Tibsovo Mechanism of Action

Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents. ATC code: L01XM02.
Pharmacology: Pharmacodynamics: Mechanism of action: Ivosidenib is an inhibitor of the mutant 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.
Pharmacodynamic effects: Multiple doses of ivosidenib 500 mg daily decreased plasma concentrations of 2-HG in patients with hematological malignancies and cholangiocarcinoma with mutated IDH1 to levels approximating those observed in healthy subjects. In bone marrow of patients with hematological malignancies and in tumour biopsy of patients with cholangiocarcinoma, the mean (% coefficient of variation [%CV]) reduction in 2-HG concentrations were 93.1% (11.1%) and 82.2% (32.4%), respectively.
Using an ivosidenib concentration-QTc model, a concentration-dependent QTc interval prolongation of approximately 17.2 msec (90% CI: 14.7, 19.7) was predicted at the steady-state C_max based on an analysis of 173 patients with AML who received 500 mg ivosidenib once daily. A concentration-dependent QTc interval prolongation of approximately 17.2 msec (90% CI: 14.3, 20.2) was observed at the steady-state C_max following a 500 mg daily dose based on an analysis of 101 patients with cholangiocarcinoma who received ivosidenib 500 mg daily (see Dosage & Administration and Precautions).
Clinical efficacy: Newly diagnosed acute myeloid leukaemia in combination with azacitidine: The efficacy and safety of Tibsovo was evaluated in a randomised, multicenter, double-blind, placebo-controlled clinical study (AG120-C-009) of 146 adult patients with previously untreated AML with an IDH1 mutation who were ineligible for intensive induction chemotherapy, based on at least one of the following criteria: 75 years or older, Eastern Cooperative Oncology Group (ECOG) performance status of 2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, creatinine clearance <45 mL/min, or other comorbidity. Gene mutation analysis for central confirmation of IDH1 mutation from bone marrow and/or peripheral blood were conducted for all subjects using the Abbott RealTime IDH1 Assay. Patients were randomised to receive either Tibsovo 500 mg or matched placebo orally once daily with azacitidine 75 mg/m²/day subcutaneously or intravenously for 1 week every 4 weeks until the end of the study, disease progression or unacceptable toxicity.
The median age of patients treated with Tibsovo was 76 years (range: 58 to 84); 58% were male; 21% Asian, 17% were White, 61% not reported; and had an ECOG performance status of 0 (19%), 1 (44%), or 2 (36%). Seventy-five percent of patients had de novo AML. Overall, patients had documented favourable (4%), intermediate (67%) or poor/other (26%) cytogenetic risk as assessed by investigators based on the National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology (2017).
Efficacy was based on the primary efficacy endpoint event-free survival (EFS), measured from the date of randomisation until treatment failure, relapse from remission, or death by any cause. Treatment failure was defined as failure to achieve complete remission (CR) by week 24. Overall survival (OS), CR rate, CR + CR with partial hematologic recovery (CR + CRh) rate and objective response rate (ORR) were key secondary efficacy endpoints (Table 1 and Figure 1). (See Table 1 and Figure 1.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

An updated OS analysis, carried out at 64.2% (N=95) of events, confirmed the overall survival benefit of Tibsovo in combination with azacitidine compared to placebo in combination with azacitidine with a median OS of 29.3 months vs 7.9 months, respectively (HR=0.42; 95% CI: 0.27 to 0.65).
Previously treated, locally advanced or metastatic cholangiocarcinoma: The efficacy of Tibsovo was evaluated in a randomised (2:1), multicenter, double-blind, placebo-controlled, phase 3 clinical trial (Study AG120-C-005) of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation whose disease had progressed following at least 1 but not more than 2 prior treatment regimens including at least one gemcitabine- or 5-FU-containing regimen and an expected survival of ≥3 months.
Patients were randomised to receive either Tibsovo 500 mg orally once daily or matched placebo until disease progression or development of unacceptable toxicity. Randomisation was stratified by number of prior therapies (1 or 2). Eligible patients who were randomised to placebo were allowed to cross over to receive Tibsovo after documented radiographic disease progression as assessed by the Investigator. Gene mutation analysis for central confirmation of IDH1 mutation from tumour tissue biopsy were conducted on all subjects using the Oncomine Dx Target Test.
