Method of treating melanocortin-4 receptor pathway-associated disorders
The disclosure is related to a method of treating a disorder, such as Prader Willi Syndrome (PWS), obesity or hyperphagia, in a subject using a melanocortin-4 receptor (MC4R) agonist. Also described is method of treating a subject having a deficiency in the pro-opiomelanocortin (POMC)-MC4R pathway, such as a POMC-null or a PCSK-null subject, using a MC4R agonist.
1. A method of treating a disorder in a subject in need thereof, comprising:
administering an agonist of the melanocortin-4 receptor (MC4R) at a daily dosage of about 0.1 mg to about 10 mg,
wherein the disorder is characterized by one or more mutations in a gene associated with Bardet-Biedl syndrome,
wherein the agonist is a MC4R agonist having a structure of Formula (I)
(R 2 R 3 )-A 1 - c (A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I),
wherein:
A 1 is Acc, HN—(CH 2 ) m —C(O), L- or D-amino acid, or deleted;
A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu;
A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or deleted;
A 4 is H is, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 , X 2 , X 3 , X 4 , X 5 )Phe;
A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe, L-Phe or D-(Et)Tyr;
A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O);
A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal or D-Bip;
A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN—(CH 2 ) s —C(O), or deleted;
A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;
A 10 is Acc, HN—(CH 2 ) r —C(O), L- or D-amino acid, or deleted;
R 1 is OH or NH 2 ;
each of R 2 and R 3 is, independently for each occurrence, selected from the group consisting of H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 1 -C 30 )acyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 1 -C 30 )acyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 -C 30 )alkynyl, substituted aryl(C 1 -C 30 )alkyl, and substituted aryl(C 1 -C 30 )acyl;
each of R 4 and R 5 is, independently for each occurrence, H, (C 1 -C 40 )alkyl, (C 1 -C 40 )heteroalkyl, (C 1 -C 40 )acyl, (C 2 -C 40 )alkenyl, (C 2 -C 40 )alkynyl, aryl(C 1 -C 40 )alkyl, aryl(C 1 -C 40 )acyl, substituted (C 1 -C 40 )alkyl, substituted (C 1 -C 40 )heteroalkyl, substituted (C 1 -C 40 )acyl, substituted (C 2 -C 40 )alkenyl, substituted (C 2 -C 40 )alkynyl, substituted aryl(C 1 -C 40 )alkyl, substituted aryl(C 1 -C 40 )acyl, (C 1 -C 40 )alkylsulfonyl, or —C(NH)—NH 2 ;
m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;
n is, independently for each occurrence, 1, 2, 3, 4 or 5;
s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
X′, X 2 , X 3 , X 4 , and X 8 each is, independently for each occurrence, H, F, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, (C 2-10 )alkenyl, substituted (C 2-10 )alkenyl, (C 2-10 )alkynyl, substituted (C 2-10 )alkynyl, aryl, substituted aryl, OH, NH 2 , NO 2 , or CN.
2. The method of claim 1 , comprising administering the MC4R agonist in a unit dosage suitable for injection.
3. The method of claim 2 , wherein the unit dosage is disposed within a delivery device.
4. The method of claim 1 , wherein the MC4R agonist is administered subcutaneously.
5. The method of claim 1 , wherein the subject is obese.
6. The method of claim 1 , wherein the subject has a body mass index (BMI) greater than 35 kg/m 2 prior to administration of the agonist or at the time of the first administration.
7. The method of claim 1 , wherein:
(i) the subject has failed one or more previous therapies prior to administration of the agonist or at the time of the first administration;
(ii) the subject has a lower body weight after administration of the agonist than before administration of the agonist;
(iii) administration of the agonist results in a reduction of weight in the subject compared to the weight of the subject before treatment of about 1 kg to 3 kg after 1 week of treatment;
(iv) administration of the agonist results in weight loss in the subject at a rate of about 1-2 kg/week;
(v) administration of the agonist results in a reduction in hunger level in the subject compared to the hunger level of the subject before treatment;
(vi) administration of the agonist results in a significant decrease in resting energy expenditure (REE) in the subject;
(vii) administration of the agonist results in an increase in resting energy expenditure (REE) in the subject as compared to a control REE;
(viii) administration of the agonist results in a reduction in food intake by the subject compared to a control;
(ix) administration of the agonist results in a reduction in food intake of at least 100 kilocalories compared to a control;
(x) administration of the agonist results in a reduction in waist circumference of the subject compared to a control;
(xi) administration of the agonist results in a reduction in waist circumference of at least 2 cm in the subject compared to a control;
(xii) administration of the agonist results in no detectable increase in blood pressure of the subject compared to the blood pressure of the subject prior to treatment;
(xiii) administration of the agonist results in a reduction in blood pressure of the subject compared to the blood pressure of the subject prior to treatment;
(xiv) administration of the agonist results in a reduction in systolic blood of the subject of at least 3 mmHg compared to the blood pressure of the subject prior to treatment; or
(xv) administration of the agonist results in a reduction in diastolic blood pressure of the subject of at least 4 mmHg compared to the blood pressure of the subject prior to treatment.
8. The method of claim 1 , wherein the subject is a mammal.
9. The method of claim 1 , wherein the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 140).
10. The method of claim 1 , wherein the disorder is characterized by one or mutations in a BBS1-19, or 20 gene.
11. The method of claim 10 , wherein the subject is or is identified as being:
(i) a heterozygous carrier of the mutation(s), further characterized by having one functional BBS1-19, or 20 allele and one non-functional BBS1-19, or 20 allele;
(ii) a compound heterozygous carrier of the mutation(s), e.g., having two non-functional BBS1-19, or 20 alleles, further characterized by having a BBS1-19, or 20 null genotype; or
(iii) a homozygous carrier of the mutation(s), further characterized by having a BBS1-19, or 20 null genotype.
12. The method of claim 1 , wherein the disorder comprises Laurence-Moon-Biedl syndrome.
13. The method of claim 1 , wherein the one or more mutations comprise non-coding variants in one or more of the BBS1-19, or 20 genes.
14. The method of claim 1 , wherein the disorder comprises Bardet-Biedl syndrome.
15. The method of claim 1 , wherein the disorder is characterized by defective cilia or ciliary dysregulation.
16. The method of claim 1 , wherein the defective cilia comprise defective neuronal cilia.
17. The method of claim 1 , wherein the disorder further comprises impaired leptin signaling.
18. The method of claim 1 , wherein the disorder further comprises hyperleptinemia.
19. The method of claim 2 , wherein the unit dosage comprises between about 0.1 to about 0.2 mg of the agonist.
20. The method of claim 1 , wherein:
R 1 is NH 2 ;
R 2 is —H and R 3 is acyl;
A 1 is Arg;
A 2 is Cys;
A 3 is Ala;
A 4 is His;
A 5 is D-Phe;
A 6 is Arg;
A 7 is Trp;
A 8 is deleted; and/or
A 9 is Cys.
21. A method of treating a disorder in a subject in need thereof, comprising:
administering an agonist of the melanocortin-4 receptor (MC4R) at a daily dosage of about 0.1 mg to about 10 mg,
wherein the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 140), and the disorder is characterized by one or more mutations in a gene associated with Alstrom syndrome.