US20220362328A1 - Uses of bremelanotide in therapy for female sexual dysfunction - Google Patents
Uses of bremelanotide in therapy for female sexual dysfunction Download PDFInfo
- Publication number
- US20220362328A1 US20220362328A1 US17/864,486 US202217864486A US2022362328A1 US 20220362328 A1 US20220362328 A1 US 20220362328A1 US 202217864486 A US202217864486 A US 202217864486A US 2022362328 A1 US2022362328 A1 US 2022362328A1
- Authority
- US
- United States
- Prior art keywords
- bremelanotide
- pharmaceutically acceptable
- acceptable salt
- female
- sexual
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- FFHBJDQSGDNCIV-MFVUMRCOSA-N bremelanotide Chemical compound C([C@@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCNC(=O)C[C@@H](C(N[C@@H](CC=2NC=NC=2)C(=O)N1)=O)NC(=O)[C@@H](NC(C)=O)CCCC)C(O)=O)C1=CC=CC=C1 FFHBJDQSGDNCIV-MFVUMRCOSA-N 0.000 title claims abstract description 253
- 108010072543 bremelanotide Proteins 0.000 title claims abstract description 250
- 229950000740 bremelanotide Drugs 0.000 title claims abstract description 248
- 206010057671 Female sexual dysfunction Diseases 0.000 title claims abstract description 29
- 238000002560 therapeutic procedure Methods 0.000 title description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 230000000694 effects Effects 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims description 53
- 230000001568 sexual effect Effects 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 41
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 230000036470 plasma concentration Effects 0.000 claims description 30
- 238000007920 subcutaneous administration Methods 0.000 claims description 30
- 208000006262 Psychological Sexual Dysfunctions Diseases 0.000 claims description 28
- 238000010254 subcutaneous injection Methods 0.000 claims description 28
- 239000007929 subcutaneous injection Substances 0.000 claims description 28
- 206010024419 Libido decreased Diseases 0.000 claims description 24
- 208000017020 hypoactive sexual desire disease Diseases 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 206010047700 Vomiting Diseases 0.000 claims description 21
- 206010028813 Nausea Diseases 0.000 claims description 20
- 239000007864 aqueous solution Substances 0.000 claims description 20
- 230000008693 nausea Effects 0.000 claims description 20
- 230000035488 systolic blood pressure Effects 0.000 claims description 19
- 159000000021 acetate salts Chemical class 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- 230000008673 vomiting Effects 0.000 claims description 17
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 230000009429 distress Effects 0.000 claims description 15
- 235000011187 glycerol Nutrition 0.000 claims description 15
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 15
- 230000036299 sexual function Effects 0.000 claims description 13
- 230000035487 diastolic blood pressure Effects 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 230000003247 decreasing effect Effects 0.000 claims description 10
- 238000011010 flushing procedure Methods 0.000 claims description 9
- 230000006872 improvement Effects 0.000 claims description 9
- 206010019233 Headaches Diseases 0.000 claims description 6
- 231100000869 headache Toxicity 0.000 claims description 6
- 230000035946 sexual desire Effects 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 3
- 238000011282 treatment Methods 0.000 abstract description 49
- 239000000902 placebo Substances 0.000 description 49
- 229940068196 placebo Drugs 0.000 description 49
- 239000003814 drug Substances 0.000 description 27
- 230000008859 change Effects 0.000 description 26
- 229940079593 drug Drugs 0.000 description 25
- 230000002411 adverse Effects 0.000 description 24
- 208000021663 Female sexual arousal disease Diseases 0.000 description 22
- 230000037007 arousal Effects 0.000 description 19
- 230000001965 increasing effect Effects 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 11
- 230000036772 blood pressure Effects 0.000 description 11
- 201000001881 impotence Diseases 0.000 description 11
- 208000010228 Erectile Dysfunction Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 230000036332 sexual response Effects 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 8
- 239000000556 agonist Substances 0.000 description 7
- 239000000336 melanocortin receptor agonist Substances 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 208000004483 Dyspareunia Diseases 0.000 description 6
- 102000004378 Melanocortin Receptors Human genes 0.000 description 6
- 108090000950 Melanocortin Receptors Proteins 0.000 description 6
- 210000003169 central nervous system Anatomy 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000003745 diagnosis Methods 0.000 description 6
- 102000008316 Type 4 Melanocortin Receptor Human genes 0.000 description 5
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- -1 bremelanotide Chemical class 0.000 description 5
- 230000002596 correlated effect Effects 0.000 description 5
- 229940126534 drug product Drugs 0.000 description 5
- 210000004392 genitalia Anatomy 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 4
- 229940117029 Melanocortin receptor agonist Drugs 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 229940090047 auto-injector Drugs 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 208000007415 Anhedonia Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 108010008364 Melanocortins Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 3
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 3
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 239000002865 melanocortin Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229940071643 prefilled syringe Drugs 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 206010005746 Blood pressure fluctuation Diseases 0.000 description 2
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 206010057672 Male sexual dysfunction Diseases 0.000 description 2
- 238000000585 Mann–Whitney U test Methods 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001800 adrenalinergic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000030214 innervation Effects 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 210000003899 penis Anatomy 0.000 description 2
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 206010046947 vaginismus Diseases 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 206010048909 Boredom Diseases 0.000 description 1
- YOBIFVVSMGCZPD-GZGZUVKHSA-N CCCCC(NC(C)=O)C(=O)N[C@H]1CC(=O)NCCCC[C@@H](C(=O)O)NC(=O)[C@H](Cc2c[nH]c3ccccc23)CC(=O)[C@H](CCCNC(=N)N)CC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC1=O Chemical compound CCCCC(NC(C)=O)C(=O)N[C@H]1CC(=O)NCCCC[C@@H](C(=O)O)NC(=O)[C@H](Cc2c[nH]c3ccccc23)CC(=O)[C@H](CCCNC(=N)N)CC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC1=O YOBIFVVSMGCZPD-GZGZUVKHSA-N 0.000 description 1
- 229930182832 D-phenylalanine Natural products 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010016825 Flushing Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108700002232 Immediate-Early Genes Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 206010022076 Injection site infection Diseases 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 108091008698 baroreceptors Proteins 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000001856 erectile effect Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000011985 exploratory data analysis Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 210000004914 menses Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 231100001079 no serious adverse effect Toxicity 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000013186 photoplethysmography Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000003814 preoptic area Anatomy 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000036584 pressor response Effects 0.000 description 1
- 210000001774 pressoreceptor Anatomy 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 230000036259 sexual stimuli Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
Definitions
- the present invention relates to formulations and methods for treatment of sexual dysfunction, including female sexual dysfunction, by administration of selected doses of a melanocortin agonist.
- the present invention relates to methods for the treatment of female sexual dysfunction while reducing or minimizing side-effects, or adverse effects, associated with the administration of melanocortin agonists.
- the invention relates to the pharmaceutical compositions in which the melanocortin agonist is bremelanotide and methods in which these pharmaceutical compositions are administered to patients for the treatment of female sexual dysfunction, including specifically female sexual dysfunction in premenopausal women, while reducing or minimizing side effects.
- melanocortin 4 receptor agonists of the melanocortin receptor, and particular melanocortin 4 receptor (MC4-R) agonists, may be employed for treatment of sexual dysfunction. See, for example, L. H. T. Van der Ploeg, W. J. Martin, A. D. Howard, R. P. Nargund et al., A role for the melanocortin 4 receptor in sexual function. Proc. Natl. Acad. Sci. USA 99:11381-86 (2002).
- the cyclic, heptapeptide melanocortin receptor agonist Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH, with the USAN adopted name bremelanotide and formerly known as PT-141, as further disclosed in U.S. Pat. Nos. 6,579,968 and 6,794,489, has been employed in clinical trials for sexual dysfunction, including both male erectile dysfunction (ED) and female sexual dysfunction or disorder (FSD).
- ED male erectile dysfunction
- FSD female sexual dysfunction or disorder
- the female sexual response cycle is complex and dependent on physiological, psychological, and social factors. For many women, spontaneous desire is not the motivating factor to engage in sexual activity. Frequently, desire is a consequence of subjective arousal caused by a variety of sexual stimuli.
- An understanding of the female sexual response cycle provides a basis for the design and development of pharmacological interventions for treating FSAD and/or HSDD.
- male sexual response involves both central nervous system function as well as nitric oxide production leading to an increase in blood flow to the penis.
- female sexual response is dominated by central nervous system function, while the nitric oxide production pathway is of minor importance compared to results in men. Therefore, while therapies for treatment of male sexual dysfunction can be targeted to either or both mechanisms of action, therapies for treatment of female sexual dysfunction typically must be targeted to and must rely on the central nervous system function.
- A. M. Shadiack, S. D. Sharma, D. C. Earle, C. Spana and T. J. Hallam Melanocortins in the Treatment of Male and Female Sexual Dysfunction.
- phosphodiesterase 5 (PDE-5) inhibitors such as sildenafil, tadalafil or vardenafil are effective in men with erectile dysfunction through a mechanism involving selective inhibition of PDE-5, thereby preventing the hydrolysis of cyclic guanosine monophosphate, resulting in increased blood flow to the penis.
- PDE-5 inhibitors have some effect on genital vasocongestion, the drugs have little or no effect on treatment of female sexual dysfunction, including treatment of sexual arousal problems.
- M. L. Chivers and R. C. Rosen Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? J. Sex. Med. 7:858-72 (2010).
- bremelanotide has central nervous system effects unrelated to local genital vasocongestion.
- animal studies utilizing female rats a selective pharmacological effect on appetitive sexual behavior was observed, with subcutaneous injections of bremelanotide inducing the immediate-early gene product Fos in a variety of limbic and hypothalamic structures, and increasing dopamine release in the medial preoptic area.
- J. G. Pfaus, A. Shadiack, T. Van Soest, M. Tse and P. Molinoff Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc. Natl. Acad. Sci. USA 101:10201-4 (2004); J.
- melanocortin agonists including bremelanotide, primarily relating to an increase in blood pressure, and nausea and vomiting, both immediate and delayed.
- a therapeutic method for treatment of sexual dysfunction including but not limited to FSD, by means of administration of a melanocortin agonist which provides the desired therapeutic benefit, but which does not induce, or does not significantly induce, or which reduces or minimizes adverse cardiovascular and other effects, such adverse effects including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting. It is against this background that the invention was made.
- bremelanotide or a pharmaceutically acceptable salt thereof are provided herein.
- the low dose may be administered via subcutaneous injection.
- the low doses of bremelanotide or a pharmaceutically acceptable salt thereof as provided herein were found to be efficacious, despite previous indications that a higher dose may be required to treat FSD.
- the low doses of bremelanotide or a pharmaceutically acceptable salt thereof as provided herein were also found to be associated with fewer side effects compared to administration of higher doses of the compound.
- compositions and methods provided herein including, without limitation, when administered by subcutaneous injection, may additionally be associated with lower side effects compared to intranasal administration of a comparable dose, such as a comparable dose based on peak plasma concentration within 60 minutes after administration of bremelanotide.
- the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD while reducing undesirable side effects.
- no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered by subcutaneous injection.
- between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered.
- between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered.
- the composition for subcutaneous injection may be an aqueous solution comprising acetate salt of bremelanotide and glycerin.
- the composition is an aqueous solution consisting essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v).
- the acetate salt of bremelanotide may be between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide.
- the composition is at a pH of about 5.0, and further comprises agents to adjust pH, which agents to adjust pH may comprise, without limitation, hydrochloric acid and sodium hydroxide.
- the undesirable side effects that are reduced are selected from the group consisting of nausea, emesis, flushing and an increase in blood pressure.
- the female patient is premenopausal, and in another aspect, the female patient is postmenopausal.
- the invention further provides for use of a formulation dose comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide in the manufacture of a subcutaneous injectable medicament for the treatment of FSD in a female patient diagnosed with FSD and anticipating sexual activity.
- the formulation dose comprises between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, or between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- the invention provides a prefilled dose unit comprising an aqueous solution of acetate salt of no more than about 1.75 mg of bremelanotide.
- the prefilled dose unit may include a prefilled syringe, or may include a cartridge adapted for use in a subcutaneous administration drug delivery device.
- the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising bremelanotide or a pharmaceutically acceptable salt of bremelanotide in an amount sufficient to result in a peak plasma concentration within 60 minutes after administration of bremelanotide in the female patient of no more than about 120 ng/mL, thereby treating FSD while reducing undesirable side effects.
- the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising bremelanotide or a pharmaceutically acceptable salt of bremelanotide in an amount sufficient to result in a peak plasma concentration with 60 minutes resulting from subcutaneous administration of a dose of between about 1.0 mg and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD while reducing undesirable side effects.
- the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD while reducing one or more side effects compared to intranasal administration of an equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- the side effects comprise one or more of nausea, flushing, headache, changes in systolic blood pressure, changes in diastolic blood pressure, changes in heart rate, vomiting, and hypertension.