The median age was 62 years (range: 33 to 83). Majority of patients were female (63%), 57% were White and 37% had an ECOG performance status of 0 (37%) or 1 (62%). All patients received at least 1 prior line of systemic therapy and 47% received two prior lines. Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease. Across both arms, 70% patients had an R132C mutation, 15% had an R132L mutation, 12% had an R132G mutation, 1.6% had an R132S mutation, and 1.1% had an R132H mutation.
The primary efficacy outcome measure was progression free survival (PFS) as determined by Independent Radiology Center (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, which was defined as time from randomisation to disease progression or death due to any cause.
Overall survival (OS) was a secondary efficacy endpoint. As allowed per protocol, a large proportion (70.5%) of patients in the placebo arm crossed over to receive Tibsovo following radiographic disease progression as assessed by the Investigator.
Efficacy results are summarised in Table 2. (See Table 2, Figures 2 and 3.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Tibsovo in all subsets of the paediatric population in the treatment of all conditions included in the category of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms) and in the treatment of malignant neoplasms of the central nervous system.
The European Medicines Agency has deferred the obligation to submit the results of studies with Tibsovo in one or more subsets of the paediatric population in the treatment of acute myeloid leukaemia (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: A total of 10 clinical studies have contributed to the characterisation of the clinical pharmacology of ivosidenib. Five studies have been conducted in healthy subjects and 3 studies have been conducted in patients with advanced malignancies including 2 studies in patients with cholangiocarcinoma. Two studies have been conducted in patients with newly diagnosed AML receiving ivosidenib in combination with azacitidine. Pharmacokinetic endpoints have been assessed in plasma and urine. Pharmacodynamic endpoints have been assessed in plasma, urine, tumour biopsy, and bone marrow (for studies in patients with advanced malignancies only).
The steady-state pharmacokinetics of ivosidenib 500 mg were comparable between patients with newly diagnosed AML and cholangiocarcinoma.
Absorption: After a single 500 mg oral dose, the median time to C_max (T_max) was approximately 2 hours in newly diagnosed AML patients treated with a combination of ivosidenib and azacitidine and in cholangiocarcinoma patients.
In patients with newly diagnosed AML treated with a combination of ivosidenib (500 mg daily dose) and azacitidine, the mean steady-state C_max was 6,145 ng/mL (CV%: 34) and the mean steady-state AUC was 106,326 ng hr/mL (CV%: 41).
In patients with cholangiocarcinoma, the mean C_max was 4,060 ng/mL (%CV: 45) after a single dose of 500 mg and 4,799 ng/mL (CV%: 33) at steady state for 500 mg daily. The AUC was 86,382 ng·hr/mL (CV%: 34).
Accumulation ratios were approximately 1.6 for AUC and 1.2 for C_max in patients with newly diagnosed AML treated with a combination of ivosidenib and azacitidine and approximately 1.5 for AUC and 1.2 for C_max in patients with cholangiocarcinoma, over one month, when ivosidenib was administered at 500 mg daily. Steady-state plasma levels were reached within 14 days of once daily dosing.
Significant increases in ivosidenib C_max (by approximately 98%; 90% CI: 79, 119) and AUC_inf (by approximately 25%) were observed following administration of a single dose with a high-fat meal (approximately 900 to 1,000 calories, 56% to 60% fat) in healthy subjects (see Dosage & Administration).
Distribution: Based on a population pharmacokinetic analysis the mean apparent volume of distribution of ivosidenib at steady-state (Vc/F) is 3.20 L/kg (CV%: 47.8) in patients with newly diagnosed AML treated with a combination of ivosidenib and azacitidine and 2.97 L/kg (CV%: 25.9) in patients with cholangiocarcinoma treated with ivosidenib monotherapy.
Biotransformation: Ivosidenib was the predominant component (>92%) of total radioactivity in plasma from healthy subjects. It is primarily metabolised by oxidative pathways mediated largely by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.
