Summary Basis of Decision for Voranigo

Clinical Pharmacology

Vorasidenib, the medicinal ingredient in Voranigo, is a small molecule inhibitor of the isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) enzymes. It has been shown to inhibit IDH1 and IDH2 wild type and variants, including IDH1 R132H in both in vitro and in vivo tumour models expressing IDH1 or IDH2 proteins. Vorasidenib has also been shown to decrease the production of 2-hydroxyglutarate (2-HG) and may restore cellular differentiation.

Pharmacodynamics

The pharmacodynamics of vorasidenib were evaluated in the perioperative Study AG120-881-C-001, conducted in participants with recurrent non-enhancing Grade 2/3 lower grade glioma with an IDH1 R132H mutation for whom surgical resection was indicated. Subjects who were candidates for clinical resection were treated during a pre-surgery period for 4 weeks (+7 days additional dosing was allowed) up to and including the day of surgery to allow time to achieve steady state exposure in the tumour.

Overall, the results of this study demonstrated the brain penetrance of vorasidenib at different doses. Following pre-surgical treatment with vorasidenib, the concentration of the oncometabolite 2-HG decreased in resected tumour tissue from patients with IDH1 mutated gliomas. The percentage reduction of 2-HG was 92.6% in tumours from participants treated with vorasidenib 50 mg once daily (QD), and 63.5% in tumours from subjects treated with vorasidenib 10 mg QD, relative to tumours from subjects in the untreated group. It is noted that the brain tumour tissue drug concentration seemed to correlate with higher dosing.

Cardiac Electrophysiology

Vorasidenib did not prolong the QT interval to any clinically relevant extent at four times the recommended therapeutic dosage.

Pharmacokinetics

Absorption

Vorasidenib maximum plasma concentration (C_max) and area under the concentration-time curve (AUC) increase in a proportional manner between 10 and 50 mg.

Vorasidenib steady state mean (CV%) C_max was 133 ng/mL (73%) and AUC was 1,988 hr∙ng/mL (95%). Accumulation ratios were approximately 3.83 for C_max and 4.43 for AUC. Steady-state plasma levels were reached after 14 days of once-daily dosing.

The comparative bioavailability of two different formulations of vorasidenib tablets (50 mg) was assessed in healthy participants under fasted conditions in Study AG881-C-007. Furthermore, this study investigated the effect of high-fat, high-calorie fed conditions as well as the effect of an acid-reducing agent (omeprazole) on the absorption of vorasidenib. In addition, data was provided from Study PKH-95032-009 (Substudy A), which evaluated the effect of low-fat, low-calorie, fed conditions on the absorption of vorasidenib administered as a single oral dose (40 mg) to healthy participants.

The mean C_max and the AUC over the dosing interval (AUC_T) increased by 3.1-fold and 1.4-fold, respectively, when vorasidenib was administered with a high-fat meal. The administration of vorasidenib with a low-fat meal resulted in increases in C_max and AUC_T of 2.3- and 1.4-fold, respectively. In both cases, meals were administered 30 minutes prior to the administration of Voranigo.

The potential effect of increased vorasidenib exposure after administration with food is unknown as Voranigo was administered under modified fasted conditions in the pivotal Phase III INDIGO Study (discussed in the Clinical Efficacy section). The Product Monograph for Voranigo includes the recommendation that food not be consumed for at least 2 hours before and 1 hour after administration of Voranigo.

Distribution

The vorasidenib steady state mean (CV%) volume of distribution (Vd/F) is 3,930 L (40%). The mean plasma protein binding of vorasidenib is 97%, independent of concentration. The brain tumour-to-plasma concentration ratio is 1.6.

Metabolism

Vorasidenib is primarily metabolized by cytochrome P450 (CYP)1A2 with minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. Non-CYP pathways may contribute up to 30% of vorasidenib liver metabolic clearance.

Elimination

Following oral administration of radiolabeled vorasidenib, 85% of the dose was recovered in feces and 4.5% in urine. Most of the administered radioactivity that was recovered in feces was unchanged vorasidenib (55%) while no unchanged vorasidenib was detected in urine.

Special Populations

Population pharmacokinetic modeling and multivariate analysis showed that important covariates for vorasidenib exposure levels were sex, body weight, and race. Subjects with low body weight (e.g., 40 to 60 kg) tended to have approximately 36% higher exposure levels (C_max and AUC) compared to the reference group. This result should be interpreted with caution considering the presence of a confounding factor, sex, on body weight (sex-ratio imbalance for lower body weight, with females being more represented than males).

