leukemia Patients AML is a cancer of the blood and bone marrow marked by rapid disease progression and is the most common acute leukemia affecting adults with 1,315 new cases diagnosed in Canada in 2013.4,5,6 Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. At first, patients with AML often have non-specific symptoms usually associated with more common ailments such as fever, shortness of breath, weight loss or loss of appetite, weakness or feeling tired. Often, signs and symptoms result from a shortage of normal blood cells, which happens when the leukemia cells crowd out the normal blood-making cells in the bone marrow.5
"AML is a debilitating disease that progresses rapidly, having a negative impact on the quality of life for patients and their families," said Jackie Manthorne, President and CEO of the Canadian Cancer Survivor Network. "It is our vision that AML patients have numerous treatment options available to them to help manage their disease and we are encouraged to see a new door open for those with the IDH2 mutation."
The AML incidence increases with age. According to the Canadian Cancer Society, the median age of onset is 67.7 While many patients with AML respond to treatment, the majority eventually experience relapse.6 Overall survival for patients who become relapsed or refractory to initial therapy is estimated at less than six months.2,6 For 8 to 19 per cent of AML patients, the mutated IDH2 enzyme blocks normal blood cell development and results in an overabundance of immature blood cells.3
"Celgene Inc. is committed to driving innovation and improving the lives of patients across Canada. With Health Canada's issuance of a Notice of Compliance with conditions for IDHIFA, we are able to fill an unmet need for the small population of relapsed or refractory acute myeloid leukemia patients with the IDH2 mutation. We will be working closely with the payer community to ensure this population of patients have access to this treatment option." said Kevin Leshuk, Vice President and General Manager of Celgene Inc.
About the Clinical Trial1 The efficacy of IDHIFA in the treatment of patients with relapsed or refractory AML with an IDH2 mutation was evaluated from the phase 2 portion of the AG221-C-001 study. The Phase 2 study is an open-label, single-arm, international, multicentre clinical trial of 105 adult patients who received a 100-mg daily dose until disease progression or unacceptable toxicity. The IDH2 mutation was prospectively identified in all subjects. The Abbott RealTime™ IDH2 assay was used in the majority of patients. IDHIFA was given orally at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Adverse events were managed with dose reductions. Patients had a median age of 68 years (range of 32 to 89) and received a median of two prior anticancer regimens (ranging from one to five). Over a third (34.3%) were primary refractory.
In this trial, response was assessed by the investigator and retrospectively by an Independent Adjudication Committee (IRAC). Overall Response Rate (ORR) was defined as the rate of responses, including complete remission (CR), CR with incomplete neutrophil recovery (CRi), CR with incomplete platelet recovery (CRp), partial remission (PR), and morphologic leukemia-free state (MLFS). IDHIFA demonstrated a combined overall response rate (ORR) of 37.1% (n=39) (95% CI: 27.9, 47.1) based on investigator assessment and 31.4% (n=33) (95% CI: 22.7, 41.2) based on IRAC assessment. The median duration of ORR was 5.6 months (95% CI: range 3.7, 7.4) based on investigator assessment and 6.5 months (95% CI: range 4.6, 9.2) based on IRAC assessment. The median time to first response (2.7 months) was shorter than the median time to best response (3.7 months) for ORR, indicating that responses can improve with continued treatment from the first evidence of response. For subjects who achieved a best response of CR, 14.3% achieved a CR by Cycle 3, 57.1% by Cycle 5, and 95.2% achieved a CR by Cycle 7, indicating that in the absence of disease progression, subjects should be treated for at least 6 months.
Among the 76 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 27 (35.5%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 29 patients who were independent of both RBC and platelet transfusions at baseline, 19 (65.5%) remained transfusion independent during any 56-day post-baseline period.
About Celgene Celgene Inc is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of novel therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the company's website at www.celgene.ca.
About Agios Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has two approved oncology precision medicines and multiple first-in-class investigational medicines in clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging our knowledge of metabolism, biology and genomics. For more information, please visit the company's website at www.agios.com.
Indication and Clinical Use NOC/c: IDHIFA has been approved under the Notice of Compliance with Conditions (NOC/c) policy for its indicated uses, pending the results of trials to verify its clinical benefit. Patients should be advised as to the nature of this approval.
IDHIFA (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. Treatment with IDHIFA should be initiated following confirmation of IDH2 mutation through a validated test.
Contraindications IDHIFA 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.
Serious Warnings and Precautions
Serious Warnings and Precautions
Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include unexplained fever, dyspnea, acute respiratory distress represented by dyspnea and/or hypoxia with need for supplemental oxygen, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. Differentiation syndrome has been observed as early as 10 days and up to 5 months after initiation of IDHIFA. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution. Hospitalization for close observation and monitoring of patients with pulmonary and / or renal manifestation is recommended.
