IP Library › Granted Patent US 12,569,480
Granted Patent B2
US 12,569,480 · App. 17/614,815 · Granted Mar 10, 2026

Methods of treating fibrosis using compounds that promote glucose oxidation

Inventors: Andrew D. Levin (Newton, MA); David-Alexandre Gros (Rancho Santa Fe, CA); Jaikrishna Patel (Cary, NC)
Assignee: IMBRIA PHARMACEUTICALS, INC.
A61K31/495A61K31/455A61K31/496A61K45/06
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,569,480
App. No.
17/614,815
Granted
Mar 10, 2026
Kind
B2
Abstract

The invention provides methods for treating or preventing fibrosis in a subject by providing a compound that shifts cellular metabolism from fatty acid oxidation to glucose oxidation.

Claims (8)

1 . A method of treating or preventing fibrosis in a subject, the method comprising providing to a subject that has developed fibrosis a compound that shifts cellular metabolism from fatty acid oxidation, wherein the compound is represented by formula (X):

wherein the fibrosis is associated with reduced energy production of an organ and/or tissue.

2 . The method of claim 1 , wherein the fibrosis comprises one selected from the group consisting of adhesive capsulitis, aneurysm, angina, arterial stiffness, arthrofibrosis, atherosclerosis, atrial fibrosis, cardiomyopathy, cerebral vascular disease, cirrhosis, congenital heart disease, coronary artery disease, coronary heart disease, Crohn's disease, cystic fibrosis, diabetic cardiomyopathy, Dupuytren's contracture, endomyocardial fibrosis, glial scar, heart attack, heart failure, high blood pressure (hypertension), idiopathic pulmonary fibrosis, ischemic heart disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, old myocardial infarction, pericardial disease, peripheral arterial disease, Peyronie's disease, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma, stroke, systemic sclerosis transient ischemic attacks, and valvular heart disease.

3 . A method of treating or preventing fibrosis in a subject, the method comprising providing to a subject that has developed fibrosis a pharmaceutical composition comprising a compound that shifts cellular metabolism from fatty acid oxidation, wherein the compound is represented by formula (X):

wherein the fibrosis is associated with reduced energy production of an organ and/or tissue.

4 . The method of claim 3 , wherein the composition is formulated for administration to a subject by way of a method selected from the group consisting of buccally, by injection, dermally, enterally, intraarterially, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, or with or on an implantable medical device.

5 . The method of claim 4 , wherein the composition is formulated for oral administration in a form chosen from the group consisting of a tablet, a troche, a lozenge, a fast-melt, an aqueous suspension, an oily suspension, a dispersible powder, a dispersible granule, an emulsion, a hard capsule, a soft capsule, a syrup, and an elixir.

