Drug Trials Snapshots: VEOZAH

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the key clinical trials that supported the original FDA approval of this drug, and whether there were differences among sex, race, age, and ethnic groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your healthcare provider about the benefits and risks of a drug.

Some of the information in this Snapshot is for presentation purposes and does not represent the approved conditions of use of this drug. Refer to the VEOZAH Prescribing Information for all of the approved conditions of use of this drug (e.g., indication(s), population(s), dosing regimen(s), safety information).

Snapshots are limited to the information available at the time of the original approval of the drug and do not provide information on who participated in clinical trials that supported later approvals for additional uses of the drug (if applicable).

VEOZAH (fezolinetant)
vee-O-zah
Astellas Pharma US, Inc.
Original Approval date: May 12, 2023

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

VEOZAH is a neurokinin 3 (NK3) receptor antagonist indicated for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause.

How is this drug used?

VEOZAH is a 45 mg oral tablet that is taken once daily with or without food.

Who participated in the clinical trials?

The FDA approved VEOZAH based on evidence from three clinical trials of 2,859 participants with a minimum average of seven moderate to severe VMS per day, of which 2,852 received treatment with VEOZAH 45 mg, fezolinetant 30 mg, or placebo. These trials were conducted at 368 clinical sites in nine countries including the United States, Canada, Spain, Hungary, Latvia, Ukraine, Czech Republic, the United Kingdom, and Poland. Trial 1 (NCT04003155) and Trial 2 (NCT04003142) were used to assess the efficacy of VEOZAH. Trials 1, 2, and Trial 3 (NCT04003389) were used to assess the safety of VEOZAH. Only Trial 3 was placebo-controlled for the duration of 52 weeks.

How were the trials designed?

VEOZAH was only studied in females. There were 1,022 postmenopausal participants who received treatment in Trial 1 and Trial 2. There were 1,830 postmenopausal participants who received treatment in Trial 3.

The total number of postmenopausal participants receiving VEOZAH in the combined trials (Trial 1, Trial 2, and Trial 3), which includes re-randomized participants previously receiving placebo in Trials 1 and 2, was 2,203.

Efficacy and safety of VEOZAH were evaluated in two 52-week clinical trials (Trial 1 and Trial 2) of 1,028 participants who reported a minimum of seven moderate to severe VMS (hot flashes or hot flushes) per day. In the first 12 weeks, these patients were randomized to VEOZAH 45 mg, fezolinetant 30 mg, or placebo. After completing the first 12 weeks of treatment, placebo patients were re-randomized to VEOZAH 45 mg or fezolinetant 30 mg while VEOZAH and fezolinetant patients continued their treatment. In a separate 52-week long-term safety trial that evaluated general and endometrial safety and chronic use exposure, 1,831 patients were randomized to VEOZAH 45 mg, fezolinetant 30 mg, or placebo.

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.

DEMOGRAPHICS SNAPSHOT

Figure 1 summarizes the percentage of females by their self-identified race who were enrolled in the combined clinical Trials 1 and 2 used to evaluate the efficacy of VEOZAH.

Figure 1. Baseline Demographics by Self-Identified Race, Efficacy Population

Source: Adapted from FDA Review
* Other includes: Four participants (0.4% of total) were American Indian or Alaska Native, one participant (0.1% of total) was a Native Hawaiian or other Pacific Islander, four participants (0.4% of total) were Other Race and one participant had missing information.

Figure 2 summarizes the percentage of females by their self-identified race who were enrolled in the combined clinical Trials 1, 2, and 3, used to evaluate the side effects of VEOZAH.

Figure 2. Baseline Demographics by Self-Identified Race, Safety Population

Source: Adapted from FDA Review
* Other includes: 12 participants (0.4% of total) were American Indian or Alaska Native, one participant (<0.1% of total) was a Native Hawaiian or other Pacific Islander, 20 participants (0.4% of total) were Other Race, and three had missing information.

Figure 3 summarizes the percentage of females by their self-identified age who were enrolled in the combined clinical Trials 1 and 2 used to evaluate the efficacy of VEOZAH.

Figure 3. Baseline Demographics by Self-Identified Age, Efficacy Population

Source: Adapted from FDA Review

 

Figure 4 summarizes the percentage of females by their self-identified age who were enrolled in the combined clinical Trials 1, 2, and 3, used to evaluate the side effects of VEOZAH.

Figure 4. Baseline Demographics by Self-Identified Age, Safety Population

Source: Adapted from FDA Review

Figure 5 summarizes the percentage of females by their self-identified ethnicity who were enrolled in the combined clinical Trials 1 and 2 used to evaluate the efficacy of VEOZAH.

