Drug Trials Snapshots: VEOZAH

How were the trials designed?

The first two trials (Trial 1 and Trial 2) were identical in trial design and randomized 1,028 postmenopausal females, of which 1,022 received treatment (522 in Trial 1 and 500 in Trial 2), with a minimum average of seven moderate to severe VMS per day to VEOZAH 45 mg, fezolinetant 30 mg, or placebo. Randomization was also stratified by smoking status. Trial 1 was conducted at 96 centers that enrolled participants in eight countries including the United States, Canada, Spain, Hungary, Ukraine, Czech Republic, the United Kingdom, and Poland. Trial 2 was conducted at 91 centers that enrolled participants in eight countries including the United States, Canada, Spain, Hungary, Latvia, Czech Republic, the United Kingdom, and Poland.

In both Trials 1 and 2, the mean age of the postmenopausal participants was 54 years. In these trials, participants self-identified as White (81%), Black or African American (17%), Asian (1%), and Hispanic or Latina ethnicity (24%). The trial population included menopausal females with one or more of the following: prior hysterectomy (32.1%), oophorectomy (21.6%), and hormone therapy use (19.9%, who underwent a wash-out period prior to trial participation).

The co-primary efficacy endpoints for both trials were the mean change from baseline in moderate to severe VMS frequency and severity at Weeks 4 and 12. Data from each trial demonstrated statistically significant and clinically meaningful reduction from baseline in the frequency of moderate to severe VMS (≥2 hot flashes over 24 hours) for VEOZAH 45 mg when compared to placebo at Weeks 4 and 12. Data from each trial also demonstrated a statistically significant reduction from baseline in the severity of moderate to severe VMS (over 24 hours) at Weeks 4 and 12 for VEOZAH 45 mg compared to placebo.

In Trial 3, 1,831 postmenopausal females were randomized to VEOZAH 45 mg (n=609), fezolinetant 30 mg, or placebo; 1,830 participants received treatment. Trial 3 was conducted at 181 centers that enrolled participants in eight countries including the United States, Canada, Spain, Latvia, Ukraine, Czech Republic, the United Kingdom, and Poland. Trial 3 evaluated the long-term general and endometrial safety and chronic use exposure and tolerability of VEOZAH. The mean age of participants in Trial 3 was 54.7 years. In this trial, participants self-identified as White (79.9%), Black or African American (17.2%), Asian (1.6%), and Hispanic and Latina ethnicity (20.1%). The trial population included menopausal females with one or more of the following: prior hysterectomy (18.6%), oophorectomy (13.5%), and hormone therapy use (17.0%). No efficacy data was collected in Trial 3.

Who participated in the trials?

Table 1. Baseline Demographics

Source: Adapted from FDA Review

What are the benefits of this drug (results of trials used to assess efficacy)?

The efficacy of VEOZAH for the treatment of moderate to severe VMS due to menopause was evaluated in the first 12-week double-blind and placebo-controlled segment of each of two randomized phase 3 clinical trials (Trial 1 and Trial 2). The co-primary efficacy endpoints in both trials were the mean change from baseline in the frequency and severity of moderate to severe VMS at Week 4 and Week 12 when compared to placebo. To demonstrate substantial evidence of efficacy, the VEOZAH arm of each trial had to be statistically superior to placebo in the reduction of the frequency and severity of VMS. In addition, the reduction in frequency in the VEOZAH arm had to exceed the clinical threshold of two VMS per day (or 14 per week) when compared to placebo in each trial.

Table 2 and Table 3 summarize the results of the co-primary efficacy endpoints for Trial 1 and Trial 2.

Table 2. Mean Baseline and Change From Baseline to Weeks 4 and 12 for Mean Frequency of Moderate to Severe Vasomotor Symptoms Over 24 Hours in Trial 1 and Trial 2

Source: Adapted from VEOZAH Prescribing Information
^a Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.
Abbreviations: CI, confidence interval; LS mean, least squares mean estimated from a mixed model for repeated measures analysis of covariance; SD, standard deviation; SE, standard error

Table 3. Mean Baseline and Change From Baseline to Weeks 4 and 12 for Mean Severity of Moderate to Severe Vasomotor Symptoms Over 24 Hours in Trial 1 and Trial 2

Source: Adapted from VEOZAH Prescribing Information
^a Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.
Abbreviations: CI, confidence interval; LS mean, least squares mean estimated from a mixed model for repeated measures analysis of covariance; SD, standard deviation; SE, standard error

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

Table 4 and Table 5 summarize the results of the co-primary efficacy endpoints by race for Trial 1 and Trial 2.