- the equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide comprises a dose resulting in a substantially similar peak plasma concentration within 60 minutes after administration of bremelanotide compared to subcutaneous injection of the composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- the substantially similar peak plasma concentration can be a mean peak plasma concentration in a patient population of between about 60 and 120 ng/mL of bremelanotide.
- no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered by subcutaneous injection.
- composition of the method can be an aqueous solution comprising acetate salt of bremelanotide and glycerin, and can consist essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v).
- the acetate salt of bremelanotide is between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide.
- the composition can be at a pH of about 5.0, and further comprise one or more agents to adjust pH, including where the one or more agents to adjust pH comprise hydrochloric acid and sodium hydroxide.
- the female patient may be premenopausal or alternatively postmenopausal.
- the variability in peak plasma concentration within 60 minutes after subcutaneous injection administration is a % CV less than 30.
- Reduction in side effects comprises the variability in peak plasma concentration within 60 minutes after subcutaneous injection administration of the composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide being is less than the variability in peak plasma concentration within 60 minutes after intranasal administration of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- the variability in peak plasma concentration within 60 minutes after intranasal administration can be a % CV greater than 30. Variability in peak plasma concentration can be determined in a patient population.
- the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity comprising administering the female patient by subcutaneous injection a composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD, wherein the treatment has increased efficacy compared to intranasal administration of an equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- the increased efficacy is indicated by an increase in frequency of satisfying sexual events upon administration of the bremelanotide or pharmaceutically acceptable salt thereof.
- Increased efficacy may be indicated by an increase in frequency of satisfying sexual events upon administration of the bremelanotide or pharmaceutically acceptable salt thereof, or by improved overall sexual function, including where improved overall sexual function is measured by the Female Sexual Function Index, such as a Female Sexual Function Index total score improvement of 3 or greater. Increased efficacy may also be indicated by reduced associated distress related to sexual dysfunction, including where reduced associated distress related to sexual dysfunction is measured by the Female Sexual Distress Scale-DAO.
- an equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide comprises a dose resulting in a substantially similar peak plasma concentration within 60 minutes after administration of bremelanotide compared to subcutaneous injection of the composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- the substantially similar peak plasma concentration may be a mean peak plasma concentration of between about 60 and 120 ng/mL of bremelanotide in a patient population.
- no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered by subcutaneous injection, or alternatively between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, or alternatively between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered.
- the composition of the method can be an aqueous solution comprising acetate salt of bremelanotide and glycerin, and can consist essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v).
- the acetate salt of bremelanotide is between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide.
- the composition can be at a pH of about 5.0, and further comprise one or more agents to adjust pH, including where the one or more agents to adjust pH comprise hydrochloric acid and sodium hydroxide.
- the female patient may be premenopausal or alternatively postmenopausal.
- the invention provides for use of a formulation dose comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide in the manufacture of a subcutaneous injectable medicament for the treatment of FSD in a female patient diagnosed with FSD and anticipating sexual activity.
- a formulation dose comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide in the manufacture of a subcutaneous injectable medicament for the treatment of FSD in a female patient diagnosed with FSD and anticipating sexual activity.
- Such formulation may comprise no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, and may further comprise between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide or alternatively between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- the formulation of this use can be an aqueous solution comprising acetate salt of bremelanotide and glycerin, and can consist essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v).
- the acetate salt of bremelanotide is between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide.
- the formulation can be at a pH of about 5.0, and further comprise one or more agents to adjust pH, including where the one or more agents to adjust pH comprise hydrochloric acid and sodium hydroxide.
- a primary object of the present invention is to provide methods for the treatment of FSD which employ bremelanotide while limiting adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting.
- Another object of the present invention is to provide methods for the treatment of FSD which employ bremelanotide while reducing the incidence of adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting, compared with alternative prior art doses and methods of administering bremelanotide.
- Another object of the present invention is to provide methods for the treatment of FSD which employ bremelanotide while minimizing adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting, compared with alternative prior art doses and methods of administering bremelanotide.
- Another object of the present invention is to provide a dose of bremelanotide, such as a dose delivered by subcutaneous injection, which is efficacious in treating FSD but which does not induce, or which does not significantly induce, drug-associated adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting.
- a dose of bremelanotide such as a dose delivered by subcutaneous injection
- FIG. 1 is a plot showing resulting peak plasma concentrations of bremelanotide, measured in ng/mL, following intranasal administration of 5, 7.5, 10, 12.5, and 15 mg of bremelanotide in an aqueous solution, and subcutaneous administration 2.5 mg of bremelanotide in an aqueous solution.
- FIG. 2 is plot showing mean plasma concentrations (in ng/mL) of bremelanotide (Y axis) over time (X axis, in hours) following subcutaneous administration of 0.3 ( ⁇ ), 1.0 ( ⁇ ), 3.0 ( ⁇ ), 5.0 (triangle, apex up), 7.5 (inverted triangle, apex down) and 10 ( ⁇ ) mg of bremelanotide in an aqueous solution in healthy adult males.
- FIG. 3 is a plot showing mean plasma concentrations (in ng/mL) of bremelanotide over time following subcutaneous administration of 0.75, 1.25 and 1.75 mg of bremelanotide in an aqueous solution in premenopausal women diagnosed with FSD.
- FIG. 4A is a graph of mean change in satisfying sexual events (SSEs) from double-blind baseline to end-of-study among at-home users of double-blind study drug in the Study of Example 1.
- SSEs sexual events
- the mean absolute number of SSEs for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 0.7 to 0.8 and 1.5 to 1.9, respectively.
- FIG. 4B is a graph of mean change in Female Sexual Function Index (FSFI) total score from double-blind baseline to end-of-study among at-home users of double-blind study drug in the Study of Example 1.
- the mean absolute FSFI Score for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 17.09 to 18.22 and 21.52 to 22.75, respectively.
- the total possible score is from 2 to 36. Higher scores indicate a greater level of sexual function.
- P for the 1.25 mg dose was ⁇ 0.05 and for the 1.75 mg dose was ⁇ 0.01, as determined by Van Elteren test.
- FIG. 4C is a graph of mean decrease in Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1.
- the mean absolute FSDS-DAO Score for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 38.9 to 41.7 and 30.5 to 33.2, respectively. Total score can range from 0 to 60. The higher the score the greater the distress associated with sexual dysfunction. P ⁇ 0.001 for the 1.75 mg dose, as determined by Van Elteren test.
- FIG. 5A is a graph of mean change in the desire sub-domain of the FSFI from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. **P ⁇ 0.01 as determined by ANCOVA, ANOVA, or Van Elteren test.
- FIG. 5B is a graph of mean change in the arousal sub-domain of the FSFI from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. **P ⁇ 0.01 as determined by ANCOVA, ANOVA, or Van Elteren test.
- FIG. 5C is a graph of mean change in the desire sub-domain of the FSDS-DAO (Item 13) from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. **P ⁇ 0.01 as determined by ANCOVA, ANOVA, or Van Elteren test.
- FIG. 5D is a graph of mean change in the arousal sub-domain of the FSDS-DAO (Item 14) from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. *P ⁇ 0.05 as determined by ANCOVA, ANOVA, or Van Elteren test.
- FIG. 6A is a graph of mean change in FSFI total score from double-blind baseline to end-of-study among at-home users of double-blind study drug diagnosed with mixed HSDD/FSAD in the study of Example 1. *P ⁇ 0.05 as determined by Wilcoxon rank-sum test.
- FIG. 6B is a graph of mean change in FSFI total score from double-blind baseline to end-of-study among at-home users of double-blind study drug diagnosed with HSDD only in the study of Example 1. **P ⁇ 0.01 as determined by Wilcoxon rank-sum test.
- FIG. 7A is a plot of mean change of FSFI total score from baseline over time for a three month period with subcutaneous administration of placebo ( ⁇ ) or 0.75 ( ⁇ ), 1.25 ( ⁇ ) or 1.75 ( ⁇ ) mg of bremelanotide in the study of Example 1.
- FIG. 7B is a plot of mean change of FSDS-DAO total score change from baseline over time for a three month period with subcutaneous administration of placebo ( ⁇ ) or 0.75 ( ⁇ ), 1.25 ( ⁇ ) or 1.75 ( ⁇ ) mg of bremelanotide in the study of Example 1.
- FIG. 8 is a plot of Cmax (ng/mL) against AUC for zero to two hours (hours times ng/mL), utilizing combined data from visits 5 and 7 of the trial study of Example 1, illustrating that a linear relationship exists between these parameters.
- amino acid and amino acids used in this invention, and the terms as used in the specification and claims, include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A Users Guide , G. A. Grant, editor, W.H. Freeman & Co., New York, 1992, the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24.
- amino acid also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User's Guide cited above; V. J. Hruby, F. Al-Obeidi and W. Kazmierski: Biochem. J. 268:249-262, 1990; and C. Toniolo: Int. J. Peptide Protein Res. 35:287-300, 1990; the teachings of all of which are incorporated herein by reference.
- amino acid residues have their conventional meaning as given in Chapter 2400 of the Manual of Patent Examining Procedure, 8 th Ed.
- “Nle” is norleucine
- “Asp” is aspartic acid
- “His” is histidine
- “D-Phe” is D-phenylalanine
- “Arg” is arginine
- “Trp” is tryptophan
- “Lys” is lysine
- Ac refers to a peptide or amino acid sequence that is acetylated [(CH 3 )—CO—].
- composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- pharmaceutical compositions utilized in the present invention encompass any composition made by admixing an active ingredient and one or more pharmaceutically acceptable carriers.
- “Sexual dysfunction” means any condition that inhibits or impairs normal sexual function, including coitus. The term is not limited to physiological conditions, and includes psychogenic conditions or perceived impairment without a formal diagnosis of pathology or disorder.
- Sexual dysfunction includes ED in a male mammal and FSD in a female mammal.
- “Erectile dysfunction” (ED) is a disorder involving the failure of a male mammal to achieve functional erection, ejaculation, or both. Erectile dysfunction is accordingly synonymous with impotence, and includes the inability to attain or sustain an erection of sufficient rigidity for coitus.
- FSD Male sexual dysfunction
- FSAD female sexual arousal disorder
- HSDD hypoactive sexual desire disorder
- Sexual dysfunction in females can also include inhibited orgasm and dyspareunia, which is painful or difficult coitus.
- Female sexual dysfunction includes, but is not limited to, a number of categories of diseases, conditions and disorders including HSDD, sexual anhedonia, sexual arousal disorder, dyspareunia and vaginismus.
- Hypoactive sexual desire disorder includes a disorder in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties.
- Hypoactive sexual desire disorder can be related to boredom or unhappiness in a long-standing relationship, depression, dependence on alcohol or psychoactive drugs, side effects from prescription drugs, or hormonal deficiencies.
- Sexual anhedonia includes decreased or absent pleasure in sexual activity.
- Sexual anhedonia can be caused by depression, drugs, or interpersonal factors.
- Sexual arousal disorder can be caused by reduced estrogen, illness, or treatment with diuretics, antihistamines, antidepressants, or antihypertensive agents.
- Dyspareunia and vaginismus are sexual pain disorders characterized by pain resulting from penetration and may be caused, for example, by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
- melanocortin receptor “agonist” is meant an endogenous or drug substance or compound, including a compound such as bremelanotide, which can interact with a melanocortin receptor and initiate a pharmacological response, including but not limited to adenyl cyclase expression, characteristic of the melanocortin receptor.
- % CV the coefficient of variation, which is the ratio of the standard deviation (SD) to the mean expressed as a percentage.
- weight of bremelanotide or a pharmaceutically acceptable salt of bremelanotide per dose such as, e.g., administering a dose of 1.75 mg bremelanotide or a pharmaceutically acceptable salt of bremelanotide
- weight is net peptide weight, that is, net of the salt in the instance of a pharmaceutically acceptable salt.
- the methods and pharmaceutical compositions disclosed herein can be used for both medical applications and animal husbandry or veterinary applications. Typically, the methods are used in humans, including specifically female humans, but may also be used in other mammals.
- the term “patient” is intended to denote a mammalian individual, and is so used throughout the specification and in the claims.
- the primary applications of this invention involve human female patients, but this invention may be applied to laboratory, farm, zoo, wildlife, pet, sport or other animals.
- the melanocortin receptor agonist is:
- the peptide of bremelanotide has a formula of C 50 H 68 N 14 O 10 , and a net molecular weight of 1025.18.
- This peptide may be synthesized by conventional means, including either solid-phase or liquid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water.
- the structure of bremelanotide is:
- bremelanotide is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare bremelanotide.
- Bremelanotide may be in the form of any pharmaceutically acceptable salt.
- Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, citric, tartaric, oxalic, succinic or methanesulfonic acid.