Blood and Lymphatic System Disorder
IDHIFA can induce myeloid proliferation resulting in a rapid increase in white blood cell count without evidence of infection or clinical signs of differentiation syndrome. In the pooled Phase 1/2 clinical trial, 13.6% of patients were reported with a treatment emergent adverse event (TEAE) of noninfectious leukocytosis with 6.5% of cases reported as serious. The majority of cases occurred within the first 3 months of treatment. Non-infectious leukocytosis led to dose interruption in 1.9% of patients and treatment discontinuation in 0.9% of patients.
Metabolism and Nutrition Disorders
Tumor Lysis Syndrome
An increase in uric acid associated with imbalance in electrolytes, consistent with signs and symptoms of tumor lysis syndrome (TLS), has been observed. A TEAE of TLS was reported in 6.1% of patients of the pooled Phase 1/2 clinical trial with 4.7% of cases reported as serious. TLS usually occurred within the first 3 months of treatment. TLS led to treatment discontinuation in 0.9% of patients.
In the pooled Phase 1/2 clinical trial, 13.1% patients treated with IDHIFA experienced a TEAE of differentiation syndrome, which may be life-threatening or fatal if not treated. 7.5% of patients experienced differentiation syndrome that was reported as serious. Additionally, differentiation syndrome with fatal outcome has been reported outside of clinical trials related to a delay in recognition or to a delay in treatment initiation. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms reported by more than 50% of patients included acute respiratory distress represented by dyspnea and/or hypoxia with need for supplemental oxygen, unexplained fever, pulmonary infiltrates and renal impairment. Less common symptoms may include pleural effusion, lymphadenopathy, bone pain, peripheral edema with rapid weight gain, and pericardial effusion. ALT or AST elevation has been observed.
Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and as early as 10 days and up to 5 months after IDHIFA initiation.
If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.
Prescribers should inform patients of the risk of differentiation syndrome. Patients will be given a Patient Wallet Card and a Companion Wallet Card in the IDHIFA carton. The cards list differentiation syndrome symptoms and provides a section for physician and/or hospital/centre contact information. The card is to be used in the event any of the symptoms of differentiation syndrome are observed. Prescribers should encourage patients to keep the Patient Wallet Card with them and share the Companion Card with a caregiver. The patient or caregiver should show this card to any new treating healthcare professionals.
Fertility No reproductive toxicity study in animals has been conducted to assess the effect of enasidenib on fertility. However, repeat dose oral toxicity studies in rats revealed dose-dependent histopathologic changes in testes, epididymides and/or ovary, suggesting the potential for enasidenib -related effects on male and female fertility
There are no adequate and well controlled studies of IDHIFA in pregnant women. Based on animal embryo-fetal toxicity studies, IDHIFA may cause embryo-fetal harm when administered to pregnant women. Oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality (post implantation loss or abortion) and alternations to growth (decreased mean fetal body weight and/or skeletal variation of sternebrae not ossified) starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose of 100 mg once daily. In both rats and rabbits, enasidenib and its metabolite, AGI-16903, were detected in fetal plasma indicating transfer through the blood placental barrier. Use IDHIFA during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. If a patient or partner becomes pregnant while taking IDHIFA, advise the patient of the potential risk to a fetus.
Females of child-bearing potential are advised to use effective contraception during treatment with IDHIFA and for 8 weeks after the last dose of IDHIFA. Males with female partners of child-bearing potential are advised to use effective contraception during treatment with IDHIFA and for 8 weeks after the last dose of IDHIFA. IDHIFA may affect the effectiveness of combined hormonal contraceptives.
It is unknown whether enasidenib or its metabolites are excreted in human milk. Because many small molecule drugs are excreted in human milk and the potential for adverse reactions in nursing infants from enasidenib, women should be advised not to breastfeed during treatment with IDHIFA and for 8 weeks after the last dose.
ADVERSE REACTIONS The safety evaluation of single-agent IDHIFA is based on the pooled Phase 1/2 data from the clinical study, AG221-C-001. The most common adverse reactions (≥15%) as assessed as related to treatment by the investigator were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite The most frequent serious adverse reactions to IDHIFA were differentiation syndrome (7.5%), febrile neutropenia (4.2%), leukocytosis (3.7%), nausea (3.3%), dyspnea (2.8%), decreased appetite (1.9%), pyrexia (1.9%), and vomiting (1.9%). Dose interruptions due to adverse reactions to IDHIFA were required for 20.6% of patients. The most common adverse reactions leading to dose interruption were differentiation syndrome (3.7%), dyspnea (1.4%), fatigue (1.4%), and leukocytosis (1.4%). Dose reductions due to adverse reactions to IDHIFA were required for 4.2% of patients, most commonly for peripheral sensory neuropathy (1.4%). Discontinuations due to adverse reactions were required for 4.2% of patients.
Please consult the Product Monograph at www.celgene.ca for important information relating to, warnings and precautions, adverse reactions, drug interactions, and dosing information, which has not been discussed in this piece. The Product Monograph is also available by calling 1-877-923-5436.
Product Monograph including Patient Medication Information, IDHIFA. Celgene Inc. 2019.
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