Table 4. Mean Change From Baseline to Weeks 4 and 12 for Mean Frequency of Moderate to Severe Vasomotor Symptoms by Race

Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; LS, least squares; SE, standard error

Table 5. Mean Change From Baseline to Weeks 4 and 12 for Mean Severity of Moderate to Severe Vasomotor Symptoms by Race

Source: Adapted from FDA Review
Abbreviations: CI, confidence interval; LS, least squares; SE, standard error

What are the possible side effects (results of trials used to assess safety)?

The adverse reactions reported in at least 2% of participants receiving VEOZAH 45 mg, and greater than those receiving placebo, are presented in Table 6.

Table 6. Adverse Reactions Reported in at Least 2% of Participants Receiving VEOZAH 45 mg (and Greater Than Placebo) in Trial 3

Source: VEOZAH Prescribing Information
¹ EAIR = Number of individuals experiencing an adverse event divided by exposure time (total person-years) x 100
² Abdominal pain including abdominal pain, abdominal pain lower, and abdominal pain upper
³ Hepatic transaminase elevations including alanine aminotransferase abnormal, alanine aminotransferase increased, aspartate aminotransferase abnormal, and aspartate aminotransferase increased
Abbreviations: EAIR, exposure-adjusted incidence rate

Safety review issues of special interest included an increase in the incidence of hepatic transaminase elevations in VEOZAH and fezolinetant treatment groups compared to placebo. The clinical trial data demonstrated a higher incidence of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation in participants exposed to VEOZAH compared to participants on placebo, but the overall frequency of AST and ALT elevations was low. There was no clear dose-response relationship with ALT or AST elevations. Additionally, there was no evidence of jaundice associated with aminotransferase elevations.

Hepatic transaminase elevations >3 times the upper limit of normal that were approximately 2-fold greater in VEOZAH 45 mg compared with placebo were observed. These hepatic transaminase elevations occurred at various timepoints in the 12-month phase 3 clinical trials, were generally transient, and resolved either while on VEOZAH or shortly after discontinuation. There were eight cases assessed as probable or possible drug-induced liver injury (DILI) (four participants with probable DILI and four others with at least possible DILI). No cases of Hy's law were observed. The cases of DILI were predominantly hepatocellular with a median latency from drug start of 56 days, but the latency range was wide at 14 to 250 days.

In addition to the above noted hepatic transaminase elevations, there initially appeared to be an imbalance in number and percentages of malignancies in participants exposed to VEOZAH compared to those participants exposed only to placebo. The review of safety noted a dose-dependent numeric imbalance in the incidence of malignancy in VEOZAH treatment groups when compared to placebo groups.

The cases of malignancy were not of a single cancer type or apparent associated cluster of cancer types. There was no obvious pattern or distribution by duration of drug exposure or body system. Most cancers were singularly occurring from disparate organ origins with the exception of two cases of colon cancer, three cases of squamous cell skin cancer, and three cases of endometrial cancer.

Upon further evaluation many of the noted malignancies were determined to be preexisting. The evidence for implicating VEOZAH in the development of malignancy was considered weak, and any causal association between VEOZAH exposure and neoplasms could not be established based on the clinical trial data.

Based on the nonclinical information provided by the applicant and available in the published literature, no biological mechanism was identified that indicated an increased risk of malignancy with VEOZAH or NK3 receptor antagonism.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Adverse reactions reported by race in Trial 3 is shown in Table 7.

Table 7. Adverse Reactions Reported by Race in at Least 2% of VEOZAH 45 mg and Greater Than Placebo in Trial 3

Source: Adapted from FDA Review
¹ Abdominal pain including abdominal pain, abdominal pain lower, and abdominal pain upper
² Hepatic transaminase elevations including alanine aminotransferase abnormal, alanine aminotransferase increased, aspartate aminotransferase abnormal, and aspartate aminotransferase increased