222 The Neurobiology and Efficacy of Bremelanotide in HSDD Presented at the 22nd Annual Fall Scientific Meeting of 1 2 2 2 3 Sexual Medicine Society of North America Anita H. Clayton, Johna Lucas, Robert Jordan, Carl Spana, James G. Pfaus November 3– 6, 2016 Scottsdale, AZ 1University of Virginia, Charlottesville, VA, USA; 2Palatin Technologies, Cranbury, NJ, USA; 3Concordia University, Montréal, Québec, Canada • Introduction Mechanism of Sexual and Reward Circuitry Rat Study Human Study — Decreased (less distress) both the total score and • These neurochemicals act on similar regions of the brain, • BMT’s downstream CNS effects of increasing arousal • Among premenopausal women with HSDD with or scores on the desire, arousal, and orgasm items of • Female sexual dysfunctions are classified as dysfunctions Sexual Response such as the medial preoptic area (mPOA) in the hypothalamus, and desire are thought to result from its action as a without FSAD, subcutaneous (SC) administration of the FSDS–Desire-Arousal-Orgasm measure. Mean of desire (eg, hypoactive sexual desire disorder [HSDD]), attention- and reward-related regions of the limbic system, MC-receptor agonist BMT 1.25 or 1.75 mg: (SE) change, –11.1 (12.0) vs –6.8 (13.6); BMT vs arousal (eg, female sexual arousal disorder [FSAD]), • Excitatory signals are regulated by dopamine (DA), placebo, respectively ( P=0.0014; Figure 7 )11 and the prefrontal cortex • Among female rats primed with estrogen and proges - — Significantly increased the number of sexually satisfying delay or absence of orgasm, or sexual pain (dyspareunia norepinephrine (NE), oxytocin, and the melanocortins 5,6 — Gamma aminobutyric acid projections help regulate DA terone or estrogen alone, BMT significantly increased events (SSEs) vs placebo when taken 45 minutes or vaginismus) 1 (MCs) Figure 7. Mean Change in FSDS-DAO Total Score After signaling in the brainstem via the nucleus accumbens measures of solicitation without altering pacing or before sexual activity. Mean (standard error [SE]) 11 — DA and the MCs stimulate attention and desire BMT Treatment • These are distressing conditions, particularly for younger (NAcc) and ventral pallidum ( Figure 3 )4 lordosis when administered peripherally or via infusion change from baseline to study end was +0.7 (2.4)

2 e 0.0 women , for which few treatment options exist — NE and oxytocin stimulate sexual arousal directly into the lateral ventricles or mPOA, but not the events/month vs +0.2 (2.3); BMT 1.25/1.75 mg pooled r 4 o Figure 3. Sexual and Reward Center Circuitr y 10 11 c

ventromedial hypothalamus ( Figure 4 ) vs placebo, respectively ( P=0.018; Figure 5 ) S

• In a 2008 study, up to 43% of women aged ≥18 years • Inhibitory signals are regulated by serotonin (5-HT), opioids, l

a –3.0 5,6 t reported having a sexual problem; 12% also reported distress and endocannabinoids (ECBs) o T PFC Figure 4. Dos e– Response Effects of BMT on Sexual Figure 5. Mean Change in SSEs/Month After 3 (score ≥ 15 on the Female Sexual Distress Scale [FSDS]) 10 11 O

BMT Treatment A — 5-HT regulates satiety, opioids manage sexual rewards, Behavior in Rats –6.0 D -

• In a 2012 clinical sample, the overall prevalence of HSDD was and ECBs play a role in sedation 1. 5 0 S

Solicitations D

7.4%; HSDD was slightly more common among pre- (50%) E+P E Alone All subjects S F h

