Summary Basis of Decision for Veozah

Clinical Pharmacology

The submitted clinical pharmacology data support the use of Veozah (fezolinetant) for the specified indication.

The pharmacokinetics of fezolinetant was studied in healthy male and female adults, and in postmenopausal women with vasomotor symptoms. In healthy women, the maximum observed plasma concentration (C_max) and the area under concentration-time curve (AUC) of fezolinetant increased proportionally with once-daily doses in the range of 20 to 60 mg. After once-daily dosing, steady-state plasma concentrations of fezolinetant were generally reached by Day 2, with minimal fezolinetant accumulation. The median time to reach the C_max of fezolinetant was 1.5 (range: 1 to 4) hours in healthy women. Based on population pharmacokinetic analysis, the pharmacokinetics of fezolinetant is similar in healthy premenopausal women and in postmenopausal women with vasomotor symptoms.

Fezolinetant is primarily metabolized by cytochrome P450 (CYP) 1A2 (and to a lesser extent by CYP2C9 and CYP2C19). The major metabolite, ES259564, is approximately 20-fold less potent than the parent compound. Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged).

Concomitant use of fezolinetant with CYP1A2 inhibitors can increase fezolinetant exposure to varying degree. Based on data from drug interaction studies and a model-based predictions, Veozah is contraindicated in patients using concomitant moderate or strong CYP1A2 inhibitors.

A model-based approach was conducted to assess the risk of QT prolongation potential of fezolinetant. At a dose 20 times the maximum recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent.

Veozah has not been studied in individuals with severe hepatic impairment. Based on the available pharmacokinetic data, Veozah is not recommended for use in individuals with moderate or severe hepatic impairment. Furthermore, it is contraindicated in individuals with cirrhosis. Veozah is also contraindicated in individuals with severe (estimated glomerular filtration rate [eGFR] less than 30 mL/min/1.73 m²) renal impairment and individuals with end-stage renal disease (eGFR less than 15 mL/min/1.73 m²).

No dose modification of Veozah is recommended for individuals with mild hepatic impairment and for individuals with mild or moderate renal impairment.

The exposure-response analyses for safety identified a potential association between fezolinetant exposure and the incidence of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than three times the upper limit of normal (ULN), based on data combined from Phase II and Phase III studies.

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

Clinical Efficacy

The primary evidence for the efficacy of Veozah in the treatment of moderate to severe vasomotor symptoms associated with menopause is derived from two pivotal Phase III studies of identical design, 2693-CL-0301 and 2693-CL-0302. Both studies included a 12-week double-blind placebo-controlled period followed by a 40-week extension period of active treatment without placebo control. The eligibility criteria were identical for both studies. Participants were between 40 and 65 years old and had moderate or severe vasomotor symptoms associated with clinically or hormonally confirmed menopause. The study population included postmenopausal women with one or more of the following: prior hysterectomy (32.1%), prior oophorectomy (21.6%), or prior hormone replacement therapy use (19.9%). At least seven moderate to severe episodes of vasomotor symptoms per day in the ten days before randomization into the studies were required.

In total, 341 postmenopausal women (174 in Study 2693-CL-0301 and 167 in Study 2693-CL-0302) received Veozah 45 mg daily and 342 postmenopausal women (175 in Study 2693-CL-0301 and 167 in Study 2693-CL-0302) received placebo. Both studies evaluated four co-primary efficacy endpoints:

• Mean change in frequency of moderate to severe vasomotor symptoms from baseline to Week 4

• Mean change in frequency of moderate to severe vasomotor symptoms from baseline to Week 12

• Mean change in severity of moderate to severe vasomotor symptoms from baseline to Week 4

• Mean change in severity of moderate to severe vasomotor symptoms from baseline to Week 12

In both studies, once-daily treatment with 45 mg of Veozah led consistently to statistically significant reductions from baseline in the frequency and severity of moderate to severe vasomotor symptoms compared to placebo at Week 4 and Week 12.

In Study 2693-CL-0301, Veozah reduced the frequency of moderate to severe vasomotor symptoms per 24 hours by 5.39 episodes from baseline to Week 4 and by 6.44 episodes from baseline to Week 12, compared to reductions of 3.32 and 3.90 episodes, respectively, in the placebo group. In Study 2693-CL-0302, Veozah reduced the frequency of moderate to severe vasomotor symptoms per 24 hours by 6.26 episodes from baseline to Week 4 and by 7.50 episodes from baseline to Week 12, while the placebo group showed reductions of 3.72 and 4.97 episodes, respectively.