Ivosidenib induces CYP3A4 (including its own metabolism), CYP2B6, CYP2C8, CYP2C9, and may induce CYP2C19 and UGTs. Therefore, it may decrease systemic exposure to substrates of these enzymes (see Precautions, Interactions and Use in Pregnancy & Lactation).
Ivosidenib inhibits P-gp in vitro and has the potential to induce P-gp. Therefore, it may alter systemic exposure to active substances that are predominantly transported by P-gp (see Contraindications and Interactions).
In vitro data suggest that ivosidenib has the potential to inhibit OAT3, OATP1B1 and OATP1B3 at clinically relevant concentrations and it may, therefore, increase systemic exposure to OAT3, OATP1B1 or OATP1B3 substrates (see Interactions).
Elimination: In patients with newly diagnosed AML treated with a combination of ivosidenib and azacitidine, the mean apparent clearance of ivosidenib at steady state was 4.6 L/hour (35%) with a mean terminal half-life of 98 hours (42%).
In patients with cholangiocarcinoma, the mean apparent clearance of ivosidenib at steady state was 6.1 L/hour (31%) with a mean terminal half-life of 129 hours (102%).
In healthy subjects, 77% of a single ivosidenib oral dose was found in the faeces of which 67% was recovered unchanged. Approximately 17% of a single oral dose was found in the urine of which 10% was recovered unchanged.
Linearity/non-linearity: The AUC and C_max of ivosidenib increased in a less than dose proportional manner from 200 mg to 1,200 mg once daily (0.4 to 2.4 times the recommended dose).
Special populations: Elderly: No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed in older patients up to 84 years. The pharmacokinetics of ivosidenib in patients 85 years of age or older is unknown (see Dosage & Administration).
Renal impairment: No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed in patients with mild or moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or renal impairment requiring dialysis are unknown (see Dosage & Administration).
Hepatic impairment: Using the NCI classification, no clinically meaningful effects on the pharmacokinetics of ivosidenib were observed in patients with mild hepatic impairment. The pharmacokinetics of ivosidenib in patients with moderate and severe hepatic impairment are unknown in patients with newly diagnosed AML and with cholangiocarcinoma (see Dosage & Administration). No PK data in patients with hepatic impairment stratified by the Child-Pugh classification are available.
Other: No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on gender, race, body weight or ECOG performance status.
Toxicology: Preclinical safety data: Safety pharmacology: The potential of ivosidenib for QT prolongation was evidenced in in vitro and in vivo preclinical studies at clinically relevant plasma levels.
Repeat-dose toxicity: In animal studies at clinically relevant exposures, ivosidenib induced haematologic abnormalities (bone marrow hypocellularity, lymphoid depletion, decreased red cell mass together with extramedullary haematopoiesis in the spleen), gastrointestinal toxicity, thyroid findings (follicular cell hypertrophy/hyperplasia in rats), liver toxicity (elevated transaminases, increased weights, hepatocellular hypertrophy and necrosis in rats and hepatocellular hypertrophy associated with increased liver weights in monkeys) and kidney findings (tubular vacuolation and necrosis in rats). Toxic effects observed on haematologic system, GI system and kidney were reversible whereas the toxic effects observed on liver, spleen and thyroid were still observed at the end of the recovery period.
Genotoxicity and carcinogenicity: Ivosidenib was not mutagenic or clastogenic in conventional in vitro and in vivo genotoxicity assays. Carcinogenicity studies have not been conducted with ivosidenib.
Reproductive and developmental toxicity: Fertility studies have not been conducted with ivosidenib. In the 28-day repeat dose toxicity study in rats, uterine atrophy was observed in females at non-tolerated dose levels approximately 1.7-fold the clinical exposure (based on AUC) and 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 animals prematurely euthanized.
In embryofoetal development studies in rats, lower foetal body weights and delayed skeletal ossification occurred in the absence of maternal toxicity. In rabbits, maternal toxicity, spontaneous abortions, decreased foetal body weights, increased post implantation loss, delayed skeletal ossification and visceral development variation (small spleen) were observed. Animal studies indicate that ivosidenib crosses the placenta and is found in foetal plasma. In rats and rabbits, the no adverse effect levels for embryofoetal development were 0.4-fold and 1.4-fold the clinical exposure (based on AUC), respectively.