Regulatory Decision Summary for Veozah

This New Drug Submission (NDS) was filed to obtain market authorization for Veozah (fezolinetant) for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause. The Canadian regulatory decision on the review of Veozah was based on a critical assessment of the data package submitted to Health Canada.

Menopause, occurring at a median age of 51.4 years, is defined as the permanent cessation of ovarian function, following 12 consecutive months of amenorrhea. It is frequently accompanied by vasomotor symptoms (VMS) such as hot flashes and night sweats, affecting up to 80% of women.

In Canada, menopausal hormone therapy (MHT) is the primary and most effective treatment for VMS, with options including oral, transdermal, and vaginal formulations. However, MHT has contraindications and associated serious health risks, notably the potential for endometrial cancer with unopposed estrogen therapy and breast cancer with combined estrogen and progestin therapy. As a result, non-hormonal options like selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin and clonidine provide alternative treatment, with clonidine being the only non-hormonal therapy approved for VMS in Canada. These alternatives, however, are generally not as effective as MHT.

The efficacy assessment of Veozah relies on two identically designed pivotal phase 3 trials. In study 2693-CL-0301 and study 2693-CL-0302, a total of 341 (174 and 167, respectively) post-menopausal women received Veozah 45 mg and 342 (175 and 167, respectively) received placebo. The 4 co-primary endpoints supporting the indication were the same in both studies: the change from baseline in moderate to severe VMS frequency and severity to weeks 4 and 12. Veozah 45 mg achieved statistical significance versus placebo consistently across the 4 co-primary VMS endpoints in both study at Week 4 through Week 12. In study 2693-CL-0301, Veozah reduced VMS frequency by 5.39 episodes at week 4 and 6.44 episodes at week 12 versus placebo reductions of 3.32 and 3.90 episodes, respectively. In study 2693-CL-0302, Veozah reduced frequency by 6.26 and 7.50 episodes at week 4 and 12 respectively, compared to 3.72 and 4.97 episodes with placebo. Veozah also reduced daily severity by 0.46 and 0.57 points at week 4 and 12 in study 2693-CL-0301, while placebo reductions were 0.27 points and 0.37 points, respectively. In study 2693-CL-0302, severity reductions were 0.61 and 0.77 points at week 4 and 12 with Veozah, versus 0.32 and 0.48 points with placebo.

The reduction in hot flash frequency with Veozah was also clinically significant in both studies, with the decrease compared to placebo exceeding 2 episodes per day. By Week 4, the reduction difference was 2.1 episodes in Trial 2693-CL-0301 and 2.6 episodes in Trial 2693-CL-0302, with this effect remaining consistent through Week 12, with differences of 2.6 and 2.5 episodes, respectively.

In addition to the 2 pivotal trials, a long-term 52-week placebo-controlled safety study (Study 2693-CL-0304) provided the primary safety data for Veozah. In the 12-week placebo-controlled phase of the pivotal studies 2693-CL-0301 and 2693-CL-0302, the most common adverse drug reactions (ADRs) in patients treated with Veozah 45 mg compared to patients treated with placebo (≥2% and more frequent than placebo) were liver test elevation (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, a total of 1220 women (609 on Veozah 45 mg) were administered fezolinetant once daily. The ADRs reported in at least 2% in Veozah 45 mg were headaches (9.7% vs 9.5%), liver function increased (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 flush (2.5% vs 1.6%).

Elevated hepatic transaminases were identified as a significant safety concern. In the 52-week study, alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations >3x upper limit of normal (ULN) occurred in 2.0% of patients on Veozah 45 mg, compared to 1.0% on placebo. No cases of Hy’s Law were observed. One case of severe AST elevation (>20x ULN) was observed in Study 293-CL-0301, and while most liver enzyme elevations were asymptomatic and resolved without complications, the potential for liver damage in a broader population remains an uncertainty.

In the post-marketing setting, cases of serious but reversible hepatotoxicity have been reported within the first few weeks of treatment, with transaminase elevations (over 10 times ULN) often accompanied by increased bilirubin and/or ALP. Symptoms such as fatigue, pruritus, jaundice, dark urine, or abdominal pain were sometimes observed. Baseline assessment and liver function monitoring during treatment is recommended in the Product Monograph to mitigate this risk.

There was a numeric imbalance in malignancy cases between the Veozah and placebo groups in study 2693-CL-0304, however no clear evidence linked Veozah to increased malignancy risk. Regarding endometrial safety, across the three phase 3 studies, the incidence of endometrial hyperplasia or malignancy remained low (≤1%), below the upper bound of the one-sided 95% confidence interval (≤4%). Based on animal studies, fezolinetant is not expected to be genotoxic or carcinogenic at clinically relevant doses.

Fezolinetant is primarily metabolized by CYP1A2. Following oral administration, most of the dose was excreted in urine. Concomitant use of strong or moderate CYP1A2 inhibitors with fezolinetant is contraindicated. Fezolinetant is not recommended for use in individuals with moderate or severe hepatic impairment. Fezolinetant is contraindicated in individuals with severe renal impairment or end-stage renal disease. Food had no clinically significant effect on the extent of absorption of fezolinetant. Veozah may be administered with or without food.

In embryo-fetal toxicity animal studies with fezolinetant, embryo-lethality occurred at high doses above the human therapeutic dose in rats and rabbits, but no teratogenicity was observed. Veozah is contraindicated in pregnancy. Fezolinetant-derived components were transferred into the tissues of infant rats via breast milk. In the pre- and post-natal development study, fezolinetant delayed male reproductive maturation in rats. The use of Veozah in breast-feeding women is not recommended. Given that the intended treatment population is postmenopausal women, the effects on reproduction and development are not considered to be clinically relevant.

The 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.

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

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-risk assessment of Veozah is considered favorable for use in post-menopausal women for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause as described in the Product Monograph.

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