The reduction in the frequency of hot flashes observed in the Veozah-treated participants was considered clinically meaningful in both studies, as it exceeded a clinically meaningful threshold reduction in the frequency of hot flashes defined by at least 2 episodes per day when compared to the placebo group. By Week 4, the reduction difference between the Veozah group and the placebo group was 2.07 episodes in Study 2693-CL-0301 and 2.55 episodes in Study 2693-CL-0302. The effect remained consistent through Week 12: the reduction differences between the Veozah group and the placebo group were 2.55 and 2.53 episodes in Study 2693-CL-0301 and Study 2693-CL-0302, respectively.

In study 2693-CL-0301, Veozah reduced the daily severity of vasomotor symptoms by 0.46 points at Week 4 and by 0.57 points at Week 12, compared to reductions of 0.27 points and 0.37 points, respectively, in the placebo group. In study 2693-CL-0302, Veozah reduced severity of vasomotor symptoms by 0.61 and 0.77 points at Week 4 and Week 12, respectively, while the placebo group showed reductions of 0.32 at Week 4 and 0.48 points at Week 12.

Indication

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

Veozah (fezolinetant film-coated tablets) is a non-hormonal selective neurokinin 3 receptor antagonist indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause.

Upon minor revisions, Health Canada approved the following indication:

Veozah (fezolinetant film-coated tablets) is indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause.

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

Clinical Safety

The primary evidence for the safety of Veozah in the treatment of moderate to severe vasomotor symptoms associated with menopause is derived from the two pivotal Phase III studies (2693-CL-0301 and 2693-CL-0302, described in the Clinical Efficacy section) and a Phase III, long-term, 52-week, placebo-controlled safety study (Study 2693-CL-0304).

In the three Phase III clinical studies, 2,203 participants received Veozah 30 mg or Veozah 45 mg once daily. Of these participants, 1,900 entered the 52-week treatment period, while 303 entered the 40-week treatment period.

In the 12-week placebo-controlled periods of the two pivotal studies, the most commonly reported adverse drug reaction in participants treated with Veozah 45 mg once daily (occurring in at least 2% of participants and more frequently than in participants treated with placebo) were liver test elevations (3.2% vs 2.6%) and abdominal pain (2.1% vs 2.0%).

In the 52-week placebo-controlled period of Study 2693-CL-0304, 1,220 women (609 of whom were receiving Veozah 45 mg once daily) were exposed to Veozah. The adverse drug reactions reported in at least 2% in participants treated with Veozah 45 mg and at higher incidence than in placebo-treated participants were headaches (9.7% vs 9.5%), liver test elevations (5.3% vs 4.8%), abdominal pain (4.4% vs 2.1%), diarrhea (3.9% vs 2.6%), insomnia (3.9% vs 1.8%), nausea (3.1.% vs 2.5%), fatigue (2.8% vs 2.6%), and hot flushes (2.5% vs 1.6%).

The primary safety concern identified for Veozah is the risk of elevated hepatic transaminases. In Study 2693-CL-0304, ALT or AST elevations greater than three times the ULN were reported in 2.0% (12/589) of women in the 45 mg Veozah group, compared to 1.0% (6/583) of women in the placebo group.

Across the three Phase III clinical trials, elevation in serum transaminases (ALT and/or AST) greater than three times the ULN occurred in 2.3% of women receiving Veozah (exposure-adjusted incidence rate [EAIR] of 2.7 per 100 person-years) compared to 0.9% of women receiving placebo (EAIR of 1.5 per 100 person-years). No cases of Hy’s Law were observed; however, one case of AST elevation greater than 20 times the ULN occurred during the first 12 weeks in the group receiving a lower dose of Veozah (30 mg) in Study 2693-CL-0301. Most women with ALT or AST elevations were asymptomatic, and transaminase levels generally returned to pretreatment levels without sequelae with dose continuation, and upon dose interruption or discontinuation.

It was concluded that Veozah, at the dosing regimens used in the clinical studies, is generally safe for the liver. However, given that these studies excluded patients with active liver disease, very high body mass index, or those taking drugs that strongly inhibit the metabolism of Veozah, the potential for more serious or progressive liver damage in the general population cannot be ruled out. Since Veozah is expected to be used in a large and diverse population, it remains possible that rare liver-related adverse events could occur. Based on the available clinical data, such cases are anticipated to be uncommon.

