IP Library › Granted Patent US 12,233,107
Granted Patent B2
US 12,233,107 · App. 18/351,169 · Granted Feb 25, 2025

GHRH or analogues thereof for use in treatment of hepatic disease

Inventor: Steven K. Grinspoon (Weston, MA)
Assignee: The General Hospital Corporation
A61K38/25A61P1/16A61K9/0019
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Quick Facts
Patent No.
US 12,233,107
App. No.
18/351,169
Granted
Feb 25, 2025
Kind
B2
Abstract

The present application relates to novel methods for preventing, slowing the progression of, or treating nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and/or liver fibrosis, and/or reducing the risks of liver cancer in subjects, such as HIV-infected subjects, using a GHRH molecule, e.g., trans-3-hexenoyl-GHRH (1-44) -NH 2 , or a pharmaceutically acceptable salt thereof. The subjects may have particular pathological features such as liver fibrosis, a hepatic fat fraction (HFF) of at least about 10%, serum alanine aminotransferase (ALT) levels of at least about 30 U/L, and/or a NAFLD Activity Score (NAS) of at least 4 or 5.

Claims (26)

1. A method for reducing visceral fat in a subject suffering from nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH), comprising administering an effective amount of trans-3-hexenoyl-GHRH(1-44)-NH 2 or a pharmaceutically acceptable salt thereof to said subject, wherein said subject has at least one of:

(a) a hepatic fat fraction (HFF) of at least about 10%;

(b) a reduction of hepatic fat fraction (HFF) by at least 4% (absolute reduction) following the treatment; and

(c) liver fibrosis with a fibrosis score of at least 1C prior to the treatment.

2. The method of claim 1 , wherein said subject has a hepatic fat fraction (HFF) of at least about 10%.

3. The method of claim 1 , wherein said subject has a hepatic fat fraction (HFF) of at least about 15%.

4. The method of claim 1 , wherein said subject has a hepatic fat fraction (HFF) of at least about 20%.

5. The method of claim 1 , wherein said subject has serum ALT levels of at least about 30 U/L.

6. The method of claim 1 , wherein said subject has serum ALT levels of at least about 35 U/L.

7. The method of claim 1 , wherein said subject has a NAFLD Activity Score (NAS) of at least 1 as measured by the NAS Clinical Research Network (NAS CRN) scoring system.

8. The method of claim 1 , wherein said subject has a NAFLD Activity Score (NAS) of at least 2 as measured by the NAS Clinical Research Network (NAS CRN) scoring system.

9. The method of claim 1 , wherein said subject has a NAFLD Activity Score (NAS) of at least 3 as measured by the NAS Clinical Research Network (NAS CRN) scoring system.

10. The method of claim 1 , wherein said subject has a NAFLD Activity Score (NAS) of at least 4 as measured by the NAS Clinical Research Network (NAS CRN) scoring system.

11. The method of claim 1 , wherein said subject has a reduction of hepatic fat fraction (HFF) by at least 4% (absolute reduction) following the treatment.

12. The method of claim 1 , wherein said subject has liver fibrosis.

13. The method of claim 12 , wherein said subject has a fibrosis score of at least 1C prior to the treatment.

14. The method of claim 13 , wherein said subject has a fibrosis score of at least 2 prior to the treatment.

15. The method of claim 1 , wherein said subject suffers from human immunodeficiency virus (HIV) infection.

16. The method of claim 1 , wherein said subject has a body mass index (BMI) of at least about 25.

17. The method of claim 1 , wherein said pharmaceutically acceptable salt of trans-3-hexenoyl-GHRH (1-44) -NH 2 is an acetate salt.

18. The method of claim 1 , wherein said trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is administered by subcutaneous injection.

19. The method of claim 1 , wherein said trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

20. The method of claim 19 , wherein said trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is present in said pharmaceutical composition at a dose of about 1 mg/ml to about 10 mg/ml.

21. The method of claim 19 , wherein said trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is present in said pharmaceutical composition at a dose of about 1 mg/ml to about 8 mg/ml.

22. The method of claim 19 , wherein said trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is present in said pharmaceutical composition at a dose of about 4 mg/ml to about 8 mg/ml.

