Summary Basis of Decision for Tibsovo

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)

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

Recent Activity for Tibsovo

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Tibsovo. When the PAAT for Tibsovo becomes available, it will be incorporated into this SBD.

The following table describes post-authorization activity for Tibsovo, a product which contains the medicinal ingredient ivosidenib. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: SBD Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Summary Basis of Decision (SBD) for Tibsovo

Date SBD issued: 2025-01-21

The following information relates to the New Drug Submission for Tibsovo.

Ivosidenib

Drug Identification Number (DIN): DIN 02549980 – 250 mg ivosidenib, tablet, oral administration

Servier Canada Inc

New Drug Submission Control Number: 277139

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): L01 Antineoplastic agents

Date Filed: 2023-07-11

Authorization Date: 2024-07-19

On July 19, 2024, Health Canada issued a Notice of Compliance to Servier Canada Inc for the drug product Tibsovo.

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 Tibsovo is favourable when used:

In combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive intensive induction chemotherapy.
As monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy.

Documentation of an IDH1 R132 mutation using an appropriate diagnostic test is required prior to treatment with Tibsovo.

1 What was approved?

Tibsovo, an antineoplastic agent, was authorized for use:

In combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive intensive induction chemotherapy.
As monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy.

Documentation of an IDH1 R132 mutation using an appropriate diagnostic test is required prior to treatment with Tibsovo.

Tibsovo is not authorized for use in pediatric patients (<18 years of age), as its safety and effectiveness have not been established in this population.

No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.

Tibsovo (250 mg ivosidenib) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains colloidal silica (anhydrous), croscarmellose sodium, hypromellose, hypromellose acetate succinate, indigo carmine aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, titanium dioxide, and triacetin.

The use of Tibsovo 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;
who are taking strong cytochrome P450 (CYP) 3A4 inducers or dabigatran;
with congenital long QT syndrome;
with a family history of sudden death or polymorphic ventricular arrythmia; or
with a QT/corrected QT (QTc) interval >500 msec, regardless of the correction method used.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Tibsovo Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Tibsovo approved?

Health Canada considers that the benefit-harm-uncertainty profile of Tibsovo is favourable for use:

In combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive intensive induction chemotherapy.
As monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy.

Documentation of an IDH1 R132 mutation using an appropriate diagnostic test is required prior to treatment with Tibsovo.

Acute myeloid leukemia is an aggressive, rapidly progressive malignancy. It is characterized by the clonal proliferation of myeloid precursors resulting from various genetic aberrations. Immature precursors, or myeloblasts, accumulate in the bone marrow, peripheral blood, and organs and disrupt the production of normal blood cells. The clinical manifestations of AML are attributable to the replacement of normal, functional hematopoietic cells by immature leukemic blasts, causing anemia, neutropenia, and thrombocytopenia.

In Canada, all leukemia cases account for 3% of new cancers, making it a rare disease. Acute myeloid leukemia makes up 24% of all leukemia cases or approximately 1% of cancers, but is a leading cause of adult leukemia deaths. The median age at diagnosis is 65 years. The AML incidence rate in Canada is 4.0-4.7 per 100,000 individuals and the 5-year overall survival is approximately 23%. Mutations in IDH1 have been documented in approximately 6-10% of AML cases; however, there is no clear evidence of an important difference in prognosis.

In Canada, up to 50% of newly diagnosed patients with AML are determined to be unfit for intensive induction chemotherapy according to the Canadian Leukemia Study Group. In this population, the standard of care is treatment with the combination of venetoclax and azacitidine, which has been shown to have a survival advantage over azacitidine alone. Currently, there are no approved treatments specifically available for patients with IDH1-mutated AML who are ineligible for induction chemotherapy in Canada.

Cholangiocarcinomas are a heterogeneous group of cancers arising from the epithelium of the bile duct. These aggressive tumours are highly lethal, as most are advanced and incurable at the time of diagnosis. The clinical manifestations of cholangiocarcinoma include symptoms related to biliary tract obstruction, including jaundice, abdominal pain, weight loss, fever, fatigue and abnormal liver function tests.

