WO2024177907A4 - Methods of treating cancer and/or chemotherapy related conditions using non-naturally occurring melanocortin analogs - Google Patents

Methods of treating cancer and/or chemotherapy related conditions using non-naturally occurring melanocortin analogs Download PDF

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WO2024177907A4
WO2024177907A4 PCT/US2024/016295 US2024016295W WO2024177907A4 WO 2024177907 A4 WO2024177907 A4 WO 2024177907A4 US 2024016295 W US2024016295 W US 2024016295W WO 2024177907 A4 WO2024177907 A4 WO 2024177907A4
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Russell Potterfield
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Endevica Bio Inc
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    • A61K38/00—Medicinal preparations containing peptides
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    • 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
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    • C07K14/665—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

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Abstract

Provided herein are methods of treating, preventing, or reducing conditions and/or side effects associated with anti-cancer agents (e.g., chemotherapeutic agents) via administration of a non-naturally occurring melanocortin analog prior to, during, and/or after administration of the anti-cancer agents. The methods reduce adverse effects associated with the anti-cancer agent, such as anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, thereby enhancing tolerance of the anti-cancer agents and survival of the subject having cancer or having a disease or condition that is not cancer but is treated, reduced, or prevented by administration of an anti-cancer agent.

Claims

AMENDED CLAIMS received by the International Bureau on 07 November 2024 (07.11 .2024) l/We claim:
1. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
2. A method of maintaining or increasing weight in a subject prior to, during, and/or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
3. A method of maintaining or increasing weight in a subject prior to, during, and/or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anticancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
4. The method of claim 2 or 3, wherein the subject experiences an increase in weight by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.
5. A method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring
360
AMENDED SHEET (ARTICLE 19) melanocortin analog to the subject prior to, during, and/or after administration of the anticancer agent.
6. The method of claim 5, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.
7. A method of preventing, reducing, or restoring weight loss induced by an anticancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent.
8. The method of claim 7, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.
9. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
10. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
361
AMENDED SHEET (ARTICLE 19)
11 . The method of claim 10, wherein the subject experiences an increase in bone density by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.
12. A method of preventing or reducing an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and a non- naturally occurring melanocortin analog to the subject.
13. A method of treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.
14. A method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) score and/or Karnofsky performance status (KPS) score of a subject having cancer, comprising administering an anti-cancer agent and a non- naturally occurring melanocortin analog to the subject.
15. The method of claim 14, wherein the subject experiences a reduction in ECOG performance score by about 1 , 2, or 3 compared to baseline or control.
16. The method of claim 14, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.
17. The method of claim 1 , wherein the method maintains or increases lean body mass, fat body mass, and/or weight of the subject.
18. The method of claim 5, wherein the method maintains or increases lean body mass, fat body mass, and/or body weight of the subject.
362
AMENDED SHEET (ARTICLE 19)
19. The method of claim 9, wherein the failure to respond to an antiemetic treatment further comprises clinically and/or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and/or increased food intake in the subject.
20. The method of claim 10, wherein the nutritional intervention further comprises nutritional supplementation.
21. The method of claim 12, wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
22. The method of claim 13, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
23. The method of claim 14, wherein the ECOG score and/or KPS score is improved, maintained, and/or reduction of is prevented by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
24. The method of any one of claims 1-10, wherein the subject has a cancer.
25. The method of any one of claims 1-14, wherein the anti-cancer agent comprises a chemotherapy.
26. The method of claim 25, wherein the method reduces chemotherapy induced mass loss and/or wasting in the subject and increases lean body mass and body weight of the subject.
363
AMENDED SHEET (ARTICLE 19)
27. The method of claim 25, wherein the method maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and/or wasting in the subject.
28. The method of any one of claims 1 -14, wherein the anorexia is associated with weight loss.
29. The method of any one of claims 1-14, wherein the administration of the non- naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.
30. The method of claim 29, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and/or an increased duration of administration of the anti-cancer agent, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.
31. The method of claim 29, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.
32. The method of any one of claims 1-14, wherein the administration of the non- naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent.
33. The method of claim 32, wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and/or a decreased duration of administration, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin
364
AMENDED SHEET (ARTICLE 19) analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
34. The method of any one of claims 1-14, wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and/or weight loss prior to the administration of the non-naturally occurring melanocortin analog.
35. The method of claim 34, wherein the loss of appetite, reduced appetite, decreased food consumption, and/or weight loss is caused by a cancer.
36. The method of claim 34, wherein the loss of appetite, reduced appetite, decreased food consumption, and/or weight loss is caused by the anti-cancer agent.
37. The method of any one of claims 1-14, wherein the subject is receiving an antiemetic.
38. The method of claim 37, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.
39. The method of any one of claims 1-14, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.
40. The method of any one of claims 1-14, wherein the non-naturally occurring melanocortin analog is administered before and/or after the anti-cancer agent.
