Regulatory Decision Summary for Voranigo

The purpose of this New Drug Submission (NDS) was for Servier Canada Inc. to obtain market authorization for Voranigo (vorasidenib) 10 milligrams (mg) and 40 mg for oral administrations (recommended dose 40 mg once daily).

The proposed indication was for the treatment of predominantly non-enhancing astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) or or isocitrate dehydrogenase-2 (IDH2) mutation in adults and pediatric patients 12 years and older following surgical intervention. Upon review, the final accepted indication for Voranigo (vorasidenib) was for the treatment of Grade 2^a astrocytoma or oligodendroglioma with a susceptible IDH1 mutation or IDH2 mutation in adults and pediatric patients aged 12 years and older following surgical intervention.

^aWorld Health Organization (WHO) 2016, 2021 grading system

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

The NDS for Voranigo was filed and accepted for review under the Priority Review Policy. This review was conducted under Project Orbis Type A, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the United States FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada, Switzerland’s SwissMedic, and Israel’s Ministry of Health (IMoH). The Canadian regulatory decision on the review of vorasidenib was based on a critical assessment of the data package submitted to Health Canada.

Gliomas (astrocytoma or oligodendroglioma) are the most common primary malignant brain tumours, and IDH1 and IDH2 mutations occur in approximately 80% and 4% of the Grade 2 and Grade 3 tumours, respectively. These tumours occur in young, otherwise healthy patients with a median age of approximately 40 years (range 12 to 75 years) and reduce the patient’s overall life expectancy. Low-grade gliomas (LGGs) are continuous indolently growing tumours that generally progress over months to years but over time can cause mass effect on the surrounding brain structures. IDH is part of the normal Kreb’s cycle – with mutation of this enzyme being a gain of function event resulting in overproduction of 2-hydroxyglutarate (2-HG). Nicotinamide adenine dinucleotide phosphate (NADPH) production is impaired in gliomas with IDH mutations, which may sensitize the tumours to radiation and chemotherapy, explaining why typically patients with IDH mutant neoplasms live longer. The mechanism of action of vorasidenib is that it is potent, selective, reversible, brain-penetrant, dual inhibitor of IDH1- and IDH2-mutant proteins.

There are currently no approved therapies for Grade 2 IDH-mutant diffuse gliomas, and current available therapies are limited and adapted from the higher-grade setting. These treatments are not curative and are associated with short- and long-term toxicities including neurocognitive decline. Following maximal safe surgical resection, “watch and wait” is considered the standard of care.

The pivotal study Indigo (AG881-C-004) was a Phase 3, randomized, multicenter, double-blind, placebo-controlled trial. Efficacy was evaluated in total of 331 patients with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery (n = 168 received vorasidenib and n = 163 placebo). Patients were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity. Patients randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression. Patients who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.

Vorasidenib demonstrated significant clinical activity across the primary and key secondary efficacy outcome measures. Specifically, vorasidenib met its primary endpoint with a statistically significant improvement in progression-free survival (PFS) (defined as the time from randomization to the first occurrence of radiologic disease progression by Response Assessment in Neuro-Oncology – Low grade gliomas (RANO-LGG) per blinded independent central review (BICR) or death due to any cause whichever occurred first) in non-enhancing Grade 2 IDH-mutant gliomas compared with placebo with an hazard ratio (HR) of 0.39 (95% confidence interval [CI], 0.27, 0.56; P = 0.000000067). It also showed a statistically significant improvement in the key secondary endpoint, time to next intervention (TTNI) (defined by time from randomization to the initiation of first subsequent anticancer therapy or death of any cause) 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 which further supports the clinical benefit in delaying disease progression.

The safety profile of Voranigo was primarily supported by the pivotal study Indigo (AG881-C-004) which included 167 patients who received at least one dose of vorasidenib 40 mg. The most common (≥ 10%) adverse reactions including laboratory abnormalities reported were alanine aminotransferase (ALT) increased (36.5%), aspartate aminotransferase (AST) increased (24.6%), gamma-glutamyl transferase (GGT) increased (13.2%) and diarrhea (12.0%). These events were reversible with dose modification or discontinuation.

The most common grade ≥ 3 adverse reactions were ALT increased (9.6%), AST increased (4.2%) and GGT increased (2.4%). Serious adverse reactions were reported in 0.6% of patients who received Voranigo. The most common serious adverse reaction was ALT increased (0.6%). Permanent discontinuation of Voranigo was reported in 3% of patients. The most common grade ≥ 3 adverse reactions leading to permanent discontinuation was ALT increased (3.0%). Dose interruptions due to an adverse reaction occurred in 18.6% of patients treated with Voranigo. The most common adverse reactions requiring dose interruption were ALT increased (14.4%) and AST increased (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 ALT increased (7.8%).