In Canada, cholangiocarcinomas account for less than 1% of cancers. Intrahepatic cholangiocarcinomas account for up to 20% of cholangiocarcinoma diagnoses, and approximately 18% of these harbour an IDH1 mutation. The median age at diagnosis is 68 years, and the incidence increases with age. Despite advances in awareness, diagnosis, and therapies, patient prognosis has not improved substantially over the past decade, with a 5-year survival rate of 7-20%. For patients with distant metastases, 5-year survival drops to 2% and median overall survival for unresectable disease with active palliative treatment is 10.6 months.

Although there are treatment options for patients with cholangiocarcinoma, patients may not be eligible for certain types of treatment and disease progression can occur while on treatment. In Canada, there are no treatments specifically indicated for cholangiocarcinoma with an IDH1 mutation, irrespective of line of therapy.

Ivosidenib, the medicinal ingredient in Tibsovo, is a small molecule inhibitor of mutated IDH1, and therefore a targeted therapeutic candidate for the treatment of patients with cancers harbouring IDH1 mutations. Cancer-associated mutations of IDH1 cause the overproduction of 2-hydroxyglutarate (2-HG), a metabolite that blocks cellular differentiation and promotes tumorigenesis in both hematologic and non-hematologic malignancies. Direct inhibition of mutated IDH1 suppresses production of 2-HG, restoring differentiation and reducing proliferation of cancerous cells.

The clinical efficacy of Tibsovo (ivosidenib) was evaluated primarily in two pivotal studies:

AGILE (AG120-C-009), in which the combination of ivosidenib and azacitidine was evaluated for the treatment of adult patients with previously untreated IDH1 mutation-positive acute myeloid leukemia (AML) who are not eligible to receive intensive induction chemotherapy, and
ClarIDHy (AG120-C-005), in which ivosidenib monotherapy was evaluated for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma (CCA) with an IDH1 mutation, who were previously treated by at least one prior line of systemic therapy.

AGILE

Participants in the Phase III study AGILE were randomized 1:1 to receive a 500 mg oral dose of Tibsovo once daily or matched placebo once daily, both administered in combination with subcutaneous or intravenous azacitidine 75 mg/m²/day for the first week of each 4-week cycle. Treatment continued for a minimum of 6 cycles of combination therapy unless one of the following occurred:

relapse after achieving a complete remission (CR), complete remission with incomplete hematologic recovery (CRi) (including complete remission with incomplete platelet recovery [CRp]), or morphologic leukemia-free state (MLFS);
disease progression prior to achieving CR, CRi (including CRp), or MLFS;
unacceptable toxicity (adverse event);
confirmed pregnancy;
withdrawal by patient;
protocol violation;
death; or
end of study.

For all participants, the extent of disease was assessed by bone marrow aspirate and peripheral blood samples.

The primary efficacy endpoint for the AGILE study was event-free survival (EFS), defined as the time from randomization until treatment failure, relapse from complete remission (CR), or death from any cause, whichever occurs first. Treatment failure was defined as failure to achieve CR by Week 24. This study met its primary endpoint, demonstrating a statistically significant improvement in EFS for patients randomized to the Tibsovo + azacitidine arm relative to the placebo + azacitidine arm (hazard ratio [HR] = 0.33; 95% confidence interval [CI]: 0.16-0.69; one-sided p = 0.0011).

The safety analysis set included 146 patients, with 72 in the Tibsovo + azacitidine (experimental) arm and 74 in the placebo + azacitidine (control) arm. The median duration of exposure was 286 days in the experimental arm and 95.5 days in the control arm. The main reason for treatment discontinuation in both treatment arms was adverse events.

Overall, the combination of Tibsovo + azacitidine was well-tolerated. Twenty-two participants (30.1%) in the experimental arm and 21 (28.0%) participants in the control arm discontinued treatment due to adverse events.

The incidence of treatment-emergent adverse events (TEAEs) was similar between the experimental and control arms (98.6% and 100%, respectively).

The incidence of treatment-related adverse events that were assessed by the investigator as related to Tibsovo or placebo was higher in the experimental arm than in the control arm (41.7% and 29.7%, respectively). The most common adverse reactions related to Tibsovo were vomiting (22%), neutropenia (19%), electrocardiogram QT prolonged (19%), differentiation syndrome (14%), and thrombocytopenia (14%).