- the acetate salt form is especially useful.
- bremelanotide is an acetate salt form, and is formulated in a buffered aqueous solution including glycerin, and prepackaged in a syringe and auto-injector device.
- bremelanotide is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides or polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives.
- Bremelanotide Uses of Bremelanotide. Over 2500 subjects have received bremelanotide in a total of 30 clinical trials, with bremelanotide administered via intravenous, intranasal and subcutaneous routes. The majority of studies conducted were of men diagnosed with erectile dysfunction. Bremelanotide administered intranasally demonstrated promising clinical activity in pre- and postmenopausal women with FSAD. However, with intranasal administration significant variability was seen in bremelanotide C max and the area under the concentration-time curve (AUC) compared to subcutaneous administration, as is shown generally in FIG. 1 (data derived from men administered intranasal or subcutaneous bremelanotide).
- AUC concentration-time curve
- Intranasal bremelanotide was shown to increase sexual desire and arousal compared to placebo in both premenopausal and postmenopausal women with FSAD in two Phase 2 trials.
- use of intranasal bremelanotide was associated with increased adverse events compared to placebo in both premenopausal and postmenopausal women, with 92.5% of premenopausal subjects receiving bremelanotide reporting at least one adverse event, compared to 61.1% for placebo, and 100% of postmenopausal subjects receiving bremelanotide reported at least one adverse event, compared to 47.7% for placebo.
- bremelanotide premenopausal arm 42.5% of the subjects were discontinued due to hypertension, nausea, vomiting or myalgia.
- Subjects received a 10 mg intranasal dose of bremelanotide, with premenopausal subjects determined to have a mean plasma concentration of 88.5 ⁇ 51.9 ng/mL and a % CV of 58.6, and postmenopausal subjects determined to have a mean plasma concentration of 93.2 ⁇ 68.5 ng/mL and a % CV of 73.5.
- the minimum and maximum plasma concentration levels for all women at thirty minutes post dose range from 0.0 ng/mL to 207.0 ng/mL.
- Example 1 Prior to the study disclosed hereafter as Example 1, no studies examining efficacy for FSD using subcutaneous administration had been conducted. In Phase 1 studies using normal female volunteers as discussed above, a pharmacodynamics effect was seen only at subcutaneous doses of 3 mg or greater of bremelanotide.
- bremelanotide may treat FSD primarily via a central nervous system mechanism of action, with minimal innervation or action in the genital area. This mechanism of action differs from the mechanism of action in treatment of male sexual dysfunction, in which efficacy is strongly correlated to innervation or action in the genital area, and specifically inducing an erection.
- the variability in peak plasma concentration within 60 minutes after subcutaneous injection administration is a % CV less than about 30, or alternatively less than about 25, or alternatively less than about 20.
- the variability in peak plasma concentration within 60 minutes after intranasal administration is a % CV greater than about 25, or alternatively greater than about 30, or alternatively greater than about 40, or alternatively greater than about 50, or alternatively greater than about 60, or alternatively greater than about 70.
- the dosing regimen included subcutaneous injections of either bremelanotide or placebo 3 times daily for 15 days for a total of 45 planned doses.
- the first dose was 1.25 mg with subsequent doses of 1.0 mg.
- the first daily dose was 2.5 mg with second and third daily doses of 2.0 mg.
- No measure of sexual response was made in this study.
- Three subjects were withdrawn from the trial prematurely due to adverse events of vomiting (placebo group), hypertension (noted prior to daily dosing, bremelanotide group), and nausea (bremelanotide group), respectively, all of which were assessed as mild in intensity and probably (vomiting and hypertension) or possibly (nausea) related to trial drug. All 3 events resolved by trial conclusion. All subjects who participated in the trial experienced at least 1 treatment-emergent adverse event and all subjects experienced at least 1 treatment-related adverse event.
- FSEP-R Female Sexual Encounter Profile - Revised FSDS-DAO Female Sexual Distress Scale - Desire/Arousal/Orgasm FSFI Female Sexual Function Index GAQ General Assessment Questions SIDI-F sexual Interest and Desire Inventory - Female WITS-9 Women's Inventory of Treatment Satisfaction Electronic diary devices can be employed for use by subjects to complete questionnaires, including but not limited to the FSEP-R questionnaire, which can be completed outside of the clinic (at home) following a sexual encounter.
- a prefilled syringe may be utilized, optionally with an auto-injector device, permitting a patient to rapidly and simply self-administer a subcutaneous dose of bremelanotide.
- Bremelanotide injection a parenteral drug product for subcutaneous injection, is formulated in an aqueous system containing 2.5% w/v glycerin at pH 5. It is packaged in single-use Type I glass 1 mL prefilled syringes with staked one-half inch 29 gauge needles fitted with a needle shield and closed with gray Flurotec plunger stoppers. The primary container is secondarily fitted with a plunger rod for actuation and a safety device to prevent accidental access to the needle after use. Each unit is filled to deliver a minimum volume of 0.3 mL.
- the bremelanotide drug product for subcutaneous injection is packaged in single-use pre-filled syringes with Flurotec plunger stoppers, a plunger rod for actuation, and a plastic safety device.
- the package components are further described below:
- Subjects were randomized (1:1:1:1) to one of four study treatment groups (placebo or doses with 0.75, 1.25, or 1.75 mg net weight bremelanotide). Randomization occurred immediately prior to the first in-clinic dose of double-blind treatment. Study drug and placebo was provided as pre-filled syringes in 0.3 mL volume, with subjects instructed on self-administration into the anterior thigh or abdomen.
- Ambulatory blood pressure monitoring was conducted following both placebo and randomized treatment group in-clinic administrations. Three periods of ambulatory blood pressure monitoring were included, the first period was from before to 24 hours after a single, in-clinic dose of placebo (to establish a baseline); the second and third periods occurred from before to 24 hours after each of 2 single, in-clinic doses of double-blind treatment, administered within 14 days of each other. Blood samples for pharmacokinetic analysis were collected before and at 0.5, 1.0, and 2.0 hours after each in-clinic bremelanotide single-dose treatment (double-blind only), to permit analysis of concentration-response relationships.
- Enrolled subjects were premenopausal women who met the diagnostic criteria for FSAD, HSDD, or mixed FSAD/HSDD, utilizing a diagnostic screening guide including categorization of the sexual dysfunction as both acquired (vs. lifelong) and generalized (vs. situational).
- Subjects enrolled had previously been sexually “functional;” that is, experienced sexual arousal during sexual activity and/or a normal level of desire at some point in the past for a period of at least 2 years.
- Table 2 below shows the FSD measures at double-blind baseline, which defines a modified intent to treat (modified ITT) population.
- Enrolled subjects were provided with an electronic diary system (eDiary) with instructions to complete an FSEP-R questionnaire with each sexual encounter.
- eDiary electronic diary system
- subjects completed other assessment questionnaires, including SIDI-F, FSDS-DAO, FSFI, GAQ and WITS-9.
- various vital sign measures were conducted and blood and urine samples collected at selected in-clinic visits.
- the study met its primary endpoint by demonstrating a clinically meaningful and statistically significant improvement in the change from baseline to end of study in the number of SSEs.
- the measurement period was defined as the number of events during the last four weeks of treatment minus the number of events during the baseline period, with outcomes reported for pooled results of women taking the two highest bremelanotide dose levels versus placebo.
- the following shows p values for changes in SSEs for three bremelanotide doses and pooled 1.25 and 1.75 mg bremelanotide over the measurement period:
- the relationship between key efficacy endpoints and weight-normalized dose (mg/kg) shows that the FSDS-DAO Total Score was statistically significantly correlated by weight-normalized dose.
- the FSFI Total Score trended toward a statistically significant correlation. Only the FSDS-DAO Total Score was significantly correlated with Cmax. Both FSDS-DAO Total Score and FSFI Total Score were significantly correlated with AUC(0-2 h) (p ⁇ 0.0485).
- the Cmax for the mean curve was calculated by averaging the concentrations at each time point (0.5, 1, 2 and 4 hours), and this is shown in FIG. 3 .
- Efficacy outcomes are graphed by dosage and FSD diagnosis in FIG. 6 .
- exploratory analyses demonstrated statistically significant efficacy or a clinically significant trend versus placebo in the HSDD-only and mixed HSDD/FSAD subgroups at 1.25 mg, 1.75 mg, and/or 1.25/1.75 mg pooled.
- Bremelanotide administration resulted in a small increase in both systolic and diastolic pressures, with a maximal change in systolic pressure of 3.15 mm Hg (average of Visits 5 and 7) in the 1.75 mg dosing group.
- the 0 to 4 hour changes were statistically different than placebo (95% CI not intersecting 0) for the 2 high dose groups only.
- the increase in systolic blood pressure was confined to the first 4 hours following bremelanotide administration. In all cases, the 4-to-8-hour interval and later intervals were not statistically different from placebo.
- Bremelanotide was well-tolerated during the trial.
- the most common types of treatment-emergent adverse events reported more frequently in the bremelanotide arms were facial flushing, nausea, emesis and headache.
- bremelanotide self-administered at home at 1.25 and 1.75 mg SC was effective in decreasing distress, increasing arousal and desire, and increasing the number of SSEs, with robust dose response and consistency of effect across all key endpoints. Efficacy was seen in both HSDD and mixed HSDD/FSAD populations. These improvements continued throughout the treatment period, indicating that patients may be able to continue improving after three months of treatment. Women receiving bremelanotide were more likely than placebo-treated women to reach key score thresholds for both FSFI and FSDS-DAO. Bremelanotide was generally well tolerated.
Abstract
Description
- This application is a continuation application of U.S. Ser. No. 14/704,223, entitled “Uses of Bremelanotide in Therapy for Female Sexual Dysfunction”, filed May 5, 2015, which will issue as U.S. Pat. No. 9,700,592, on Jul. 11, 2017; which in turn is a continuation application of International Application No. PCT/US13/68386, published as International Publication No. WO 2014/071339, entitled “Uses of Bremelanotide in Therapy for Female Sexual Dysfunction”, filed on Nov. 5, 2013; which in turn claims priority to and the benefit of the filing of U.S. Provisional Patent Application Ser. No. 61/722,511 entitled “Uses of Melanocortin Agonists in Therapy for Female Sexual Dysfunction”, filed Nov. 5, 2012; and U.S. Provisional Patent Application Ser. No. 61/770,535 entitled “Uses of Bremelanotide in Therapy for Female Sexual Dysfunction”, filed Feb. 28, 2013; and is related to U.S. Ser. No. 14/313,258, entitled “Uses of Bremelanotide in Therapy for Female Sexual Dysfunction”, filed Jun. 24, 2014, which issued as U.S. Pat. No. 9,352,013, on May 31, 2016; and the specification and claims of each of the foregoing are incorporated herein by reference.
- The present invention relates to formulations and methods for treatment of sexual dysfunction, including female sexual dysfunction, by administration of selected doses of a melanocortin agonist. In particular, the present invention relates to methods for the treatment of female sexual dysfunction while reducing or minimizing side-effects, or adverse effects, associated with the administration of melanocortin agonists. More specifically, the invention relates to the pharmaceutical compositions in which the melanocortin agonist is bremelanotide and methods in which these pharmaceutical compositions are administered to patients for the treatment of female sexual dysfunction, including specifically female sexual dysfunction in premenopausal women, while reducing or minimizing side effects.
- Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
- It is known that agonists of the melanocortin receptor, and
particular melanocortin 4 receptor (MC4-R) agonists, may be employed for treatment of sexual dysfunction. See, for example, L. H. T. Van der Ploeg, W. J. Martin, A. D. Howard, R. P. Nargund et al., A role for themelanocortin 4 receptor in sexual function. Proc. Natl. Acad. Sci. USA 99:11381-86 (2002). The cyclic, heptapeptide melanocortin receptor agonist Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH, with the USAN adopted name bremelanotide and formerly known as PT-141, as further disclosed in U.S. Pat. Nos. 6,579,968 and 6,794,489, has been employed in clinical trials for sexual dysfunction, including both male erectile dysfunction (ED) and female sexual dysfunction or disorder (FSD). - There has been substantial progress in the definition and classification of the range of disorders that comprise FSD. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) recognizes four major disorders that define FSD: decreased sexual desire, decreased sexual arousal, dyspareunia, and difficulty in achieving orgasm. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision ed. Washington, D.C.: American Psychiatric Publishing, Inc., 2000. In the United States approximately 43% of adult women experience some form of female sexual arousal disorder (FSAD) and/or hypoactive sexual desire disorder (HSDD), with approximately 22% of these women reporting being distressed by their sexual dysfunction. E. O. Laumann, A. Paik and R. C. Rosen, Sexual dysfunction in the United States: prevalence and predictors. JAMA 281:537-544 (1999); and, J. L. Shifren, B. U. Monz, P. A. Russo, A. Segreti and C. B. Johannes, Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol 112:970-978 (2008). The current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), released in May 2013 by the American Psychiatric Association, revised the classification of female sexual dysfunction, replacing FSAD and HSDD with a new diagnosis of female sexual interest and arousal disorder (FSI/AD), and expanding the current concept of FSD to include receptivity to and initiation of sexual activity as part of the diagnostic heuristic. However, definitions of FSAD and HSDD remain in use, and are consistent with the description of female sexual dysfunction in the current version of the International Classification of Diseases (ICD-10).
