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Sexuality: Original Research
Bremelanotide for the Treatment of
Hypoactive Sexual Desire Disorder
Two Randomized Phase 3 Trials
Sheryl A. Kingsberg, PhD, Anita H. Clayton, MD, David Portman, MD, Laura A. Williams, MD,MPH,
Julie Krop, MD, Robert Jordan, BS, Johna Lucas, MD, and James A. Simon, MD
OBJECTIVE: To evaluate the safety and efficacy of
bremelanotide for the treatment of premenopausal
women with hypoactive sexual desire disorder.
METHODS: Two identical phase 3, randomized, double-
blind, placebo-controlled, multicenter clinical trials (RE-
CONNECT) evaluated the safety and efficacy of breme-
lanotide 1.75 mg administered subcutaneously as needed
in premenopausal women with hypoactive sexual desire
disorder. Patients were randomized 1:1 to 24 weeks of
treatment with bremelanotide or placebo. Sample size
was estimated based on simulations from key endpoints
in patients with hypoactive sexual desire disorder from
a prior trial. Coprimary efficacy endpoints were change
from baseline to end-of-study in the Female Sexual
Function Index–desire domain score and Female Sexual
Distress Scale–Desire/Arousal/Orgasm item 13.
RESULTS: Study 301 began on January 7, 2015, and
concluded on July 26, 2016. Study 302 began on January
28, 2015, and concluded on August 4, 2016. Of the 1,267
women randomized, 1,247 and 1,202 were in the safety
See related editorial on page 897.
From the University Hospitals Cleveland Medical Center, Cleveland, Ohio;
University of Virginia, Charlottesville, Virginia; Sermonix Pharmaceuticals,
Columbus, Ohio; AMAG Pharmaceuticals, Inc., Waltham, Massachusetts;
Palatin Technologies, Inc., Cranbury, New Jersey; and George Washington
University and IntimMedicine Specialists, Washington, DC.
The RECONNECT studies were sponsored by Palatin Technologies, Inc., the
innovator of bremelanotide. Editorial support in the preparation of this manu-
script was provided by Phase Five Communications, supported by AMAG Phar-
maceuticals, Inc., the licensee of bremelanotide.
Presented at the ISSWSH Annual Meeting in Atlanta, Georgia, February 23–26, 2017.
The authors thank all participants in these studies, their families, and personnel
at all study sites.
Each author has confirmed compliance with the journal’s requirements for authorship.
Corresponding author: Sheryl A. Kingsberg, PhD, Division of Behavioral
Medicine, MacDonald Women’s Hospital, University Hospitals Cleveland Med-
ical Center, Cleveland, OH; email: Sheryl.Kingsberg@UHhospitals.org.
Financial Disclosure
Dr. Kingsberg has served on advisory boards or has been a consultant for AMAG
Pharmaceuticals, Inc., Daré Bioscience, Duchesnay, Emotional Brain, Valeant,
Endoceutics, Ivix, Palatin Technologies, Inc., Pfizer, Shionogi, Materna, Nuelle,
Mitsubishi Tanaka North America, TherapeuticsMD, SST, and Lupin/Symbio-
mix. She has stock options in Viveve Medical. Dr. Clayton has served on advisory
boards or has been a consultant for Acadia, Alkermes, Allergan, AMAG Pharma-
ceuticals, Inc., Fabre Kramer, Lundbeck, Palatin Technologies, Inc., S1 Biophar-
ma, Sage Therapeutics, Sprout, and Takeda. She has received grants from
Endoceutics, Inc., Janssen, Sage Therapeutics, and Takeda. In addition, she has
received royalties and/or owns the copyright to works published by Ballantine
Books/Random House and Guilford Publications, and the Changes in Sexual
Functioning Questionnaire. She has shares or restricted stock units in Euthymics
and S1 Biopharma. Dr. Portman has served on advisory boards or has been
a consultant to AMAG Pharmaceuticals, Inc., Palatin Technologies, Inc.,
Endoceutics, Valeant Pharmaceuticals, and Sprout, and is on the speaker’s bureau
for AMAG Pharmaceuticals, Inc.; he is an employee and stockholder of Sermonix
Pharmaceuticals. Dr. Williams and Dr. Krop are employees and stockholders of
AMAG Pharmaceuticals, Inc. (the licensee of bremelanotide). Mr. Jordan is Vice
President, Clinical Operations and Project Management, and a stockholder of
Palatin Technologies, Inc. (the sponsor of the trial). He has a BS in Biology
and has worked in clinical development for over 20 years. He led the Palatin
team in the development of bremelanotide (clinical, regulatory, etc.) since 2007,
including having a very significant role in designing the phase 3 studies, conduct of
the studies, and analysis of the data. Dr. Lucas was an employee of Palatin
Technologies, Inc. at the time of the study. She has no remaining financial interests