41. The method of claim 1 , wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.
42. The method of claim 2, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing
365
AMENDED SHEET (ARTICLE 19) anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
43. The method of claim 3, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
44. The method of claim 5, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject.
45. The method of claim 7, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject.
46. The method of claim 9, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and/or therapeutically to an antiemetic treatment.
47. The method of claim 10, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and/or therapeutically to nutritional intervention.
48. The method of claim 12, wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject.
49. The method of claim 13, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject.
366
AMENDED SHEET (ARTICLE 19)
50. The method of claim 14, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and/or Karnofsky performance status score of the subject.
51. The method of any one of claims 1-14, wherein the subject’s mass and/or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
52. The method of any one of claims 1-14, wherein the subject’s mass and/or weight is not more than 10% reduced from baseline prior to administration of the non- naturally occurring melanocortin analog and/or the anti-cancer agent.
53. The method of any one of claims 1 -14, wherein the subject has a performance status on the ECOG scale of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
54. The method of any one of claims 1 -14, wherein the subject has a performance status on the ECOG scale of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
55. The method of claim 53 or 54, wherein the method lowers the ECOG scale of the subject.
56. The method of any one of claims 1-14, wherein the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
57. The method of any one of claims 1-14, wherein the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
367
AMENDED SHEET (ARTICLE 19)
58. The method of claim 56 or 57, wherein the method increases the subject’s KPS score.
59. The method of any one of claims 1-58, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),
X1X2X3R1 R2R3R4R5R6R7R8R9R10R11 R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8 (I) wherein:
R1 is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;
R2 is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);
R3 is absent or is selected from the group consisting of histidine, D-proline, L-prol ine, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), betaalanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);
R4 is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine,
368
AMENDED SHEET (ARTICLE 19) para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(l)dPhe);
R5 is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(l)dPhe;
R6 is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine;
R7 is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);
R8 is absent or is lysine or arginine;
R9 is absent or is tryptophan;
R10 is absent or is lysine;
R11-R20 are absent;
X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine;
X2 is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;
X3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;
369
AMENDED SHEET (ARTICLE 19) Y1 is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;
Y2 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;
Y3 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine;
Y4 is absent or is D-proline or D-valine;
Y5 is absent or is D-proline or D-valine;
Y6 is absent or is D-proline or D-valine;
Y7 is absent or is D-proline or D-valine;
Y8 is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or X1 when R1 or R2 is cysteine and R7 or X1 is cysteine; a disulfide bond between R2 and any one of R5-R20 when R2 and the any one of R5- R20 are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7when R1 or R2 is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7 is lysine or ornithine; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; a side-chain lactam bridge between R2 or R4 and R10when R2 is glutamic acid or aspartic acid and R10 is lysine;
370
AMENDED SHEET (ARTICLE 19) provided that: when R2 is dAsp, then R7 is not dLys; when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys; and when Y1 is dPro, Y2 is dVal, and Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified; when R7 is Aia, R4 is dNal(2’); when R4 is p(l)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1 and R7, then R2 is His; when R2-R7 is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2 is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2 and R8, and R3 is Pro, then R7 is not Pro and Y1 is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2 is not absent.
60. The method of any one of claims 1-59, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, 172 188-190, 228-231 , and 252-255.
61. The method of any one of claims 1-59, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
62. The method of claim 25, wherein the chemotherapy comprises at least one chemotherapeutic agent.
63. The method of claim 62, wherein the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic.
371
AMENDED SHEET (ARTICLE 19)
64. The method of claim 63, wherein the at least one chemotherapeutic agent comprises a platinum-coordination complex.
65. The method of claim 63, wherein the at least one chemotherapeutic agent comprises an antimetabolite.
66. The method of claim 63, wherein the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.
67. The method of claim 63, wherein the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent.
68. The method of claim 63, wherein the at least one chemotherapeutic agent comprises a cytotoxic antibiotic.
69. The method of claim 64, wherein the platinum-coordination complex is carboplatin and/or cisplatin.
70. The method of claim 65, wherein the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.
71 . The method of claim 66, wherein the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.
72. The method of claim 67, wherein the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine,
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AMENDED SHEET (ARTICLE 19) cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.
73. The method of claim 68, wherein the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.
74. The method of claim 64, wherein the platinum-coordination complex is cisplatin.
75. The method of claim 74, wherein the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
76. The method of claim 65, wherein the antimetabolite is 5-fluorouracil (5-FU).
77. The method of claim 76, wherein the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
78. The method of claim 66, wherein the tubulin binding agent or the plant alkaloid is vincristine.
79. The method of claim 67, wherein the alkylating antineoplastic agent is cyclophosphamide.
80. The method of claim 68, wherein the cytotoxic antibiotic is doxorubicin.
81. The method of claim 80, wherein the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
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82. The method of any one of claims 12-14, or 24, wherein the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, and melanoma.