- Sexual therapy and education presently form the basis of treatment for FSAD and/or HSDD. Pharmaceutical treatments are limited; no drug is currently approved in the United States and one drug was approved in the European Union but subsequently withdrawn (INTRINSA®, a testosterone transdermal patch previously marketed by Warner Chilcott).
- The female sexual response cycle is complex and dependent on physiological, psychological, and social factors. For many women, spontaneous desire is not the motivating factor to engage in sexual activity. Frequently, desire is a consequence of subjective arousal caused by a variety of sexual stimuli. An understanding of the female sexual response cycle provides a basis for the design and development of pharmacological interventions for treating FSAD and/or HSDD.
- The mechanisms and corresponding pharmaceutical therapies underlying female sexual response are different from those underlying male sexual response. For instance, male sexual response involves both central nervous system function as well as nitric oxide production leading to an increase in blood flow to the penis. Conversely, female sexual response is dominated by central nervous system function, while the nitric oxide production pathway is of minor importance compared to results in men. Therefore, while therapies for treatment of male sexual dysfunction can be targeted to either or both mechanisms of action, therapies for treatment of female sexual dysfunction typically must be targeted to and must rely on the central nervous system function. A. M. Shadiack, S. D. Sharma, D. C. Earle, C. Spana and T. J. Hallam, Melanocortins in the Treatment of Male and Female Sexual Dysfunction. Current Topics in Medicinal Chemistry 7:1137-1144 (2007). Thus phosphodiesterase 5 (PDE-5) inhibitors such as sildenafil, tadalafil or vardenafil are effective in men with erectile dysfunction through a mechanism involving selective inhibition of PDE-5, thereby preventing the hydrolysis of cyclic guanosine monophosphate, resulting in increased blood flow to the penis. However, in women with female sexual dysfunction while PDE-5 inhibitors have some effect on genital vasocongestion, the drugs have little or no effect on treatment of female sexual dysfunction, including treatment of sexual arousal problems. M. L. Chivers and R. C. Rosen,
Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? J. Sex. Med. 7:858-72 (2010). - Both animal and human studies have suggested that bremelanotide has central nervous system effects unrelated to local genital vasocongestion. In animal studies utilizing female rats, a selective pharmacological effect on appetitive sexual behavior was observed, with subcutaneous injections of bremelanotide inducing the immediate-early gene product Fos in a variety of limbic and hypothalamic structures, and increasing dopamine release in the medial preoptic area. J. G. Pfaus, A. Shadiack, T. Van Soest, M. Tse and P. Molinoff, Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc. Natl. Acad. Sci. USA 101:10201-4 (2004); J. Pfaus, F. Giuliano and H. Gelez, Bremelanotide: an overview of preclinical CNS effects on female sexual dysfunction. J. Sex. Med. 4:269-279 (2007). In humans, statistically relevant reported feelings of sexual arousal in women diagnosed with sexual arousal disorder were observed following a single intranasal dose of 20 mg of bremelanotide, but without statistically relevant differences, compared to placebo, in vaginal pulse amplitude measures. L. E. Diamond, D. C. Earle, J. R. Heiman, R. C. Rosen, M. A. Perelman and R. Harning, An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J. Sex. Med. 3:628-638 (2006). This is in contrast to the effect in men diagnosed with erectile dysfunction, where statistically significant erectile response compared to placebo, as determined by a plethysographic device measuring penile responses, with concomitant increased blood flow in the genital region, were seen with subcutaneous injection of either a 4 or 6 mg dose of bremelanotide. Shadiack, 2007, supra.
- It has been reported in the literature that MC4-R agonists induce an adrenergic response, resulting in an increase in blood pressure and heart rate. See, for example, J. J. Kuo, A. A. Silva and J. E. Hall, Hypothalamic melanocortin receptors and chronic regulation of arterial pressure and renal function. Hypertension 41:768-774 (2003); J. J. Kuo, A. A. da Silva, L. S. Tallam and J. E. Hall, Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation. Hypertension 43:370-375 (2004); U. Nordheim, J. R. Nicholson, K. Dokladny, P. Dunant and K. G. Hofbauer, Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats. Peptides 27:438-443 (2006).
- Adverse events have been observed with melanocortin agonists, including bremelanotide, primarily relating to an increase in blood pressure, and nausea and vomiting, both immediate and delayed.
- There is a need for a therapeutic method for treatment of sexual dysfunction, including but not limited to FSD, by means of administration of a melanocortin agonist which provides the desired therapeutic benefit, but which does not induce, or does not significantly induce, or which reduces or minimizes adverse cardiovascular and other effects, such adverse effects including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting. It is against this background that the invention was made.
- Provided herein are methods for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity by administration of a low dose of bremelanotide or a pharmaceutically acceptable salt thereof. The low dose may be administered via subcutaneous injection. The low doses of bremelanotide or a pharmaceutically acceptable salt thereof as provided herein were found to be efficacious, despite previous indications that a higher dose may be required to treat FSD. The low doses of bremelanotide or a pharmaceutically acceptable salt thereof as provided herein were also found to be associated with fewer side effects compared to administration of higher doses of the compound. Administration by subcutaneous injection resulted in a significantly lower % CV at peak plasma concentration in a patient population, compared to % CV at peak plasma concentration in a patient population administered bremelanotide or pharmaceutically acceptable salt thereof by intranasal administration. The compositions and methods provided herein, including, without limitation, when administered by subcutaneous injection, may additionally be associated with lower side effects compared to intranasal administration of a comparable dose, such as a comparable dose based on peak plasma concentration within 60 minutes after administration of bremelanotide.
- In one aspect, the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD while reducing undesirable side effects. In one aspect of this method, no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered by subcutaneous injection. In another aspect, between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered. In yet another aspect, between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered.
- The composition for subcutaneous injection may be an aqueous solution comprising acetate salt of bremelanotide and glycerin. In one aspect, the composition is an aqueous solution consisting essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v). The acetate salt of bremelanotide may be between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide. In one aspect, the composition is at a pH of about 5.0, and further comprises agents to adjust pH, which agents to adjust pH may comprise, without limitation, hydrochloric acid and sodium hydroxide.
- In another aspect, the undesirable side effects that are reduced are selected from the group consisting of nausea, emesis, flushing and an increase in blood pressure. In one aspect, the female patient is premenopausal, and in another aspect, the female patient is postmenopausal.
- The invention further provides for use of a formulation dose comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide in the manufacture of a subcutaneous injectable medicament for the treatment of FSD in a female patient diagnosed with FSD and anticipating sexual activity. In a related aspect, the formulation dose comprises between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, or between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide.
- In another aspect the invention provides a prefilled dose unit comprising an aqueous solution of acetate salt of no more than about 1.75 mg of bremelanotide. The prefilled dose unit may include a prefilled syringe, or may include a cartridge adapted for use in a subcutaneous administration drug delivery device.
- In yet another aspect, the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising bremelanotide or a pharmaceutically acceptable salt of bremelanotide in an amount sufficient to result in a peak plasma concentration within 60 minutes after administration of bremelanotide in the female patient of no more than about 120 ng/mL, thereby treating FSD while reducing undesirable side effects. In a related aspect, the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising bremelanotide or a pharmaceutically acceptable salt of bremelanotide in an amount sufficient to result in a peak plasma concentration with 60 minutes resulting from subcutaneous administration of a dose of between about 1.0 mg and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD while reducing undesirable side effects.
- In yet another aspect, the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity, while reducing side effects associated with the administration of bremelanotide, comprising administering the female patient by subcutaneous injection a composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD while reducing one or more side effects compared to intranasal administration of an equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide. In some embodiments, the side effects comprise one or more of nausea, flushing, headache, changes in systolic blood pressure, changes in diastolic blood pressure, changes in heart rate, vomiting, and hypertension. The equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide comprises a dose resulting in a substantially similar peak plasma concentration within 60 minutes after administration of bremelanotide compared to subcutaneous injection of the composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide. The substantially similar peak plasma concentration can be a mean peak plasma concentration in a patient population of between about 60 and 120 ng/mL of bremelanotide. In one aspect of the method, no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered by subcutaneous injection. In another aspect, between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered, or alternatively between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered. The composition of the method can be an aqueous solution comprising acetate salt of bremelanotide and glycerin, and can consist essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v). In such solution, the acetate salt of bremelanotide is between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide. The composition can be at a pH of about 5.0, and further comprise one or more agents to adjust pH, including where the one or more agents to adjust pH comprise hydrochloric acid and sodium hydroxide. In the method, the female patient may be premenopausal or alternatively postmenopausal. The variability in peak plasma concentration within 60 minutes after subcutaneous injection administration is a % CV less than 30. Reduction in side effects comprises the variability in peak plasma concentration within 60 minutes after subcutaneous injection administration of the composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide being is less than the variability in peak plasma concentration within 60 minutes after intranasal administration of bremelanotide or a pharmaceutically acceptable salt of bremelanotide. The variability in peak plasma concentration within 60 minutes after intranasal administration can be a % CV greater than 30. Variability in peak plasma concentration can be determined in a patient population.
- In yet another aspect, the invention provides a method for treating FSD in a female patient diagnosed with FSD and anticipating sexual activity comprising administering the female patient by subcutaneous injection a composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, thereby treating FSD, wherein the treatment has increased efficacy compared to intranasal administration of an equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide. In some embodiments, the increased efficacy is indicated by an increase in frequency of satisfying sexual events upon administration of the bremelanotide or pharmaceutically acceptable salt thereof. Increased efficacy may be indicated by an increase in frequency of satisfying sexual events upon administration of the bremelanotide or pharmaceutically acceptable salt thereof, or by improved overall sexual function, including where improved overall sexual function is measured by the Female Sexual Function Index, such as a Female Sexual Function Index total score improvement of 3 or greater. Increased efficacy may also be indicated by reduced associated distress related to sexual dysfunction, including where reduced associated distress related to sexual dysfunction is measured by the Female Sexual Distress Scale-DAO. In this method, an equivalent dosage of bremelanotide or a pharmaceutically acceptable salt of bremelanotide comprises a dose resulting in a substantially similar peak plasma concentration within 60 minutes after administration of bremelanotide compared to subcutaneous injection of the composition comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide. The substantially similar peak plasma concentration may be a mean peak plasma concentration of between about 60 and 120 ng/mL of bremelanotide in a patient population. In one aspect of the method, no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered by subcutaneous injection, or alternatively between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, or alternatively between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide is administered. The composition of the method can be an aqueous solution comprising acetate salt of bremelanotide and glycerin, and can consist essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v). In such solution, the acetate salt of bremelanotide is between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide. The composition can be at a pH of about 5.0, and further comprise one or more agents to adjust pH, including where the one or more agents to adjust pH comprise hydrochloric acid and sodium hydroxide. In the method, the female patient may be premenopausal or alternatively postmenopausal.
- In yet another aspect, the invention provides for use of a formulation dose comprising no more than about 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide in the manufacture of a subcutaneous injectable medicament for the treatment of FSD in a female patient diagnosed with FSD and anticipating sexual activity. Such formulation may comprise no more than 1.25 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide, and may further comprise between about 1.00 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide or alternatively between about 1.25 and 1.75 mg of bremelanotide or a pharmaceutically acceptable salt of bremelanotide. The formulation of this use can be an aqueous solution comprising acetate salt of bremelanotide and glycerin, and can consist essentially of acetate salt of bremelanotide and 2.5% glycerin (w/v). In such solution, the acetate salt of bremelanotide is between about 6% and 12% (w/w) acetic acid in an aqueous solution of bremelanotide. The formulation can be at a pH of about 5.0, and further comprise one or more agents to adjust pH, including where the one or more agents to adjust pH comprise hydrochloric acid and sodium hydroxide.
- A primary object of the present invention is to provide methods for the treatment of FSD which employ bremelanotide while limiting adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting.
- Another object of the present invention is to provide methods for the treatment of FSD which employ bremelanotide while reducing the incidence of adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting, compared with alternative prior art doses and methods of administering bremelanotide.
- Another object of the present invention is to provide methods for the treatment of FSD which employ bremelanotide while minimizing adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting, compared with alternative prior art doses and methods of administering bremelanotide.
- Another object of the present invention is to provide a dose of bremelanotide, such as a dose delivered by subcutaneous injection, which is efficacious in treating FSD but which does not induce, or which does not significantly induce, drug-associated adverse events, including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting.