in Palatin Technologies. She was the medical lead for the entire trial. She was the
physician who ran the trial and provided safety evaluation and analysis for all
adverse events as they occurred during the trial. She was also responsible for
aggregate assessment of the adverse event database. She was the physician who
provided medical information to the DSMB during the trial. Dr. Simon has served
on advisory boards or has been a consultant for AbbVie, Allergan, AMAG Phar-
maceuticals, Inc., Amgen, Ascend Therapeutics, Azure Biotech, Bayer HealthCare
Pharmaceuticals, Inc., CEEK Enterprises, Covance Inc., Daré Bioscience, Duch-
esnay, Hologic Inc., KaNDy/NeRRe Therapeutics Ltd., Millendo, Mitsubishi Ta-
nabe Pharma, ObsEva, Radius Health, Sanofi, Sebela, Sermonix, Shionogi,
Symbiotec Pharmalab, TherapeuticsMD, and Valeant. He has also served on
the speaker’s bureau for AbbVie, AMAG Pharmaceuticals, Inc., Duchesnay, Novo
Nordisk, Shionogi, and Valeant. He has received grants/research funding from
AbbVie, Allergan, Agile Therapeutics, Bayer Healthcare LLC, Dornier MedTech,
Endoceutics Inc., GTx Inc., Hologic Inc., Myovant Sciences, New England
Research Institutes, ObsEva, Palatin Technologies, Inc., Symbio Research, Ther-
apeuticsMD, Tissue Genesis, and Viveve Medical. He owns stock in Sermonix.
© 2019 The Author(s). Published by Wolters Kluwer Health, Inc. This is an
open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND),
where it is permissible to download and share the work provided it is properly
cited. The work cannot be changed in any way or used commercially without
permission from the journal.
ISSN: 0029-7844/19
VOL. 134, NO. 5, NOVEMBER 2019 OBSTETRICS & GYNECOLOGY 899
and efficacy (modified intent-to-treat) populations,
respectively. Most participants were white (85.6%), from
U.S. sites (96.6%), and had a mean age of 39 years. From
baseline to end-of-study, women taking bremelanotide
had statistically significant increases in sexual desire
(study 301: 0.30, P,.001; study 302: 0.42, P,.001; inte-
grated studies 0.35, P,.001) and statistically significant
reductions in distress related to low sexual desire (study
301: 20.37, P,.001; study 302: 20.29, P5.005; integrated
studies 20.33, P,.001) compared with placebo. Patients
taking bremelanotide experienced more nausea, flush-
ing, and headache (10% or more in both studies) com-
pared with placebo.
CONCLUSIONS: Both studies demonstrated that bre-
melanotide significantly improved sexual desire and
related distress in premenopausal women with hypoac-
tive sexual desire disorder. The safety profile was favor-
able. Most treatment-emergent adverse events were
related to tolerability and the majority were mild or
moderate in intensity.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
NCT02333071 (study 301) and NCT02338960 (study 302).
FUNDING SOURCE: Palatin Technologies, Inc., and
AMAG Pharmaceuticals, Inc.
(Obstet Gynecol 2019;134:899–908)
DOI: 10.1097/AOG.0000000000003500
Female sexual dysfunction refers to a heterogenous
group of sexual disorders, including difficulties
with desire, interest, arousal, orgasm, or pain (dyspar-
eunia) that may result in personal and interpersonal
distress, and impair a woman’s overall health and
quality of life.
1
The most prevalent sexual dysfunction
among women is hypoactive sexual desire disorder,
defined as persistent (or recurrent) diminished or lack
of desire for sexual activity, accompanied by distress
(not better accounted for by a medical condition, sub-
stance use, or relationship conflict).
1–3
Although hypo-
active sexual desire disorder affects ;10% of
women aged 18–44 years in the United States,
4,5
there
is only one U.S. Food and Drug Administration
(FDA)–approved therapy for hypoactive sexual desire
disorder in premenopausal women at the time of this
study, and this option is administered once daily.
6
Hypoactive sexual desire disorder may be caused
by an imbalance in the excitatory and inhibitory
neural pathways in the prefrontal cortex and limbic
system implicated in human sexual response, leading
to increased inhibition, decreased excitation, and
diminished responsiveness to sexual cues. Melano-
cortins have been associated with excitatory pathways
and linked to appetitive sexual behaviors.
6–9
Breme-
lanotide is a novel cyclic heptapeptide analog of the
endogenous neuropeptide a-melanocyte-stimulating
hormone with high affinity for the melanocortin-4
receptor.