The administration of Voranigo in participants with moderate hepatic impairment (Child-Pugh Class B) did not lead to clinically relevant changes in total or free (unbound) vorasidenib concentrations or pharmacokinetic parameters. The pharmacokinetics and safety of vorasidenib have not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

The pharmacokinetics and safety of Voranigo have not been investigated in a dedicated study for patients with renal impairment as renal excretion is a minor route of elimination (4.52% urinary total radioactivity recovery). No clinically significant effects on the pharmacokinetics of vorasidenib were observed based on mild or moderate renal impairment (creatine clearance [CrCl] greater than 40 mL/min). The pharmacokinetics of vorasidenib have not been studied in patients with CrCl 40 mL/min or lower or in patients with renal impairment requiring dialysis. Voranigo should be used with caution in patients with renal impairment.

No patients under the age of 18 were treated with Voranigo in the pivotal Phase III INDIGO study. The use of Voranigo in pediatric patients 12 years and older is supported by evidence from studies in adults with additional population pharmacokinetic data demonstrating that age had no clinically meaningful effect on the pharmacokinetics of vorasidenib. Additionally, the results indicated that the exposure of vorasidenib is mostly similar between adults and pediatric patients age 12 years and older, and that the course of disease is sufficiently similar in adult and pediatric patients to allow extrapolation of data in adults to pediatric patients. Analysis of the population pharmacokinetic modelling indicated that female pediatric patients in the 40 to 50 kg weight range may have a higher exposure and a higher risk of adverse drug reactions.

Drug-Drug Interactions

Based on the results of drug-drug interactions studies, the concomitant use of Voranigo with strong and moderate CYP1A2 inhibitors should be avoided and alternative therapies should be considered. In addition, the concomitant use of Voranigo with moderate CYP1A2 inducers, with smoking tobacco (a known CYP1A inducer), with CYP2C19, and with CYP3A4 substrates should be avoided, as minimal concentration changes may lead to reduced efficacy.

The pharmacokinetics of vorasidenib were also investigated after co-administration with an acid-reducing agent (omeprazole) under fasted conditions. Co-administration with omeprazole did not have a significant effect on vorasidenib exposure.

The clinical pharmacology data support the use of Voranigo for the recommended indication. For further details, please refer to the Voranigo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Voranigo was supported by data from the pivotal Phase III, randomized, multicentre, double-blind, placebo-controlled Indigo study (AG881-C-004). Efficacy was evaluated in 331 patients with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery. Patients were randomized 1:1 to receive once-daily oral doses of Voranigo 40 mg (total number [n] = 168) or placebo (n = 163) until radiographic disease progression or unacceptable toxicity occurred. Patients randomized to treatment with placebo were allowed to cross over to treatment with Voranigo after documented radiographic disease progression. Patients who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded from the study.

The demographic and baseline disease characteristics for both the Voranigo and placebo arms were representative of the patient population. There were slight differences in some key baseline characteristics and surgical details between the two arms. The mean time from initial diagnosis to randomization was longer by 2 months for the Voranigo group (39.60 months) versus [vs.] the placebo group (37.52 months). Imbalances also existed for the number of prior glioma surgeries, with a higher proportion of patients in the Voranigo arm having more than two surgeries as compared to the placebo arm (25.0% vs. 17.8%). These imbalances did not have an effect on the efficacy results. Among the 168 patients randomized to Voranigo, the median age was 41 years (range: 21 to 71 years), with 98.8% aged 18 to 64 years. A single pediatric patient aged 16 years was randomized to placebo, and no patient under the age of 18 years was randomized to Voranigo. Among the 168 patients randomized to Voranigo, a majority of patients were male (60.1%), 74.4% were White, 3.0% Asian, 1.2% Black, 1.2% other, and 19.6% not reported. Most patients had one prior surgery for glioma (75%) and 25% had two or more prior surgeries. Across both arms, 95% of patients had an IDH1 R132 mutation and 5% had an IDH2 R172 mutation.

The primary efficacy data were presented from the pre-specified interim analysis two (IA2) timepoint, at which point the independent data monitoring committee recommended stopping the study early due to efficacy. The primary efficacy outcome measure was radiographic progression-free survival (PFS) as evaluated by a blinded independent review committee, according to modified Response Assessment in Neuro-Oncology for Low Grade Glioma (RANO-LGG) criteria. Progression-free survival was defined as the time from randomization to the first occurrence of radiographic disease progression or death due to any cause. Time to next intervention (TTNI), the time from randomization to the initiation of first subsequent anticancer therapy or death due to any cause, was the key secondary outcome measure.

The results of the pivotal study demonstrated that Voranigo had significant clinical activity across the primary and key secondary efficacy outcome measures. Specifically, Voranigo showed a statistically significant improvement in the primary efficacy outcome of PFS in non-enhancing Grade 2 IDH-mutant gliomas compared with placebo with a hazard ratio (HR) of 0.39 (95% confidence interval [CI]: 0.27, 0.56; p = 0.000000067). Progression-free survival results were consistent (favouring Voranigo) across all prespecified subgroups, including age (less than 40 years vs. 40 years or older), baseline tumour size (less than 2 cm vs. 2 cm or larger), and 1p19q codeletion status (codeleted vs. not codeleted).