- Other aspects and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The aspects of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
- The accompanying drawings, which are incorporated into and form a part of the specification, illustrate one or more embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating one or more preferred embodiments of the invention and are not to be construed as limiting the invention. In the drawings:
-
FIG. 1 is a plot showing resulting peak plasma concentrations of bremelanotide, measured in ng/mL, following intranasal administration of 5, 7.5, 10, 12.5, and 15 mg of bremelanotide in an aqueous solution, and subcutaneous administration 2.5 mg of bremelanotide in an aqueous solution. -
FIG. 2 is plot showing mean plasma concentrations (in ng/mL) of bremelanotide (Y axis) over time (X axis, in hours) following subcutaneous administration of 0.3 (∘), 1.0 (□), 3.0 (⋄), 5.0 (triangle, apex up), 7.5 (inverted triangle, apex down) and 10 (●) mg of bremelanotide in an aqueous solution in healthy adult males. -
FIG. 3 is a plot showing mean plasma concentrations (in ng/mL) of bremelanotide over time following subcutaneous administration of 0.75, 1.25 and 1.75 mg of bremelanotide in an aqueous solution in premenopausal women diagnosed with FSD. -
FIG. 4A is a graph of mean change in satisfying sexual events (SSEs) from double-blind baseline to end-of-study among at-home users of double-blind study drug in the Study of Example 1. The mean absolute number of SSEs for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 0.7 to 0.8 and 1.5 to 1.9, respectively. P<0.05 for the 1.75 mg dose, as determined by Van Elteren test. -
FIG. 4B is a graph of mean change in Female Sexual Function Index (FSFI) total score from double-blind baseline to end-of-study among at-home users of double-blind study drug in the Study of Example 1. The mean absolute FSFI Score for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 17.09 to 18.22 and 21.52 to 22.75, respectively. The total possible score is from 2 to 36. Higher scores indicate a greater level of sexual function. P for the 1.25 mg dose was <0.05 and for the 1.75 mg dose was <0.01, as determined by Van Elteren test. -
FIG. 4C is a graph of mean decrease in Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. The mean absolute FSDS-DAO Score for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 38.9 to 41.7 and 30.5 to 33.2, respectively. Total score can range from 0 to 60. The higher the score the greater the distress associated with sexual dysfunction. P<0.001 for the 1.75 mg dose, as determined by Van Elteren test. -
FIG. 5A is a graph of mean change in the desire sub-domain of the FSFI from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. **P<0.01 as determined by ANCOVA, ANOVA, or Van Elteren test. -
FIG. 5B is a graph of mean change in the arousal sub-domain of the FSFI from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. **P<0.01 as determined by ANCOVA, ANOVA, or Van Elteren test. -
FIG. 5C is a graph of mean change in the desire sub-domain of the FSDS-DAO (Item 13) from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. **P<0.01 as determined by ANCOVA, ANOVA, or Van Elteren test. -
FIG. 5D is a graph of mean change in the arousal sub-domain of the FSDS-DAO (Item 14) from double-blind baseline to end-of-study among at-home users of double-blind study drug in the study of Example 1. *P<0.05 as determined by ANCOVA, ANOVA, or Van Elteren test. -
FIG. 6A is a graph of mean change in FSFI total score from double-blind baseline to end-of-study among at-home users of double-blind study drug diagnosed with mixed HSDD/FSAD in the study of Example 1. *P<0.05 as determined by Wilcoxon rank-sum test. -
FIG. 6B is a graph of mean change in FSFI total score from double-blind baseline to end-of-study among at-home users of double-blind study drug diagnosed with HSDD only in the study of Example 1. **P<0.01 as determined by Wilcoxon rank-sum test. -
FIG. 7A is a plot of mean change of FSFI total score from baseline over time for a three month period with subcutaneous administration of placebo (♦) or 0.75 (▪), 1.25 (▴) or 1.75 (●) mg of bremelanotide in the study of Example 1. -
FIG. 7B is a plot of mean change of FSDS-DAO total score change from baseline over time for a three month period with subcutaneous administration of placebo (♦) or 0.75 (▪), 1.25 (▴) or 1.75 (●) mg of bremelanotide in the study of Example 1. -
FIG. 8 is a plot of Cmax (ng/mL) against AUC for zero to two hours (hours times ng/mL), utilizing combined data fromvisits - Before proceeding with the description of the invention, certain terms are defined as set forth herein.
- The “amino acid” and “amino acids” used in this invention, and the terms as used in the specification and claims, include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A Users Guide, G. A. Grant, editor, W.H. Freeman & Co., New York, 1992, the teachings of which are incorporated herein by reference, including the text and table set forth at
pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User's Guide cited above; V. J. Hruby, F. Al-Obeidi and W. Kazmierski: Biochem. J. 268:249-262, 1990; and C. Toniolo: Int. J. Peptide Protein Res. 35:287-300, 1990; the teachings of all of which are incorporated herein by reference. - In the listing of compounds according to the present invention, the amino acid residues have their conventional meaning as given in Chapter 2400 of the Manual of Patent Examining Procedure, 8th Ed. Thus, “Nle” is norleucine; “Asp” is aspartic acid; “His” is histidine; “D-Phe” is D-phenylalanine; “Arg” is arginine; “Trp” is tryptophan; and “Lys” is lysine; “Ac” refers to a peptide or amino acid sequence that is acetylated [(CH3)—CO—].
- The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions utilized in the present invention encompass any composition made by admixing an active ingredient and one or more pharmaceutically acceptable carriers.
- “Sexual dysfunction” means any condition that inhibits or impairs normal sexual function, including coitus. The term is not limited to physiological conditions, and includes psychogenic conditions or perceived impairment without a formal diagnosis of pathology or disorder. Sexual dysfunction includes ED in a male mammal and FSD in a female mammal. “Erectile dysfunction” (ED) is a disorder involving the failure of a male mammal to achieve functional erection, ejaculation, or both. Erectile dysfunction is accordingly synonymous with impotence, and includes the inability to attain or sustain an erection of sufficient rigidity for coitus.
- “Female sexual dysfunction” (FSD) is recognized in DSM-IV as four major disorders that define FSD: decreased sexual desire, decreased sexual arousal, dyspareunia, and difficulty in achieving orgasm. For purposes of diagnosis and therapy, FSD may be further defined to include female sexual arousal disorder (FSAD) and hypoactive sexual desire disorder (HSDD). The Draft Guidance for Industry, Female Sexual Dysfunction: Clinical Development of Drug Products for Treatment, U.S. Food and Drug Administration, May 2000, lists four recognized components of FSD: decreased sexual desire; decreased sexual arousal; dyspareunia; and persistent difficulty in achieving or inability to achieve orgasm, with the components associated with personal distress, as determined by the affected woman. Sexual dysfunction in females can also include inhibited orgasm and dyspareunia, which is painful or difficult coitus. Female sexual dysfunction includes, but is not limited to, a number of categories of diseases, conditions and disorders including HSDD, sexual anhedonia, sexual arousal disorder, dyspareunia and vaginismus. Hypoactive sexual desire disorder includes a disorder in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties. Hypoactive sexual desire disorder can be related to boredom or unhappiness in a long-standing relationship, depression, dependence on alcohol or psychoactive drugs, side effects from prescription drugs, or hormonal deficiencies. Sexual anhedonia includes decreased or absent pleasure in sexual activity. Sexual anhedonia can be caused by depression, drugs, or interpersonal factors. Sexual arousal disorder can be caused by reduced estrogen, illness, or treatment with diuretics, antihistamines, antidepressants, or antihypertensive agents. Dyspareunia and vaginismus are sexual pain disorders characterized by pain resulting from penetration and may be caused, for example, by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
- By a melanocortin receptor “agonist” is meant an endogenous or drug substance or compound, including a compound such as bremelanotide, which can interact with a melanocortin receptor and initiate a pharmacological response, including but not limited to adenyl cyclase expression, characteristic of the melanocortin receptor.
- By the abbreviation “% CV” is meant the coefficient of variation, which is the ratio of the standard deviation (SD) to the mean expressed as a percentage.
- In the specification and claims, where there is a reference to a weight of bremelanotide or a pharmaceutically acceptable salt of bremelanotide per dose (such as, e.g., administering a dose of 1.75 mg bremelanotide or a pharmaceutically acceptable salt of bremelanotide), it is to be understood that such weight is net peptide weight, that is, net of the salt in the instance of a pharmaceutically acceptable salt.
- The methods and pharmaceutical compositions disclosed herein can be used for both medical applications and animal husbandry or veterinary applications. Typically, the methods are used in humans, including specifically female humans, but may also be used in other mammals. The term “patient” is intended to denote a mammalian individual, and is so used throughout the specification and in the claims. The primary applications of this invention involve human female patients, but this invention may be applied to laboratory, farm, zoo, wildlife, pet, sport or other animals.
- In a preferred embodiment of the present invention, the melanocortin receptor agonist is:
-
- Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH (bremelanotide)
- The peptide of bremelanotide has a formula of C50H68N14O10, and a net molecular weight of 1025.18. This peptide may be synthesized by conventional means, including either solid-phase or liquid-phase techniques, and purified to greater than 99% purity by HPLC, yielding a white powder that is a clear, colorless solution in water. The structure of bremelanotide is:
- In one embodiment of the invention, bremelanotide is synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare bremelanotide.
- Bremelanotide may be in the form of any pharmaceutically acceptable salt. Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, citric, tartaric, oxalic, succinic or methanesulfonic acid. The acetate salt form is especially useful.
- In a preferred embodiment, bremelanotide is an acetate salt form, and is formulated in a buffered aqueous solution including glycerin, and prepackaged in a syringe and auto-injector device. In alternative embodiments, bremelanotide is any pharmaceutically acceptable salt form, and is formulated in any pharmaceutically acceptable aqueous solution, the aqueous solution optionally including one or more salts, such as sodium chloride, one or more acids, such as citric acid, and one or more additional ingredients, including cellulose or derivatives thereof, saccharides or polysaccharides such as dextrose, and any of a wide variety of surfactants, chelating agents and preservatives.
- This application is related to U.S. Pat. No. 6,579,968 (application Ser. No. 09/606,501), U.S. Pat. No. 6,794,489 (application Ser. No. 10/040,547), U.S. Pat. No. 7,176,279 (application Ser. No. 10/638,071), U.S. Pat. No. 7,235,625 (application Ser. No. 11/139,730), U.S. Pat. No. 7,417,027 (application Ser. No. 10/756,212), U.S. Pat. No. 7,473,760 (application Ser. No. 11/267,271), U.S. Pat. No. 7,897,721 (application Ser. No. 12/348,489), and International Application No. PCT/US13/068386, published as International Publication No. WO 2014/071339, and the teachings, including the specification, claims and prosecution history, of each of the foregoing are incorporated here by reference as if set forth in full.