83. The method of any one of claims 12-14, or 24, wherein the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.
84. The method of any one of claims 12-14, or 24, wherein the cancer is breast cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, a taxane, and docetaxel.
85. The method of claim 84, wherein the anthracycline is doxorubicin.
86. The method of claim 84, wherein the taxane is paclitaxel.
87. The method of any one of claims 12-14, or 24, wherein the cancer is lung cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed.
88. The method of any one of claims 12-14, or 24, wherein the cancer is prostate cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, and estramustine.
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89. The method of any one of claims 1 -88, wherein the anti-cancer agent is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.
90. The method of any one of claims 1-88, wherein the subject is receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.
91. The method of any one of claims 1-88, wherein subject is not receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.
92. The method of any one of claims 1-88, wherein the cancer is melanoma, and wherein the anti-cancer agent is dacarbazine and/or temozolomide.
93. The method of any one of claims 12-14, or 24, wherein the cancer is nonHodgkin's lymphoma, and wherein the anti-cancer agent is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide, prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin.
94. The method of any one of claims 1-93, wherein the method does not reduce efficacy of the anti-cancer agent.
95. The method of any one of claims 1-94, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent.
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96. The method of claim 95, wherein the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.
97. The method of any one of claims 1-96, wherein the subject is a human.
98. The method of any one of claims 1-96, wherein the subject is an animal.
99. The method of any one of claims 1-3, 8-10, 21 -23, 42, 43, or 96, wherein the muscle mass loss is cardiac muscle mass loss, skeletal muscle mass loss, or both.
100. The method of claim 99, wherein the cardiac muscle mass loss is determined by measuring change in heart weight.
101 . The method of claim 99, wherein the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight.
102. The method of any one of claims 1-3, 9, 10, 21-23, 42, 43, 74, or 96, wherein anorexia is determined by daily food intake, daily food consumption, and/or weekly food intake.
103. The method of claim 102, wherein the daily food intake is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.
104. The method of claim 102, wherein the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject.
105. The method of claim 102, wherein the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.
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106. The method of any one of claims 1-3, 8-10, 21 -23, 42, 43, or 96, wherein the weight loss is determined by daily body weight, and/or daily body weight gain.
107. The method of any one of claims 1-106, wherein the fat mass of the subject treated with the method is at least 10% to 100% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non- naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
108. The method of any one of claims 1 -106, wherein the heart weight of the subject treated with the method is at least 0.1 % to 10% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non- naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
109. The method of any one of claims 1-106, wherein the gastrocnemius tissue weight of the subject treated with the method is at least 0.1 % to 10% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
110. The method of any one of claims 1-106, wherein the daily food intake of the subject treated with the method is at least 5% to 50% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
111. The method of any one of claims 1 -106, wherein the daily body weight of the subject treated with the method is at least 1 % to 15% greater than a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of
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AMENDED SHEET (ARTICLE 19) the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
112. The method of any one of claims 1-106, wherein appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.
113. The method of any one of claims 1-106, wherein appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog.
114. The method of claim 112 or 113, wherein appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during the administration.
115. The method of claim 112 or 113, wherein appetite is increased for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration.
116. The method of any one of claims 112-115, wherein the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.
117. The method of any one of claims 112-116, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and/or level of satiety.
118. The method of claim 117, wherein the appetite is assessed between meals.
119. The method of any one of claims 112-117, wherein the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects.
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120. The method of any one of claims 1-23, wherein anorexia is determined by food consumption.
121. The method of any one of claims 1-120, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.
122. The method of claim 121 , wherein the pharmaceutical composition further comprises a pharmaceutical salt.
123. The method of claim 121 , wherein the pharmaceutical composition further comprises a pharmaceutical carrier.
124. The method of claim 121 , wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg/mL to 500 mg/mL, relative to a total volume of the pharmaceutical composition.
125. The method of claim 124, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg/mL to 100 mg/mL, relative to a total volume of the pharmaceutical composition.
126. The method of claim 125, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, or about 60 mg/mL, relative to a total volume of the pharmaceutical composition.
127. The method of claim 126, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg/mL, relative to a total volume of the pharmaceutical composition.
128. The method of any one of claims 1-14, wherein the non-naturally occurring
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AMENDED SHEET (ARTICLE 19) melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.
129. The method of any one of claims 121-127, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.
130. The method of any one of claims 121-127, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.
131. The method of any one of claims 1-130, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.
132. The method of claim 123, wherein the pharmaceutical carrier comprises water.
133. The method of any one of claims 1-132, wherein the non-naturally occurring melanocortin analog is administered to a subject prior to or after a meal.
134. The method of any one of claims 1-132, wherein the non-naturally occurring melanocortin analog is administered to a subject with a meal.
135. The method of any one of claims 1-134, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is administered, and wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
136. The method of any one of claims 135, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg/kg to 10 mg/kg per body weight of the subject.
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137. The method of any one of claims 1-134, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
138. The method of any one of claims 1-134, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg per body weight of the subject.