40 40 –9.0 • The pathophysiology of HSDD, whether hyperactive-inhibitory, t Subjects with primarily 4 n n i

vs postmenopausal (44.2%) women ( Figure 1 ) o 1. 2 5 or solely HSDD

hypoactive-excitatory, or a combination, stems from an Medial Striatum e M g 5,6 preoptic / * n 4 imbalance of these signals ( Figure 2 ) s *

a –12.0 Figure 1. Prevalence of HSDD area E * caudate h NAcc putamen 30 30 S 1. 0 0 ** ** C

nucleus S

) r * * n e E i

Figure 2. Excitatory and Inhibitory Pathways Regulating

b *** S –15.0 All subjects ** e (

4 m ventral dorsal g

Sexual Response 0.75 n u N=701 n Subjects with primarily a a

N 20 20 * e * or solely HSDD Average age=46.2±17.6 years h n M C –18.0 a

Age range=18–70+ years * ) n = 91 76 87 76 75 66 74 63 149 129 DA ventral e 0.50 E l

5-HT M

20 clinical sites across the United States S Placebo 0.75 mg 1.25 mg 1.75 mg 1.25/1.75 mg a pallidum c Inhibitory Excitatory NE (

i Opioids c Pooled i n signals signals Oxytocin b

t 10 10 a

ECBs r e MCs m 0.25 BMT i o l l M c a o t o s a Van Elteren test stratified by diagnosis. From baseline to end of study. Decreasing values s i e r Pre- Post- e amygdala t 0.00 represent less distress. *P<0.05 vs placebo. ** P<0.01 vs placebo. *** P<0.001 vs placebo.

m 0 0 s n = 91 76 85 74 75 66 73 62 148 128 menopausal menopausal m 0 50 100 200 0 200 BMT, bremelanotide; FSDS-DAO, Female Sexual Distress Scale–Desire-Arousal-Orgasm; o (50.0%) (44.2%) r hippocampus Placebo 0.75 mg 1.25 mg 1.75 mg 1.25/1.75 mg HSDD, hypoactive sexual desire disorder; SE, standard error. g i Pacing Pooled Normal n E+P E Alone A Subjects with primarily or solely HSDD HSDD Balance of inhibitory 40 40 BMT • The most common treatment-emergent adverse events Sexual and excitatory signals (7.4%) Function Van Elteren test stratified by diagnosis. *P<0.05 vs placebo. with BMT were nausea, flushing, and headache; only No HSDD BMT, bremelanotide; HSDD, hypoactive sexual desire disorder; SE, standard error; nausea had a slight dose-dependence (92.6%) SSEs, sexually satisfying events. Indeterminate 30 30

r • Small, transient increases in ambulatory blood pressure

(5.8%) VTA SN e — Significantly increased (improvement) total scores Dysfunction that may lead to HSDD b (BP; ~3 mm Hg in systolic and diastolic BP confined m on the Female Sexual Function Index. Mean (SE) u to the first 4 hours postdose) were accompanied by N 20 20 change, +3.6 (5.7) vs +1.9 (5.9); BMT vs placebo, n

Dopaminergic projections a 11 small (~5%) decreases in heart rate

e respectively (P=0.0017; Figure 6 ) Glutamatergic projections M HSDD, hypoactive sexual desire disorder. 10 10 Figure 6. Mean Change in FSFI Total Score After GABAergic projections BMT Treatment 11 Conclusions

6.0 • BMT is a novel MC-receptor agonist with a

Aim At the center is the striatum, which contains the NAcc and caudate 0 0 e 0 50 100 200 0 200 r All subjects

o potential to modulate brain pathways involved

• To describe how bremelanotide (BMT; PT-14 1), an analog Hyperactive A combination of Hypoactive nucleus. Mesolimbic DA projections arise from the VTA and signal c Subjects with primarily S ** Lordosis ** inhibitory hyperactive inhibitory excitatory the NAcc; nigrostriatal DA projections arise from the SN and signal l 5.0 or solely HSDD in sexual response E+P E Alone a

of the naturally occurring peptide -melanocyte-stimulating t response and hypoactive response 1. 0 1. 0 o

the dorsal striatum; mesocortical DA projections arise from the VTA T

hormone ( -MSH), acts on the phαysiological and neurobio - excitatory responses I ** *** • BMT 1.25 and 1.75 mg SC, self-administered and signal the PFC; glutamatergic projections arise from the PFC, the F 4.0 ** logical components of female sexual function to improve S as desired, improve female sexual function α F 5-HT, serotonin; DA, dopamine; ECBs, endocannabinoids; HSDD, hypoactive sexual desire disorder; amygdala, and the hippocampus. 0.8 0.8 * n