- Uses of Bremelanotide. Over 2500 subjects have received bremelanotide in a total of 30 clinical trials, with bremelanotide administered via intravenous, intranasal and subcutaneous routes. The majority of studies conducted were of men diagnosed with erectile dysfunction. Bremelanotide administered intranasally demonstrated promising clinical activity in pre- and postmenopausal women with FSAD. However, with intranasal administration significant variability was seen in bremelanotide Cmax and the area under the concentration-time curve (AUC) compared to subcutaneous administration, as is shown generally in
FIG. 1 (data derived from men administered intranasal or subcutaneous bremelanotide). - In pharmacokinetic studies of subcutaneous administration of bremelanotide in a healthy adult male population, quantifiable concentrations of bremelanotide were observed in plasma within 15 minutes after subcutaneous administration, with median Tmax occurring at 0.50 to 1.0 hours after administration. See
FIG. 2 . Results of Tmax values were compared between subcutaneous administration (SC) and intranasal (IN) administration of various doses of bremelanotide, as shown inFIG. 1 . There was material and significant variability in peak plasma bremelanotide with intranasal administration, while subcutaneous injection of a dose of 2.5 mg resulted in substantially tighter peak plasma bremelanotide concentrations, with little or no excursion outside of predefined parameters. - Intranasal bremelanotide was shown to increase sexual desire and arousal compared to placebo in both premenopausal and postmenopausal women with FSAD in two
Phase 2 trials. However, use of intranasal bremelanotide was associated with increased adverse events compared to placebo in both premenopausal and postmenopausal women, with 92.5% of premenopausal subjects receiving bremelanotide reporting at least one adverse event, compared to 61.1% for placebo, and 100% of postmenopausal subjects receiving bremelanotide reported at least one adverse event, compared to 47.7% for placebo. In the bremelanotide premenopausal arm, 42.5% of the subjects were discontinued due to hypertension, nausea, vomiting or myalgia. Subjects received a 10 mg intranasal dose of bremelanotide, with premenopausal subjects determined to have a mean plasma concentration of 88.5±51.9 ng/mL and a % CV of 58.6, and postmenopausal subjects determined to have a mean plasma concentration of 93.2±68.5 ng/mL and a % CV of 73.5. The minimum and maximum plasma concentration levels for all women at thirty minutes post dose range from 0.0 ng/mL to 207.0 ng/mL. Subjects who experienced vomiting and/or nausea following in-clinic dosing had a substantially higher pharmacokinetic concentration of bremelanotide than subjects who did not experience these symptoms. Furthermore, stratification of subject arousal rate and level of desire success rate by pharmacokinetic concentration group showed a larger change in subject arousal rate and level of desire success rate from baseline to selected visits in subjects with a bremelanotide concentration between 50 to <100 ng/mL than subjects with a lower or higher bremelanotide concentration. - In a double-blind, placebo-controlled, single dose,
dose escalation Phase 1 study to determine the maximum tolerated dose in healthy adult female subjects, doses of from 0.3 to 5.0 mg (0.3, 1.0, 3.0 and 5.0 mg) of bremelanotide were administered by subcutaneous injection. However, this study specifically excluded women with a diagnosis of FSD, and thus could not determine an effective dose for treatment of FSD. The study did employ a measure of pharmacodynamic effect, defined as an increase of sexual arousal response in the presence of visual sexual stimulation as measured by vaginal blood flow with vaginal photoplethysmography (using a Geer gauge device), which measures vaginal pulse amplitude. However, by this measure a statistically significant pharmacodynamic effect was seen only in subjects receiving 3 and 5 mg of bremelanotide, with no apparent pharmacodynamic effect compared to placebo or baseline seen at 0.3 or 1.0 mg doses of bremelanotide. - Prior to the study disclosed hereafter as Example 1, no studies examining efficacy for FSD using subcutaneous administration had been conducted. In
Phase 1 studies using normal female volunteers as discussed above, a pharmacodynamics effect was seen only at subcutaneous doses of 3 mg or greater of bremelanotide. - While not intending to be bound by any particular theory, it is believed that bremelanotide may treat FSD primarily via a central nervous system mechanism of action, with minimal innervation or action in the genital area. This mechanism of action differs from the mechanism of action in treatment of male sexual dysfunction, in which efficacy is strongly correlated to innervation or action in the genital area, and specifically inducing an erection.
- In one aspect of invention, the variability in peak plasma concentration within 60 minutes after subcutaneous injection administration is a % CV less than about 30, or alternatively less than about 25, or alternatively less than about 20. The variability in peak plasma concentration within 60 minutes after intranasal administration is a % CV greater than about 25, or alternatively greater than about 30, or alternatively greater than about 40, or alternatively greater than about 50, or alternatively greater than about 60, or alternatively greater than about 70.
- Adverse Events with Subcutaneous Administration. Subcutaneous dosing was tested in 5
Phase 1 trials (3 in females, 2 in males) and onePhase 2 trial (males). The most common adverse events associated with single-dose SC bremelanotide administration (Trials-14, -06, and -10) were somnolence (30%), flushing (15%), nausea (19%), and vomiting (10%). - In a trial in males, 1 of 6 subjects at the 5-mg dose level, 1 of 6 subjects at the 7.5 mg dose level, and 3 of 6 subjects at the 10-mg dose level experienced vomiting that was mild or moderate in intensity and delayed 6 to 15 hours. Vomiting could be resolved with administration of intramuscular ondansetron (a 5-hydroxytryptamine3 antagonist). Single subcutaneous bremelanotide doses of 4 and 6 mg showed improved tolerability by male subjects with ED and preexisting hypertension.
- In a study with obese women, the dosing regimen included subcutaneous injections of either bremelanotide or
placebo 3 times daily for 15 days for a total of 45 planned doses. OnDay 1, the first dose was 1.25 mg with subsequent doses of 1.0 mg. OnDays 2 through 15, the first daily dose was 2.5 mg with second and third daily doses of 2.0 mg. No measure of sexual response was made in this study. Three subjects were withdrawn from the trial prematurely due to adverse events of vomiting (placebo group), hypertension (noted prior to daily dosing, bremelanotide group), and nausea (bremelanotide group), respectively, all of which were assessed as mild in intensity and probably (vomiting and hypertension) or possibly (nausea) related to trial drug. All 3 events resolved by trial conclusion. All subjects who participated in the trial experienced at least 1 treatment-emergent adverse event and all subjects experienced at least 1 treatment-related adverse event. - Determining Efficacy. In clinical trials to determine the efficacy of drugs and therapies for treatment of FSD, any of a number of validated patient-reported outcome questionnaires are utilized. These include:
-
FSEP-R Female Sexual Encounter Profile - Revised FSDS-DAO Female Sexual Distress Scale - Desire/Arousal/Orgasm FSFI Female Sexual Function Index GAQ General Assessment Questions SIDI-F Sexual Interest and Desire Inventory - Female WITS-9 Women's Inventory of Treatment Satisfaction
Electronic diary devices can be employed for use by subjects to complete questionnaires, including but not limited to the FSEP-R questionnaire, which can be completed outside of the clinic (at home) following a sexual encounter. - Use of Prefilled Syringes and Auto-Injector Devices. In one aspect, a prefilled syringe may be utilized, optionally with an auto-injector device, permitting a patient to rapidly and simply self-administer a subcutaneous dose of bremelanotide. Bremelanotide injection, a parenteral drug product for subcutaneous injection, is formulated in an aqueous system containing 2.5% w/v glycerin at
pH 5. It is packaged in single-useType I glass 1 mL prefilled syringes with staked one-half inch 29 gauge needles fitted with a needle shield and closed with gray Flurotec plunger stoppers. The primary container is secondarily fitted with a plunger rod for actuation and a safety device to prevent accidental access to the needle after use. Each unit is filled to deliver a minimum volume of 0.3 mL. - The following is a list of all components used in the manufacture of the drug product:
-
- Bremelanotide API
- Glycerin, USP vegetable grade
- Hydrochloric Acid, NF (if needed) for pH adjustment
- Sodium Hydroxide, NF (if needed) for pH adjustment
- Water for Injection, USP or Sterile Water for Injection, USP
-
Quantitative Composition of Bremelanotide Injection Drug Product Bremelanotide Injection (Quantity in each syringe) Component and 0.75 mg/0.3 mL 1.25 mg/0.3 mL 1.75 mg/0.3 mL Function (2.50 mg/mL) (4.17 mg/mL) (5.83 mg/mL) Bremelanotide API* 0.75 mg 1.25 mg 1.75 mg Glycerin, USP, vegetable 7.5 mg 7.5 mg 7.5 mg grade [tonicity agent] Hydrochloric Acid, NF To adjust pH To adjust pH To adjust pH [to adjust pH] Sodium Hydroxide, NF To adjust pH To adjust pH To adjust pH [to adjust pH] Water For Injection, USP QS to 0.3 mL QS to 0.3 mL QS to 0.3 mL [diluent and solubilizing agent] *Net bremelanotide (anhydrous, free base equivalent) - The bremelanotide drug product for subcutaneous injection is packaged in single-use pre-filled syringes with Flurotec plunger stoppers, a plunger rod for actuation, and a plastic safety device. The package components are further described below:
- Syringe:
BD Hypak SCF 1 mL Long Syringe Barrel with 29G×½″ 5 Bevel needle, Formulation BD260 (Primary container closure, Sterile, Clean and Ready-to-fill) (BD, Franklin Lakes, N.J., US) - Stopper:
BD Hypak NSCF 1 mL Long Plunger Stopper, Formulation W4023 Flurotec Daikyo Coated (Primary container closure, Sterile, Clean and Ready-to-fill) (BD, Franklin Lakes, N.J., US) - Plunger rod:
BD Hypak 1 mL Long Plunger Rod Polypropylene (Lies outside primary container closure, non-sterile). (BD, Franklin Lakes, N.J., US) - Auto-Injector: YpsoMate, automatic injection device for pre-filled syringe manufactured by Ypsomed (Burgdorf, Switzerland)
- A multi-centered, placebo-controlled, randomized, parallel group trial with fixed dose levels and designed to identify appropriate doses of bremelanotide administered by subcutaneous injection in premenopausal females with FSAD and/or HSDD, under the conditions of home use, was conducted. Subjects received a single dose of placebo (subject-blinded) in-clinic followed by 4 weeks of subject-blinded placebo treatment at home (subjects self-administered treatment as needed). Subjects who continued to qualify for the trial then received 2 single in-clinic doses of randomized treatment (double-blind; approximately one week apart), followed by 12 weeks of double-blind treatment at home (subjects self-administered treatment as needed). Baseline characteristic of the subjects is shown in Table 1 below.
-
TABLE 1 Subject Baseline Characteristics Bremelanotide groups Placebo group 0.75 mg 1.25 mg 1.75 mg Characteristic (N = 97) (N = 100) (N = 99) (N = 98) Age (years), 37.0 (7.7) 37.6 (7.8) 35.7 (7.2) 37.0 (7.6) mean (SD) Race, n (%) White 75 (77%) 71 (71%) 65 (66%) 70 (71%) Black 19 (20%) 25 (25%) 32 (32%) 23 (23%) Other 3 (3%) 4 (4%) 2 (2%) 5 (5%) Weight at screening 164.4 (42.1) 168.2 (37.9) 174.0 (43.2) 179.2 (45.9)a (lbs), mean (SD) Diagnosis, n (%) FSAD 4 (4%) 3 (3%) 3 (3%) 2 (2%) HSDD 24 (25%) 20 (20%) 24 (24%) 24 (24%) Mixed 69 (71%) 77 (77%) 72 (73%) 72 (72%) Menses frequency 72 (74%) 75 (75%) 86 (87%) 79 (81%) regular, n (%) Used oral contraception 12 (12%) 15 (15%) 11 (11%) 15 (15%) within the 30 days before Visit 1, n (%) aN = 97. FSAD, female sexual arousal disorder; HSDD, hypoactive sexual desire disorder; SD, standard deviation. - Subjects were randomized (1:1:1:1) to one of four study treatment groups (placebo or doses with 0.75, 1.25, or 1.75 mg net weight bremelanotide). Randomization occurred immediately prior to the first in-clinic dose of double-blind treatment. Study drug and placebo was provided as pre-filled syringes in 0.3 mL volume, with subjects instructed on self-administration into the anterior thigh or abdomen.
- Ambulatory blood pressure monitoring was conducted following both placebo and randomized treatment group in-clinic administrations. Three periods of ambulatory blood pressure monitoring were included, the first period was from before to 24 hours after a single, in-clinic dose of placebo (to establish a baseline); the second and third periods occurred from before to 24 hours after each of 2 single, in-clinic doses of double-blind treatment, administered within 14 days of each other. Blood samples for pharmacokinetic analysis were collected before and at 0.5, 1.0, and 2.0 hours after each in-clinic bremelanotide single-dose treatment (double-blind only), to permit analysis of concentration-response relationships.
- Enrolled subjects were premenopausal women who met the diagnostic criteria for FSAD, HSDD, or mixed FSAD/HSDD, utilizing a diagnostic screening guide including categorization of the sexual dysfunction as both acquired (vs. lifelong) and generalized (vs. situational). Subjects enrolled had previously been sexually “functional;” that is, experienced sexual arousal during sexual activity and/or a normal level of desire at some point in the past for a period of at least 2 years. Table 2 below shows the FSD measures at double-blind baseline, which defines a modified intent to treat (modified ITT) population.
-
TABLE 2 Subjects' FSD Measures at Double-Blind Baseline. Bremelanotide groups FSD Placebo group 0.75 mg 1.25 mg 1.75 mg parameter (N = 91) (N = 87a) (N = 75) (N = 74b) SSEs during the 28 days before randomization Mean (SD) 1.7 (1.9) 1.9 (2.1) 1.5 (1.6) 1.8 (2.6) Median [range] 1.0 [0-9] 1.0 [0-10] 1.0 [0-8] 1.0 [0-16] FSFI total score 21.94 (5.94) 22.75 (5.43) 21.52 (5.42) 21.65 (4.98) Mean (SD) FSDS-DAO total 32.1 (12.8) 30.5 (12.4) 32.7 (13.8) 33.3 (12.7) score Mean (SD) aFor SSEs, N = 85. bFor SSEs, N = 73. - Enrolled subjects were provided with an electronic diary system (eDiary) with instructions to complete an FSEP-R questionnaire with each sexual encounter. At selected in-clinic visits, subjects completed other assessment questionnaires, including SIDI-F, FSDS-DAO, FSFI, GAQ and WITS-9. In addition, various vital sign measures were conducted and blood and urine samples collected at selected in-clinic visits.