The incidence of serious adverse events was lower in the experimental arm than in the control arm (70.8% versus 83.8%, respectively). However, more serious adverse events were assessed as treatment-related in the experimental arm.

On-treatment adverse events leading to death were lower in the experimental arm (15.3%) than in the control arm (31.1%), and none were considered by the sponsor to be related to any of the study treatments.

Any event of differentiation syndrome assessed as Grade 2 or higher, irrespective of seriousness, was reported as an AESI. The incidence of differentiation syndrome was higher in the experimental arm (13.9% with 9.7% Grade 2 and 4.2% Grade 3) than in the control arm (8.1% with 4.1% Grade 2, 2.7% Grade 3, and 1.4% Grade 4). There were no Grade 4 AESIs of differentiation syndrome in the experimental arm and no deaths in either study arm. The median time to onset of differentiation syndrome was 20 days (range: 3 to 33 days).

ClarIDHy

Participants in the Phase III study ClarIDHy were 18 years of age or older with a histopathological diagnosis of nonresectable or metastatic cholangiocarcinoma and were not eligible for curative resection, transplantation, or ablative therapies. Participants were required to have documented IDH1 gene-mutated disease based on central laboratory testing and documented disease progression following at least one but not more than two prior systemic regimens for advanced disease.

Participants were randomized in a 2:1 ratio to receive a 500 mg oral dose of Tibsovo once daily or matched placebo once daily. Randomization was stratified by the number of prior therapies (one versus two). Cycles were 28 days (± 2 days) in duration, and dosing was continuous. All patients continued to receive best supportive care according to institutional practice throughout the study.

Radiographic assessment for evaluation of disease response was conducted every 6 weeks (± 5 days) for the first 8 assessments (i.e., through week 48) and every 8 weeks (± 5 days) thereafter from Cycle 1, Day 1, independent of dose delays and/or dose interruptions, and/or at any time when progression of disease was suspected. Version 1.1 (v1.1) of the Response Evaluation Criteria in Solid Tumours (RECIST) was followed with respect to target and non-target lesion selection and objective tumour response assessments, as well as an independent central review of response.

The efficacy assessment was based on the intent-to-treat (ITT) set of 187 participants. Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease. Before entering the study, 52.9% of patients had progressed after receiving one prior line of therapy and 47.1% of patients had progressed after receiving two lines of therapy.

The primary efficacy endpoint for the study was progression-free survival (PFS), defined as the time from date of randomization to date of first documented disease progression (as assessed by an Independent Radiology Center [IRC] per RECIST v1.1), or date of death due to any cause, whichever occurred first. This study met its primary endpoint, as a statistically significant improvement in PFS was observed per IRC assessment for patients randomized to Tibsovo versus patients randomized to placebo. The median PFS for patients treated with Tibsovo was 2.7 months versus 1.4 months for patients treated with placebo (HR 0.37; 95% CI: 0.25, 0.54; one-sided p-value <0.0001).

The safety analysis set included 182 participants, with 123 in the Tibsovo arm and 59 in the placebo arm. The median time on treatment was longer for patients who were randomized to and received Tibsovo (2.8 months [range: 0.1 to 45.1 months]) compared to patients who received placebo (1.6 months [range: 0.03 to 6.9 months]).

The proportion of participants who discontinued treatment due to TEAEs were 7.3% in the Tibsovo arm and 8.5% in the placebo arm. The main reason for treatment discontinuation in both arms was disease progression.

Eight participants (4.8%) had a TEAE leading to death, including 6 patients with fatal TEAEs who were randomized to and treated with Tibsovo, and 2 patients with fatal TEAEs who were randomized to placebo then crossed over to receive treatment with Tibsovo. Each fatal TEAE was assessed by the investigator as unrelated to study drug. A review of on-treatment deaths did not identify any pattern. Most deaths were attributable to progressive disease, underlying disease or comorbidities.