6 . The method of claim 3 , wherein the fibrosis comprises one selected from the group consisting of adhesive capsulitis, aneurysm, angina, arterial stiffness, arthrofibrosis, atherosclerosis, atrial fibrosis, cardiomyopathy, cerebral vascular disease, cirrhosis, congenital heart disease, coronary artery disease, coronary heart disease, Crohn's disease, cystic fibrosis, diabetic cardiomyopathy, Dupuytren's contracture, endomyocardial fibrosis, glial scar, heart attack, heart failure, high blood pressure (hypertension), idiopathic pulmonary fibrosis, ischemic heart disease, keloid, mediastinal fibrosis, myelofibrosis, nephrogenic systemic fibrosis, old myocardial infarction, pericardial disease, peripheral arterial disease, Peyronie's disease, progressive massive fibrosis, pulmonary fibrosis, radiation-induced lung injury, retroperitoneal fibrosis, scleroderma, stroke, systemic sclerosis transient ischemic attacks, and valvular heart disease.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 11, 2022
From: LEVIN, ANDREW D.; GROS, DAVID-ALEXANDRE; PATEL, JAIKRISHNA
To: IMBRIA PHARMACEUTICALS, INC.
Reel/Frame 058620/0939 →
Continuity (2)
Provisional Application 62855394 · May 31, 2019
Related Publication 20220241272A1 · Aug 4, 2022
References Cited (188)
US 4100285A · Murai et al. · 1978 [cited by applicant]
US 4166452A · Generales, Jr. · 1979 [cited by applicant]
US 4256108A · Theeuwes · 1981 [cited by applicant]
US 4265874A · Bonsen et al. · 1981 [cited by applicant]
US 4574156A · Morita et al. · 1986 [cited by applicant]
US 4845099A · Ruger et al. · 1989 [cited by applicant]
US 4876257A · Hajos et al. · 1989 [cited by applicant]
US 4885300A · Press et al. · 1989 [cited by applicant]
US 5077288A · Lavielle et al. · 1991 [cited by applicant]
US 5286728A · Ferrini · 1994 [cited by applicant]
US 5340809A · Gaudry et al. · 1994 [cited by applicant]
US 5380726A · Ferrini · 1995 [cited by applicant]
US 5384319A · Ferrini · 1995 [cited by applicant]
US 5397780A · Mizuno et al. · 1995 [cited by applicant]
US 5399557A · Mizuno et al. · 1995 [cited by applicant]
US 5401743A · Rendenbach-Mueller et al. · 1995 [cited by applicant]
US 5428038A · Chatterjee et al. · 1995 [cited by applicant]
US 5527800A · Goto et al. · 1996 [cited by applicant]
US 5591849A · Kato et al. · 1997 [cited by applicant]
US 5641779A · Halazy et al. · 1997 [cited by applicant]
US 5770735A · Emonds-Alt et al. · 1998 [cited by applicant]
US 5776937A · Gante et al. · 1998 [cited by applicant]
US 5849745A · Wierzbicki et al. · 1998 [cited by applicant]
US 5856326A · Anthony et al. · 1999 [cited by applicant]
US 5962448A · Mizuno et al. · 1999 [cited by applicant]
US 5977111A · Mizuno et al. · 1999 [cited by applicant]
US 6087346A · Glennon et al. · 2000 [cited by applicant]
US 6121267A · Glase et al. · 2000 [cited by applicant]
US 6200989B1 · De Cillis et al. · 2001 [cited by applicant]
US 6214841B1 · Jackson et al. · 2001 [cited by applicant]
US 6271223B1 · Mizuno et al. · 2001 [cited by applicant]
US 6331623B1 · Mizuno et al. · 2001 [cited by applicant]
US 6528529B1 · Brann et al. · 2003 [cited by applicant]
US 6562978B1 · Imamura et al. · 2003 [cited by applicant]
US 6693099B2 · Degenhardt et al. · 2004 [cited by applicant]
US 7638531B2 · Mutahi et al. · 2009 [cited by applicant]
US 7666866B2 · Franciskovich et al. · 2010 [cited by applicant]
US 7772251B2 · Sturzebecher et al. · 2010 [cited by applicant]
US 7968538B2 · Becker et al. · 2011 [cited by applicant]
US 8016783B2 · Pastore et al. · 2011 [cited by applicant]
US 8202901B2 · Lopaschuk et al. · 2012 [cited by applicant]
US 8461117B2 · Sufi et al. · 2013 [cited by applicant]
US 8569495B2 · Chassaing et al. · 2013 [cited by applicant]
US 8697661B2 · Kritikou · 2014 [cited by applicant]
US 9096538B2 · Nakamura et al. · 2015 [cited by applicant]
US 9120801B2 · Alisi et al. · 2015 [cited by applicant]
US 9169279B2 · Hanna et al. · 2015 [cited by applicant]
US 10167258B2 · Chuang et al. · 2019 [cited by applicant]