Voranigo also showed a statistically significant improvement in the key secondary endpoint of TTNI compared with placebo with an HR of 0.26 (95% CI, 0.15, 0.43; p = 0.000000019), indicating a delay in the need for another intervention. This further supports the clinical benefit in delaying disease progression.

Other secondary endpoints included overall survival (OS) which, in this disease setting, is expected to span over a decade, making this endpoint less practical to assess in a timely manner as a measure of the clinical benefit of Voranigo. As of the data cutoff for IA2, no death events were reported in either arm. Survival follow-up will continue to be collected per protocol for up to 5 years after randomization of the last patient or until the protocol-defined criteria are met. Of note, OS has been well correlated with PFS in large European registry studies. Further, patients treated with Voranigo showed durable response as evidenced by a duration of response of 16.6 months (95% CI: 2.8, 16.6). Prior to receiving Voranigo or placebo, tumours showed continuous growth. Post-treatment tumour volume decreased in patients randomized to Voranigo, indicating that Voranigo induced tumour shrinkage. Tumour volume increased in patients randomized to the placebo arm. Patients with progressive disease on placebo who crossed over to receive Voranigo treatment had a clinically meaningful decrease in tumour growth rate. Treatment with Voranigo preserved patients' high baseline health-related quality of life (HRQOL) and maintained seizure control and neurocognitive function, further supporting the delay in progression and time to next intervention.

In the pivotal study, patients 12 years of age and older were eligible to participate, however, only one adolescent patient enrolled. Upon unblinding, it was determined that this patient was in the placebo arm, therefore, no clinical data were available for the adolescent population. Considering the rarity of IDH mutations in adult-type gliomas occurring in pediatric or adolescent patients, it is not considered feasible to conduct adequate studies in the pediatric population. Given the epidemiology of low-grade gliomas, and the expected biological similarities in the behaviour and response of adult-type diffuse low-grade gliomas that occur in patients between 12 to 18 years of age and older patients, as well as data that support similar drug exposures and support from the population pharmacokinetic modelling in adolescent and adult patients, data generated from the adult population are considered generalizable to pediatric patients. Thus, the standards for disease similarity for the pediatric extrapolation framework based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E11A guidelines have been met.

Based on the totality of the evidence coupled with a favourable benefit-harm-uncertainty profile in adults, it was concluded that Voranigo should be granted market authorization for pediatric patients 12 years of age and older.

Indication

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

Voranigo (vorasidenib) is indicated for the treatment of predominantly non-enhancing astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, in adults and pediatric patients 12 years and older following surgical intervention.

Upon review, the proposed indication was revised to reflect the clinical study patient population. Accordingly, Health Canada approved the following indication:

Voranigo (vorasidenib) is indicated for the treatment of Grade 2 astrocytoma or oligodendroglioma (based on the World Health Organization 2016, 2021 grading system) with a susceptible IDH1 mutation or IDH2 mutation in adults and pediatric patients aged 12 years and older following surgical intervention.

Treatment with Voranigo should be initiated following confirmation of an IDH1 or IDH2 mutation through a validated test.

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

Clinical Safety

The clinical safety of Voranigo was primarily supported by data from the pivotal INDIGO study discussed in the Clinical Efficacy section. This study included 167 patients who received at least one dose of Voranigo 40 mg. Hepatotoxicity was an important identified risk of Voranigo and elevated liver transaminases were the most common adverse drug reactions. In the INDIGO study, the most common adverse reactions (occurring in 10% or more of participants) reported, including laboratory abnormalities, were increased alanine aminotransferase (ALT; 36.5%), increased aspartate aminotransferase (AST; 24.6%), fatigue (23.4%), increased gamma-glutamyl transferase (GGT; 13.2%), and diarrhea (12.0%). These events were reversible with dose modification or discontinuation. The most common Grade 3 or higher adverse reactions were increased ALT (9.6%), increased AST (4.2%), and increased GGT (2.4%).

Serious adverse reactions were reported in 0.6% of patients who were treated with Voranigo. The most common serious adverse reaction was increased ALT (0.6%). Three percent of patients discontinued Voranigo permanently. The most common Grade 3 or higher adverse reaction that led to permanent discontinuation was increased ALT (3.0%). Of the patients treated with Voranigo, 18.6% had a dose interruption due to an adverse reaction with most being due to increased ALT (14.4%) or increased AST (6.0%). Dose reductions of Voranigo due to an adverse reaction occurred in 10.2% of patients. The most common adverse reaction requiring dose reduction was increased ALT (7.8%). No deaths were observed during the pivotal study.