23. The method of claim 1 , wherein said trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is administered at a daily dose of about 1 mg to about 2 mg.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 7, 2023
From: GRINSPOON, STEVEN K.
To: THE GENERAL HOSPITAL CORPORATION
Reel/Frame 064512/0743 →
Continuity (6)
Continuation 17170579 · Feb 8, 2021
Continuation 17018878 · Sep 11, 2020
Continuation 16832128 · Mar 27, 2020
Provisional Application 62861187 · Jun 13, 2019
Provisional Application 62826284 · Mar 29, 2019
Related Publication 20240091316A1 · Mar 21, 2024
References Cited (78)
US 10799562B1 · Grinspoon · 2020 [cited by applicant]
US 10946073B2 · Grinspoon · 2021 [cited by applicant]
US 11738066B2 · Grinspoon · 2023 [cited by examiner]
US 20080249017A1 · Loughrey et al. · 2008 [cited by applicant]
US 20150174207A1 · Schally et al. · 2015 [cited by applicant]
US 20160152735A1 · Sabbadini et al. · 2016 [cited by applicant]
US 20170296628A1 · Peri · 2017 [cited by applicant]
US 20190000854A1 · Ilan et al. · 2019 [cited by applicant]
US 20220152012A1 · Kashyap et al. · 2022 [cited by applicant]
US 20230393148A1 · Grinspoon · 2023 [cited by examiner]
CA 3088177 · 2019 [cited by applicant]
WO WO2022093757 · 2022 [cited by applicant]
Pacifico et al. Pancreatic fat and beta-cell function in overweight/obese children with nonalcoholic fatty liver disease. World Journal of Gastroenterology, 21(15), 4688-4695. (Year: 2015). [cited by examiner]
Park et al. Cutoff Values for Diagnosing Hepatic Steatosis Using Contemporary MRI—Proton Density Fat Fraction Measuring Methods. KJR, 23(12): 1260-1268. (Year: 2022). [cited by examiner]
Bedossa et al., “Biopsy and Noninvasive Methods to Assess Progression of Nonalcoholic Fatty Liver Disease”. Gastroenterology: 150, pp. 1811-1822 (Year: 2016). [cited by applicant]
Braun et al, Fibroblast growth factor 21 decreases after liver fat reduction via growth hormone augmentation, Growth Hormone and IGF Research, vol. 37, 2017, pp. 1-6. [cited by applicant]
Braun LR, Feldpausch MN, Czerwonka N, et al. Effects of Pitavastatin on Insulin Sensitivity and Liver Fat: A Randomized Clinical Trial. J Clin Endocrinol Metab 2018;103:4176-86. [cited by applicant]
Bredella MA, Ghomi RH, Thomas BJ, et al. Breath-hold 1H-magnetic resonance spectroscopy for intrahepatic lipid quantification at 3 Tesla. J Comput Assist Tomogr 2010;34:372-6. [cited by applicant]
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liv… [cited by applicant]
Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med 2016;165:305-15. [cited by applicant]
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214-23. [cited by applicant]
Eckard et al, Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Therap Adv Gastroenterol 2013;6:249-59. [cited by applicant]
Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547-54. [cited by applicant]
Erlandson KM, Lake JE. Fat Matters: Understanding the Role of Adipose Tissue in Health in HIV Infection. Curr HIV/AIDS Rep 2016;13:20-30. [cited by applicant]
Extended European Search Report dated Dec. 6, 2022 for EP application 20784029.9. [cited by applicant]
Falutz et al, Effects of Tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind pl… [cited by applicant]
Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med 2007;357:2359-70. [cited by applicant]
Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two mul… [cited by applicant]
Ferdinandi et al. Non-Clinical Pharmacology and Safety Evaluation of TH9507, a Human Growth Hormone-Releasing Factor Analogue. Basic and Clincial Pharmacology and Toxicology, 100, pp. 49-58. (Year: 2007). [cited by applicant]
Foreign Search Report on PCT PCT/US2020/025180 DTD Jun. 19, 2020. [cited by applicant]
Foreign Search Report on PCT PCT/US2020/025180 DTD Aug. 14, 2020. [cited by applicant]
Fourman et al, Differential relationships of hepatic and epicardial fat to body composition in HIV, Physiological Reports, vol. 5, No. 19, Oct. 1, 2017 (Oct. 1, 2017) p. e13386. [cited by applicant]
