14 CLINICAL STUDIES

The efficacy of VYLEESI for the treatment of HSDD in premenopausal women was evaluated in two identical, Phase 3, randomized, double-blind, placebo-controlled trials: NCT02333071 and NCT02338960 (Study 1 and Study 2). Both trials included premenopausal women with acquired, generalized HSDD of at least 6 months' duration. All patients in heterosexual relationships were required to use an effective form of contraception. A majority of patients (74% in Study 1 and 67% in Study 2) reported HSDD with concomitant decreased arousal. The trials consisted of two phases: a Core Study Phase (24-week placebo-controlled, double-blind treatment period) and an uncontrolled, 52-week Open-label Extension Study Phase.

Study participants were randomized to subcutaneous injections of VYLEESI 1.75 mg (n= 635) or placebo (n= 632), self-administered by an autoinjector on an as-needed basis. Patients were instructed to administer the drug approximately 45 minutes prior to anticipated sexual activity. Patients were not to administer more than one dose within a 24-hour period and no more than twelve doses per month. Trial participants were mostly Caucasian (86%) or Black (12%). The mean age of study participants was 39 years old (range 19 to 56 years old); the mean duration in a monogamous relationship was 12 years, and the mean duration of HSDD was approximately 4 years. Across the two trials, the median number of VYLEESI injections was 10 in the 24-week double-blind treatment period and 12 during the uncontrolled open-label extension. Most patients used VYLEESI two to three times per month and no more than once a week.

Study 1 and Study 2 had the following co-primary efficacy endpoints:

Change from baseline to end of study (EOS) in the Desire domain from the Female Sexual Function Index (FSFI) (Questions 1 and 2). Question 1 asks patients “Over the past 4 weeks, how often did you feel sexual desire or interest?”, with responses ranging from 1 (almost never or never) to 5 (almost always or always). Question 2 asks patients “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”, with responses ranging from 1 (very low or none at all) to 5 (very high). The FSFI Desire domain score was calculated by adding the patient's responses to these two questions then multiplying that sum by 0.6. The FSFI Desire Domain score ranged from 1.2 to 6. An increase in the FSFI Desire domain score over time denotes improvement in sexual desire.
Change from baseline to EOS in the score for feeling bothered by low sexual desire as measured by the Female Sexual Distress Scale – Desire/Arousal/Orgasm Question 13 (FSDS-DAO Q13). This question asks patients, “How often did you feel: Bothered by low sexual desire?”Patients assessed their sexual distress over a 30-day recall period and responded on a scale of 0 (never) to 4 (always). A decrease in the FSDS-DAO Q13 score over time denotes improvement in the level of distress associated with low sexual desire.

EOS is defined as the patient's last study visit during the double-blind treatment period. For patients who completed the double-blind treatment period, the EOS visit occurred at Week 24.

Efficacy results for these co-primary endpoints from Study 1 and Study 2 are summarized in Table 2and Table 3. In both studies, VYLEESI showed a statistically significant increase in the FSFI Desire Domain score and a statistically significant decrease in the FSDS-DAO Q13 score from baseline to the EOS visit compared to placebo. The magnitude of the treatment differences was similar in both studies.

Table 2: Efficacy Results for the FSFI-Desire Domain Score in Premenopausal HSDD Patients in Study 1 and Study 2 (MITT* Population)
1FSFI Desire score range: 1.2 to 6.0, with higher scores indicating greater desire.
2p-value from unadjusted Wilcoxon rank-sum test.
* MITT: modified intent to treat defined as all patients who were randomized, used at least one dose of double-blind study drug, and had at least one double-blind follow-up visit. However, one VYLEESI patient and one placebo patient in Study 1 and two placebo patients in Study 2 did not have either a baseline or EOS efficacy measurement and change from baseline could not be calculated. Therefore, N = the number of patients in the MITT population with an evaluable change measurement.
	Study 1		Study 2
	VYLEESI 1.75 mg (N= 313)	Placebo (N= 315)	VYLEESI 1.75 mg (N= 282)	Placebo (N=288)
Mean Baseline (SD) 1	2.1 (0.9)	2.0 (0.8)	2.0 (0.8)	2.1 (0.8)

Mean Change from Baseline (SD)	0.5 (1.1)	0.2 (1.0)	0.6 (1.0)	0.2 (0.9)
Median Change from Baseline	0.6	0	0.6	0
p-value 2	0.0002		< 0.0001