Voranigo is intended to be used until radiographic or clinical disease progression or unacceptable toxicity occurs, which may be for a prolonged period of time. The long-term safety of Voranigo is not known, however this will be monitored in the post-market setting, including for pediatric patients.

Overall, the safety profile of Voranigo was considered acceptable and manageable. Appropriate warnings and precautions are in place in the approved Voranigo Product Monograph to address the identified safety concerns.

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

Data from in vitro and in vivo tumour models expressing IDH1 or IDH2 proteins showed that vorasidenib inhibited the IDH1 and IDH2 wild type and variants, including IDH1 R132H, R132C, R132L, R132G, R132H and R132 and IDH2 R140Q. In addition, vorasidenib decreased the production of 2-HG and may restore cellular differentiation.

Vorasidenib was evaluated for its potential to inhibit binding and enzymatic activity in a panel of 89 receptors, ion channels, and enzymes. Further, vorasidenib is a weak inhibitor of the adenosine A3 receptor, however, it is not expected to cause the inhibition of this receptor at therapeutic concentrations. The pharmacokinetics of vorasidenib is characterized by rapid oral absorption; low total plasma clearance (CLp) in mice, rats, and monkeys, and high CLp in dogs; and high volume of distribution at steady state in mice, rats, dogs, and monkeys.

The half-life of vorasidenib was difficult to calculate in repeat-dose studies in rats and monkeys, but in single oral dose studies, half-life varied from 9 h in mice to 16 h in dogs and 31 h monkeys. In the same repeat-dose studies, plasma accumulation of vorasidenib ranged from 2.7- to 8.5-fold in rats and 1.5- to 5.0-fold in monkeys over the duration of the study. Vorasidenib is a highly bound drug with 95% or greater plasma protein binding with slight interspecies variability (among human, monkey, dog, rat, and mouse). The binding of the drug in plasma was not dependent on its concentration. In non-clinical species, metabolism is the major elimination pathway for vorasidenib. The excretion of unchanged vorasidenib in the bile of rat and in the urine of rat, dog, and monkey were negligible.

In repeat-dose studies, vorasidenib was administered orally in Sprague Dawley rats (both sexes) for 13 weeks at daily doses of 5, 15, and 50 mg/kg (up to 176-fold the maximum recommended human dose [MRHD] of 40 mg based on AUC), and in cynomolgus monkeys (both sexes) for 13 weeks at daily doses of 2, 6, and 20 mg/kg (up to 73-fold the MRHD of 40 mg based on AUC). Some of the vorasidenib-related effects observed in the two species were considered relevant to humans, such as hepatocellular hypertrophy and changes in liver enzymes, changes in some hematology (e.g., red blood cell count and reticulocyte count) and coagulation parameters (e.g., fibrinogen), and adverse effects on reproductive organs (both species). Effects on the neuromuscular system (e.g., tremor, decrease in muscle tone), on the skin (e.g., redness and hyperplasia), and on the kidneys (e.g., tubular degeneration) were observed in the mid and/or high dose groups of both species (rats and monkeys) and may be relevant to humans.

Vorasidenib does not present a genotoxic risk at maximum recommended concentrations/dose limits. Also, the metabolite AGI-69460 was not mutagenic.

The fertility data in both male and female rats from a general toxicology study were considered acceptable in lieu of a long-term fertility animal study. The main toxicity findings on fertility were adverse effects in both female and male rat reproductive organs (i.e., changes in organ weights and microscopic findings) at doses of 5 mg/kg/day or more (approximately 29-fold the daily MRHD based on AUC). After a recovery phase of 4 weeks, partial recovery was observed in both sexes at doses of at least 15 mg/kg/day (at least 77-fold the MRHD of 40 mg based on AUC).

Embryo-fetal development was evaluated in pregnant rats and pregnant rabbits administered vorasidenib orally during organogenesis. Following daily administration, increases in embryo-fetal resorptions and post-implantation losses were observed, and fetal body weights were lower than concurrent controls. In rats, a higher incidence of visceral abnormalities were observed at highest dose and higher incidences of skeletal abnormalities were observed at all dose levels (at least 31-fold the MRHD based on AUC). In rabbits, a higher incidence of delayed ossification and other skeletal variations were observed at daily doses of at least 6 mg/kg/day (exposure of at least 5-fold the MRHD based on AUC). In both species, dose-dependent decreases in maternal food intake and body weight gain were observed during gestation.

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

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

The quality (chemistry and manufacturing) information submitted for Voranigo 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 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

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.

One excipient in the film coating material, lactose monohydrate, is of animal origin. The milk used in the manufacture of the lactose monohydrate component is sourced from healthy animals under the same conditions as those used to collect milk for human consumption. A statement confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this drug product indicating that it is considered to be safe for human use.