Georgoff P, Thomasson D, Louie A, et al. Hydrogen-1 MR spectroscopy for measurement and diagnosis of hepatic steatosis. AJR Am J Roentgenol 2012; 199:2-7. [cited by applicant]
Gines, P. et al., Screening for liver fi brosis in the general population: a call for action, Lancet Gastroenterol Hepatol. 2016; 1: 256-60. [cited by applicant]
Guaraldi G, Squillace N, Stentarelli C, et al. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis 2008;47:250-7. [cited by applicant]
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Bio… [cited by applicant]
Iogna Prat L, Roccarina D, Lever R, et al. Etiology and Severity of Liver Disease in HIV-Positive Patients With Suspected NAFLD: Lessons From a Cohort With Available Liver Biopsies. J Acquir Immune Defic Syndr 2019;80:4… [cited by applicant]
Kang et al., “Normal serum alanine aminotransferase and non-alcoholic fatty liver disease among Korean adolescents: a cross-sectional study using data from KNHANES 2010-2015”, BMC Pediatrics, 2018, p. 215, vol. 18. [cited by applicant]
Katsagoni CN, Georgoulis M, Papatheodoridis GV, Panagiotakos DB, Kontogianni MD. Effects of lifestyle interventions on clinical characteristics of patients with non-alcoholic fatty liver disease: A meta-analysis. Metabo… [cited by applicant]
Kim et al., “Comparative MR Study of Hepatic Fat Quantification Using Single-Voxel Proton Spectroscopy, Two-Point Dixon and Three-Point IDEAL”, Magnetic Resonance in Medicine, Feb. 27, 2008, p. 521-527, vol. 59, No. 3, … [cited by applicant]
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21. [cited by applicant]
Koutkia P, Canavan B, Breu J, Grinspoon S. Growth hormone (GH) responses to GH-releasing hormone-arginine testing in human immunodeficiency virus lipodystrophy. J Clin Endocrinol Metab 2005;90:32-8. [cited by applicant]
Koutkia P, Canavan B, Breu J, Torriani M, Kissko J, Grinspoon S. Growth Hormone-Releasing Hormone in HIV-Infected Men With Lipodystrophy: A Randomized Controlled Trial 10.1001/jama.292.2.210.JAMA 2004;292:210-8. [cited by applicant]
Kriska AM, Knowler WC, LaPorte RE, et al. Development of questionnaire to examine relationship of physical activity and diabetes in Pima Indians. Diabetes Care 1990;13:401-11. [cited by applicant]
Lake JE, Stanley TL, Apovian CM, et al. Practical Review of Recognition and Management of Obesity and Lipohypertrophy in Human Immunodeficiency Virus Infection. Clin Infect Dis 2017;64:1422-9. [cited by applicant]
Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659-68. [cited by applicant]
Makimura H, Stanley T, Mun D, You SM, Grinspoon S. The effects of central adiposity on growth hormone (GH) response to GH-releasing hormone-arginine stimulation testing in men. J Clin Endocrinol Metab 2008;93:4254-60. [cited by applicant]
Maurice JB, Patel A, Scott AJ, Patel K, Thursz M, Lemoine M. Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection. AIDS 2017;31:1621-32. [cited by applicant]
Miller ER, 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46. [cited by applicant]
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lanc… [cited by applicant]
Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment. Guidance for Industry. U.S. Department of Health and Human Services, 2018. (Accessed Mar. 17, 2019, 2019, at https://www.fda… [cited by applicant]
Nou E, Lo J, Hadigan C, Grinspoon SK. Pathophysiology and management of cardiovascular disease in patients with HIV. Lancet Diabetes Endocrinol 2016;4:598-610. [cited by applicant]
Press Release. 2019. (Accessed Mar. 14, 2019, 2019, at http://ir.interceptpharma.com/news-releases/news-release-details/intercept-announces-positive-topline-results-pivotal-phase-3.). [cited by applicant]
Press Release. Galmed Pharmaceuticals, 2018. (Accessed Mar. 14, 2019, 2019, at http://galmedpharma.investorroom.com/2018-02-14-Galmed-Announces-ARRIVE-Study-Data.). [cited by applicant]