10
Preclinical studies suggest that bremelano-
tide acts on physiologic and neurobiologic compo-
nents of female sexual function by modulating
neurotransmitter pathways involved in sexual desire
and arousal in women with hypoactive sexual desire
disorder.
8
A phase 2b, randomized, double-blind, placebo-
controlled, dose-finding trial (NCT01382719) was
conducted with 397 premenopausal women with
hypoactive sexual desire disorder, female sexual
arousal disorder, or both. Self-administered subcuta-
neous bremelanotide, taken as needed for up to 12
weeks, showed dose-responsive improvements in
desire, arousal, and associated distress, as well as
increases in the number of satisfying sexual events
compared with placebo. The 1.75 mg dose of breme-
lanotide was selected for phase 3 studies based on
optimal efficacy and an acceptable safety profile.
11
After discussion with the FDA, two separate,
identically designed phase 3 clinical trials were con-
ducted as per their recommendation. The current
report details the individual study results and the
integrated data from the core phase 3 RECONNECT
pivotal studies, designed to evaluate the safety and
efficacy of bremelanotide in premenopausal women
with acquired, generalized hypoactive sexual desire
disorder.
ROLE OF THE FUNDING SOURCE
The two studies, NCT02333071 (study 301) and
NCT02338960 (study 302), were sponsored by Pala-
tin Technologies, Inc., the innovator of bremelano-
tide. The sponsor had a role in the design, execution,
analysis, reporting, and funding of the studies. The
authors had access to relevant individual and aggre-
gated study data and other information (such as study
protocol, analytic plan and report, validated data
tables, and clinical study report) required to under-
stand and report research findings. The authors take
responsibility for the presentation and publication of
the research findings, have been fully involved at all
stages of publication and presentation development,
and are willing to take public responsibility for all
aspects of the work. All individuals included as
authors and contributors who made substantial intel-
lectual contributions to the research, data analysis,
and publication or presentation development are
listed appropriately. The role of the sponsor in the
design, execution, analysis, reporting, and funding is
fully disclosed. The authors’personal interests,
900 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder OBSTETRICS & GYNECOLOGY
financial or nonfinancial, relating to this research and
its publication have been disclosed.
METHODS
The RECONNECT studies were two identically
designed, randomized, double-blind, placebo-con-
trolled, multicenter trials evaluating the safety and
efficacy of bremelanotide administered subcutane-
ously as needed compared with placebo in premen-
opausal women with hypoactive sexual desire
disorder (Appendix 1, available online at http://
links.lww.com/AOG/B585). “RECONNECT”refers
to a common response from patient interviews, during
which women expressed their wish to reconnect to the
desire they had lost with hypoactive sexual desire dis-
order. Investigators obtained approval from institu-
tional review boards (U.S.) or independent ethics
committees (Canada) from all related study sites.
The studies were conducted in accordance with Good
Clinical Practice requirements, and all patients pro-
vided written informed consent.
The studies included a core study phase consisting
of a 4-week screening period, a 4-week baseline period
(single-blind, placebo-only treatment period), and a 24-
week randomized, double-blind, placebo-controlled
treatment period. A 52-week open-label extension
study phase was optional for patients who completed
the core study phase. A total of 1,500 premenopausal
female patients were planned to be screened in each
study to obtain approximately 550 patients for ran-
domization and to provide 2 or more months of data
from the double-blind treatment period in 450 patients
or more. Sample sizes were based on simulations from
the observed distributions of the coprimary and key
secondary endpoints in patients with hypoactive
sexual desire disorder (with and without arousal) in
a phase 2 study.
11
Simulations predicted the estimated
mean treatment difference (placebo compared with
bremelanotide 1.75 mg) of 1.0 for change from baseline
for the Female Sexual Function Index-desire domain
(FSFI-D) and 20.43 for the Female Sexual Distress
Scale-Desire/Arousal/Orgasm (FSDS-DAO) item 13.
Based on these simulations, it was calculated that 450
evaluable patients would provide 100% power to detect
a difference between the two treatment groups for
both FSFI-D and FSDS-DAO item 13. As there were
two primary endpoints, the inference threshold was
0.025. Similar calculations established that 480
evaluable patients would provide 93.8% power to
detect a difference between the two groups for the-
key secondary endpoint. Patients were randomized
in a 1:1 ratio to receive bremelanotide 1.75 mg or
placebo using an Interactive Response System.
The randomization scheme was generated using
permuted blocks by country.
After completing the 4-week screening period (visit
1), all patients were included in the 4-week, single-blind,
placebo-only treatment period (visit 2) and were ex-
pected to engage in sexual activity at least once. This
single-blind placebo period was used to establish the
baseline to which end-of-treatment changes were com-
pared and to minimize the placebo effect typically
associated with subjective-endpoint trials. All patients
who completed the placebo run-in period were ran-
domized at visit 3 to a 24-week, double-blind treatment
period of either bremelanotide or placebo administered
subcutaneously. In a prior dose-finding trial, the breme-
lanotide 1.75 mg dose showed optimal efficacy and an
acceptable safety profile.