In the post-marketing setting, cases of serious but reversible hepatotoxicity have been reported within the first few weeks of treatment with Veozah: transaminase elevations (over 10 times the ULN) accompanied by increased bilirubin and/or alkaline phosphatase. Symptoms such as fatigue, pruritus, jaundice, dark urine, or abdominal pain were sometimes observed.

The risk of hepatotoxicity is addressed by appropriate warnings in the Veozah Product Monograph. Baseline evaluation of hepatic function (including ALT, AST, and serum bilirubin [total and direct]) is recommended prior to the initiation of treatment. Veozah should not be started if ALT or AST is equal to or exceeds two times the ULN or if the total bilirubin is elevated. If the ALT or AST level is greater than 1.5 times the ULN but lower than 2 times the ULN, Veozah should be used with caution. Furthermore, the Veozah Product Monograph recommends follow-up hepatic laboratory tests monthly for the first 3 months, at 6 months, and at 9 months after initiation of therapy and when symptoms (such as nausea, vomiting, or jaundice) suggest liver injury.

Additionally, in the long-term safety study (2693-CL-0304), a numeric imbalance was observed in the incidence of malignancy between the Veozah and placebo treatment groups: there were four cases of malignancy in three participants in the Veozah 30 mg treatment group, nine cases in seven participants in the Veozah 45 mg group, and one case in the placebo group. Two cases of basal cell carcinoma in one participant, one case of endometrial adenocarcinoma, and one case of squamous cell carcinoma of skin were reported in the Veozah 30 mg group. In the Veozah 45 mg group, there were two cases of endometrial adenocarcinoma, two cases of colon cancer, one case of malignant melanoma in situ, one case of non-small cell lung cancer with one case of hepatic cancer (suspected metastases) in one participant, and one case of squamous cell carcinoma of the oral cavity with one case of bone cancer (local advanced) in the mandible in one participant. The placebo group reported one case of squamous cell carcinoma of the forehead. These findings led to a thorough post hoc review across the Phase II and III studies, with a specific focus on malignant neoplasms. No potential concerns for malignant neoplasms in Phase IIa and IIb studies were identified by the sponsor. In Study 2693-CL-0301, one participant in the Veozah 45 mg group had benign lung neoplasm which was a pulmonary hematoma confirmed by histology, and one participant in the placebo group had apocrine breast carcinoma and squamous cell carcinoma of the skin. In Study 2693-CL-0302, two cases of squamous cell carcinoma were reported in two participants in the Veozah 45 mg group; one of the two cases was keratoacanthoma. One case of invasive breast carcinoma was reported in the placebo/Veozah 30 mg group (onset on Day 151).

The malignancies observed were consistent with the types commonly seen in the study population, and no clear evidence links Veozah to an increased risk of malignancy. However, there are insufficient data to exclude an association between exposure to Veozah and an increased risk of malignancy or an increased risk of progression in patients with pre-existing neoplastic lesions. This information is included in the Warnings and Precautions section of the Veozah Product Monograph.

Endometrial safety was also evaluated in the clinical studies of Veozah. Endometrial biopsy assessments in Study 2693-CL-0304 detected simple hyperplasia without atypia in one participant in the Veozah 45 mg group and endometrial adenocarcinoma in one participant in the Veozah 30 mg group. Across the three Phase III studies, the Veozah 45 mg group had one case of endometrial hyperplasia and one case of endometrial malignancy (0.6%, with a one-sided 95% confidence upper bound of 1.8%). The incidence of these events remained less than or equal to 1%, with the upper bound of the one-sided 95% confidence interval less than or equal to 4%. No cases of endometrial hyperplasia or carcinoma were observed in the placebo group.

Overall, based on the reviewed data, the safety profile of Veozah is considered acceptable for the intended patient population. Appropriate warnings and precautions are in place in the approved Veozah Product Monograph to address the identified safety concerns.

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

Fezolinetant, the medicinal ingredient in Veozah is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center.

In vitro, fezolinetant demonstrates a high affinity for the human NK3 receptor (with inhibitory constant [Ki] values of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than its binding affinity to human NK1 or human NK2 receptors. The major metabolite, ES259564, has approximately a 20-fold weaker affinity for human NK3 receptors as compared to fezolinetant. Both fezolinetant and its major metabolite have no significant off-target effects (as tested on other receptors, ion channels, transporters, and enzymes).