No deaths were observed during the pivotal trial duration.

Vorasidenib is meant to be used until disease progression or toxicity occurs, which may be for a prolonged period of time. Long-term safety is not known for vorasidenib, however will be monitored in the post-market setting, including for pediatric patients. Overall, the safety profile of Voranigo was considered acceptable and manageable.

Patients who received vorasidenib with moderate hepatic impairment (Child Pugh B) did not go on to have clinically relevant changes in total or free (unbound) vorasidenib concentrations and pharmacokinetic (PK) parameters. The PK and safety of vorasidenib have not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Population PK modeling showed that the important covariates for vorasidenib exposure levels were sex, body weight and race. Patients with low body weight (e.g., 40-60 kilograms [kg]) tended to have approximately 36% higher exposure levels (C_max, area under the curve (AUC) and C_trough) compared to the reference group. In repeat dose animal studies, some of the vorasidenib-related effects observed in 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 (RBC) count, reticulocyte count) and coagulation parameters (e.g., fibrinogen), 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. 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 ≥ 5 mg/kg/day (approximately 29-fold the daily maximum recommended human dose (MRHD) based on AUC).

The recommended dose of vorasidenib for patients with glioma who harbor IDH1 and/or IDH2 mutations is 40 mg (F2) taken orally once daily (QD). No significant clinical effect was observed with food (low-fat meal compared to fasted condition). The potential effect of increased vorasidenib exposure after administration of Voranigo with food is unknown as the proposed product was administered under modified fasted conditions in the pivotal Phase 3 Indigo study. Voranigo is proposed to be taken under modified fasted conditions (food restricted for 2 hours before and 1 hour after dosing).

Co-administration with omeprazole did not have a significant effect on vorasidenib exposure. Drug-Drug Interactions (DDI) studies showed that concomitant use of strong and moderate CYP1A2 inhibitors with Voranigo should be avoided and alternative therapies should be considered. The concomitant use of Voranigo with moderate CYP1A2 inducers, with smoking tobacco (a known CYP1A inducer), with CYP2C19 and with CYP3A4 substrates where minimal concentration changes may lead to reduced efficacy also should be avoided.

One of the review issues was the inclusion of the pediatric indication for patients ≥ 12 years of age given that there was no clinical data available. Pediatric IDH1/2 mutated LGGs are exceedingly rare but can cause significant disease burden in children whose only current treatment options are off-label use of drugs and radiation that are adapted from the high-grade glioma setting. These current treatments have a significant morbidity, both in the short- and long-term, for a pediatric population. Thus, treatment of these tumours remains a significant unmet medical need. In the pivotal study (Indigo, AG881-C-004) patients ≥ 12 years of age were eligible to participate; however, there was only 1 adolescent patient that was enrolled. Upon unblinding, this patient was determined to be in placebo arm; thus, no clinical data was 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. In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human use (ICH) E11 guidelines, the pathophysiology and expected biological similarities in the behaviour and response of adult-type diffuse LGGs that occur in patients between 12 to 18 years of age are reasonably similar. Additionally, using an exposure matching approach, simulations of vorasidenib PK in adolescent patients were performed, which showed that adult exposures could be matched with the exposure of 40 mg in adolescent patients with a body weight ≥ 40 kg or the exposure of 20 mg in the adolescent patients with a body weight < 40 kg, whereas patients between 40 and 50 kg may have a higher exposure. This may result in a higher risk of elevated liver enzymes in the female adolescent population between 40 and 50 kg. This uncertainty has been explicitly labelled for in the Product Monograph. Based on the totality of data, including similarity of disease between adults and pediatrics and the acceptability of the PK modelling, pediatric extrapolation for patients ≥ 12 years of age was felt to be acceptable.

A Risk Management Plan (RMP) for Voranigo (vorasidenib) was submitted by the Sponsor (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.

Taken together, there was substantial evidence to demonstrate a favorable benefit-risk profile for vorasidenib for the treatment the treatment of Grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation or isocitrate dehydrogenase-2 (IDH2) mutation in adults and pediatric patients aged 12 years and older following surgical intervention. On the basis of the information reviewed, Voranigo presented an acceptable and manageable safety profile in consideration of the intended populations. Based on the benefit-risk-uncertainty profile of the product, it was recommended that Voranigo be granted authorization.

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