- The primary endpoint data analysis of 327 pre-menopausal women with FSD showed a clinically meaningful and statistically significant improvement (p=0.018) in the frequency of Satisfying Sexual Events (SSEs) in women taking bremelanotide doses (mean change from 1.6 at baseline increasing to 2.4; pooled 1.25 mg and 1.75 mg doses) versus placebo (mean change from 1.7 at baseline increasing to 1.9) over the study period, resulting in a 50% increase in SSEs with bremelanotide versus 12% with placebo. The study met its primary endpoint by demonstrating a clinically meaningful and statistically significant improvement in the change from baseline to end of study in the number of SSEs. The measurement period was defined as the number of events during the last four weeks of treatment minus the number of events during the baseline period, with outcomes reported for pooled results of women taking the two highest bremelanotide dose levels versus placebo. The following shows p values for changes in SSEs for three bremelanotide doses and pooled 1.25 and 1.75 mg bremelanotide over the measurement period:
-
- Bremelanotide (1.25 and 1.75 mg pooled vs. placebo) p=0.0180
- Bremelanotide (1.75 mg vs. placebo) p=0.0215
- Bremelanotide (1.25 mg vs. placebo) p=0.0807
- Bremelanotide (0.75 mg vs. placebo) p=0.4430
- Preliminary analysis of key secondary endpoints showed clinically meaningful and statistically significant improvement in patients who received bremelanotide vs. placebo (mean change from baseline to end of study; pooled 1.25 mg and 1.75 mg bremelanotide doses):
-
- Improved overall sexual functioning, as measured by the Female Sexual Function Index (FSFI). The FSFI is a 19-item questionnaire which provides for an additional measurement of changes over a longer recall period.
- FSFI total score improvement (mean change of 3.55 vs. 1.88, p=0.0017)
- Reduced associated distress related to sexual dysfunction, as measured by the Female Sexual Distress Scale-DAO (FSDS-DAO). The FSDS-DAO 15-item questionnaire is designed to assess and quantify the change in personal distress associated with FSD.
- FSDS-DAO total score improvement (mean change of −11.1 vs. −6.8, p=0.036).
- Improved overall sexual functioning, as measured by the Female Sexual Function Index (FSFI). The FSFI is a 19-item questionnaire which provides for an additional measurement of changes over a longer recall period.
- The FSDS Total Score and FSFI Total Score were each significantly correlated to dose (p=0.00277 and 0.00767, respectively); the correlation between the number of SSEs and actual dose was not significant. The relationship between key efficacy endpoints and weight-normalized dose (mg/kg) shows that the FSDS-DAO Total Score was statistically significantly correlated by weight-normalized dose. The FSFI Total Score trended toward a statistically significant correlation. Only the FSDS-DAO Total Score was significantly correlated with Cmax. Both FSDS-DAO Total Score and FSFI Total Score were significantly correlated with AUC(0-2 h) (p≤0.0485). Thus the correlation of FSDS-DAO Total Score with Cmax was statistically significant, as were the correlations for FSDS-DAO Total Score and FSFI Total Score with AUC(0-2 h). Accordingly, the 1.75 mg dose was the most optimal dose for efficacy.
- Mean pharmacokinetic parameters were determined by bremelanotide dose and visit, including Cmax determinations (the highest ng/mL concentration at either 0.5 or 1 hour post administration) and AUC determinations at two hours and, for a subset of subjects in each group, at four hours. The results are shown in Table 3 below:
-
TABLE 3 Mean Pharmacokinetic Parameters by Bremelanotide Dose and Visit Bremelanotide Visit 5 Visit 7Dose Cmax AUC(0-2 h) AUC(0-4 h) Cmax AUC(0-2 h) AUC(0-4 h) (mg) Statistic (ng/mL) (h · ng/mL) (h · ng/mL) (ng/mL) (h · ng/mL) (h · ng/mL) 0.75 N 95 95 31 86 86 27 Mean 37 53 84 38 53 80 Median 36 52 80 37 52 79 % CV 27 24 23 27 24 20 Min 17 25 50 20 26 51 Max 60 85 126 78 92 120 1.25 N 96 96 31 81 81 26 Mean 60 86 138 60 84 142 Median 56 81 136 60 84 144 % CV 31 25 20 33 25 25 Min 29 42 86 18 24 39 Max 126 148 187 150 144 199 1.75 N 92 92 31 86 86 27 Mean 77 112 178 78 112 184 Median 78 112 179 77 111 180 % CV 25 23 29 25 25 25 Min 15 17 25 27 28 72 Max 115 171 289 127 176 276 % CV, coefficient of variation; AUC, area under the curve; Cmax, maximum observed concentration; AUC(0-4 h) was computed for fewer subjects than AUC(0-2 h) because of elimination of the 4-hour blood sample by protocol amendment during the study. - The Cmax for the mean curve was calculated by averaging the concentrations at each time point (0.5, 1, 2 and 4 hours), and this is shown in
FIG. 3 . - There was a high correlation between the Cmax and AUC, and a linear relationship exists between these parameters, as shown on
FIG. 8 . Therefore, either parameter can be used when assessing PK correlations to dose, efficacy, or safety. - Mean changes in blood pressure were characterized in all subjects based on sequential supervised dosing of single-blind subcutaneous placebo and two doses of randomized study drug. The primary analysis for mean changes was the difference between treatment groups in the change from single-blind placebo to randomized drug (Visit 2
vs. Visits 5/7). These changes are summarized in Table 4. There were between 86 to 100 subjects in each dose group. -
TABLE 4 Treatment Group Difference (from Placebo) in Mean Change in Blood Pressure from Corresponding Period during Single-blind Placebo BMT Dose Interval SBP DBP Pulse HR-BP Product (mg) (h) V5 V7 V5 V7 V5 V7 V5 V7 0.75 0-4 1.8 1.1 1.5 0.6 −5.2* −4.8* −492.8* −491.9* 4-8 0.9 1.6 1.3 1.7 −6.2* −5.5* −676.5* −503.3* 8-24 0.9 1.6 1.0 1.3* −0.4 0.1 5.2 114.9 0-24 1.1 1.5 1.1* 1.3* −2.2* −1.6 −187.7 −82.3 1.25 0-4 2.4* 2.1* 3.0* 2.2* −5.2* −6.1* −436.4* −583.3* 4-8 1.4 1.3* 2.2* 0.9 −6.1* −6.5* −621.0* −669.7* 8-24 0.7 1.5* 1.4* 1.7* −1.5 −0.7 −127.4 4.2 0-24 1.1 1.6* 1.9* 1.7* −2.9* −2.6* −265.9 −206.5 1.75 0-4 3.1* 2.5* 3.2* 2.6* −4.6* −4.7* −305.9 −375.4* 4-8 2.1 2.2 2.3* 2.2* −6.6* −6.6* −608.1* −624.5* 8-24 0.9 0.6 1.4* 1.4 −0.8 −0.5 −23.7 −31.3 0-24 1.6 1.3 1.9* 1.8* −2.2* −2.2* −139.1 −184.1 Abbreviations: BMT, bremelanotide; DBP, diastolic blood pressure; HR-BP, heart rate-blood pressure; SBP, systolic blood pressure; V, visit. Asterisks denote P ≤ 0.05. - Efficacy outcomes are graphed by dosage and FSD diagnosis in
FIG. 6 . On all key endpoints, exploratory analyses demonstrated statistically significant efficacy or a clinically significant trend versus placebo in the HSDD-only and mixed HSDD/FSAD subgroups at 1.25 mg, 1.75 mg, and/or 1.25/1.75 mg pooled. - The data also showed that the mean change from baseline scores with the FSFI and FSDS-DAO were still increasing in the third treatment month, as shown in
FIG. 7 . In addition, an exploratory analysis showed a higher percentage of women who were administered bremelanotide (versus placebo) had end-of-study scores for the FSFI and FSDS-DAO total score levels above 26.5 and 18. - The most common adverse events during study-drug treatment (occurring in >5% in any group) were nausea, flushing, and headache. Drug treated subjects had ˜2 mm Hg change in blood pressure, predominantly within 4 hours of dosing; patients meeting the predefined blood pressure withdrawal criteria were evenly distributed among placebo and active arms of the study. Of 7 serious adverse events, none were considered related to bremelanotide treatment.
- Bremelanotide administration resulted in a small increase in both systolic and diastolic pressures, with a maximal change in systolic pressure of 3.15 mm Hg (average of
Visits 5 and 7) in the 1.75 mg dosing group. The 0 to 4 hour changes were statistically different than placebo (95% CI not intersecting 0) for the 2 high dose groups only. Importantly, the increase in systolic blood pressure was confined to the first 4 hours following bremelanotide administration. In all cases, the 4-to-8-hour interval and later intervals were not statistically different from placebo. - The small changes in systolic and diastolic pressures were accompanied by decrease in heart rate of between 3 to 6 beats per minute. These changes were statistically separable and occurred between 0 and 8 hours after bremelanotide administration. While it is not known whether these changes represent a baroreceptor reflex to the increase in blood pressure, a central process, or some combination of processes, available data suggests that the reduction in pulse and pulse-blood pressure product may be physiologically adaptive and reduce any potential cardiac risk of the small concurrent increase in systolic blood pressure.
- Although there were an increased number of outliers for maximal changes from baseline in systolic blood pressure in drug-treated patients, the duration of these events was quite limited. The interrogation interval during ambulatory blood pressure monitoring assessments of 15 minutes allowed definition of the maximal duration of such excursions. As can be seen from Table 5 below, few changes of greater than 10 mm Hg systolic lasted greater than 30 minutes, while no increases of 15 mm Hg systolic or greater lasted longer than 30 minutes. These data included are not selected with regard to concomitant activity, concomitant medications or other potential clinical contributory factors. The clinical significance of such changes, if any, is small.
-
TABLE 5 Systolic Blood Pressure Shifts by Duration Treatment ΔSBP > 10 mm Hg, ΔSBP > 15 mm Hg, Arm Duration > 30 minutes Duration > 30 minutes Placebo 1 1 BMT 0.75 mg 1 0 BMT 1.25 mg 2 0 BMT 1.75 mg 0 0 Abbreviations: Δ, change; BMT, bremelanotide; SBP, systolic blood pressure. - Bremelanotide was well-tolerated during the trial. The most common types of treatment-emergent adverse events reported more frequently in the bremelanotide arms were facial flushing, nausea, emesis and headache. The study dosed 395 patients. A total of 26 patients discontinued from the study based on preset blood pressure change criterion spread across all arms (N=26, Placebo: 6, bremelanotide arms—0.75 mg: 4, 1.25 mg: 9, 1.75 mg: 7). A total of 19 patients discontinued from the study based on adverse events spread across all arms (N=19, Placebo: 5, bremelanotide arms—0.75 mg: 2, 1.25 mg: 4, 1.75 mg: 8). The adverse events that most commonly lead to discontinuation (other than meeting the blood pressure criterion) were flushing, nausea and emesis. Based on a safety review by an independent Data Safety Monitoring Board, no significant safety issues or concerns were identified during the study. There were no serious adverse events reported attributable to bremelanotide. Adverse events during the double-blind treatment period are shown on Table 6 below.
-
TABLE 6 Adverse Events During Double-Blind Treatment. Bremelanotide groups Adverse Placebo group 0.75 mg 1.25 mg 1.75 mg event (N = 97) (N = 100) (N = 99) (N = 98) Anya 49 (51%) 64 (64%) 61 (62%) 67 (68%) Nausea 3 (3%) 18 (18%) 22 (22%) 24 (24%) Flushing 0 17 (17%) 14 (14%) 17 (17%) Headache 3 (3%) 9 (9%) 9 (9%) 14 (14%) Injection-site pain 3 (3%) 6 (6%) 6 (6%) 7 (7%) Upper respiratory 4 (4%) 8 (8%) 5 (5%) 4 (4%) tract infection Injection-site 0 4 (4%) 4 (4%) 6 (6%) pruritus Any leading to 5 (5%) 2 (2%) 4 (4%) 8 (8%) withdrawalb Vomiting 0 0 1 (1%) 3 (3%) Hypertension 2 (2%) 2 (2%) 0 1 (1%) Nausea 0 0 0 3 (3%) Flushing 0 0 1 (1%) 1 (1%) aThe types listed are those with incidence ≥5% among bremelanotide users at any dose. bThe types listed are those that occurred in >1 bremelanotide user across dosing groups. - Thus in premenopausal women with FSDs, bremelanotide self-administered at home at 1.25 and 1.75 mg SC was effective in decreasing distress, increasing arousal and desire, and increasing the number of SSEs, with robust dose response and consistency of effect across all key endpoints. Efficacy was seen in both HSDD and mixed HSDD/FSAD populations. These improvements continued throughout the treatment period, indicating that patients may be able to continue improving after three months of treatment. Women receiving bremelanotide were more likely than placebo-treated women to reach key score thresholds for both FSFI and FSDS-DAO. Bremelanotide was generally well tolerated.
