Veozah for the Treatment of Vasomotor Symptoms Due to Menopause

In May 2023, Veozah (fezolinetant; Astellas Pharma US, Inc) became the first medication within its class to be approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe vasomotor symptoms due to menopause. These symptoms are also colloquially known as hot flashes. 

Veozah acts as a neurokinin 3 (NK3) receptor antagonist, which inhibits the binding of neurokinin B to kisspeptin/neurokinin B/dynorphin neurons in the thermoregulatory center of the hypothalamus. Veozah is highly selective for the NK3 receptor compared with the NK1 and NK2 receptors. It does not appear to affect sex hormones (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women other than causing a transient decrease in luteinizing hormone levels.

Clinical Trials

Veozah gained FDA approval for the treatment of moderate to severe vasomotor symptoms due to menopause by demonstrating efficacy and safety across two phase 3 trials, along with long-term safety in a third phase 3 trial.

Efficacy and safety were first evaluated in postmenopausal women enrolled into 2 multicenter, randomized, double-blind, placebo-controlled phase 3 studies (SKYLIGHT 1 [ClinicalTrials.gov identifier: NCT04003155] and SKYLIGHT 2 [ClinicalTrials.gov identifier: NCT04003142]). Study participants were randomly assigned to once-daily treatment with Veozah 45 mg, fezolinetant 30 mg, or placebo; randomization was stratified by self-reported smoking status. These 2 identically designed studies were split into 2 phases measuring exposure over 52 weeks: a 12-week initial treatment period and a 40-week extension where participants in the placebo arm were re-randomized to once-daily Veozah.

More than 1000 postmenopausal women were included in the trials (SKYLIGHT 1: N=522; SKYLIGHT 2: N=500). Study participants experienced, on average, at least 7 moderate to severe vasomotor symptoms per day. 

The coprimary endpoints measured during the initial 12-week treatment phase were the mean change from baseline in frequency and severity of vasomotor symptoms at weeks 4 and 12. A clinically meaningful reduction in the frequency of moderate to severe vasomotor symptoms was defined as at least 2 fewer hot flashes over 24 hours. 

Results from SKYLIGHT 1 showed that treatment with Veozah 45 mg reduced the frequency of moderate to severe vasomotor symptoms compared with placebo at week 4 (difference vs placebo, -2.1 [95% CI, -2.9, -1.3; P <.001]) and at week 12 (difference vs placebo, -2.6 [95% CI, -3.4, -1.7; P <.001]). Similar results were observed in SKYLIGHT 2 at week 4 (difference vs placebo, -2.6 [95% CI, -3.5, -1.6; P <.001]) and week 12 (difference vs placebo, -2.5 [95% CI, -3.6, -1.5; P <.001]).

The 45 mg dosage strength was also associated with a statistically significant reduction from baseline in the severity of moderate to severe vasomotor symptoms (over 24 hours) compared with placebo at week 4 (SKYLIGHT 1: difference vs placebo, -0.2 [95% CI, -0.3, -0.1; P =.002]; SKYLIGHT 2: difference vs placebo, -0.3 [95% CI, -0.4, -0.2; P <.001]) and week 12 (SKYLIGHT 1: difference vs placebo, -0.2 [95% CI, -0.4, -0.1; P =.007]; SKYLIGHT 2: difference vs placebo, -0.3 [95% CI, -0.5, -0.1; P <.001]).

The safety profile of Veozah was determined by pooling the 52-week results from the initial two phase 3 trials (SKYLIGHT 1 and 2) and a third phase 3 trial (SKYLIGHT 4 [ClinicalTrials.gov identifier: NCT04003389]). 

Findings from SKYLIGHT 4, which included 609 patients who received Veozah 45 mg once daily, showed that the most common adverse reactions (≥2% of participants and more frequently than placebo) were abdominal pain, including lower abdominal pain and upper abdominal pain (4.3% vs 2.1%); diarrhea (3.9% vs 2.6%); insomnia (3.9% vs 1.8%); back pain (3% vs 2.1%); hot flush (2.5% vs 1.6%); and hepatic transaminase elevation, including abnormal alanine aminotransferase (ALT), increased ALT, abnormal aspartate aminotransferase (AST), and increased AST (2.3% vs 0.8%).

The pooled phase 3 data across the 3 trials included a total of 1100 women who received Veozah 45 mg. Elevation of hepatic transaminases greater than 3 times the upper limit of normal (ULN) occurred in 2.3% of women (2.7 exposure adjusted incidence rate [EAIR]) on Veozah 45 mg compared with 0.9% (1.5 EAIR) of the 952 women who received placebo.

The effects of Veozah 45 mg on the endometrium were also investigated across the 3 trials. Endometrial biopsy assessments revealed 1 case of endometrial simple hyperplasia without atypia and 1 case of endometrial adenocarcinoma among 350 patients treated with Veozah 45 mg. No cases were reported among patients in the placebo group (n=186). 