Table 3: Efficacy Results for the FSDS-DAO Q13 Score in Premenopausal HSDD Patients in Study 1 and Study 2 (MITT* Population)
1FSDS-DAO Q13 score range: 0 to 4, with higher scores indicating greater bother.
2p-value from unadjusted Wilcoxon rank-sum test.
*MITT: modified intent to treat defined as all patients who were randomized, used at least one dose of the double-blind drug and had at least one double-blind follow-up visit. However, one VYLEESI patient and two placebo patients in Study 1 and five placebo patients in Study 2 did not have either a baseline or EOS efficacy measurement and change from baseline could not be calculated. Therefore, N = the number of patients in the MITT population with an evaluable change measurement.
	Study 1		Study 2
	VYLEESI 1.75 mg (N = 313)	Placebo (N = 314)	VYLEESI 1.75 mg (N=282)	Placebo (N= 285)
Mean Baseline (SD) 1	2.9 (1.0)	2.8 (0.9)	2.9 (0.9)	2.9 (0.9)

Mean Change from Baseline (SD)	-0.7 (1.2)	-0.4 (1.1)	-0.7 (1.1)	-0.4 (1.1)
Median Change from Baseline	-1	0	-1	0
p- value 2	< 0.0001		0.0053

Supplementary analyses were conducted to help interpret clinical meaningfulness of the observed score change from baseline to EOS in the FSFI-Desire Domain and FSDS-DAO Q13. These analyses defined responders for each coprimary efficacy endpoint by anchoring change from baseline to EOS with multiple anchor measures. Each anchor analysis considered responders to be those who reported experiencing meaningful change at their EOS visit according to the respective anchor measure.

Because a greater percentage of MITT patients in the VYLEESI group prematurely discontinued the 24-week double-blind treatment period compared to placebo patients (40% vs. 13% for Study 1 and 39% vs. 25% for Study 2), an exploratory analysis was performed examining the percentages of patients who were able to complete the treatment period and improved from baseline. Figure 2displays the percentages of the MITT patients in the two Phase 3 trials who completed the 24-week double-blind treatment period and achieved various levels of increase in the FSFI-Desire Domain Score from baseline (higher scores indicate increased sexual desire). Figure 3displays the percentages of the MITT patients in the two clinical trials who completed the 24-week double-blind treatment period and achieved various levels of reduction in the FSDS-DAO Q13 score from baseline (higher scores indicate greater reduction in distress).

Figure 2: Percent of Patients (MITT Population) who Completed the 24-Week Double-Blind Treatment Period and Achieved Various Levels of Increases in the FSFI-Desire Domain Score

Patients who did not complete the double-blind treatment period or were missing baseline scores are not considered to have experienced an increase in FSFI-Desire Domain score at the end of the double-blind treatment period.

Responder threshold: at least 1.2-point increase from baseline in FSFI-Desire Domain score. The threshold was defined for these studies by anchoring change from baseline to end of treatment with multiple anchor measures.

Figure 3: Percent of Patients (MITT Population) who Completed the 24-Week Double-Blind Treatment Period and Achieved Various Levels of Reductions in the FSDS-DAO Q13 Score

Patients who did not complete the double-blind treatment period or were missing change from baseline scores are not considered to have experienced a decrease in FSDS-DAO Q13 score at the end of the double-blind treatment period.

Responder threshold: at least 1-point decrease from baseline in the FSDS-DAO Q13 score. The threshold was defined for these studies by anchoring change from baseline to end of treatment with multiple anchor measures.

There was no significant difference between treatment groups in the change from baseline to end of study visit in the number of satisfying sexual events (SSEs), a secondary endpoint.

Efficacy results for the number of SSEs are summarized in Table 4.

Table 4: Efficacy Results for the Number of Satisfying Sexual Events in Premenopausal HSDD Patients in Study 1 and Study 2 (MITT* Population)
1p-value from unadjusted Wilcoxon rank-sum test.
*MITT: modified intent to treat defined as all patients who were randomized, used at least one dose of double-blind drug and had at least 1 double-blind follow-up visit. N = the number of patients in the MITT population.
	Study 1		Study 2
	VYLEESI 1.75 mg (N = 314)	Placebo (N = 316)	VYLEESI 1.75 mg (N=282)	Placebo (N= 290)
Mean Baseline (SD)	0.7 (1.0)	0.8 (1.1)	0.8 (1.1)	0.7 (1.0)
Mean Change from Baseline (SD)	0.0 (1.4)	-0.1 (1.4)	0.0 (1.3)	0.0 (1.2)
Median Change from Baseline	0	0	0	0
p- value 1	0.76		0.70