139. The method of claim 138, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
140. The method of claim 138, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.5 mg/kg to 10 mg/kg per body weight of the subject.
141. The method of any one of claims 1-140, wherein the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.
142. The method of any one of claims 1-140, wherein the non-naturally occurring melanocortin analog is administered to the subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.
143. The method of any one of claims 1-142, wherein the anti-cancer agent and the non-naturally occurring melanocortin analog are administered simultaneously as a single composition.
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144. The method of claim 143, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 0.1 mg/mL to 500 mg/mL, relative to a total volume of the single composition.
145. The method of claim 144, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 5 mg/mL to 100 mg/mL, relative to a total volume of the single composition.
146. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, or about 60 mg/mL, relative to a total volume of the single composition.
147. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 50 mg/mL, relative to a total volume of the single composition.
148. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
149. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
150. The method of claim 145, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5
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AMENDED SHEET (ARTICLE 19) times, or 10 times per day.
151. The method of any one of claims 148-150, wherein the administration is performed once per day.
152. The method of any one of claims 1-142, wherein: the anti-cancer agent is present in a first pharmaceutical composition; and the non-naturally occurring melanocortin analog is present in a second pharmaceutical composition.
153. The method of claim 152, wherein the first and the second pharmaceutical compositions are different and are administered sequentially.
154. The method of claim 152, wherein the first and the second pharmaceutical compositions are different and are administered simultaneously but separately.
155. The method of any one of claims 152-154, wherein the second pharmaceutical composition is administered subcutaneously.
156. The method of any one of claims 152-155, wherein anti-cancer agent comprises a chemotherapy, and the chemotherapy is present in the first pharmaceutical composition in a concentration of 0.001 mg/mL to 1 ,000 mg/mL, relative to a total volume of the first pharmaceutical composition.
157. The method of claim 156, wherein the chemotherapy is cisplatin, and cisplatin is present in the first pharmaceutical composition in a concentration of 0.01 mg/mL to 50 mg/mL, relative to a total volume of the first pharmaceutical composition.
158. The method of claim 156, wherein the chemotherapy is 5-FU, and 5-FU is present in the first pharmaceutical composition in a concentration of 0.1 mg/mL to 500 mg/mL, relative to a total volume of the first pharmaceutical composition.
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159. The method of claim 156, wherein the chemotherapy is doxorubicin, and doxorubicin is present in the first pharmaceutical composition in a concentration of 0.01 mg/mL to 50, relative to a total volume of the first pharmaceutical composition.
160. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg/mL to 500 mg/mL, relative to a total volume of the second pharmaceutical composition.
161. The method of claim 160, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 5 mg/mL to 100 mg/mL, relative to a total volume of the second pharmaceutical composition.
162. The method of claim 161 , wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, or about 60 mg/mL, relative to a total volume of the second pharmaceutical composition.
163. The method of claim 161 , wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 50 mg/mL, relative to a total volume of the second pharmaceutical composition.
164. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
165. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is
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AMENDED SHEET (ARTICLE 19) performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
166. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.
167. The method of any one of claims 164-166, wherein the administration is performed once per day.
168. The method of claim 152, wherein the anti-cancer agent comprises cisplatin, and wherein cisplatin is administered orally and/or intraperitoneally.
169. The method of claim 152, wherein the anti-cancer agent comprises 5-FU, and wherein 5-FU is administered orally and/or intraperitoneally.
170. The method of claim 152, wherein the anti-cancer agent comprises doxorubicin, and wherein doxorubicin is administered intraperitoneally.
171. The method of claim 152, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
172. The method of any one of claims 152-171 , wherein a therapeutically effective amount of the anti-cancer agent is administered at least once per week.
173. The method of claim 172, wherein the anti-cancer agent comprises cisplatin, and the therapeutically effective amount of cisplatin is from 0.01 mg/kg to 25 mg/kg per body weight of the subject.
174. The method of claim 173, wherein the therapeutically effective amount of cisplatin is about 2.5 mg/kg per body weight of the subject.
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175. The method of claim 172, wherein the anti-cancer agent comprises 5-FU, and the therapeutically effective amount of 5-FU is from 0.1 mg/kg to 700 mg/kg per body weight of the subject.
176. The method of claim 175, wherein the therapeutically effective amount of 5- FU is about 70 mg/kg per body weight of the subject.
177. The method of claim 172, wherein the anti-cancer agent comprises doxorubicin, and the therapeutically effective amount of doxorubicin is from 0.005 mg/kg to 50mg/kg per body weight of the subject.
178. The method of claim 177, wherein the therapeutically effective amount of doxorubicin is about 2 mg/kg per body weight of the subject.
179. The method of any one of claims 172-178, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg/kg to 25 mg/kg per body weight of the subject.
180. The method of any one of claims 172-178, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg/kg to about 10 mg/kg per body weight of the subject.
