Female sexual dysfunction

Abstract

The success of the erectile dysfunction market ushered in a new era of opportunity for the pharmaceutical industry, one in which major companies have begun to devote time and resources to conditions that were previously considered part of the natural course of life¹. Following in the footsteps of Pfizer, big pharma has used a vast amount of direct-to-consumer (DTC) and 'free-TC' advertising to create a US$3-billion-plus market that has merged the strategies of mass consumer marketing with a traditional pharma sell.

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Female sexual dysfunction
David Fitzhenry and Leslie Sandberg
FROM THE ANALYST’S COUCH
NEWS & ANALYSIS
NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | FEBRUARY 2005 | 99
The success of the erectile dysfunction market
ushered in a new era of opportunity for the
pharmaceutical industry, one in which major
companies have begun to devote time and
resources to conditions that were previously
considered part of the natural course of life
1
.
Following in the footsteps of Pfizer, big pharma
has used a vast amount of direct-to-consumer
(DTC) and ‘free-TC’ advertising to create a
US$3-billion-plus market that has merged the
strategies of mass consumer marketing with a
traditional pharma sell.
The development of products to alleviate
female sexual dysfunction (FSD) has lagged
considerably behind that for male sexual dys-
function. Population-based studies published
during the past decade have confirmed the
far-reaching extent of FSD, but fears about
the mixed aetiology of the disease, including
psychological as well as physiological compo-
nents, might have delayed pharma’s interest.
Moreover, the endpoint for FSD trials, usually
measured as an increase in the number of
satisfying sexual encounters, is much less tan-
gible than the male equivalent: erections that
can be measured in the clinic by a device such
as the RigiScan.
The recent high-profile rejection of Procter
and Gamble’s (P&G) testosterone patch,
Intrinsa, by the FDA advisory panel might
indicate the setting of a new bar for lifestyle
drugs. P&G will, at a minimum, have to submit
safety and efficacy data from ongoing and
recently completed Phase III trials in naturally
menopausal women, and might have to con-
duct additional trials to confirm the long-term
safety of testosterone administration in women.
This mandate represents an enormous barrier
to entry, putting the further development of
testosterone-based therapies at significant risk
and expanding the opportunity for novel
mechanisms of action.
FSD — the next big thing?
With more than 50 million potential sufferers in
the United States, FSD could offer a larger
market than male sexual dysfunction. Up to
63% of sexually active women might be affected
by FSD, according to the National Health and
Social Life Survey of nearly 2,000 women
between the ages of 18 and 59
(REF. 2). FSD is an
umbrella term for at least four separate dis-
orders. Many women suffer from more than
one disorder, with associated impact on their
personal relationships as well as self-esteem.
To address the multi-faceted symptomology
of FSD, several routes of pharmacotherapy are
probably needed. Off-label treatment of FSD
currently includes hormone-replacement
therapies, such as Solvay’s androgen/oestrogen
combination EstraTest, and phosphodiesterase
5 (PDE5) inhibitors such as sildenafil citrate
(Viagra; Pfizer). Several drug-development
strategies have focused on the 20 million post-
menopausal women in the US, in whom well-
documented hormonal changes are highly
correlated with the onset of FSD.
Emerging agents
P&G, partnered with Watson Pharmaceuticals,
has been leading the way for FSD drug develop-
ment. Their twice-weekly testosterone patch,
Intrinsa, offers a novel application of the age-old
knowledge that low levels of testosterone can
lead to decreased libido in both men and
women. In two pivotal Phase III trials, Intrinsa
demonstrated statistically significant efficacy,
increasing the number of satisfying sexual
encounters by 51–74% in surgically meno-
pausal women suffering from hypoactive sexual
desire disorder. However, in absolute terms, this
increase represents only about one additional
sexual event per month, and though the panel
agreed that this was clinically meaningful by a
14-to-3 vote, some questioned the clinical rele-
vance. The lack of long-term safety data in
women using testosterone with a required
oestrogen supplement raised red flags, and the
FDA experts expressed concern that off-label
usage in pre-menopausal women would expose
these women to significant risks beyond those
seen in the post-menopausal trials. In light of
the Women’s Health Initiative study findings,
which indicated an increased risk of cardio-
vascular events and breast cancer in patients on
long-term hormone-replacement therapy, the
current safety data were not deemed acceptable.
Other companies with new testosterone
applications, including non-localized gel formu-
lations by BioSante and Cellegy, are considering
their options in the wake of the FDA decree.
Decisions on whether to continue development
of both Intrinsa and other formulations will
ultimately be based on a risk/benefit analysis of
potential return weighed against the expenses
of the required trials. The void left in the wake of
the Intrinsa ruling creates a market primed for
other novel mechanisms of action. Stemming
from the knowledge that the clitoris and the penis
originate from the same stem cells in develop-
ment, some clinicians hoped to capitalize on the
ability of PDE5 inhibitors to increase blood flow
as a therapeutic in FSD. Both sildenafil citrate and
tadalafil (Cialis, Lilly/ICOS) were under investi-
gation for female sexual arousal disorder, but
their trials have been halted due to lack of efficacy
compared with placebo. Interestingly, although
sildenafil citrate failed in its primary endpoint,
it showed a positive effect on rates of orgasm.
Other novel agents, including alprostadil,
tibolone and apomorphine, are also being
studied, but are further off on the horizon for
FSD treatment. Trials for these drugs are likely
to continue as planned, but given their early
stage of development, they harbour signifi-
cantly more technical and clinical risk than
established hormonal therapies.
Market forecast
Market development, as with erectile dys-
function, will be contingent on the ability of
pharmaceutical companies to harness the psy-
chology of the mass market consumers. The
recent proliferation of press coverage preceding
the advisory committee review of Intrinsa
closely resembles the pre-launch of sildenafil
citrate, and has led to soaring rates of awareness
among potential sufferers. In our forecast,
awareness, coupled with an effort to seek help,
are the two most sensitive correlates with mar-
ket value. However, in the case of FSD, unlike
erectile dysfunction, some of this awareness
might be negative due to the safety concerns.
The potential size of the FSD market means
that discovery efforts are unlikely to cease,regard-
less of the fate of Intrinsa and the testosterone
therapies. The FSD market value could exceed
US$4 billion in the US alone with only 15% of
patients captured on therapy. But many hurdles
could prevent the realization of this market
value. The mixed aetiology of disease could
limit the uptake of drugs into niche segments.
Moreover, an indication that limits therapy to
post-menopausal women will weed out 75%
of the sexually active population. Lastly, chronic
therapies that must be used daily are less
attractive options than PRN (as-needed) treat-
ments such as sildenafil citrate, which could
deter some users.
▲