Prolongation of the QT interval is a known adverse reaction of Tibsovo and was identified as an adverse event of special interest (AESI). The incidence of QT prolongation of any grade was higher in the Tibsovo arm (9.8% with 1.6% of Grade 3 or higher) than in the placebo arm (3.4% with no events Grade 3 or higher). A prolonged QT interval led to treatment interruption in one case (0.8%) and dose reduction in 4 cases (3.3%). There were no patients that required treatment discontinuation due to a prolonged QT interval. There were no events of fatal arrythmia or Torsades de Pointes. The median time to first AESI of prolonged QT in the Tibsovo arm was 28 days (range: 1 to 698 days) with 16.7% of first events occurring after 60 days.

The risks of differentiation syndrome (only in patients with AML) and of QT interval prolongation and ventricular arrhythmias have been highlighted in a Serious Warnings and Precautions box in the Tibsovo Product Monograph, along with signs and symptoms, and recommendations for monitoring and intervention.

A Risk Management Plan (RMP) for Tibsovo was submitted by Servier Canada Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

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

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Tibsovo was accepted.

Tibsovo has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Tibsovo 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 issued 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 Tibsovo?

The review of the quality and clinical components of the New Drug Submission (NDS) for Tibsovo was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Tibsovo NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Submission Milestones: Tibsovo

Submission Milestone	Date
Pre-submission meeting	2023-05-16
New Drug Submission filed	2023-07-11
Screening
Screening Deficiency Notice issued	2023-08-10
Response to Screening Deficiency Notice filed	2023-09-22
Screening Acceptance Letter issued	2023-09-26
Review
Review of Risk Management Plan completed	2024-07-03
Biostatistics evaluation completed	2024-07-08
Quality evaluation completed	2024-07-09
Non-clinical evaluation completed	2024-07-17
Clinical/medical evaluation completed	2024-07-18
Labelling review completed	2024-07-18
Notice of Compliance issued by Director General, Pharmaceutical Products Directorate	2024-07-19

4 What follow-up measures will the company take?

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

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

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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 Tibsovo. 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:

See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Guidance Document: Notice of Compliance with Conditions (NOC/c), if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
See the Patent Register for patents associated with medicinal ingredients, if applicable.
See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.

7 What was the scientific rationale for Health Canada’s decision?

Refer to the What steps led to the approval of Tibsovo? section for more information about the review process for this submission.

7.1 Clinical Basis for Decision

Clinical Pharmacology

Ivosidenib, the medicinal ingredient in Tibsovo, is an inhibitor of the mutant isocitrate dehydrogenase-1 (IDH1) enzyme. Mutant IDH1 converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which blocks cellular differentiation and promotes tumorigenesis in both hematologic and non-hematologic malignancies. The mechanism of action of ivosidenib beyond its ability to reduce 2-HG and restore cellular differentiation is not fully understood across indications.

The major aspects of absorption, distribution, metabolism, and elimination of ivosidenib have been characterized. In participants with newly diagnosed acute myeloid leukemia (AML) treated with ivosidenib and azacitidine and in participants with cholangiocarcinoma, the median time to maximum plasma concentration (C_max) was approximately 2 hours. In participants with newly diagnosed AML treated with ivosidenib and azacitidine, the mean steady-state C_max was 6,145 ng/mL and the mean steady-state exposure, as measured by the area under the concentration-time curve (AUC), was 106,326 ng·hr/mL. In patients with cholangiocarcinoma, the mean steady-state C_maxwas 4,799 ng/mL and the mean steady-state exposure, as measured by the AUC, was 86,382 ng·hr/mL. Steady-state plasma levels were reached within 14 days of once daily dosing.

Ivosidenib was the predominant component (over 92%) of total radioactivity in plasma from healthy participants. Ivosidenib is mainly metabolized by cytochrome P450 (CYP) 3A4, with minor contributions from CYP2B6 and CYP2C8. The co-administration of strong CYP3A4 inducers with ivosidenib is contraindicated, as this is expected to decrease plasma concentrations of ivosidenib. Ivosidenib also has the potential to induce uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes and decrease the systemic exposure of substrates of UGT enzymes. Additionally, ivosidenib is a substrate for P-glycoprotein (P-gp) and has the potential to induce P-gp.

