A double-blind, randomized, placebo-controlled, proof of concept study to investigate the differences between the combined administration of 0.5 mg sublingual testosterone and 10 mg buspirone and 10 mg buspirone administration alone in women with hypoactive sexual desire disorder

Lybridos (0.5 mg testosterone + 10 mg buspirone) is under development by
Emotional Brain BV as an on-demand treatment for (the subset of) women with
hypoactive sexual desire disorder (HSDD) characterized by maladaptive activity
of sexual inhibitory systems. Lybridos is intended for use on a per need (i.e.,
not continuous) basis before proposed sexual activity. The cause of maladaptive
activity of sexual inhibitory systems is not well elucidated, but both
physiological and psychological factors are believed to be involved. Thus a
combined treatment targeting the motivational sensitivity for sexual stimuli
(testosterone) and enhancing a potential genital sexual response by decreasing
possible inhibitory factors (buspirone) may increase genital arousal, as well
as the frequency and quality of sexual encounters.

Our previous studies have shown that women with HSDD can be subdivided on the
base of their pre-attentional bias for sexual stimuli (1,2). Although these
women may be diagnosed with Female Sexual Dysfunction (FSD) according to the
Diagnostic and Statistical Manual of Mental disorders, fourth edition (text
revision) (DSM IV-TR), they appear to process sexual stimuli differently.
When women with low sensitivity for sexual cues receive testosterone,
alterations in pre-attentional bias for sexual stimuli occur, which could be an
important condition for the induction of sexual motivation and sexual desire.
Several studies have demonstrated that for women suffering from HSDD whose low
initial sensitivity to sexual cues was boosted by sublingual testosterone, the
combination of testosterone and a PDE-5 inhibitor (Lybrido) induced higher
levels of vaginal blood flow when exposed to sexual stimuli (1,2), coupled with
subjective reports of more intense genital sensations and sexual lust (1). It
was also shown that neither testosterone nor a PDE-5 inhibitor produced these
effects in women with HSDD when administered separately (1,2). In these same
studies, subjects who did show an increased pre-attentional bias for sexual
stimuli before testosterone administration, showed a decrease in
pre-attentional bias after testosterone administration. Since these women
showed no increase in vaginal blood flow or subjective reports of genital
sensations in any of the drug conditions, and because most of them had a
history of negative sexual experiences, it was hypothesized that this group
suffered from maladaptive activity of sexual inhibitory systems. Acute 5HT1a
agonism decreases serotonergic activity (3,4), an important mediator of
inhibitory mechanisms (5). It was postulated that these individuals might
benefit from the inhibition of these inhibitory mechanisms through acute 5HT1a
agonism, especially in conjunction with testosterone-induced intensified sexual
stimulation. In a study investigating the efficacy of the combination of
testosterone and a PDE-5 inhibitor and of the combination of testosterone and a
5HT1a agonist it was indeed shown that women with HSDD who did not respond to
the combination of testosterone and a PDE-5 inhibitor, responded positively to
the combination of testosterone and a 5HT1a agonist (Lybridos), as measured by
event logs and week diaries pertaining to their sexual activities at home
(Tuiten et al., 2012 in preparation).

Sublingually administered testosterone (0.5mg) has been shown to have a delay
in effect of about 4 hours on subjective and peripheral sexual arousal (6,7) in
sexually functional women, but not in women with HSDD (1,2). If this central
effect of testosterone administration is coupled with the use of buspirone, an
increase in subjective and peripheral sexual arousal may be observed in women
with HSDD. However, the peak effect of buspirone must coincide with the peak
effect of the 4 hour delay effect of testosterone. So for buspirone (Tmax
approx. 60 minutes), one would have to administer the sublingual testosterone
first, and after 2-3 hours the buspirone.

The present small exploratory study is directed at investigating the efficacy
of the combination of a single dose of 0.5 mg sublingual testosterone with 10
mg buspirone compared to placebo and buspirone (10 mg) alone, as part of the
ongoing drug development program for Lybridos.

To investigate the differences between the combined administration of 0.5 mg
sublingual testosterone and 10 mg buspirone and 10 mg buspirone administration
alone in increasing sexual satisfaction during sexual activity in the domestic
setting in healthy female subjects with hypoactive sexual desire disorder
(HSDD).
To investigate the differences between the combined administration of 0.5 mg
sublingual testosterone and 10 mg buspirone and 10 mg buspirone administration
alone in increasing vaginal pulse amplitude (VPA), clitoral blood volume (CBV)
and subjective ratings of sexual desire and arousal in the laboratory, in
healthy female subjects with hypoactive sexual desire disorder (HSDD).

This is a double blind, randomized, placebo controlled proof of concept (small
exploratory) study, with 3 psychophysiological laboratory measurement sessions
(placebo, buspirone administration, combined testosterone and buspirone
administration) separated by at least 1 day, followed by a 3-week at home
period where subjects have 3 coital events after using the study medication,
separated by at least 1 day.
Subjects will visit the study site a total of 5 times: 1 screening visit, 3
visits for psychophysiological measurement and 1 follow up visit. During the
psychophysiological measurement visits, VPA, CBV and subjective desire and
arousal will be measured, and the subject*s health will also be monitored. At
the end of the last psychophysiological measurement visit, study medication for
the 3-week at home period will be dispensed. Subject receive 1 dose of each
study medication and are instructed to have an coital event following each
medication intake. After each coital event at home, sexual satisfaction will be
measured using a sexual satisfaction questionnaire (which will be distributed
at the last psychophysiological measurement visit).

Three interventions will be performed on all participants:
sublingual testosterone (0.5mg) and a tablet buspirone (10mg)
placebo solution and a tablet buspiron (10mg)
placebo solution and aplacebo tablet.

The main adverse reactions to exogenous androgens given chronically in
physiological to slightly supraphysiological concentrations are androgenic side
effects, primarily hirsutism and acne. We consider it to be highly unlikely
that testosterone administration in the doses and frequency to be used in this
study will give rise to any serious health risks. In our previous studies, no
serious health risks/adverse reactions were observed. Within 15 minutes of
testosterone (0.5 mg, sublingually) intake plasma testosterone concentration
increased 10-fold, and returned to baseline levels within 150 minutes
Testosterone is administered over two admission periods with a 7 day wash-out
between the admission periods. The dosing regimen regarding testosterone is
therefore considered to be safe.
The combined use of sublingual testosterone and buspirone is considered safe
because buspirone efficacy is not influenced when testosterone is given
concomitantly. Moreover, the dose of buspirone in one dose of Lybridos is at
most two thirds of the starting daily dose and less than a half (2/5) of the
lightest weekly dose of buspirone prescribed for use as an anxiolytic drug. A
previous home study (EB70) showed that Lybridos is well tolerated on long term,
see the Investigator*s Brochure for Lybridos for additional information. Data
on the effect of buspirone and testosterone on oral contraceptives is lacking.
For this reason, participants on oral contraceptives will be instructed to use
a second anti-conception method (double barrier). All participants will be
instructed not to become pregnant during the study.
Clinically relevant abnormalities in ECG or chemistry may be noticed, in which
case a medical specialist may be asked for advice, upon decision of the
research team. If the specialist confirms that medical treatment is necessary,
the participant*s GP physician will be informed. This procedure is mandatory
and explained to the subject in the Informed Consent form.