Figure 5. Baseline Demographics by Self-Identified Ethnicity, Efficacy Population

Source: Adapted from FDA Review
Note: Two participants (0.2% of total) had missing information.

Figure 6 summarizes the percentage of females by self-identified ethnicity who were enrolled in the combined clinical Trials 1, 2, and 3, used to evaluate the side effects of VEOZAH.

Figure 6. Baseline Demographics by Self-Identified Ethnicity, Safety Population

Source: Adapted from FDA Review
Note: Four participants (0.1% of total) had missing information.

Who participated in the trials?

Table 1. Baseline Demographics

Category	Trials 1 and 2 Efficacy Population N=1022	Trials 1, 2, and 3 Safety Population N=2852
Self-identified race, n (%)
White	828 (81.0)	2288 (80.2)
Black or African American	174 (17.0)	489 (17.1)
Asian	10 (1.0)	39 (1.4)
American Indian or Alaska Native	4 (0.4)	12 (0.4)
Native Hawaiian or other Pacific Islander	1 (0.1)	1 (<0.1)
Other	4 (0.4)	20 (0.7)
Missing	1 (0.1)	3 (0.1)
Age, years
Mean (SD)	54.3 (5.0)	54.6 (4.9)
Median (min, max)	54 (40, 65)	55.0 (40, 65)
Age group, years, n (%)
<55	625 (61.2)	1667 (58.5)
55 to 65	397 (38.8)	1185 (41.5)
Self-identified ethnicity, n (%)
Hispanic or Latino	243 (23.8)	610 (21.4)
Not Hispanic or Latino	777 (76.0)	2238 (78.5)
Missing	2 (0.2)	4 (0.1)

Source: Adapted from FDA Review

What are the benefits of this drug?

VEOZAH reduces the frequency and severity of moderate to severe VMS in non-hysterectomized and hysterectomized postmenopausal females.

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

Parameter	Trial 1		Trial 2
	VEOZAH 45 mg N=174	Placebo N=175	VEOZAH 45 mg N=167	Placebo N=167
Baseline
Mean (SD)	10.4 (3.92)	10.5 (3.79)	11.8 (8.26)	11.6 (5.02)
Change from Baseline to Week 4
LS mean (SE)	-5.4 (0.30)	-3.3 (0.29)	-6.3 (0.33)	-3.7 (0.33)
Difference (95% CI)	-2.1 (-2.9, -1.3)		-2.6 (-3.5, -1.6)
p-value	<0.001a		<0.001a
Change from Baseline to Week 12
LS mean (SE)	-6.4 (0.31)	-3.9 (0.31)	-7.5 (0.39)	-5.0 (0.39)
Difference (95% CI)	-2.6 (-3.4, -1.7)		-2.5 (-3.6, -1.5)
p-value	<0.001a		<0.001a

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

Parameter	Trial 1		Trial 2
	VEOZAH 45 mg N=174	Placebo N=175	VEOZAH 45 mg N=167	Placebo N=167
Baseline
Mean (SD)	2.4 (0.35)	2.4 (0.35)	2.4 (0.34)	2.4 (0.32)
Change from Baseline to Week 4
LS mean (SE)	-0.5 (0.04)	-0.3 (0.04)	-0.6 (0.05)	-0.3 (0.05)
Difference (95% CI)	-0.2 (-0.3, -0.1)		-0.3 (-0.4, -0.2)
p-value	0.002a		<0.001a
Change from Baseline to Week 12
LS mean (SE)	-0.6 (0.05)	-0.4 (0.05)	-0.8 (0.06)	-0.5 (0.06)
Difference (95% CI)	-0.2 (-0.4, -0.1)		-0.3 (-0.5, -0.1)
p-value	0.007a		<0.001a

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?

• Sex: VEOZAH was only studied in healthy postmenopausal females.
• Race: VEOZAH worked similarly in White and Black or African American participants.
• Age: Females 65 years of age and older were not included in VEOZAH clinical trials .

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

Self-Identified Race	Statistic	Trial 1		Trial 2
		VEOZAH 45 mg	Placebo	VEOZAH 45 mg	Placebo
Week 4
White	LS mean (SE)	-5.2 (0.33)	-3.1 (0.32)	-6.1 (0.34)	-4.1 (0.34)
	Difference (95% CI)	-2.1 (-3.0, -1.2)		-2.1 (-3.0, -1.1)
Black or African American	LS mean (SE)	-6.4 (0.76)	-4.3 (0.72)	-6.6 (1.01)	-2.4 (1.03)
	Difference (95% CI)	-2.1 (-4.1, 0.0)		-4.2 (-7.1, -1.4)
Week 12
White	LS mean (SE)	-6.3 (0.34)	-3.8 (0.35)	-7.2 (0.36)	-5.3 (0.37)
	Difference (95% CI)	-2.5 (-3.4, -1.5)		-1.9 (-2.9, -0.9)
Black or African American	LS mean (SE)	-7.4 (0.73)	-4.3 (0.73)	-7.7 (1.04)	-3.3 (1.06)
	Difference (95% CI)	-3.1 (-5.1, -1.0)		-4.5 (-7.4, -1.6)