11
Patients were observed while
self-administering an in-clinic dose, and blood pressure
(BP) measurements were taken at up to 1 hour predose
and 1.0, 1.5, and 2 hours postdose. They could self-
administer a maximum of 12 doses as needed (approx-
imately 45 minutes before anticipated sexual activity) in
each 4-week period as outpatients, with no more than
one dose per 24-hour period. Safety evaluations were
performed at screening, then monthly to the end of the
core study phase (visit 9 at 8 months or at premature
discontinuation). Patients had a physical examination,
including BP assessments and other vital sign data col-
lection, measurement of electrocardiograms, clinical lab-
oratory testing, adverse event monitoring, and
administration of the Beck Scale for Suicidal Ideation.
12
The studies recruited healthy, premenopausal
women 18 years of age or older in stable monogamous
relationships with a male or female partner. Patients
were recruited from clinical sites such as private
practices, academic medical centers, and research
clinics. Diagnosis of the patient with hypoactive sexual
desire disorder (with or without symptoms of
decreased arousal) was performed using the Diagnostic
Screening Guide for hypoactive sexual desire disorder
and was completed by the investigator or an appropri-
ately licensed health care provider. All patients had
a diagnosis of acquired, generalized hypoactive sexual
desire disorder, with or without decreased arousal, for
6 months or more; had prior experience of normal
sexual function (self-defined) for 2 years or more; and
were willing to engage in sexual activities one or more
times per month during the study. Patients were
excluded if they were pregnant or nursing; had any
other female sexual dysfunction; or were diagnosed
with or being treated for depression, psychosis, bipolar
disorder, or substance abuse within 6 months before
screening. Patients taking neuroleptics, lithium, anti-
depressants, mood stabilizers, benzodiazepines,
VOL. 134, NO. 5, NOVEMBER 2019 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder 901
cognitive enhancers, or g-aminobutyric acid antago-
nists within 3 months of screening were also excluded.
Coprimary efficacy endpoints were change from
baseline to end-of-study (defined as the patients’last
visit) in the FSFI-D score, comprised of questions 1
and 2, and change from baseline to end-of-study in the
score for feeling bothered by low sexual desire as
measured by the FSDS-DAO item 13 (Appendix 2,
available online at http://links.lww.com/AOG/B585).
The key secondary endpoint was the change from
baseline to end-of-study in satisfying sexual events
that occurred within 16 hours of study drug dosing
and reported within 72 hours.
The primary efficacy analysis used the last-
observation-carried-forward approach for primary
and secondary endpoints in the modified intent-to-
treat population, which was defined as all patients in
the safety population who had one or more double-
blind follow-up visits. The safety population was
defined as all patients who were randomized and
received one or more doses of double-blind medica-
tion (in or outside the clinic). An Independent Anchor
Assessment Committee evaluated anchors used to
define responders and to determine clinically mean-
ingful responder thresholds for the coprimary and
secondary endpoints before unblinding. As the con-
duct of both studies was identical (inclusion and
exclusion criteria, and all efficacy and safety assess-
ments), data from the individual studies are presented
and were integrated for this publication. P-values were
reported to no more than three decimal places per
journal requirements.
RESULTS
A total of 1,267 women were randomized in the two
trials; 1,247 comprised the safety population, and
1,202 comprised the primary efficacy, modified
intent-to-treat population. In studies 301 and 302,
the modified intent-to-treat populations consisted of
630 and 572 patients, respectively, and the safety
populations comprised 643 and 604 patients, respec-
tively. Patient disposition in each study is presented
in Appendix 3, available online at http://links.lww.
com/AOG/B585. Study 301 began on January 7,
2015, and concluded on July 26, 2016; study 302
began on January 28, 2015, and concluded on
August 4, 2016. Participants were mostly white
(85.6%) and non-Hispanic or Latina (91.5%)
(Table 1). Demographics were well balanced
between the groups in both studies. Almost all ran-
domized patients were from U.S. sites (96.6%).