181. The method of claim 152, wherein the anti-cancer agent comprises cisplatin, and cisplatin is administered at a dose of 0.01 mg/kg to 25 mg/kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.
182. The method of claim 152, wherein the anti-cancer agent comprises 5-FU, and 5-FU is administered at a dose of 0.1 mg/kg to 700 mg/kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.
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183. The method of claim 152, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3, and the non-naturally occurring melanocortin analog is administered at a daily dose of 0.001 mg/kg to 25 mg/kg per body weight of the subject.
184. Use of a non-naturally occurring melanocortin analog to treat, prevent, or reduce one or more side effects associated with an anti-cancer agent in a subject, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, wherein the non- naturally occurring melanocortin analog is administered to the subject prior to, during, and/or after administration of the anti-cancer agent
185. Use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and/or after administration of an anti-cancer agent, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
186. Use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and/or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
187. The use of claim 185 or 186, wherein the subject experiences an increase in weight by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.
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188. Use of a non-naturally occurring melanocortin analog to maintain or increase muscle mass, fat mass, or cardiac mass in a subject prior to, during, and/or after administration of an anti-cancer agent.
189. The use of claim 188, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.
190. Use of a non-naturally occurring melanocortin analog to maintain or increase bone density in a subject prior to, during, and/or after administration of an anti-cancer agent.
191. The use of claim 190, wherein the subject experiences an increase in bone density by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.
192. Use of a non-naturally occurring melanocortin analog to stimulate appetite or reduce loss of appetite induced by an anti-cancer agent in a subject.
193. The use of claim 192, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.
194. Use of a non-naturally occurring melanocortin analog for preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject.
195. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, the one or more side effects are selected from
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AMENDED SHEET (ARTICLE 19) the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
196. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
197. Use of a non-naturally occurring melanocortin analog for preventing or reducing an anti-cancer agent induced side effect in a subject having cancer.
198. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer.
199. Use of a non-naturally occurring melanocortin analog prior to, during, and/or after administration of an anti-cancer agent for preventing reduction of, maintaining, or improving ECOG score and/or KPS score of a subject having cancer relative to a baseline or a control.
200. The use of claim 199, wherein the subject experiences a reduction in ECOG performance score by about 1 , 2, or 3 compared to baseline or control.
201. The use of claim 199, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.
202. The use of claim 184, wherein the use maintains or increases lean body mass, fat body mass, and/or weight of the subject relative to a baseline or a control.
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203. The use of claim 192, wherein the use maintains or increases lean body mass, fat body mass, and/or body weight of the subject relative to a baseline or a control.
204. The use of claim 195, wherein the failure to respond to an antiemetic treatment further comprises clinically and/or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and/or increased food intake in the subject.
205. The use of claim 196, wherein the nutritional intervention further comprises nutritional supplementation.
206. The use of claim 197, wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, vomiting, diarrhea, nausea, and fatigue.
207. The use of claim 198, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
208. The use of claim 199, wherein the improvement, maintenance, or prevented reduction of ECOG score and/or KPS score occurs by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
209. The use of any one of claims 184-208, wherein the subject has a cancer.
210. The use of any one of claims 184-209, wherein the anti-cancer agent comprises a chemotherapy.
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211. The use of claim 210, wherein the use reduces chemotherapy induced mass loss and/or wasting in the subject and increases lean body mass and body weight of the subject relative to a baseline or a control.
212. The use of claim 210, wherein the use maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the use reduces mass loss and/or wasting in the subject relative to a baseline or a control.
213. The use of any one of claims 184-199, wherein the anorexia is associated with weight loss.
214. The use of any one of claims 184-213, wherein the subject has not previously received an anti-cancer agent.
215. The use of any one of claims 184-213, wherein the subject has previously received an anti-cancer agent.
216. The use of any one of claims 184-213, wherein the subject is receiving an anticancer agent.
217. The use of any one of claims 184-216, wherein the administration of the non- naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.
218. The use of claim 217, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and/or an increased duration of administration of the anti-cancer agent, relative to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
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AMENDED SHEET (ARTICLE 19)
219. The use of claim 217, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.
220. The use of any one of claims 184-219, wherein the administration of the non- naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent relative to a baseline or a control.
221 . The use of claim 220, wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and/or a decreased duration of administration, compared to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
222. The use of any one of claims 184-221 , wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and/or weight loss prior to the administration of the non-naturally occurring melanocortin analog.
223. The use of claim 222, wherein the loss of appetite, reduced appetite, decreased food consumption, and/or weight loss is caused by a cancer.
224. The use of claim 222, wherein the loss of appetite, reduced appetite, decreased food consumption, and/or weight loss is caused by the anti-cancer agent.
225. The use of any one of claims 184-224, wherein the subject is receiving or has received an antiemetic.
226. The use of claim 225, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.
392
AMENDED SHEET (ARTICLE 19)
227. The use of any one of claims 184-226, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.
228. The use of any one of claims 184-226, wherein the non-naturally occurring melanocortin analog is administered before and/or after the anti-cancer agent.