US 10556013B2 · Levin · 2020 [cited by applicant]
US 10918728B2 · Levin · 2021 [cited by applicant]
US 10953102B2 · Levin · 2021 [cited by applicant]
US 11376330B2 · Levin · 2022 [cited by applicant]
US 12318382B2 · Levin · 2025 [cited by examiner]
US 20030191182A1 · Lopaschuk et al. · 2003 [cited by applicant]
US 20030232877A1 · Sikorski et al. · 2003 [cited by applicant]
US 20040082564A1 · Arrhenius et al. · 2004 [cited by applicant]
US 20050004121A1 · Palani et al. · 2005 [cited by applicant]
US 20070004750A1 · Lorsbach et al. · 2007 [cited by applicant]
US 20080108618A1 · Brann et al. · 2008 [cited by applicant]
US 20080161400A1 · Virsik et al. · 2008 [cited by applicant]
US 20090197891A1 · Lecanu et al. · 2009 [cited by applicant]
US 20090258064A1 · Newell et al. · 2009 [cited by applicant]
US 20100022530A1 · Schiemann et al. · 2010 [cited by applicant]
US 20110046370A1 · Sim et al. · 2011 [cited by applicant]
US 20110137362A1 · Foreman et al. · 2011 [cited by applicant]
US 20110212072A1 · Henkel et al. · 2011 [cited by applicant]
US 20120214818A1 · Dudley · 2012 [cited by applicant]
US 20160060530A1 · Archetti et al. · 2016 [cited by applicant]
US 20160346397A1 · Milne et al. · 2016 [cited by applicant]
US 20170008950A1 · Capon · 2017 [cited by applicant]
US 20170105414A1 · Nakano et al. · 2017 [cited by applicant]
US 20180360975A1 · Levin · 2018 [cited by applicant]
US 20190084917A1 · Savourey et al. · 2019 [cited by applicant]
US 20190216936A1 · Levin · 2019 [cited by applicant]
US 20200138963A1 · Levin · 2020 [cited by applicant]
US 20210353617A1 · Levin · 2021 [cited by examiner]
US 20220249463A1 · Levin et al. · 2022 [cited by applicant]
CA 2170615A1 · 1995 [cited by applicant]
CA 2186010A1 · 1995 [cited by applicant]
CN 101747292B · 2011 [cited by applicant]
DE 2714996A1 · 1977 [cited by applicant]
EP 0144991A2 · 1985 [cited by applicant]
EP 0251141A1 · 1988 [cited by applicant]
EP 615855A1 · 1994 [cited by applicant]
EP 661266A1 · 1995 [cited by applicant]
EP 749967A1 · 1996 [cited by applicant]
EP 1634598A1 · 2006 [cited by applicant]
EP 1886994A1 · 2008 [cited by applicant]
EP 2727916A1 · 2014 [cited by applicant]
JP S57131777 · 1982 [cited by applicant]
JP 2000147773A · 2000 [cited by applicant]
JP 2006113343A · 2006 [cited by applicant]
JP 2009539802A · 2009 [cited by applicant]
JP 2015017236A · 2015 [cited by applicant]
JP 2016527261A · 2016 [cited by applicant]
JP 2019507771A · 2019 [cited by applicant]
NO 2003006628A2 · 2003 [cited by applicant]
NO 2011032099A1 · 2011 [cited by applicant]
RU 2377989C2 · 2010 [cited by applicant]
WO 1995000165A1 · 1995 [cited by applicant]
WO 9626196A2 · 1996 [cited by applicant]
WO 9630054A1 · 1996 [cited by applicant]
WO 9630343A1 · 1996 [cited by applicant]
WO 9728141A1 · 1997 [cited by applicant]
WO 9746549A1 · 1997 [cited by applicant]
WO 9858638A1 · 1998 [cited by applicant]
WO 9950247A1 · 1999 [cited by applicant]
WO 2001005763A2 · 2001 [cited by applicant]
WO 2002058698A2 · 2002 [cited by applicant]
WO 2002064576A1 · 2002 [cited by applicant]
WO 2006027223A1 · 2006 [cited by applicant]
WO 2006117686A2 · 2006 [cited by applicant]
WO 2006133784A1 · 2006 [cited by applicant]
WO 2007075629A2 · 2007 [cited by applicant]
WO 2007096251A1 · 2007 [cited by applicant]
WO 2007116074A1 · 2007 [cited by applicant]
WO 2007116243A2 · 2007 [cited by applicant]
WO 2008109991A1 · 2008 [cited by applicant]
WO 2009015485A1 · 2009 [cited by applicant]
WO 2009058818A2 · 2009 [cited by applicant]
WO 2009066315A2 · 2009 [cited by applicant]
WO 2009156479A1 · 2009 [cited by applicant]
WO 2012049101A1 · 2012 [cited by applicant]
WO 2015018660A1 · 2015 [cited by applicant]
WO 2016005576A1 · 2016 [cited by applicant]
WO 2016107603A1 · 2016 [cited by applicant]
WO 2018236745A1 · 2018 [cited by applicant]
WO 2020081361A1 · 2020 [cited by applicant]
WO 2020243119A1 · 2020 [cited by applicant]
WO 2020243120A1 · 2020 [cited by applicant]
WO 2021225950A1 · 2021 [cited by applicant]