The major routes of excretion for ivosidenib were feces and urine. In participants with newly diagnosed AML treated with ivosidenib and azacitidine, the mean apparent clearance of ivosidenib at steady-state was 4.6 L/hour, with a mean terminal half-life of 98 hours. In participants with cholangiocarcinoma, the mean apparent clearance of ivosidenib at steady-state was 6.1 L/hour, with a mean terminal half-life of 129 hours.

No clinically meaningful effects were observed on the pharmacokinetics of ivosidenib in participants with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 mL/min/1.73 m² or higher). The pharmacokinetics of ivosidenib in individuals with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or renal impairment requiring dialysis are unknown. No clinically meaningful effects were observed on the pharmacokinetics of ivosidenib in participants with mild hepatic impairment. The pharmacokinetics of ivosidenib in individuals with moderate and severe hepatic impairment are unknown in patients with newly diagnosed AML and with cholangiocarcinoma.

Individuals treated with ivosidenib can develop prolongation of the corrected QT (QTc) interval (QTc prolongation) and ventricular arrhythmias. An ivosidenib concentration-QTc model based on data from participants with advanced hematological malignancies (primarily relapsed or recurring AML) predicted a concentration-dependent QTc prolongation of approximately 16.1 msec (90% confidence interval [CI]: 13.3, 18.9) at the steady-state C_max in participants who received 500 mg ivosidenib once daily. From a concentration-QTc model based on data from participants with solid tumours (45.5% cholangiocarcinoma), a concentration-dependent prolongation of approximately 17.2 msec (90% CI: 14.3, 20.2) was predicted at the steady-state C_max following a 500 mg daily dose using data from 166 patients with cholangiocarcinoma.

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

Clinical Efficacy

The clinical efficacy of Tibsovo (ivosidenib) was evaluated in two pivotal studies:

AGILE (AG120-C-009), in which the combination of ivosidenib and azacitidine was evaluated for the treatment of adult patients with previously untreated IDH1 mutation-positive acute myeloid leukemia (AML) who are not eligible to receive intensive induction chemotherapy, and
ClarIDHy (AG120-C-005), in which ivosidenib monotherapy was evaluated for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma (CCA) with an IDH1 mutation, who were previously treated by at least one prior line of systemic therapy.

AGILE

The pivotal Phase III study AGILE assessed the efficacy of ivosidenib and azacitidine combination therapy versus placebo and azacitidine in participants 18 years of age or older with previously untreated AML who were not eligible for intensive induction chemotherapy. Participants had documented IDH1 gene-mutated disease (in their bone marrow aspirate or peripheral blood sample if bone marrow aspirate was not available) based on central laboratory testing.

Participants were randomized 1:1 to receive a 500 mg oral dose of Tibsovo once daily or matched placebo once daily, both administered in combination with subcutaneous or intravenous azacitidine 75 mg/m²/day for the first week (7 days) (or on a 5-2-2 schedule) of each 4-week (28-day) cycle. Randomization was stratified based on de novo status (de novo AML or secondary AML) and geographic region. Treatment continued for a minimum of 6 cycles of combination therapy unless one of the following occurred:

relapse after achieving a complete remission (CR), complete remission with incomplete hematologic recovery (CRi) (including complete remission with incomplete platelet recovery [CRp]), or morphologic leukemia-free state (MLFS);
disease progression prior to achieving CR, CRi (including CRp), or MLFS;
unacceptable toxicity (adverse event);
confirmed pregnancy;
withdrawal by patient;
protocol violation;
death; or
end of study.

For all participants, the extent of disease was assessed by bone marrow aspirate and peripheral blood samples at the following points:

screening and Day 1 (± 7 days) of Weeks 9, 17, 25, 33, 41, 53 and every 24 weeks thereafter;
at end of treatment (EOT);
during event-free survival (EFS) follow-up on the same schedule;
as clinically indicated; and/or
any time that disease progression was suspected.

During treatment, participants’ responses were evaluated by the investigator based on modified International Working Group (IWG) response criteria for AML and European LeukemiaNet (ELN) guidelines to determine patient status and continuation on study treatment.