In vivo pharmacodynamic studies demonstrated that fezolinetant attenuated hot flash-like symptoms in ovariectomized rats (a non-clinical model for menopausal vasomotor symptoms). In these rats, fezolinetant decreased plasma levels of luteinizing hormone, but it had no effect on plasma levels of follicle-stimulating hormone, estradiol, progesterone, and testosterone.

The safety pharmacology studies of fezolinetant did not reveal any serious adverse effects on the central nervous, cardiovascular, and respiratory systems at clinically relevant doses.

The pharmacokinetics of fezolinetant was thoroughly evaluated in rats and cynomolgus monkeys. After oral dosing, fezolinetant is rapidly and readily absorbed, broadly distributed into tissues, extensively metabolized, and most of the dose is excreted via urine or feces within 48 hours of administration. Following administration of radiolabelled fezolinetant to pregnant rats, radioactive components were found in the amniotic fluid and in the fetus, indicating transplacental transfer. Furthermore, following administration of radiolabelled fezolinetant to lactating rats, radioactive components were present in the milk and in the tissues of offspring.

Repeated-dose toxicity studies of fezolinetant were conducted in rats for 4, 13, and 26 weeks. Total cholesterol levels were increased at all doses used (greater than or equal to 30 mg/kg). At doses greater than or equal to 100 mg/kg, drug-related adverse effects included sedation-like central nervous system clinical signs, increase in liver and thyroid weights, and microscopic findings of centrilobular hepatocellular hypertrophy and thyroid follicular cell hypertrophy. At the no-adverse-effect level (NOAEL; 30 mg/kg/day), the safety margin was approximately 58-fold the area under the concentration-time curve from zero to 24 hours (AUC₂₄) at the human therapeutic dose. Secondary effects seen in the liver and thyroid are considered to be an adaptive response to the enzyme induction specific to rats.

Repeated-dose toxicity studies of fezolinetant were also conducted in cynomolgus monkeys (with duration of 5, 13, and 39 weeks). A dose of 40 mg/kg/day was associated with mortality in one animal. The moribund animal showed acute hemorrhagic anemia and severe thrombocytopenia. Thrombocytopenia was also observed in one surviving animal at the dose of 40 mg/kg/day, but not in the remaining two animals. At the NOAEL (25 mg/kg/day), the safety margin was 43-fold the AUC₂₄ at the human therapeutic dose. Bone mass of cynomolgus monkeys was not affected after long-term administration of fezolinetant.

In genotoxicity studies, fezolinetant and ES259564 did not exhibit genotoxic potential. In a 2-year rat carcinogenicity study, an increased incidence of thyroid follicular cell adenoma was reported at the dose of 100 mg/kg dose (186-fold the human AUC₂₄ at the human therapeutic dose). The increase is considered to be a rat-specific effect secondary to the induction of hepatocyte metabolic enzymes and, therefore, does not constitute a clinical carcinogenic risk. Additionally, increased incidence of benign thymomas, which slightly exceeded the historical control range, was observed at the dose of 100 mg/kg. Given that these findings were only noted at exposure levels significantly in excess (greater than 50-fold) of the clinical exposure at the human therapeutic dose, they are not expected to be relevant to humans.

In reproductive and developmental toxicity studies, fezolinetant had no effect on female fertility or early embryonic development at doses of up to 100 mg/kg/day in rats (143-fold the AUC₂₄ at the human therapeutic dose). Embryo lethality was noted at a dose of 100 mg/kg/day in rats and 125 mg/kg/day in rabbits. The NOAEL for embryo-fetal toxicity was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16-fold the AUC₂₄ at the human therapeutic dose, respectively). Fezolinetant did not show teratogenic potential in either rats or rabbits. In the prenatal and postnatal development study in rats, the male offspring (F1 generation) showed delayed male reproductive maturation that affected fertility. The NOAEL for F1 generation development was determined to be 10 mg/kg/day for males (11-fold the AUC₂₄ at the human therapeutic dose) and 100 mg/kg/day for females (204-fold the AUC₂₄ at the human therapeutic dose). The adverse effects of fezolinetant on pregnancy and male offspring were considered to be part of its pharmacological actions. Given that the intended treatment population is postmenopausal women, these effects on reproduction and development are not considered to be clinically relevant. Importantly, based on the animal studies, Veozah is contraindicated in pregnancy.

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

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

The quality (chemistry and manufacturing) information submitted for Veozah has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies). 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. In addition, none of the excipients are of human or animal origin.