MCs, melanocortins; NE, norepinephrine. i

sexual arousal and desire in women with HSDD t and SSEs in women with HSDD e DA, dopamine; GABAergic, gamma aminobutyric acid; NAcc nucleus accumbens; PFC, prefrontal cortex; n 3.0 g e SN, substantia nigra; VTA, ventral tegmental area. i n t a o • BMT was safe and well tolerated h u 0.6 0.6 C Q

2.0

Bremelanotide ) This study was funded by Palatin Technologies, Inc. Editorial assistance was provided by The Curry Rockefeller Group, LLC, which was s i Support E s S ( o funded by Palatin T echnologies, Inc. • MCs (eg, -endorphin, adrenocorticotrophic hormone, and d 0.4 0.4 n Dr Clayton has received royalties from the r 1. 0 Disclosures a o -MSH) are a diverse set of neuropeptides derived from e

β L Changes in Sexual Functioning Questionnaire, Guilford Publications; References 1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, Text Revision (DSM-IV-TR). Washington, DC: American pαroopiomelanocortin (POMC) M has received research support or consulting fees from Auspex, Psychiatric Association; 2000. 2. Hayes RD, Dennerstein L, Bennett CM, et al. Fertil Steril. 2007;87(1):107 –112. 3. Shifren JL, Monz BU, Russo PA, 0.2 0.2 0.0 • Neurons may stimulate DA release in the mPOA, a locus n = 91 76 87 76 75 66 74 63 149 129 Forest Research Institute, Inc, now Allergan, Genomind, Palatin Tech - Segreti A, Johannes CB. Obstet Gynecol. 2008;112(5):97 0–978. 4. Rosen RC, Connor MK, Miyasato G, et al. J Womens Health (Larchmnt). Placebo 0.75 mg 1.25 mg 1.75 mg 1.25/1.75 mg nologies, Inc, Pfizer Inc, S1 Biopharma, and Sprout Pharmaceuticals, 2012;21(5):50 5–515. 5. Pfaus JG. J Sex Med. 2009;6(6):150 6–1533. 6. Stahl SM. J Clin Psychiatry. 2010;71(7):821 –822. 7. Wikberg JE, implicated in the sexual behavior of both sexes of several Pooled a division of Valeant; and has stocks, stock options, or ownership 7 0 0 BMT Muceniece R, Mandrika I, et al. Pharmacol Res. 2000;42(5):39 3–420. 8. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. Ann N Y Acad species 0 50 100 200 0 200 interest, excluding diversified mutual funds, from Euthymics and S1 Biopharma. Dr Lucas, Mr Jordan, and Dr Spana Sci. 2003;994:9 6–102. 9. Pfaus J, Giuliano F, Gelez H. J Sex Med. 2007;4 (suppl 4):26 9–279. 10. Pfaus JG, Shadiack A, Van Soest T, Tse M, • BMT is a novel cyclic 7-amino acid MC-receptor agonist, Dose of BMT (µg/kg) Van Elteren test stratified by diagnosis. From baseline to end of study. *P<0.05 vs placebo. ** P<0.01 vs placebo. *** P<0.001 vs placebo. are employees and stockholders of Palatin T echnologies, Molinoff P. Proc Natl Acad Sci U S A. 2004;101(27):10201 –10204. 11. Clayton AH, Althof SE, Kingsberg S, et al. Womens Health (Lond). 8 with high affinity for the type-4 receptor, giving it a potential Data are mean s± SEM. *P<0.05 versus control. BMT, bremelanotide; FSFI, female sexual function index; HSDD, hypoactive sexual desire Inc. Dr Pfaus has received consulting fees from Emotional 2016;12(3):32 5–337. to modulate brain pathways involved in sexual response 9 BMT, bremelanotide; E, estrogen; P, progesterone; SEM, standard error of mean. disorder; SE, standard error. Brain and Palatin Technologies, Inc.

Subjects with primarily or solely HSDD