Relative to placebo, women in the bremelanotide
group had statistically significant increases in sexual
desire from baseline to end-of-study, as measured by
FSFI-D scores (study 301: 0.30, P,.001; study 302:
0.42, P,.001; integrated studies 0.35, P,.001), and
had statistically significant reductions in distress
related to low sexual desire from baseline to end-of-
study, as measured by FSDS-DAO item 13 scores
(study 301: 20.37, P,.001; study 302: 20.29,
P5.005; integrated studies 20.33, P,.001). In the
integrated dataset, the effect size of bremelanotide
(relative to placebo) for improving sexual desire was
0.39, and the effect size associated with reducing
related distress was 0.27. For both coprimary end-
points, changes were observed at week 4 (earliest eval-
uated time point) and sustained over the course of the
study (Fig. 1A and B). By comparing the empirical
distribution for the coprimary endpoints between
the two treatment groups, the cumulative distribution
showed highly statistical significant differences (FSFI-
D: P,.001; FSDS-DAO: P,.001) for both studies
(data not shown). These statistically significant
Table 1. Baseline Characteristics (Safety
Population)
Characteristic
Placebo
(n5620)
BMT 1.75 mg
(n5627)
Age (y) 38.867.1 38.567.1
Weight (kg) 77.3619.0 79.0619.9
BMI (kg/m
2
) 28.666.9 29.067.0
HSDD diagnosis
With decreased arousal 434 (71.6) 420 (70.5)
Without decreased
arousal
172 (28.4) 176 (29.5)
FSFI desire score at
baseline*
2.060.8 2.160.8
FSDS-DAO item 13 at
baseline*
2.960.9 2.961.0
Race
American Indian or
Alaska native
2 (0.3) 5 (0.8)
Asian 7 (1.1) 7 (1.1)
Black or African
American
71 (11.5) 73 (11.6)
White 531 (85.6) 536 (85.5)
Other 9 (1.5) 6 (1.0)
Reproductive status
Childbearing potential 466 (75.2) 473 (75.4)
Surgically sterile 154 (24.8) 154 (24.6)
Gender of partner
Male 610 (98.4) 614 (97.9)
Female 10 (1.6) 13 (2.1)
BMT, bremelanotide; BMI, body mass index; HSDD, hypoactive
sexual desire disorder; FSFI, Female Sexual Function Index;
FSDS-DAO, Female Sexual Distress Scale–Desire/Arousal/
Orgasm.
Data are mean6SD or n (%).
* Based on the modified intent-to-treat population.
902 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder OBSTETRICS & GYNECOLOGY
differences between treatment groups in favor of bre-
melanotide in both studies were supported by an
anchored responder analysis, with prespecified defini-
tions to support clinical meaningfulness.
1
The General
Assessment Questionnaire question 3 primary
dynamic anchor assessment of the coprimary end-
points (patients’perceived benefit of study drug)
yielded clinically meaningful and statistically signifi-
cant (P,.001) differences between the treatment
groups in each study, with 58.3% and 58.2%
responder rates for bremelanotide and 36.1% and
35.4% for placebo in studies 301 and 302, respectively
(Fig. 1C). In a sensitivity analysis, three additional
static anchor assessments, Elements of Desire Ques-
tionnaire question 9, FSDS-DAO item 1, and FSFI
question 16, yielded similar responder rates for both
studies. Importantly, additional sensitivity analyses
demonstrated treatment benefits favoring bremelano-
tide even when all premature discontinuations were
assumed to be nonresponders (data not shown).
Because the difference in the change from
baseline to end-of-study for the number of satisfying
sexual events reported did not reach statistical
significance between treatment groups (study 301:
bremelanotide 0.0, placebo 20.1, P5.764; study
302: bremelanotide 0.0, placebo 0.0, P5.702; inte-
grated studies: bremelanotide 0.0, placebo 20.1,
P5.630), the remaining ranked secondary endpoints
became supportive and exploratory per the statistical
analysis plan. A post hoc exploratory analysis
showed that the difference in the percentages of sex-
ual events that were considered satisfying sexual
events (number of satisfying sexual events per total
number of sexual encounters) increased substantially
in the bremelanotide group compared with the pla-
cebo group. Across both studies, the difference in the
percentages of satisfying sexual events increased
greater than two-fold in the bremelanotide group
compared with the placebo group (25.0% vs 9.8%,
P,.001) (Fig. 2).
Overall sexual function and associated distress
were assessed according to mean changes from
baseline to end-of-study for FSFI and FSDS-DAO
total scores, respectively. The bremelanotide to pla-
cebo odds ratios for the proportion of responders
(defined as 4.2 or more and –10 or below for FSFI and
FSDS-DAO total scores, respectively) significantly
favored bremelanotide for those endpoints (Fig. 3).
Overall, the bremelanotide groups in both studies
demonstrated a trend of having a greater number of
responders compared with placebo for secondary
endpoints measuring changes in the mean levels of
desire and arousal per FSFI, as well as satisfaction with
those aspects of sexual function.
In both studies, the most common treatment-
emergent adverse events that occurred at a higher rate
in the bremelanotide group (10% or more in both
studies) than the placebo group were nausea, flushing,
and headache (Table 2). The majority of treatment-
emergent adverse events in both studies were mild or
moderate in severity. In both studies, severe
treatment-emergent adverse events that occurred in
more than one patient who received bremelanotide
included nausea (13 [2.1%] patients), headache (5
[0.8%]), vomiting (3 [0.5%]), and myalgia (2 [0.3%]).
