IP Library › Granted Patent US 12,268,669
Granted Patent B2
US 12,268,669 · App. 17/415,902 · Granted Apr 8, 2025

Pharmaceutical compositions and methods comprising a combination of a benzoxazole transthyretin stabilizer and an additional therapeutic agent

Inventors: Christine Ellen Bulawa (Arlington, MA); James Allan Fleming (Arlington, MA)
Assignee: Pfizer Inc.
A61K31/423A61K31/4025A61K31/4245A61P25/00C07K16/18C12N15/113
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Quick Facts
Patent No.
US 12,268,669
App. No.
17/415,902
Granted
Apr 8, 2025
Kind
B2
Abstract

The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a benzoxazole derivative transthyretin stabilizer or a pharmaceutically acceptable salt or prodrug thereof and an additional therapeutic agent for the treatment of transthyretin amyloidosis. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof and one or more additional therapeutic agent for the treatment of transthyretin amyloidosis.

Claims (5)

1. A method of treating TTR amyloidosis in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents wherein the additional therapeutic agent is ataluren.

2. The method of claim 1 wherein ataluren is administered to the patient orally three times a day for a total dosage of approximately 40 mg/kg and tafamidis or a pharmaceutically acceptable salt thereof is administered to the patient orally once a day.

3. The method of claim 2 wherein 80 mg of tafamidis meglumine or 61 mg of tafamidis free acid is administered.

4. The method of claim 1 wherein ataluren and tafamidis meglumine or tafamidis free acid are administered to the patient together orally three times a day wherein the first and second doses comprise 10 mg/kg ataluren and either 20 mg tafamidis meglumine or 15.25 mg tafamidis free acid; and the third dose comprises either 40 mg tafamidis meglumine or 30.5 mg tafamidis free acid.

5. A method of inhibiting TTR fibril formation in a patient, the method comprising administering a therapeutically effective amount of ataluren or a pharmaceutically acceptable salt thereof to a patient.