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

Self-Identified Race	Statistic	Trial 1		Trial 2
		VEOZAH 45 mg	Placebo	VEOZAH 45 mg	Placebo
Week 4
White	LS mean (SE)	-0.5 (0.05)	-0.3 (0.05)	-0.6 (0.05)	-0.3 (0.05)
	Difference (95% CI)	-0.2 (-0.3, -0.1)		-0.3 (-0.4, -0.2)
Black or African American	LS mean (SE)	-0.5 (0.10)	-0.3 (0.10)	-0.6 (0.12)	-0.3 (0.13)
	Difference (95% CI)	-0.2 (-0.5, 0.1)		-0.3 (-0.6, 0.1)
Week 12
White	LS mean (SE)	-0.6 (0.06)	-0.4 (0.06)	-0.8 (0.06)	-0.5 (0.06)
	Difference (95% CI)	-0.2 (-0.4, -0.0)		-0.3 (-0.5, -0.1)
Black or African American	LS mean (SE)	-0.6 (0.14)	-0.4 (0.14)	-0.7 (0.15)	-0.4 (0.15)
	Difference (95% CI)	-0.3 (-0.7, 0.1)		-0.3 (-0.7, 0.1)

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

What are the possible side effects?

The safety of VEOZAH was evaluated in three 52-week clinical trials. Across the three clinical trials, a total of 2,203 females received VEOZAH. Trials 1 and 2 were placebo-controlled for the first 12 weeks, followed by re-randomization of participants previously receiving placebo to either VEOZAH 45 mg or fezolinetant 30 mg (participants previously randomized to VEOZAH or fezolinetant continued on treatment) for an additional 40 weeks of uncontrolled treatment. Trial 3 was a randomized, placebo-controlled, double-blind safety study evaluating the safety of VEOZAH for 52 weeks.

The most common adverse reactions in the 52-week Trial 3 included abdominal pain, diarrhea, insomnia, back pain, hot flush, and hepatic transaminase elevation.

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

Adverse Reaction	VEOZAH 45 mg N=609 Total Person-Years=504.2 n (%, EAIR1)	Placebo N=610 Total Person-Years=475.0 n (%, EAIR1)
Abdominal pain2	26 (4.3%, 5.2)	13 (2.1%, 2.7)
Diarrhea	24 (3.9%, 4.8)	16 (2.6%, 3.4)
Insomnia	24 (3.9%, 4.8)	11 (1.8%, 2.3)
Back pain	18 (3.0%, 3.6)	13 (2.1%, 2.7)
Hot flush	15 (2.5%, 3.0)	10 (1.6%, 2.1)
Hepatic transaminase elevation3	14 (2.3%, 2.8)	5 (0.8%, 1.1)

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?

• Sex: VEOZAH was only studied in postmenopausal females.
• Race: The occurrence of side effects was similar in participants who self-identified as White and those who self-identified as Black or African American.
• Age: Females 65 years of age and older were not included in VEOZAH clinical trials.

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

Adverse Reaction	Self-Identified Race	VEOZAH 45 mg n/N (%)	Placebo n/N (%)
Abdominal pain1	White	20/479 (4.2)	13/502 (2.6)
	Black or African American	5/110 (4.5)	0
	Asian	0	0
	Other	1/6 (16.7)	0
Diarrhea	White	17/479 (3.5)	12/502 (2.4)
	Black or African American	5/110 (4.5)	4/91 (4.4)
	Asian	1/13 (7.7)	0
	Other	1/6 (16.7)	0
Insomnia	White	22/479 (4.6)	9/502 (1.8)
	Black or African American	2/110 (1.8)	1/91 (1.1)
	Asian	0	0
	Other	0	1/9 (11.1)
Back pain	White	12/479 (2.5)	10/502 (2.0)
	Black or African American	5/110 (4.5)	3/91(3.3)
	Asian	0	0
	Other	1/6 (16.7)	0
Hot flush	White	14/479 (2.9)	9/502 (1.8)
	Black or African American	1/110 (0.9)	1/91 (1.1)
	Asian	0	0
	Other	0	0
Hepatic transaminase elevation2	White	12/479 (2.5)	5/502 (1.0)
	Black or African American	1/110 (0.9)	0
	Asian	1/13 (7.7)	0
	Other	0	0

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

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

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