No other severe treatment-emergent adverse events
were reported by more than one patient in the breme-
lanotide group, and there were no severe treatment-
emergent adverse events that occurred in more than
one patient in the placebo group.
The incidence of nausea with bremelanotide was
40.0% compared with 1.3% with placebo across both
studies. Nausea had a median onset of 30 minutes
after dosing, with a median duration of 2.4 hours,
tended to occur sporadically with dosing, and was
mild to moderate in severity (approximately 98% of
cases in both studies) with most cases resolving
spontaneously (Appendix 4, available online at
http://links.lww.com/AOG/B585). Among the subset
with one or more nausea events who chose to use an
antiemetic, the subsequent nausea rate was lower
(;5%) compared with those who did not use an anti-
emetic (;15%). Although 40% of patients taking bre-
melanotide experienced nausea, only 8.1%
discontinued study drug during the two studies due
to nausea, and only 3.5% simultaneously reported
vomiting.
Across both studies, seven patients who received
bremelanotide reported 10 treatment-emergent seri-
ous adverse events, and three patients who received
placebo reported four treatment-emergent serious
adverse events. No specific treatment-emergent seri-
ous adverse event occurred more than once (Appen-
dix 5, available online at http://links.lww.com/AOG/
B585). There was one treatment-emergent serious
adverse event in study 301 that was considered related
to the study drug in a patient who had received bre-
melanotide and subsequently experienced vomiting
and headache. Both symptoms were resolved after
overnight hospitalization with hydromorphone
hydrochloride, ketorolac tromethamine, morphine
sulfate, and intravenous sodium chloride for the head-
ache, and promethazine and ondansetron for nausea
and vomiting. No treatment-emergent serious adverse
VOL. 134, NO. 5, NOVEMBER 2019 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder 903
events in study 302 were considered related to study
drug, and no deaths occurred during either study.
In both studies, placebo-adjusted changes in BP
for patients taking bremelanotide were consistent
with ambulatory BP readings from the phase 2
studies, with a mean increase of approximately
3 mm Hg for systolic BP and 2 mm Hg for diastolic
BP. These mild transient changes were noted approx-
imately 0–2 hours postbremelanotide dosing, re-
turned to baseline within 8–10 hours, and were
accompanied by similarly mild decreases in pulse
rates, such that there were no mean increases in over-
all myocardial workload. No clinically significant ef-
fects on clinical laboratory tests, electrocardiograms,
weight, depression, or suicidal ideation were
observed in either study. There were no differences
in the adverse event profiles among patients based
on the amount of alcohol they consumed during the
study.
Among the 856 patients who completed the
double-blind core study phase, approximately 80%
(684 patients) elected to participate in the open-label
extension. This included 87% (430/493) of patients
from the placebo groups and 70% (254/363) of pa-
tients from the bremelanotide groups.
DISCUSSION
These two large, identically designed, randomized,
phase 3, double-blind, placebo-controlled registration
trials evaluating the safety and efficacy of
Fig. 1. Co-primary endpoints and key dynamic anchor over the course of the core phase of the phase 3 studies (modified
intent-to-treat population). A. Female Sexual Function Index–desire domain (FSFI-D). B. Female Sexual Distress Scale–
Desire/Arousal/Orgasm (FSDS-DAO). C. General Assessment Questionnaire (GAQ) question 3 responders ($5, dynamic
anchor). Aand B. Estimated treatment difference and Pvalue from mixed-model repeated measures using change from
baseline of all double-blind period data (baseline through core week 24), with uncorrelated covariance structure.
C.Pvalue from unadjusted Wilcoxon rank-sum test. Scores range from 1 (very much worse) to 7 (very much better).
Summary statistics are based on the number of nonmissing values. Error bars for integrated populations represent
95% CIs. BMT, bremelanotide.
Kingsberg. Bremelanotide for Hypoactive Sexual Desire Disorder. Obstet Gynecol 2019.
904 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder OBSTETRICS & GYNECOLOGY
bremelanotide compared with placebo successfully
met their coprimary efficacy endpoints of improving
sexual desire and related distress in premenopausal
women with hypoactive sexual desire disorder. Addi-
tionally, the bremelanotide group showed signifi-
cantly greater numbers of responders compared with
placebo, thus demonstrating clinically meaningful
benefits from bremelanotide treatment in alignment
with FDA guidances.
1
The coprimary endpoints used
components of the FSFI and FSDS-DAO, namely, the
desire domain and item 13, respectively, which are
robust and validated instruments for the assessment
of hypoactive sexual desire disorder.