The efficacy assessment was based on the full analysis set (FAS) of 146 patients. The majority of participants were male (54.8%), over the age of 75 years (56.2%), had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 (44.4%), and had de novo AML at initial diagnosis (73.3% per investigator [76% per Interactive Web Response System]). Race and ethnicity were unreported for most participants. Cytogenetic risk status, as assessed by the investigators, was intermediate (63.0%) or poor (24.7%) for most participants at baseline based on the 2017 National Comprehensive Cancer Network (NCCN) guidelines.

Overall survival was a key secondary endpoint. After a median follow-up time of approximately 15 months in both treatment arms, the median overall survival was reported as 24.0 months (95% CI: 11.3-34.1 months) in the Tibsovo + azacitidine arm and 7.9 months (95% CI: 4.1-11.3 months) in the placebo + azacitidine arm (HR = 0.44; 95% CI: 0.27-0.73; p = 0.001). An updated analysis of overall survival was provided after 95 events occurred (median follow-up time of 29.3 months in the Tibsovo + azacitidine arm and 26.7 months in the placebo + azacitidine arm). The significant improvement for participants randomly assigned to the Tibsovo + azacitidine arm relative to the placebo + azacitidine arm was maintained (one-sided p-value <0.0001; HR = 0.42; 95% CI: 0.27-0.65), with a median overall survival of 29.3 months (95% CI: 13.2 months-not estimable) in the Tibsovo + azacitidine arm and 7.9 months (95% CI: 4.1-11.3 months) in the placebo + azacitidine arm.

The remaining key secondary endpoints, including CR rate, CR + CR with partial hematologic recovery (CRh) rate and overall response rate (ORR), continued to demonstrate consistent statistically significant improvements for patients randomized to the Tibsovo + azacitidine arm.

ClarIDHy

The pivotal Phase III study ClarIDHy was designed to evaluate the efficacy and safety of Tibsovo monotherapy versus placebo for the treatment of adult participants with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation, who were previously treated by at least one prior line of systemic therapy. Participants were 18 years of age or older with a histopathological diagnosis of nonresectable or metastatic cholangiocarcinoma and were not eligible for curative resection, transplantation, or ablative therapies. Participants were required to have documented IDH1 gene-mutated disease (from a fresh tumour biopsy or the most recent banked tumour tissue available) based on central laboratory testing as well as documented progression of disease following at least one but not more than two prior systemic regimens for advanced disease. At least one of the prior regimens must have included gemcitabine or 5-fluorouracil (FU).

Radiographic assessment (computed tomography [CT] or magnetic resonance imaging [MRI]) for evaluation of disease response was conducted every 6 weeks (± 5 days) for the first 8 assessments (i.e., through week 48) and every 8 weeks (± 5 days) thereafter from Cycle 1, Day 1, independent of dose delays and/or dose interruptions, and/or at any time when progression of disease was suspected. Version 1.1 (v1.1) of the Response Evaluation Criteria in Solid Tumours (RECIST) was followed with respect to target and non-target lesion selection and objective tumour response assessments, as well as an independent central review of response.

Participants continued their assigned study treatment until disease progression, development of unacceptable toxicity, confirmed pregnancy, death, withdrawal of consent, loss to follow-up, or the sponsor unblinded or ended the study, whichever occurred first. Upon request of the investigator, participants and site staff could be unblinded to treatment assignment after documented disease progression. Participants randomized to the placebo arm who continued to meet eligibility criteria were given the opportunity to cross over to the active treatment arm and receive Tibsovo, and continued to be evaluated for tumour response by the investigator.

The efficacy assessment was based on the intent-to-treat (ITT) set of 187 participants. The majority of participants were female (63.6%), 45 to <65 years old (54.0%), white (56.7%) not Hispanic or Latino (66.3%), and had an ECOG performance status of 0 (36.8%). Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease. Before entering the study, 52.9% of patients had progressed after receiving one prior line of therapy and 47.1% of patients had progressed after receiving two lines of therapy.