WO 2022150403A1 · 2022 [cited by applicant]
Fang et al., Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle's cycle. J Mol Med 90, 31-43 (2012) (Year: 2012). [cited by examiner]
Bhosle, 2006, Mutual Prodrug Concept: Fundamentals and Applications, Indian Journal of Pharmaceutical Sciences, May-June, pp. 286-294. [cited by applicant]
Cheng, 2006, Discovery of Potent and Orally Available Malonyl-CoA Decarboxylase Inhibitors as Cardioprotective Agents, J. Med. Chem. 49:4055-4058. [cited by applicant]
Cheng, 2006, Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase Inhibitors, J. Med. Chem. 49:1517-1525. [cited by applicant]
Das, 1995, Essential Fatty Acid Metabolism in Patients with Essential Hypertension, Diabetes Mellitus and Coronary Heart Disease, Prostaglandins Leukotrienes and Essential Fatty Acids, 52, 387-391. [cited by applicant]
Extended European Search Report issued in European Application No. 18821590.9, date of mailing: Oct. 5, 2020, 33 pages. [cited by applicant]
Fillmore, 2014, Malonyl CoA: A Promising Target for the Treatment of Cardiac Disease, Int. Union of Biochem. and Mol. Biol., 66(3):139-146. [cited by applicant]
Fillmore, 2014, Mitochondrial fatty acid oxidation alterations in heart failure, ischemic heart disease and diabetic cardiomyopathy, Brit. J. Pharmacol. 171:2080-2090. [cited by applicant]
Folmes, 2005, Fatty Acid Oxidation Inhibitors in the Management of Chronic Complications of Atherosclerosis, Current Atherosclerosis Reports 2005, 7, 63-70. [cited by applicant]
Gallaher, 1993, Viscosity and Fermentability as Attributes of Dietary Fiber Responsible of rhte Hypocholesterolemic Effect in Hamsters, J Nutr., 123, pp. 244-252. [cited by applicant]
Gao, 2011, Echocardiography in Mice. Curr Protoc Mouse Biol, 1:71-83. [cited by applicant]
Gibbs, 1995, Cardiac efficiency, Cardiovasc. Res. 30:627-634. [cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2020/034611, date of mailing: Oct. 14, 2020, 45 pages. [cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2020/34608, date of mailing: Oct. 14, 2020, 28 pages. [cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2020/34609, date of mailing: Oct. 14, 2020, 22 pages. [cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2021/039303, date of mailing: Nov. 26, 2021, 19 pages. [cited by applicant]
International Search Report and Written Opinion mailed Nov. 5, 2018, for International Patent Application PCT/US2018/038067 with International filing date Jun. 18, 2018 (11 pages). [cited by applicant]
International Search Report issued in an International Application No. PCT/US2021/030450, date of mailing: Sep. 27, 2021, 9 pages. [cited by applicant]
Kantor, 2000, The Antianginal Drug Trimetazidine Shifts Cardiac Energy Metabolism From Fatty Acid Oxidation to Glucose Oxidation by Inhibiting Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A Thiolase, Circulation Researc… [cited by applicant]
Kotreka, 2011, Gastroretentive Floating Drug-Delivery Systems: A Critical Review, Critical Reviews in Therapeutic Drug Carrier Systems, 28(1):47-99. [cited by applicant]
Leriche, 2012, Cleavable linkers in chemical biology, Bioorg. Med. Chem. 20:571-582. [cited by applicant]
Levy, 2014, Vasodilators in Acute Heart Failure: Review of the Latest Studies, Curr Emerg Hosp Med Rep, 2(2):126-134. [cited by applicant]
Lopaschuk, 2010, Myocardial Fatty Acid Metabolism in Health and Disease, Phys. Rev. 90:207-258. [cited by applicant]
Morin, 1998, Evidence for the existence of [3H]-trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore, Brit. J. Pharmacol. 123:1385-1394. [cited by applicant]
Non-Final Office Action issued in U.S. Appl. No. 16/722,691, date of mailing: Aug. 19, 2020, 12 pages. [cited by applicant]
Pubchem, CID 2223657, Jul. 15, 2005, pp. 1-14. [cited by applicant]
Reddy, 2006, Lipid Metabolism and Liver Inflammation. II. Fatty liver disease and fatty acid oxidation, Am J Physiol Gastrointest Liver Physiol, 290: G852-G858. [cited by applicant]