13–17
Moreover,
the independently defined thresholds for the dynamic
Fig. 2. Percentage of sexual en-
counters that were satisfying sexual
events (modified intent-to-treat
populations, post hoc analysis). No
significant difference between
treatment groups was observed for
satisfying sexual events associated
with study drug and reported within
72 hours.
Kingsberg. Bremelanotide for
Hypoactive Sexual Desire
Disorder. Obstet Gynecol 2019.
Fig. 3. Forest plot of supportive secondary efficacy endpoints in the phase 3 studies (modified intent-to-treat population). Q,
question; FSEP-R, Female Sexual Encounter Profile–Revised; BMT, bremelanotide; FSDS-DAO, Female Sexual Distress
Scale–Desire/Arousal/Orgasm; FSFI, Female Sexual Function Index; PBO, placebo.
Kingsberg. Bremelanotide for Hypoactive Sexual Desire Disorder. Obstet Gynecol 2019.
VOL. 134, NO. 5, NOVEMBER 2019 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder 905
anchor assessment of the coprimary endpoints con-
firmed both clinically meaningful and statistically sig-
nificant differences between treatment groups in both
studies. This was achieved despite the high placebo
response rates of approximately 35%; as there was
a 25% increase in the percentage of satisfying sexual
events among patients who received placebo, 40% of
the relative increase among patients treated with bre-
melanotide could be attributed to the placebo effect. A
high placebo response rate is typical of subjective end-
points where expectations, anxiety, and reward are
likely involved.
18
Effect size is important to consider as it indicates
the magnitude of the treatment’s effect: an effect size
of 0.2 is considered small, 0.5 medium, and 0.8
large.
19
In the RECONNECT trials, the effect size
of as-needed bremelanotide alone for improving sex-
ual desire ranged from 0.49 to 0.61, and from 0.60 to
0.62 in reducing related distress. Relative to placebo,
these values were 0.29–0.43 and 0.26–0.32, respec-
tively. Across three phase 3 studies, the effect size of
once-daily flibanserin relative to placebo was reported
to range from 0.29 to 0.44 in improving sexual desire,
and from 0.24 to 0.44 in reducing related distress.
20,21
For additional perspective, an analysis of pharmaco-
logic treatments for generalized anxiety disorder re-
ported effect sizes relative to placebo of 0.36 and 0.38
for SSRIs and benzodiazepines, respectively.
22
Prespecified exploratory subgroup analyses of the
integrated phase 3 studies have demonstrated that
bremelanotide is efficacious across all age and weight
quartiles and all baseline FSFI total, FSFI-D, and
FSDS-DAO total scores in premenopausal women
with HSSD, supporting its use across a wide range of
patients (unpublished data). The totality of improve-
ment in the supportive secondary efficacy endpoints
that evaluated overall sexual function and distress
related to level of sexual function (total scores for FSFI
and FSDS-DAO), as well as specific aspects of sexual
distress and arousal, all provide robust and consistent
data that align with the statistically significant results
for the coprimary endpoints. The FSFI total score,
although not specific to low sexual desire, reflects
other important components of sexual function (eg,
arousal, orgasm, satisfaction) that are affected by low
sexual desire and provides additional insight to
patients and prescribers around overall sexual health.
The FSFI total score is often improved by treating low
desire, as evidenced by the RECONNECT studies.
Similarly, the FSDS-DAO total score highlights
reduction in overall distress and parallels the overall
improvement in the FSFI-D score.