Key secondary endpoints included overall survival and ORR based on IRC. The results for overall survival were not statistically significant, with a median overall survival of 10.3 months (95% CI: 7.8-12.4 months) for patients randomized to Tibsovo and 7.5 months (95% CI: 4.8-11.1 months) for patients randomized to placebo (HR = 0.79; 95% CI: 0.56-1.12 months; one-sided p-value = 0.093). These results were confounded by the crossover of patients in the placebo arm (70.5%) to the Tibsovo arm following radiographic progression. The median overall survival for placebo after adjusting for the effect of crossover was 5.1 months. Due to the exploratory nature of this analysis, bias cannot be excluded.

As key secondary endpoints were tested using a hierarchical procedure and the overall survival result was not significant, ORR was not formally tested and results are considered exploratory.

Indication

Health Canada approved the following indications:

Tibsovo (ivosidenib) in combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an IDH1 R132 mutation, who are not eligible to receive intensive induction chemotherapy.
Tibsovo (ivosidenib) monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase 1 (IDH1) R132 mutation who were previously treated by at least one prior line of systemic therapy.

Documentation of an IDH1 R132 mutation using an appropriate diagnostic test is required prior to treatment with Tibsovo.

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

Clinical Safety

The clinical safety of Tibsovo was evaluated primarily in the two studies described in the Clinical Efficacy section, AGILE and ClarIDHy.

AGILE

In the AGILE study, the safety analysis set included 146 patients, with 72 in the Tibsovo + azacitidine (experimental) arm and 74 in the placebo + azacitidine (control) arm. The median duration of exposure was 286 days in the experimental arm and 95.5 days in the control arm. Thirty-one participants (43.1%) who received Tibsovo + azacitidine and seven participants (9.5%) who received placebo + azacitidine remained on treatment for over 60 weeks. The maximum treatment duration for a patient randomized to receive Tibsovo + azacitidine was 48.9 months. The main reason for treatment discontinuation in both treatment arms was adverse events.

Overall, the combination of Tibsovo + azacitidine was well-tolerated. Twenty-two participants (30.1%) in the experimental arm and 21 participants (28.0%) in the control arm discontinued treatment due to adverse events.

The incidence of treatment-emergent adverse events (TEAEs) was similar between the experimental and control arms (98.6% and 100%, respectively). The most common TEAEs in the experimental arm were hematologic and gastrointestinal toxicities including nausea (44.4%), vomiting (41.7%), diarrhea (36.1%), pyrexia (37.5%), anemia (33.3%), constipation (31.9%), neutropenia (30.6%), thrombocytopenia (29.2%), febrile neutropenia (27.8%), and pneumonia (23.6%). The incidence of Grade ≥3 TEAEs was similar between the experimental (91.7%) and control (95.9%) arms. Grade ≥3 TEAEs reported at a ≥5% higher incidence in the experimental arm included neutropenia (22 [30.6%] vs. 16 [21.6%]), thrombocytopenia (18 [25.0%] vs. 14 [18.9%]), neutrophil count decreased (9 [12.5%] vs. 5 [6.8%]), and electrocardiogram QT prolonged (8 [11.1%] vs. 2 [2.7%]).

Any QT prolongation event assessed as Grade 3 or higher was reported as an adverse event of special interest (AESI). The incidence of QT prolongation was higher in the experimental arm (22.2% with 12.5% Grade 3 or higher) than in the control arm (6.8% with 4.1% assessed as Grade 3 or higher); however, there were no Grade 4 or 5 TEAEs of electrocardiogram QT prolonged, Torsades de Pointes, or fatal arrythmias. One percent (1%) of patients discontinued Tibsovo treatment due to electrocardiogram QT prolonged, while dose interruption and reduction were required in 8% and 10% of patients, respectively. These figures correspond to QT prolonged as assessed by the investigator as related to ivosidenib.

Any event of differentiation syndrome assessed as Grade 2 or higher, irrespective of seriousness, was reported as an AESI. The incidence of differentiation syndrome was higher in the experimental arm (13.9% with 9.7% Grade 2 and 4.2% Grade 3) than in the control arm (8.1% with 4.1% Grade 2, 2.7% Grade 3, and 1.4% Grade 4) . There were no Grade 4 AESIs of differentiation syndrome in the experimental arm and no deaths in either study arm. The median time to onset of differentiation syndrome was 20 days (range: 3 to 33 days).