Disordered proliferative endometrium was reported in 5 women receiving Veozah 45 mg compared with 4 women receiving placebo. The EAIR was reported to be 1.4 per 100 person-years vs 2 per 100 person-years for Veozah 45mg and placebo, respectively.

Dosage and Administration

Veozah is manufactured as a 45-mg film-coated tablet stored at room temperature. This film coating should remain intact during administration, and thus Veozah should be swallowed whole with liquids. The recommended dose of Veozah is a single 45-mg tablet taken orally once daily with or without food. 

Veozah is intended to be administered at approximately the same time each day, and missed doses should be taken as soon as possible unless there is less than 12 hours until the next scheduled dose. If that is the case, then the patient should resume the regular dosing schedule the following day.

Before starting patients on Veozah, it is recommended that baseline bloodwork be performed to evaluate for hepatic function and injury.

Contraindications, Warnings, Precautions, and Adverse Reactions

Known Cirrhosis

Veozah is contraindicated in patients with known cirrhosis, as the drug is primarily metabolized by the liver. Compared with women with normal hepatic function, those with Child-Pugh class A or B hepatic impairment experienced an increase in exposure to Veozah. Clinical trials did not include patients with Child-Pugh class C hepatic impairment.

Severe Renal Impairment or End-Stage Renal Disease

Veozah is contraindicated in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to <30 mL/min/1.73 m²)  or end-stage renal disease (eGFR <15 mL/min/1.73 m²). Following administration, over 75% of the drug is excreted in the urine. Patients with severe renal impairment experienced a 380% increase in AUC of the major metabolite of fezolinetant following a single 30-mg dose. Veozah was not studied in patients with end-stage renal disease. 

Concomitant Use With CYP1A2 Inhibitors

Veozah is contraindicated in patients being treated concomitantly with medications that inhibit the CYP1A2 enzyme because the patient will experience increased exposure to Veozah. The drug is primarily metabolized by CYP1A2 and only 1.2% of the dose is excreted unchanged. Inhibition of the CYP1A2 enzymes will inhibit the metabolism of Veozah and thus increase the risk of adverse events. Weak (cimetidine), moderate (mexiletine), and strong (fluvoxamine) CYP1A2 inhibitors increased the maximum serum concentration of Veozah by 30%, 40%, and 80%, respectively, and the AUC by 100%, 360%, and 840%, respectively.

Hepatic Transaminase Elevation

Clinical safety data gathered across 3 pivotal trials have provided evidence that baseline bloodwork should be performed and assessed for serum concentration elevations of ALT, AST, and total bilirubin (see Dosage and Administration). Women treated with Veozah experienced elevations of ALT and/or AST greater than 3 times the ULN at a rate of 2.3% (EAIR of 2.7 per 100 patient-years) compared with 0.9% (EAIR of 1.5 per 100 patient-years) of those treated with placebo. There were no reports of total bilirubin serum concentration exceeding 2 times the ULN in these trials. 

Most women with ALT or AST elevations remained asymptomatic, and serum concentrations returned to or close to baseline without additional signs or symptoms while the patients were on treatment, upon interrupting treatment, or once treatment was discontinued. It should be noted that women with cirrhosis were not included in the clinical trials.

Drug Interactions

Veozah is contraindicated in patients using CYP1A2 inhibitors because the drug is primarily metabolized by the CYP1A2 enzyme. Concomitant use with weak, moderate, or strong CYP1A2 inhibitors increases Veozah exposure. In vitro studies show that Veozah is a substrate of CYP1A2 and does not inhibit or induce CYP1A2.  

Considerations for Specific Populations

Veozah is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause and was only studied in menopausal women. No data currently exist evaluating the safety of Veozah in pregnant women.

The absence of data extends into safety assessments regarding the drug’s presence in human milk, its effects on breastfed children, and its effects on milk production.

Efficacy and safety data in women aged over 65 years are insufficient to determine differences from younger women due to the small sample size of geriatric participants in the clinical trials. The safety and efficacy of Veozah have not been established in patients aged younger than 18 years.

Veozah is contraindicated in patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m²) or end-stage renal disease (eGFR <15 mL/min/1.73 m²). No dose adjustments are recommended in the presence of mild (eGFR 60 to <90 mL/min/1.73 m²) or moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment. 

Veozah is also contraindicated in patients with cirrhosis and has not been studied in patients with Child-Pugh class C hepatic impairment. Patients with Child-Pugh class A or B hepatic impairment will experience increased exposure to Veozah.

Reference

Veozah™. Prescribing information. Astellas Pharma US, Inc; 2023. Accessed June 1, 2023. https://www.astellas.com/us/system/files/veozah_uspi.pdf.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Reviewed June 2023