Two-Center, In-Patient, Randomized, Placebo and Active Comparator Evaluation of the Pharmacokinetics (PK) and Safety, Along with Initial Pharmacodynamic (PD) Efficacy of Three Dose Levels of TBS-2 Intranasal Gel Applied Twice-Daily (BID) for up to Three Days in Female Patients with Hypoactive Sexual Desire Disorder (HSDD) or Anorgasmia (ANOR).

In contrast to the role in men, the function of testosterone in women has not
been investigated as thoroughly as that of estrogen and progesterone. Studies
that have investigated the conversion of testosterone to dihydrotestosterone
(DHT) in women in comparison to men (Mahoudeau, Bardin, Lipsett. 1971) or the
daily testosterone synthesis in women and men, indicate that the synthesis in
women is approximately one tenth that observed in men (Korenman, Wilson,
Lipsett. 1963).

The concentrations of testosterone, its precursors, and metabolites decrease
significantly in women aged 30-40 years (Labrie, Luu-The, Labrie et al. 2003).
In contrast to the abrupt decline in estrogens and progesterone after the
menopause, the decline of testosterone is more gradual over a longer period in
the pre-menopause (Padero, Bhasin, & Friedman. 2002), indicating that the
decline in testosterone production is a phenomenon of an overall aging process,
and not primarily a result of a menopausal decline in ovarian testosterone
production. In addition, the data show that free testosterone is the more
suitable measure of androgen homeostasis in women. In the postmenopausal woman,
testosterone levels are approximately one half of that observed in young women,
primarily due to a decrease in the production of adrenal androgen precursors.
The interpretation of the androgen status in postmenopausal women is further
complicated by the fact that the majority of biologically active androgen in
these women is synthesized from inactive precursors such as DHEA and DHEA-S in
the peripheral tissues and may act in those tissues in a paracrine or
intracrine fashion with only the testosterone metabolites appearing in the
serum (Labrie, Luu-The, Labrie et al. 2003).

More recent studies indicate that testosterone plays an important physiological
role in women regarding their mood, body composition, bone health, physical and
mental strength and sexual function (Davis 1999). A consensus conference held
in Princeton in 2001 defined the clinical construct of an androgen
insufficiency syndrome and recommended a trial of testosterone therapy for
women fulfilling the criteria (Bachmann, Bancroft, Braunstein, et al. 2002). A
position paper from the North American Menopause Society has made a similar
recommendation (Menopause 2005), although a position paper from the Endocrine
Society recommended that more research be performed before testosterone is used
as part of the hormone treatment of postmenopausal women (Wierman, Basson,
Davis, et al. 2006).

At present the only registered indication of testosterone administration in
women is the treatment of FSD after surgical menopause. Studies carried out on
women with surgical or natural menopause who fulfil the definition of
hypoactive sexual desire disorder (HSDD) have shown that the administration of
exogenous testosterone through the oral, transdermal or parental route with or
without concomitant estrogen therapy results in an increase in desire, arousal,
frequency of satisfactory sexual activity, pleasure, and responsiveness
(Braunstein, 2006; Alexande, Dennerstein, Burger, et al. 2006; Somboonporn,
2006).

This clinical trial is being performed to evaluate the PK profile of TBS-2
administered as single and multiple (BID) doses in patients with HSDD or ANOR.
In addition, the study will evaluate the initial PD efficacy and safety of
intranasal TBS-2 BID and compare the safety to Intrinsa in the HSDD population
and to placebo in the ANOR population. PD efficacy will be determined using
implicit as well as psychophysiological tests. These tests have shown to
discriminate between women with acquired HSDD and controls. Recently, automatic
affective associations with sexual stimuli were assessed in premenopausal US
and Dutch women with acquired HSDD (n = 42) and a control group of sexually
functional women (n = 42) using two implicit tasks (single target Implicit
Association Task and the Picture Association Task). Results of both tasks
showed that women with acquired HSDD displayed less positive automatic
associations with sexual stimuli than sexually functional women (Brauer, van
Leeuwen, Janssen, et al. submitted). A dot-probe task assessing attentional
preference for sexual and neutral visual stimuli did not discriminate between
groups, but was found to be sensitive to testosterone in earlier studies, and
will therefore be used as well (van der Made, Bloemers, Yassem, et al. 2009;
van der Made, Bloemers, van Ham, et al. 2009).

In the same sample of premenopausal US and Dutch women, HSDD-women*s genital
(VPA- vaginal pulse amplitude) response and reports of subjective sexual
arousal to low, medium and high-intensity erotic film stimuli were
significantly lower than those of sexually functional women (Laan, Brauer,
Janssen, et al in preparation). Psychophysiological testing in the present
study will therefore involve assessment of vaginal pulse amplitude (VPA) and
subjective sexual arousal during sexual to self-induced erotic fantasy, a
low-intensity erotic film clip, and a high-intensity erotic film clip.
Psychophysiological testing will take place 0.5 hours and 4.5 hours after
dosing. The rationale for this repeated testing is based on a 4-hour delay
effect of testosterone on VPA (Tuiten, Van Honk, Koppeschaar, et al. 2000;
Tuiten, Van Honk, Verbaten, et al. 2002). This finding was replicated in
another laboratory (Heard-Davison, Heiman, Kuffel. 2007).

This is a Phase I, two-center, randomized, placebo-controlled and double-blind
(ANOR arms), parallel-groups, 4-arm (equal balance), active-controlled (HSDD
arms) study in female patients. Both pre- and post- menopausal women will be
enrolled in the ANOR cohort for the TBS-2 treatment arms (with a majority of
the patients pre-menopausal). Only post-menopausal women will be randomized
into the HSDD cohort.

TBS-2 intranasal gel or Intrinsa transdermal patch

Please refer to the relevant pages of the study protocol.