229. The use of claim 184, wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.
230. The use of claim 185, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
231. The use of claim 186, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
232. The use of claim 192, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject relative to a baseline or a control.
233. The use of claim 194, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject relative to a baseline or a control.
234. The use of claim 195, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject
393
AMENDED SHEET (ARTICLE 19) who failed to respond clinically and/or therapeutically to an antiemetic treatment, relative to a baseline or a control.
235. The use of claim 196, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and/or therapeutically to nutritional intervention, relative to a baseline or a control.
236. The use of claim 197, wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject, relative to a baseline or a control.
237. The use of claim 198, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject, relative to a baseline or a control.
238. The use of claim 199, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and/or KPS score of the subject, relative to a baseline or a control.
239. The use of any one of claims 184-199, wherein the subject’s mass and/or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
240. The use of any one of claims 184-199, wherein the subject’s mass and/or weight is not more than 10% reduced from baseline prior to administration of the non- naturally occurring melanocortin analog and/or the anti-cancer agent.
241 . The use of any one of claims 184-240, wherein the subject has an ECOG score of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
394
AMENDED SHEET (ARTICLE 19)
242. The use of any one of claims 184-240, wherein the subject has an ECOG score of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
243. The use of claim 241 or 242, wherein the use lowers the ECOG score of the subject, relative to a baseline or a control.
244. The use of any one of claims 184-243, wherein the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
245. The use of any one of claims 184-243, wherein the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
246. The use of claim 244 or 245, wherein the use increases the subject’s KPS score relative to a baseline or control.
247. The use of any one of claims 184-246, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),
X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8 (I) wherein:
R1 is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;
395
AMENDED SHEET (ARTICLE 19) R2 is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);
R3 is absent or is selected from the group consisting of histidine, D-proline, L-prol ine, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), betaalanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);
R4 is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(l)dPhe);
R5 is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(l)dPhe;
R6 is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine;
R7 is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);
R8 is absent or is lysine or arginine;
R9 is absent or is tryptophan;
R10 is absent or is lysine;
396
AMENDED SHEET (ARTICLE 19) R11-R20 are absent;
X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine;
X2 is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;
X3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;
Y1 is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;
Y2 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;
Y3 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine;
Y4 is absent or is D-proline or D-valine;
Y5 is absent or is D-proline or D-valine;
Y6 is absent or is D-proline or D-valine;
Y7 is absent or is D-proline or D-valine;
Y8 is absent or is D-proline or D-valine;
397
AMENDED SHEET (ARTICLE 19) the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or X1 when R1 or R2 is cysteine and R7 or X1 is cysteine; a disulfide bond between R2 and any one of R5-R20 when R2 and the any one of R5- R20 are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7when R1 or R2 is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7 is lysine or ornithine; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; a side-chain lactam bridge between R2 or R4 and R10when R2 is glutamic acid or aspartic acid and R10 is lysine; provided that: when R2 is dAsp, then R7 is not dLys; when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys; and when Y1 is dPro, Y2 is dVal, and Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified; when R7 is Aia, R4 is dNal(2’); when R4 is p(l)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1 and R7, then R2 is His; when R2-R7 is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2 is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2 and R8, and R3 is Pro, then R7 is not Pro and Y1 is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2 is not absent
398
AMENDED SHEET (ARTICLE 19)
248. The use of any one of claims 184-199, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, 172 188-190, 228-231 , and 252-255.
249. The use of any one of claims 184-199, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
250. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject, comprising administering the non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
251. Use of a non-naturally occurring melanocortin analog for maintaining or increasing weight in a subject prior to, during, and/or after administration of an anti-cancer agent, comprising administering the non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
252. Use of a non-naturally occurring melanocortin analog for maintaining or increasing weight in a subject prior to, during, and/or after administration of an anti-cancer agent, comprising administering the non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
399
AMENDED SHEET (ARTICLE 19)
253. The use of claim 251 or 252, wherein the subject experiences an increase in weight by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.
254. Use of a non-naturally occurring melanocortin analog for stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering the non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent.
255. The use of claim 254, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.
256. Use of a non-naturally occurring melanocortin analog preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject, comprising administering the non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent.
257. The use of claim 256, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.
258. A use of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent, wherein the one or more side
400
AMENDED SHEET (ARTICLE 19) effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
259. A use of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and/or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
260. The use of claim 259, wherein the subject experiences an increase in bone density by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.
261. Use of a non-naturally occurring melanocortin analog preventing or reducing an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and the non-naturally occurring melanocortin analog to the subject.
262. Use of a non-naturally occurring melanocortin analog treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and the non-naturally occurring melanocortin analog to the subject.
263. Use of a non-naturally occurring melanocortin analog preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) score and/or Karnofsky performance status (KPS) score of a subject having cancer, comprising administering an anti-cancer agent and the non-naturally occurring melanocortin analog to the subject.