Treatment effects were noted early after treatment
initiation, with statistically significant treatment bene-
fits in both studies in favor of bremelanotide, and
were maintained throughout the 24-week double-
Table 2. Treatment-Emergent Adverse Events Reported More Frequently in the Bremelanotide Treatment
Group (1% or More in Bremelanotide Group With Incidence 1% or Higher Than for Placebo
Patients) by Preferred Term (Safety Population)
Treatment-Emergent
Adverse Event
Placebo Bremelanotide 1.75 mg
Study 301
(n5319)
Study 302
(n5301)
Integrated
(n5620)
Study 301
(n5324)
Study 302
(n5303)
Integrated
(n5627)
Any treatment-emergent
adverse event
190 (59.6) 170 (56.5) 361 (58.2) 256 (79.0) 224 (73.9) 480 (76.6)
Nausea 7 (2.2) 0 8 (1.3) 138 (42.6) 111 (36.6) 251 (40.0)
Flushing 2 (0.6) 0 2 (0.3) 84 (25.9) 43 (14.2) 127 (20.3)
Headache 8 (2.5) 4 (1.3) 12 (1.9) 32 (9.9) 38 (12.5) 71 (11.3)
Injection site reaction 3 (0.9) 0 3 (0.5) 18 (5.6) 16 (5.3) 34 (5.4)
Vomiting 0 1 (0.3) 1 (0.2) 17 (5.2) 13 (4.3) 30 (4.8)
Cough 4 (1.3) 4 (1.3) 8 (1.3) 8 (2.5) 13 (4.3) 21 (3.3)
Fatigue 1 (0.3) 2 (0.7) 3 (0.5) 12 (3.7) 8 (2.6) 20 (3.2)
Injection site erythema 1 (0.3) 0 1 (0.2) 8 (2.5) 10 (3.3) 18 (2.9)
Hot flush 1 (0.3) 0 1 (0.2) 6 (1.9) 11 (3.6) 17 (2.7)
Paresthesia 0 0 0 7 (2.2) 9 (3.0) 16 (2.6)
Dizziness 1 (0.3) 2 (0.7) 3 (0.5) 10 (3.1) 4 (1.3) 14 (2.2)
Injection site pruritus 1 (0.3) 0 1 (0.2) 7 (2.2) 6 (2.0) 13 (2.1)
Abdominal pain upper 3 (0.9) 1 (0.3) 4 (0.6) 7 (2.2) 5 (1.7) 12 (1.9)
Myalgia 0 1 (0.3) 1 (0.2) 5 (1.5) 6 (2.0) 11 (1.8)
Data are n (%). The integrated analysis included treatment-emergent adverse events that followed the core phase of the study, but occurred
prior to open-label extension phase dosing.
906 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder OBSTETRICS & GYNECOLOGY
blind treatment period. Early onset of treatment effect
and as-needed dosing will allow patients to quickly
decide whether they are benefiting from the drug,
thereby minimizing unnecessary exposure and
unwanted tolerability issues.
As with any investigational drug, patients may
speculate whether they are on active drug by experi-
encing adverse events or the perception of efficacy.
Although 40.0% of patients in the bremelanotide arm
(vs 1.3% in the placebo arm) reported nausea, the
overall incidence of treatment-emergent adverse
events was more similar between the two study arms
(76.6% vs 58.2%). Moreover, the high placebo effect
rate in sexual dysfunction studies suggests that those
taking placebo could also have falsely speculated that
they were on active drug. Thus, the randomized,
placebo-controlled design of the study shields specu-
lation that efficacy was driven by patient speculation
to any significant extent.
The effects of bremelanotide on BP have been
well characterized in several clinical studies, which
consistently revealed small, transient BP increases that
peak within 4 hours postdose and return toward
baseline by approximately 8–10 hours. These small
changes in BP were accompanied by corresponding
reductions in heart rate, resulting in lower or neutral
heart rate-BP product values. There have been no
cumulative or sustained effects on BP related to bre-
melanotide and, given the limited intermittent use of
the product, no untoward cardiovascular effects
would be anticipated.
The most common treatment-emergent adverse
events occurring in more than 10% of bremelanotide
patients compared with placebo were nausea, flush-
ing, and headache. The majority of treatment-
emergent adverse events in the bremelanotide group
were transient and mild to moderate in severity.
Furthermore, the most common adverse events were
related to tolerability issues that patients may be
willing to accept and manage in exchange for im-
provements in sexual desire and reductions in associ-
ated distress.
Clinical research questions remain as the safety
and efficacy of bremelanotide has yet to be established
in postmenopausal women and in women whose
comorbidities include psychiatric disorders requiring
medication. The majority of the study population was
white and non-Hispanic, and further clinical data are
needed to establish the efficacy and safety of breme-
lanotide in other populations. Finally, a differential
study withdrawal rate was observed in both studies
(study 301: 41.9% bremelanotide vs 16.0% placebo;
study 302: 43.8% bremelanotide vs 28.4% placebo).
The data obtained from these two identically
designed, phase 3, randomized, double-blind, pla-
cebo-controlled trials demonstrate that bremelanotide
can improve sexual desire and decrease distress
related to sexual desire with a manageable side-
effect profile as an as-needed potential treatment for
premenopausal women with hypoactive sexual desire
disorder independent of decreased arousal.
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Authors’ Data Sharing Statement
Will individual participant data be available (including
data dictionaries)? No.
What data in particular will be shared? Not available.
What other documents will be available? Not available.
When will data be available (start and end dates)? Not
applicable.
By what access criteria will data be shared (including
with whom, for what types of analyses, and by what
mechanism)? Not applicable.
PEER REVIEW HISTORY
Received April 22, 2019. Received in revised form June 19, 2019.
Accepted July 11, 2019. Peer reviews are available at http://links.
lww.com/AOG/B586.
908 Kingsberg et al Bremelanotide for Hypoactive Sexual Desire Disorder OBSTETRICS & GYNECOLOGY