The risks of differentiation syndrome in patients with AML and of QT interval prolongation and ventricular arrhythmias have been highlighted in a Serious Warnings and Precautions box in the Tibsovo Product Monograph, along with signs and symptoms, and recommendations for monitoring and intervention.

ClarIDHy

In the ClarIDHy study, the safety analysis set included 182 participants (123 in the Tibsovo arm and 59 in the placebo arm). The median time on treatment was longer for patients who were randomized to and received Tibsovo (2.8 months [range: 0.1 to 45.1 months]) compared to patients who received a placebo (1.6 months [range: 0.03 to 6.9 months]). In the Tibsovo arm, 48% of patients were exposed to the study drug for longer than 3 months and 15.4% of patients were exposed for longer than 12 months.

Despite a longer treatment duration for Tibsovo compared to placebo, similar incidences of patients reported TEAEs in both arms (97.6% vs. 96.6%). However, the incidence of Grade 3 or higher TEAEs was higher in the Tibsovo arm than in the placebo arm (51.2% vs 37.3%). The incidence of serious adverse events was also higher in the Tibsovo arm (35.0% vs 23.7%). The most frequent TEAEs in patients randomized to Tibsovo were gastrointestinal events (nausea [42.3%], diarrhea [35.0%], abdominal pain [24.4%], vomiting [22.8%], and ascites [22.8%]), fatigue (30.9%), cough (25.2%), and decreased appetite (24.4%). In the Tibsovo arm, the Grade 3 or higher TEAEs that occurred in 5% of participants or more were ascites (8.9%), anemia (7.3%), blood bilirubin increased (5.7%), and hyponatremia (5.7%).

Eight participants (4.8%) had a TEAE leading to death, including 6 patients with fatal TEAEs who were randomized to and treated with Tibsovo, and 2 patients with fatal TEAEs who were randomized to a placebo and then crossed over to receive treatment with Tibsovo. Each fatal TEAE was assessed by the study investigator as unrelated to study drug. A review of on-treatment deaths did not identify any pattern. Most deaths were attributable to progressive disease, underlying disease, or comorbidities.

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

7.2 Non-Clinical Basis for Decision

Ivosidenib (the medicinal ingredient in Tibsovo) is a selective inhibitor of mutant isocitrate dehydrogenase-1 (IDH1) with no significant off-target activity. Data from in vitro and in vivo non-clinical studies indicated that at clinically relevant plasma levels, ivosidenib has the potential for QT prolongation.

In animal studies, ivosidenib induced hematologic abnormalities, gastrointestinal toxicity, thyroid findings, liver toxicity, and kidney findings at clinically relevant exposures. Toxic effects observed on the hematologic system, gastrointestinal system and kidney were reversible. Toxic effects observed on the liver, spleen, and thyroid were still observed at the end of the recovery period.

No dedicated carcinogenicity studies have been conducted with ivosidenib.

Ivosidenib was not mutagenic or clastogenic in conventional in vitro and in vivo genotoxicity assays.

Fertility studies have not been conducted with ivosidenib. A 28-day repeat-dose toxicity study in rats showed uterine atrophy in females at non-tolerated dose levels approximately 1.7-fold the clinical exposure (based on the area under the concentration-time curve [AUC]). This effect was reversible after a 14-day recovery period. Testicular degeneration was observed in males at non-tolerated dose levels approximately 1.2-fold the clinical exposure (based on AUC).

In embryofetal development studies in rats, lower fetal body weights and delayed skeletal ossification occurred in the absence of maternal toxicity. Maternal toxicity, spontaneous abortions, decreased fetal body weights, increased post implantation loss, delayed skeletal ossification, and visceral development variation (small spleen) were observed in rabbits. Findings from animal studies indicate that ivosidenib crosses the placenta and is found in fetal plasma. In rats and rabbits, the no adverse effect levels for embryofetal development were 0.4-fold and 1.4-fold the clinical exposure (based on AUC), respectively.

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

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

7.3 Quality Basis for Decision

The quality (chemistry and manufacturing) information submitted for Tibsovo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 5 years is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC) and protected from moisture.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.

Date modified:: 2025-11-10

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