401
AMENDED SHEET (ARTICLE 19)
264. The use of claim 263, wherein the subject experiences a reduction in ECOG performance score by about 1 , 2, or 3 compared to baseline or control.
265. The use of claim 263, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.
266. The use of claim 250, wherein the use maintains or increases lean body mass, fat body mass, and/or weight of the subject.
267. The use of claim 254, wherein the use maintains or increases lean body mass, fat body mass, and/or body weight of the subject.
268. The use of claim 258, wherein the failure to respond to an antiemetic treatment further comprises clinically and/or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and/or increased food intake in the subject.
269. The use of claim 259, wherein the nutritional intervention further comprises nutritional supplementation.
270. The use of claim 261 , wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
271 . The use of claim 262, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
272. The use of claim 263, wherein the ECOG score and/or KPS score is improved, maintained, and/or reduction of is prevented by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
402
AMENDED SHEET (ARTICLE 19)
273. The use of any one of claims 250-259, wherein the subject has a cancer.
274. The use of any one of claims 250-263, wherein the anti-cancer agent comprises a chemotherapy.
275. The use of claim 274, wherein the use reduces chemotherapy induced mass loss and/or wasting in the subject and increases lean body mass and body weight of the subject.
276. The use of claim 274, wherein the use maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the use reduces mass loss and/or wasting in the subject.
277. The use of any one of claims 250-263, wherein the anorexia is associated with weight loss.
278. The use of any one of claims 250-263, wherein the administration of the non- naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.
279. The use of claim 278, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and/or an increased duration of administration of the anti-cancer agent, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.
280. The use of claim 278, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.
403
AMENDED SHEET (ARTICLE 19)
281 . The use of any one of claims 250-263, wherein the administration of the non- naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent.
282. The use of claim 281 , wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and/or a decreased duration of administration, compared to a baseline or control subject, wherein the baseline or control subject is the subject prior to the administration of the non-naturally occurring melanocortin analog and/or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.
283. The use of any one of claims 250-263, wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and/or weight loss prior to the administration of the non-naturally occurring melanocortin analog.
284. The use of claim 283, wherein the loss of appetite, reduced appetite, decreased food consumption, and/or weight loss is caused by a cancer.
285. The use of claim 283, wherein the loss of appetite, reduced appetite, decreased food consumption, and/or weight loss is caused by the anti-cancer agent.
286. The use of any one of claims 250-263, wherein the subject is receiving an antiemetic.
287. The use of claim 286, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.
288. The use of any one of claims 250-263, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.
404
AMENDED SHEET (ARTICLE 19)
289. The use of any one of claims 250-263, wherein the non-naturally occurring melanocortin analog is administered before and/or after the anti-cancer agent.
290. The use of claim 250, wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.
291. The use of claim 251 , wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and/or loss of appetite in the subject.
292. The use of claim 252, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.
293. The use of claim 254, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject.
294. The use of claim 256, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject.
295. The use of claim 258, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and/or therapeutically to an antiemetic treatment.
405
AMENDED SHEET (ARTICLE 19)
296. The use of claim 259, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and/or therapeutically to nutritional intervention.
297. The use of claim 261 , wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject.
298. The use of claim 262, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject.
299. The use of claim298, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score and/or Karnofsky performance status score of the subject.
300. The use of any one of claims 250-263, wherein the subject’s mass and/or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
301. The use of any one of claims 250-263, wherein the subject’s mass and/or weight is not more than 10% reduced from baseline prior to administration of the non- naturally occurring melanocortin analog and/or the anti-cancer agent.
302. The use of any one of claims 250-263, wherein the subject has a performance status on the ECOG scale of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
303. The use of any one of claims 250-263, wherein the subject has a performance status on the ECOG scale of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
406
AMENDED SHEET (ARTICLE 19)
304. The use of claim 302 or 303, wherein the use lowers the ECOG scale of the subject.
305. The use of any one of claims 250-263, wherein the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
306. The use of any one of claims 250-263, wherein the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and/or the anti-cancer agent.