Price JC, Seaberg EC, Latanich R, et al. Risk factors for fatty liver in the Multicenter AIDS Cohort Study. Am J Gastroenterol 2014; 109:695-704. [cited by applicant]
Rietschel P, Hadigan C, Corcoran C, et al. Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. J Clin Endocrinol Metab 2001;86:504-10. [cited by applicant]
Rockstroh JK. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV. Curr HIV/AIDS Rep 2017;14:47-53. [cited by applicant]
Rotman et al., Current and upcoming 1-18 pharmacotherapy for non-alcoholic fatty liver disease, Gut Microbiota, vol. 66, No. 1, Sep. 19, 2016 (Sep. 19, 2016) pp. 180-190. [cited by applicant]
Rotman et al. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease . . . Gut; London vol. 66, Iss. 1, (Jan. 2017): pp. 180-190. (Year: 2017). [cited by applicant]
Sanyal AJ. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-85. [cited by applicant]
Sato K, Gosho M, Yamamoto T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition 2015;31:923-30. [cited by applicant]
Smith CJ, Ryom L, Weber R, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet 2014;384:241-8. [cited by applicant]
Stanley et al, Effect of Tesamorelin on Visceral Fat and LKiver Fat in HIV-infected Patients With Abdominal Fat Accumulation A Randomized Clinical Trial, The Journal of the American Medical Association, 2014, pp. 380-38… [cited by applicant]
Stanley et al, Effects of tesamorelin on inflammatory markers in HIV patients with excess abdominal fat: relationship with visceral adipose reduction, AIDS, vol. 25, No. 10, Jun. 19, 2011 (Jun. 19, 2011) pp. 1281-1288. [cited by applicant]
Stanley et al. Effect of Tesamorelin on Visceral Fat and Liver Fat in HIV-Infected Patients With Abdominal Fat Accumulation A Randomized Clinical Trial. JAMA, vol. 312, No. 4, pp. 380-389. (Year: 2014). [cited by applicant]
Stanley TL, Chen CY, Branch KL, Makimura H, Grinspoon SK. Effects of a Growth Hormone-Releasing Hormone Analog on Endogenous GH Pulsatility and Insulin Sensitivity in Healthy Men. J Clin Endocrinol Metab 2011;96:150-8. [cited by applicant]
Stanley TL, Falutz J, Marsolais C, et al. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis 2012;54:1642-51. [cited by applicant]
Stanley, T.L. et al., Growth Hormone Releasing Hormone Analogue Reduces Liver Fat in HIV-Infected Patients; Endocrine Society's 96th Annual Meeting and Expo, Jun. 21-24, 2014—Chicago, Presentation No. OR05-6, Date of Pr… [cited by applicant]
Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 2018;53:362-76. [cited by applicant]
Tafesh ZH, Verna EC. Managing nonalcoholic fatty liver disease in patients living with HIV. Curr Opin Infect Dis 2017;30:12-20. [cited by applicant]
Tesamorelin Effects on Liver Fat and Histology in HIV, ClinicalTrials.gov, first posted Jul. 22, 2014. [cited by applicant]
van der Poorten D, Milner KL, Hui J, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 2008;48:449-57. [cited by applicant]
Vodkin I, Valasek MA, Bettencourt R, Cachay E, Loomba R. Clinical, biochemical and histological differences between HIV-associated NAFLD and primary NAFLD: a case-control study. Aliment Pharmacol Ther 2015;41:368-78. [cited by applicant]
Wattacheril et al. Nonalcoholic Steatohepatitis (NASH) and Hepatic Fibrosis: Emerging Therapies. Annu. Rev. Pharmacol. Toxicol. First published Oct. 20, 2017. vol. 58, pp. 649-662. (Year: 2018). [cited by applicant]
Yu, S.J. et al., Visceral Obesity Predicts Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Disease, Medicine vol. 94, No. 48, Dec. 2015. [cited by applicant]
Brunt et al, “The NAS and The Histopathologic Diagnosis in NAFLD: Distinct Clinicopathologic Meanings”, Hepatology 53(3) 810-820 (2011). [cited by applicant]
Michelotti et al, “NAFLD, NASH and liver cancer”, Nature Reviews Gastroenterology & Hepatology, 10(11) 656-665 (2013). [cited by applicant]
Tesamorelin, Chinese Journal of Medicinal Chemistry, vol. 21, No. 3, p. 249, Jun. 2011. [cited by applicant]