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]) BMT Treatment 11 • These are distressing conditions, particularly for younger — DA and the MCs stimulate attention and desire (NAcc) and ventral pallidum ( Figure 3 )4 change from baseline to study end was +0.7 (2.4) lordosis when administered peripherally or via infusion 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 • The pathophysiology of HSDD, whether hyperactive-inhibitory, 40 40 –9.0 h Subjects with primarily 4 n t i vs postmenopausal (44.2%) women ( Figure 1 ) n 1. 2 5 or solely HSDD hypoactive-excitatory, or a combination, stems from an Medial Striatum e o g 5,6 preoptic M * n 4 imbalance of these signals ( Figure 2 ) / * a –12.0 Figure 1. Prevalence of HSDD area s * caudate h NAcc putamen 30 30 E 1. 0 0 ** ** S nucleus C ) S r * * E e Figure 2. Excitatory and Inhibitory Pathways Regulating n i *** S b –15.0 All subjects ** ( e 4 ventral dorsal m g N=701 Sexual Response 0.75 n u Subjects with primarily a n N 20 20 a * e Average age=46.2±17.6 years * or solely HSDD 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 Placebo 0.75 mg 1.25 mg 1.75 mg 1.25/1.75 mg 20 clinical sites across the United States S a pallidum Inhibitory Excitatory NE c ( 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 All subjects 0 50 100 200 0 200 e potential to modulate brain pathways involved r nucleus. Mesolimbic DA projections arise from the VTA and signal • To describe how bremelanotide (BMT; PT-14 1), an analog Hyperactive A combination of Hypoactive o Subjects with primarily Lordosis c 5.0 or solely HSDD ** ** in sexual response inhibitory hyperactive inhibitory excitatory S the NAcc; nigrostriatal DA projections arise from the SN and signal of the naturally occurring peptide -melanocyte-stimulating E+P E Alone l response and hypoactive response 1. 0 1. 0 a the dorsal striatum; mesocortical DA projections arise from the VTA t hormone ( -MSH), acts on the physiological and neurobio - o *** • BMT 1.25 and 1.75 mg SC, self-administered excitatory responses T α ** I 4.0 logical components of female sexual function to improve and signal the PFC; glutamatergic projections arise from the PFC, the F ** α 5-HT, serotonin; DA, dopamine; ECBs, endocannabinoids; HSDD, hypoactive sexual desire disorder; S as desired, improve female sexual function F * amygdala, and the hippocampus. 0.8 0.8 sexual arousal and desire in women with HSDD MCs, melanocortins; NE, norepinephrine. n i t DA, dopamine; GABAergic, gamma aminobutyric acid; NAcc nucleus accumbens; PFC, prefrontal cortex; 3.0 and SSEs in women with HSDD n e e g SN, substantia nigra; VTA, ventral tegmental area. i t n o a • BMT was safe and well tolerated u 0.6 0.6 h 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 Support i 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 αproopiomelanocortin (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. 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