307. The use of claim 305 or 306, wherein the use increases the subject’s KPS score.
308. The use of any one of claims 250-307, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),
X1X2X3R1 R2R3R4R5R6R7R8R9R10R11 R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8 (I) wherein:
R1 is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D- isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D- alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;
R2 is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine,
407
AMENDED SHEET (ARTICLE 19) arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);
R3 is absent or is selected from the group consisting of histidine, D-proline, L-prol ine, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1 ,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), betaalanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 1-amino-4-phenylcyclohexane- carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone- 2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);
R4 is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(l)dPhe);
R5 is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(l)dPhe;
R6 is absent or is selected from the group consisting of L-tryptophan, D-tryptophan, L- Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine;
R7 is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);
R8 is absent or is lysine or arginine;
R9 is absent or is tryptophan;
R10 is absent or is lysine;
R11-R20 are absent;
408
AMENDED SHEET (ARTICLE 19) X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D- valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine;
X2 is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;
X3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;
Y1 is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;
Y2 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;
Y3 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, and L-valine;
Y4 is absent or is D-proline or D-valine;
Y5 is absent or is D-proline or D-valine;
Y6 is absent or is D-proline or D-valine;
Y7 is absent or is D-proline or D-valine;
Y8 is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:
409
AMENDED SHEET (ARTICLE 19) a disulfide bond between R1 or R2 and R7 or X1 when R1 or R2 is cysteine and R7 or X1 is cysteine; a disulfide bond between R2 and any one of R5-R20 when R2 and the any one of R5- R20 are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7when R1 or R2 is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7 is lysine or ornithine; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; a side-chain lactam bridge between R2 or R4 and R10when R2 is glutamic acid or aspartic acid and R10 is lysine; provided that: when R2 is dAsp, then R7 is not dLys; when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys; and when Y1 is dPro, Y2 is dVal, and Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified; when R7 is Aia, R4 is dNal(2’); when R4 is p(l)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1 and R7, then R2 is His; when R2-R7 is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2 is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2 and R8, and R3 is Pro, then R7 is not Pro and Y1 is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2 is not absent.
410
AMENDED SHEET (ARTICLE 19)
309. The use of any one of claims 250-308, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 124, 167, 170, 172 188-190, 228-231 , and 252-255.
310. The use of any one of claims 250-308, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
311. The use of claim 274, wherein the chemotherapy comprises at least one chemotherapeutic agent.
312. The use of claim 311 , wherein the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic.
313. The use of claim 312, wherein the at least one chemotherapeutic agent comprises a platinum-coordination complex.
314. The use of claim 312, wherein the at least one chemotherapeutic agent comprises an antimetabolite.
315. The use of claim 312, wherein the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.
316. The use of claim 312, wherein the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent.
317. The use of claim 312, wherein the at least one chemotherapeutic agent comprises a cytotoxic antibiotic.
411
AMENDED SHEET (ARTICLE 19)
318. The use of claim 313, wherein the platinum-coordination complex is carboplatin and/or cisplatin.
319. The use of claim 314, wherein the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.
320. The use of claim 315, wherein the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.
321. The use of claim 316, wherein the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.
322. The use of claim 317, wherein the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.
323. The use of claim 313, wherein the platinum-coordination complex is cisplatin.
324. The use of claim 323, wherein the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
325. The use of claim 314, wherein the antimetabolite is 5-fluorouracil (5-FU).
326. The use of claim 325, wherein the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
412
AMENDED SHEET (ARTICLE 19)
327. The use of claim 315, wherein the tubulin binding agent or the plant alkaloid is vincristine.
328. The use of claim 316, wherein the alkylating antineoplastic agent is cyclophosphamide.
329. The use of claim 317, wherein the cytotoxic antibiotic is doxorubicin.
330. The use of claim 329, wherein the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3.
331 . The use of any one of claims 261 -263 and 273, wherein the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, oral cancer, skin cancer, and melanoma.
332. The use of any one of claims 261-263 and 273, wherein the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.
333. The use of any one of claims 261-263 and 273, wherein the cancer is breast cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, a taxane, and docetaxel.
334. The use of claim 333, wherein the anthracycline is doxorubicin.
413
AMENDED SHEET (ARTICLE 19)
335. The use of claim 333, wherein the taxane is paclitaxel.
336. The use of any one of claims 261-263 and 273, wherein the cancer is lung cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed.
337. The use of any one of claims 261 -263 and 273, wherein the cancer is prostate cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, and estramustine.
338. The use of any one of claims 250-337, wherein the anti-cancer agent is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.
339. The use of any one of claims 250-337, wherein the subject is receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.
340. The use of any one of claims 250-337, wherein subject is not receiving radiation therapy, and wherein the anti-cancer agent is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.
341 . The use of any one of claims 250-337, wherein the cancer is melanoma, and wherein the anti-cancer agent is dacarbazine and/or temozolomide.
342. The use of any one of claims 261-263 and 273, wherein the cancer is nonHodgkin's lymphoma, and wherein the anti-cancer agent is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide,
414
AMENDED SHEET (ARTICLE 19) prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin.
343. The use of any one of claims 250-342, wherein the use does not reduce efficacy of the anti-cancer agent.
344. The use of any one of claims 250-343, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent.
345. The use of claim 344, wherein the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.
346. The use of any one of claims 250-345, wherein the subject is a human.
347. The use of any one of claims 250-346, wherein the subject is an animal.
415
AMENDED SHEET (ARTICLE 19)
PCT/US2024/016295 2023-02-21 2024-02-16 Methods of treating cancer and/or chemotherapy related conditions using non-naturally occurring melanocortin analogs Ceased WO2024177907A2 (en)

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