- Comparison of results of the study of Example 1 with prior intranasal studies of bremelanotide in premenopausal and postmenopausal women with FSAD showed significantly different parameters for both efficacy and adverse events. Results with premenopausal women in a placebo-controlled, randomized, double-blind, parallel group, at-home exploratory study to evaluate the efficacy and safety of intranasally administered bremelanotide in subjects with female sexual arousal disorder (FSAD) were compared against results in the study of Example 1. In the intranasal study, a total of 76 premenopausal subjects were randomized, with 40 subjects to receive bremelanotide and 36 to receive placebo. Twenty-two subjects treated with bremelanotide and 29 treated with placebo completed the study, with 16 subjects who received bremelanotide (40%) discontinuing from the study due to an adverse event. This compares to the study of Example 1, in which as shown by Table 6 only 8% of subjects on the 1.75 mg subcutaneous dose discontinuing due to an adverse event.
- In the intranasal study, premenopausal women self-administered a 10 mg intranasal dose. At 30 minutes post dosing, this resulted in a Cmax mean of 88.5±51.9 ng/mL, a median Cmax of 81.1 ng/mL, % CV of 58.6, a minimum Cmax of 0 ng/mL and a maximum Cmax of 207 ng/mL. By contrast, in the study of Example 1 at the 1.75 mg subcutaneous dose level, the mean Cmax was 77.2±19.5 ng/mL, the median was 78 ng/mL, % CV was 25, the minimum was 15 ng/mL and the maximum was 115 ng/mL.
- Subjects who experienced vomiting, nausea or both following in-clinic dosing in the intranasal study had a substantial higher pK concentration of bremelanotide than subjects who did not experience these symptoms. Thus pK variability with intranasal administration had a direct impact on adverse events, and contributed to adverse events. Similarly, stratification of subject arousal rate and level of desire success rate by pK concentration group showed a larger change in subject arousal rate and level of desire success rate from baseline to
visits - Although the invention has been described in detail with particular reference to these preferred embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above are hereby incorporated by reference.
Claims (21)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/864,486 US20220362328A1 (en) | 2012-11-05 | 2022-07-14 | Uses of bremelanotide in therapy for female sexual dysfunction |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261722511P | 2012-11-05 | 2012-11-05 | |
US201361770535P | 2013-02-28 | 2013-02-28 | |
PCT/US2013/068386 WO2014071339A2 (en) | 2012-11-05 | 2013-11-05 | Uses of bremelanotide in therapy for female sexual dysfunction |
US14/704,223 US9700592B2 (en) | 2012-11-05 | 2015-05-05 | Uses of bremelanotide in therapy for female sexual dysfunction |
US15/642,772 US10286034B2 (en) | 2012-11-05 | 2017-07-06 | Uses of bremelanotide in therapy for female sexual dysfunction |
US16/368,417 US20190216888A1 (en) | 2012-11-05 | 2019-03-28 | Uses of bremelanotide in therapy for female sexual dysfunction |
US17/081,732 US20210060120A1 (en) | 2012-11-05 | 2020-10-27 | Uses of bremelanotide in therapy for female sexual dysfunction |
US17/864,486 US20220362328A1 (en) | 2012-11-05 | 2022-07-14 | Uses of bremelanotide in therapy for female sexual dysfunction |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/081,732 Continuation US20210060120A1 (en) | 2012-11-05 | 2020-10-27 | Uses of bremelanotide in therapy for female sexual dysfunction |
Publications (1)
Publication Number | Publication Date |
---|---|
US20220362328A1 true US20220362328A1 (en) | 2022-11-17 |
Family
ID=50628268
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/313,258 Active US9352013B2 (en) | 2012-11-05 | 2014-06-24 | Uses of bremelanotide in therapy for female sexual dysfunction |
US14/704,223 Active US9700592B2 (en) | 2012-11-05 | 2015-05-05 | Uses of bremelanotide in therapy for female sexual dysfunction |
US15/642,772 Active US10286034B2 (en) | 2012-11-05 | 2017-07-06 | Uses of bremelanotide in therapy for female sexual dysfunction |
US16/368,417 Abandoned US20190216888A1 (en) | 2012-11-05 | 2019-03-28 | Uses of bremelanotide in therapy for female sexual dysfunction |
US17/081,732 Abandoned US20210060120A1 (en) | 2012-11-05 | 2020-10-27 | Uses of bremelanotide in therapy for female sexual dysfunction |
US17/864,486 Pending US20220362328A1 (en) | 2012-11-05 | 2022-07-14 | Uses of bremelanotide in therapy for female sexual dysfunction |
Family Applications Before (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/313,258 Active US9352013B2 (en) | 2012-11-05 | 2014-06-24 | Uses of bremelanotide in therapy for female sexual dysfunction |
US14/704,223 Active US9700592B2 (en) | 2012-11-05 | 2015-05-05 | Uses of bremelanotide in therapy for female sexual dysfunction |
US15/642,772 Active US10286034B2 (en) | 2012-11-05 | 2017-07-06 | Uses of bremelanotide in therapy for female sexual dysfunction |
US16/368,417 Abandoned US20190216888A1 (en) | 2012-11-05 | 2019-03-28 | Uses of bremelanotide in therapy for female sexual dysfunction |
US17/081,732 Abandoned US20210060120A1 (en) | 2012-11-05 | 2020-10-27 | Uses of bremelanotide in therapy for female sexual dysfunction |
Country Status (24)
Country | Link |
---|---|
US (6) | US9352013B2 (en) |
EP (1) | EP2916856B2 (en) |
JP (1) | JP6567971B2 (en) |
KR (1) | KR102253526B1 (en) |
CN (2) | CN117860866A (en) |
AU (1) | AU2013337341B2 (en) |
BR (1) | BR112015009936A8 (en) |
CA (1) | CA2890081A1 (en) |
DK (1) | DK2916856T4 (en) |
EA (1) | EA032959B9 (en) |
ES (1) | ES2701444T3 (en) |
FI (1) | FI2916856T4 (en) |
GE (1) | GEP20196947B (en) |
HK (1) | HK1211227A1 (en) |
IL (1) | IL238276B (en) |
MX (1) | MX362610B (en) |
MY (1) | MY179755A (en) |
NZ (1) | NZ707246A (en) |
PH (1) | PH12015500915B1 (en) |
PL (1) | PL2916856T5 (en) |
SG (1) | SG11201502949QA (en) |
UA (1) | UA118656C2 (en) |
WO (1) | WO2014071339A2 (en) |
ZA (1) | ZA201503128B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11590209B2 (en) * | 2020-01-21 | 2023-02-28 | Palatin Technologies, Inc. | Use of bremelanotide in patients with controlled hypertension |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6579968B1 (en) | 1999-06-29 | 2003-06-17 | Palatin Technologies, Inc. | Compositions and methods for treatment of sexual dysfunction |
US7176279B2 (en) | 2000-06-28 | 2007-02-13 | Palatin Technologies, Inc. | Cyclic peptide compositions and methods for treatment of sexual dysfunction |
US7235625B2 (en) * | 1999-06-29 | 2007-06-26 | Palatin Technologies, Inc. | Multiple agent therapy for sexual dysfunction |
US7022674B2 (en) | 1999-12-16 | 2006-04-04 | Eli Lilly And Company | Polypeptide compositions with improved stability |
JP4943622B2 (en) * | 2000-05-31 | 2012-05-30 | ノヴォ ノルディスク アー/エス | Insulin injection system having a disposable needle with both ends pointed and the disposable needle with both ends pointed |
EP1441750A4 (en) | 2001-07-11 | 2006-10-18 | Palatin Technologies Inc | Linear and cyclic melanocortin receptor-specific peptides |
JP2008522754A (en) * | 2004-12-09 | 2008-07-03 | ウェスト ファーマシューティカル サービシズ インコーポレイテッド | Retrofit type fixed needle syringe and automatic injection apparatus having the same |
WO2009120656A1 (en) * | 2008-03-24 | 2009-10-01 | Palatin Technologies, Inc. | Pharmaceutical for ocular indications |
MX2010013436A (en) * | 2008-06-09 | 2011-06-21 | Palatin Technologies Inc | Melanocortin receptor-specific peptides for treatment of sexual dysfunction. |
ES2654147T3 (en) * | 2009-11-16 | 2018-02-12 | Ipsen Pharma S.A.S. | Pharmaceutical compositions of melanocortin receptor ligands |
JP5809242B2 (en) * | 2010-04-21 | 2015-11-10 | アッヴィ バイオテクノロジー リミテッド | Wearable automatic infusion device for controlled delivery of therapeutic agents |
-
2013
- 2013-11-05 SG SG11201502949QA patent/SG11201502949QA/en unknown
- 2013-11-05 EP EP13851014.4A patent/EP2916856B2/en active Active
- 2013-11-05 JP JP2015540853A patent/JP6567971B2/en active Active
- 2013-11-05 CN CN202410025611.5A patent/CN117860866A/en active Pending
- 2013-11-05 EA EA201590760A patent/EA032959B9/en not_active IP Right Cessation
- 2013-11-05 MY MYPI2015001016A patent/MY179755A/en unknown
- 2013-11-05 CN CN201380056487.9A patent/CN104755094A/en active Pending
- 2013-11-05 ES ES13851014T patent/ES2701444T3/en active Active
- 2013-11-05 WO PCT/US2013/068386 patent/WO2014071339A2/en active Application Filing
- 2013-11-05 AU AU2013337341A patent/AU2013337341B2/en active Active
- 2013-11-05 PL PL13851014.4T patent/PL2916856T5/en unknown
- 2013-11-05 MX MX2015005486A patent/MX362610B/en active IP Right Grant
- 2013-11-05 UA UAA201503523A patent/UA118656C2/en unknown
- 2013-11-05 DK DK13851014.4T patent/DK2916856T4/en active
- 2013-11-05 BR BR112015009936A patent/BR112015009936A8/en not_active Application Discontinuation
- 2013-11-05 NZ NZ707246A patent/NZ707246A/en unknown
- 2013-11-05 KR KR1020157014777A patent/KR102253526B1/en active IP Right Grant
- 2013-11-05 FI FIEP13851014.4T patent/FI2916856T4/en active
- 2013-11-05 CA CA2890081A patent/CA2890081A1/en active Pending
- 2013-11-05 GE GEAP201313826A patent/GEP20196947B/en unknown
-
2014
- 2014-06-24 US US14/313,258 patent/US9352013B2/en active Active
-
2015
- 2015-04-14 IL IL238276A patent/IL238276B/en active IP Right Grant
- 2015-04-23 PH PH12015500915A patent/PH12015500915B1/en unknown
- 2015-05-05 US US14/704,223 patent/US9700592B2/en active Active
- 2015-05-07 ZA ZA2015/03128A patent/ZA201503128B/en unknown
- 2015-12-08 HK HK15112118.5A patent/HK1211227A1/en unknown
-
2017
- 2017-07-06 US US15/642,772 patent/US10286034B2/en active Active
-
2019
- 2019-03-28 US US16/368,417 patent/US20190216888A1/en not_active Abandoned
-
2020
- 2020-10-27 US US17/081,732 patent/US20210060120A1/en not_active Abandoned
-
2022
- 2022-07-14 US US17/864,486 patent/US20220362328A1/en active Pending
Non-Patent Citations (6)
Title |
---|
FSFI questionnaire, 2000, pages 1-5. * |
List of Mammals, 2022, pages 1-34. * |
Long-Evans rats, from www.janvier-labs.com, 2017, page 1. * |
NCT01382719, from ClinicalTrials.gov, 6/24/2011, pages 1-21. * |
Safarinejad-Retracted, pages 1-3, accessed 12/6/2023. * |
Vagenende et al, Mechanisms of Protein Stabilization and Prevention of Protein Aggregation by Glycerol, Biochemistry, 2009, 48, pages 11084-11096. * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2769397C2 (en) | Compositions and methods of treating opioid overdose | |
SK145897A3 (en) | Methods and formulations for modulating the human sexual response | |
WO2020252384A1 (en) | Treatment methods utilizing oxytocin receptor agonists | |
TW200815014A (en) | Method of improved diuresis in individuals with impaired renal function | |
US20220362328A1 (en) | Uses of bremelanotide in therapy for female sexual dysfunction | |
US20230158118A1 (en) | Use of bremelanotide in patients with controlled hypertension | |
US20240016898A1 (en) | Treatment of exercise-induced hypoglycemia in type 1 and insulin using type 2 diabetes | |
Lin | Erectile dysfunction and premature ejaculation: underlying causes and available treatments | |
WO2022115576A9 (en) | Treatment of raynaud's disease | |
WO2019032469A1 (en) | Treatment of overweight and obesity associated with leptin deficiency |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
AS | Assignment |
Owner name: COSETTE PHARMACEUTICALS, INC., NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PALATIN TECHNOLOGIES, INC.;REEL/FRAME:066165/0212 Effective date: 20231219 |