Sabbah, 2005, Metabolic Therapy for Heart Disease: Impact of Trimetazidine, Heart Failure Reviews, 10, 281-288. [cited by applicant]
Sannino, 2009, Biodegradable Cellulose-based Hydrogels: Design and Applications, Materials, 2:353-373. [cited by applicant]
Schipke, 1994, Cardiac efficiency, Basic Res. Cardiol. 89:207-40. [cited by applicant]
Spiekerkoetter, 2010, Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening, J Inherit Metab Dis, 33:527-532. [cited by applicant]
The Merck Manual List of Diseases https://merckmanuals.com/professional (accessed Jan. 17, 2020), 4 pages. [cited by applicant]
Trammell, 2016, Nicotinamide riboside is uniquely and orally bioavailable in mice and humans, Nat. Commun. 7:12948, 14 pages. [cited by applicant]
Translation of CN101747292, retrieved from Espacenet on Dec. 5, 2018 (44 pages). [cited by applicant]
Translation of JP2000147773 retrieved from Espacenet on Apr. 25, 2019 (30 pages). [cited by applicant]
Translation of JP2006113343 retrieved from Espacenet on Apr. 25, 2019 (39 pages). [cited by applicant]
Translation of JP2015017236 retrieved from Espacenet on Apr. 25, 2019 (34 pages). [cited by applicant]
Translation of WO2006133784 retrieved from Espacenet on May 10, 2019 (24 pages). [cited by applicant]
Translation of WO2012049101 retrieved from Espacenet on May 10, 2019 (23 pages). [cited by applicant]
Translation of WO2016107603 retrieved from Espacenet on Apr. 25, 2019 (113 pages). [cited by applicant]
Translation of WO9728141 retrieved from Espacenet on May 10, 2019 (96 pages). [cited by applicant]
Msser, 2008, Measuring cardiac efficiency: is it clinically useful? Heart Metab. 39:3-4. [cited by applicant]
Yuasa, 1988, Pharmacological Studies on the Actions of Trimetazidine and Its Derivatives, The Journal of Kansai Medical University, vol. 40, Issue 1, pp. 89-116. [cited by applicant]
Extended European Search Report issued in European Application No. 19872680.4, date of mailing: Jun. 20, 2022, 7 pages. [cited by applicant]
Extended European Search Report issued in European Application No. 22169109.0, date of mailing: 7 pages. [cited by applicant]
Zhou, 2012, Trimetazidine Protects against Smoking-Induced Left Ventricular Remodeling via Attenuating Oxidative Stress, Apoptosis, and Inflammation, PLOS ONE, 7:1-7. [cited by applicant]
Gustafsson, 1999, Characterisation of particle properties and compaction behaviour of hydroxpropyl methylcellulose with different degrees of methoxy/hydroxypropyl substitution, European Journal of Pharmaceutical Science… [cited by applicant]
Handbook of Pharmaceutical Excipients, 6th Ed, 2009, pp. 326-329. [cited by applicant]
Yong-Hu Fang et al., “Therapeutic inhibition of fatty acid oxidation in reight ventricular hypertrophy”, Journal of Molecular Medicine, Springer, Berlin, DE, vol. 90, No. 1, Aug. 28, 2011 (Aug. 28, 2011), pp. 31-43. [cited by applicant]
Brand, 2013, The role of mitochondrial function and cellular bioenergetics in ageing and disease, British Journal of Dermatology, John Wiley, Hoboken, USA, 169:1-8. [cited by applicant]
Lin, 2004, Hydrophilic Excipients Modulate the Time Lag of Time-Controlled Disintegrating Press-coated Tablets, AAPS PharmSciTech, 5(4)Article 54, 5 pages. [cited by applicant]
Maggi, 1999, Formulation of biphasic release tablets containing slightly soluble drugs, European Journal of Pharmaceutics and Biopharmaceutics, 48(1):37-42. [cited by applicant]
Narokha, 2014, Antioidant effect of nicotinic acid on experimental doxorubicin-induced chronic heart failure, Current Topics in Pharmacology, 18:105-111. [cited by applicant]
Tang, 2009, The Metabolic Approach in Patients with Heart Failure: Effects on Left Ventricle Remodeling, 15(8):850-856. [cited by applicant]
Masso, 2005, Trimetazidine Indcues Parkinsonism, Gait Disorders and Tremor, Therapies, 60(4):419-422. [cited by applicant]
Fang, 2012, Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle's cycle, J Mol Med, 90(1):31-43. [cited by applicant]