FSD could be the next boon for pharma
companies that are successfully able to inte-
grate consumer mass marketing strategies
with a more traditional pharma sell (see
TABLE 1 for FSD subtypes). With more than
50 million women in the US suffering from
FSD
(FIG. 1)
, the potential market size could
rival that of erectile dysfunction
(FIG. 2),but
significant technical and clinical risks exist.
To achieve Viagra-like levels of sales, emerging
agents must have broad labels, which is less
likely for testosterone-based therapies. At
maturity, the FSD market is more likely to be
a conglomeration of mid-sized drugs, each of
which address different symptoms of the
complex disorder (
TABLE 2).
David Fitzhenry, Principal, and Leslie Sandberg,
Senior Consultant, work for Trinity Partners,
LLC, 230 Third Avenue, Waltham, Massachusetts,
02451 USA.
e-mail: dfitzhen@trinitypartners.com;
lsandberg@trinitypartners.com
doi:10.1038/nrd1636
1. Moynihan, R. The making of a disease: female sexual
dysfunction. BMJ 326, 45–47 (2003)
2. Laumann, E. O. et al. Sexual dysfunction in the United
States. JAMA 281, 537–544 (1999)
Online links
FURTHER INFORMATION
Medline:
http://www.nlm.nih.gov/medlineplus/
femalesexualdysfunction.html
MedScape:
http://search.medscape.com/px/mscpsearch?
searchfor=Clinical&QueryText=female+sexual+dysfunction
National Health and Social Life Survey:
http://www.socio.com/srch/summary/aids/aid12-13.htm
Access to this interactive links box is free online.
Prevalence Current market value
% Of market
100
90
80
70
60
50
40
30
20
10
0
Female
sexual
dysfunction
Premature
ejaculation
Erectile
dysfunction
Figure 2 | Relative size of sexual dysfunction
markets. Source: Trinity Partners, LLC estimates.
100 | FEBRUARY 2005 | VOLUME 4 www.nature.com/reviews/drugdisc
NEWS & ANALYSIS
Table 2 | FSD drugs in development
Class Product FSD subtype Company Phase Notes
Androgens Intrinsa HSDD P&G, Watson III Twice-weekly patch
(testosterone) LibiGel HSDD BioSante II Non-localized gel
Tostrelle HSDD Cellergy II Non-localized gel
Testosterone IVR HSDD Galen II Intra-vaginal; testosterone ring
Testosterone MDTS HSDD VIVUS/Acrux II Non-localized topical spray
Oestrogen/androgen EstraTest HSDD Solvay Launched/III for FSD
STEAR Tibolene HSDD/FSAD Organon Launched in Europe
Vasoactive agents Femprox (alprostadil) FSAD NexMed II/III Topical, in pre-menopausal women
Alista (alprostadil) FSAD VIVUS III Topical, in pre-menopausal women
Viagra FSAD Pfizer II/discontinued
Cialis FSAD Lilly ICOS II/discontinued
Vasofem Zonagen II/on hold
Centrally acting agents VML 670 Drug-induced FSD Lilly II/on hold Serotonin receptor agonist
Flibanserin Boehringer II Serotonin receptor agonist
Ingleheim
Apomorphine FSAD Nastech II Dopamine agonist
Wellbutrin HSDD GlaxoSmithKline Women w/o testosterone deficiency
PT-141 FSAD Palatin II Melanocortin receptor agonist
NMI 870 Nitromed II
FSD, female sexual dysfunction; FSAD, female sexual arousal disorder; HSDD, hypoactive sexual desire disorder; STEAR, selective tissue oestrogenic activity regulator.
Table 1 | Female sexual dysfunction subtype
Subtype Epidemiology Symptoms
Hypoactive sexual 31% Persistent loss of libido
desire disorder
Female sexual arousal 22% Libido is present but genitals fail to respond to sexual
disorder stimulation — for example, lack of lubrication and vaginal
engorgement
Anorgasmia 6% Delay or lack of orgasm after normal female arousal
Sexual pain disorder 6% Defined by pain associated with intercourse, as a result
of the involuntary contraction of vaginal muscles, which
makes penetration difficult
▲
FEMALE SEXUAL DYSFUNCTION
|
MARKET INDICATORS
a 50–59-year olds (3.7 million)
6%
31%
24%
6%
b 18–59-year olds (53 million)
6%
32%
18%
7%
HSDD
FSAD
Anorgasmia
Pain
Figure 1 | Prevalence of female sexual
dysfunction (US). From National Health and Social
Life Survey 1992. FSAD, female sexual arousal
disorder; HSDD, hypoactive sexual desire disorder.