Assignments (1)
ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023
From: PFIZER INC.
To: PFIZER INC.
Reel/Frame 063119/0087 →
Continuity (2)
Provisional Application 62782403 · Dec 20, 2018
Related Publication 20220071965A1 · Mar 10, 2022
References Cited (59)
US 7015315B1 · Cook et al. · 2006 [cited by applicant]
US 7101993B1 · Cook et al. · 2006 [cited by applicant]
US 7214695B2 · Kelly et al. · 2007 [cited by applicant]
US 7214696B2 · Kelly et al. · 2007 [cited by applicant]
US 7560488B2 · Kelly et al. · 2009 [cited by applicant]
US 8058069B2 · Yaworski et al. · 2011 [cited by applicant]
US 8101743B2 · Brown-Driver et al. · 2012 [cited by applicant]
US 8158601B2 · Chen et al. · 2012 [cited by applicant]
US 8168663B2 · Kelly et al. · 2012 [cited by applicant]
US 8168775B2 · Sah et al. · 2012 [cited by applicant]
US 8334373B2 · Vornlocher et al. · 2012 [cited by applicant]
US 8362231B2 · Tuschl et al. · 2013 [cited by applicant]
US 8372968B2 · Tuschl et al. · 2013 [cited by applicant]
US 8492359B2 · Yaworski et al. · 2013 [cited by applicant]
US 8552171B2 · Tuschl et al. · 2013 [cited by applicant]
US 8642076B2 · Manoharan et al. · 2014 [cited by applicant]
US 8653119B2 · Kelly et al. · 2014 [cited by applicant]
US 8697860B1 · Monia et al. · 2014 [cited by applicant]
US 8741866B2 · Sah et al. · 2014 [cited by applicant]
US 8778902B2 · Tuschl et al. · 2014 [cited by applicant]
US 8802644B2 · Chen et al. · 2014 [cited by applicant]
US 8822668B2 · Yaworski et al. · 2014 [cited by applicant]
US 8895718B2 · Tuschl et al. · 2014 [cited by applicant]
US 8895721B2 · Tuschl et al. · 2014 [cited by applicant]
US 9061044B2 · Freier · 2015 [cited by applicant]
US 9193753B2 · Tuschl et al. · 2015 [cited by applicant]
US 9234196B2 · Sah et al. · 2016 [cited by applicant]
US 9249112B2 · Labaudiniere et al. · 2016 [cited by applicant]
US 9364435B2 · Yaworski et al. · 2016 [cited by applicant]
US 9399774B2 · Monia et al. · 2016 [cited by applicant]
US 9567582B2 · Tuschl et al. · 2017 [cited by applicant]
US 9770441B1 · Girard et al. · 2017 [cited by applicant]
US 9943538B1 · Crooke · 2018 [cited by applicant]
US 9943539B1 · Crooke · 2018 [cited by applicant]
WO 2016033326 · 2016 [cited by applicant]
WO 2018112320 · 2018 [cited by applicant]
WO 2019060442 · 2019 [cited by applicant]
Cruz, Marcia W., et al., “A Review of Tafamidis for the Treament of Transthyretin-Related Amyloidosis”, Neurol Ther, 2015, pp. 61-79, vol. 4. [cited by applicant]
Adamski-Werner, Sara L., et al., “Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis”, Journal of Medicinal Chemistry, 2004, pp. 355-374, vol. 47. [cited by applicant]
Alexander, Kevin M., et al., “Novel pharmacotherapies for cardiac amyloidosis”, Pharmacology and Therapeutics, Jun. 22, 2017, pp. 129-138, vol. 180. [cited by applicant]
Anonymous, “History of Changes for Study: NCT03759379 Study Record Versions Version A B Submitted Date Changes History of Changes for Study: NCT03759379 HELIOS-A: A Study of Vutrisiran (ALN-TTRSC02) in Patients with Her… [cited by applicant]
Benson, Merrill D., et al., “Inotersen Treatment for Patiens with Hereditary Transthyretin Amyloidosis”, The New England Journal of Medicine, Jul. 5, 2018, pp. 22-31, 379(1). [cited by applicant]
Castano, Adam, et al., “Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs”, Heart Failure Review, Kluwer Academic Pu… [cited by applicant]
Coelho, Teresa, et al., “Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis”, Neurol Ther., 2016, pp. 1-25, vol. 5. [cited by applicant]
Fritschka, Max, et al., “Unusal case of ATTR amyloidosis with cardiac manifestation and situs inversus totalis”, Clincial Research in Cardiology, Berlin Heidelberg, Jan. 23, 2017, pp. 311-316, 106(4). [cited by applicant]
Gillmore, Julian D., et al., “A Phase 2 Multi-Center, Open-Label Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Exploratory Clinical Activity of Revusiran (ALN-TTRsc), and RNAi Therapeutic for the … [cited by applicant]
Gonalves, et al., “Glial cells in familial amyloidotic poyneuropathy”, Acta Neuropathologica Communications, 2014, pp. 1-25, vol. 2. [cited by applicant]
Green, Nora S., et al., “Synthesis and Characterization of Potent Bivalent Amyloidosis Inhibitors That Bind Prior to Transthyretin Tetramerization”, Journal American Chemical Society, 2003, pp. 13404-13414, vol. 125. [cited by applicant]
Hawkins, Philip N., et al., “Evolving landscape in the management of transthyretin amyloidosis”, Annals of Medicine, Nov. 17, 2015, pp. 625-638, 47(8). [cited by applicant]
International Written Opinion and Search Report mailed on Jul. 6, 2020 for Application No. PCT/IB2019/060899, filed on Dec. 17, 2019, 26 pages. [cited by applicant]
Maurer, Mathew S., et al., “Tafamidis in Transthyretin Amyloid Cardiomyopathy Effects on Transthyretin Stablizatoin and Clinical Outcomes”, Circulation Heart Failure, 2015, pp. 519-526, 8(3). [cited by applicant]
Oza, Vibha B., et al., “Synthesis, Structure, and Acitvity of Disclofenac Analogues as Transthyretin Amyloid Fibril Formation Inhibitors”, Journal of Medicinal Chemistry, 2002, pp. 321-332, 45(2). [cited by applicant]
Petrassi, H. Michael, et al., “Structure-Based Design of N-Phenyl Phenoxazine Transthyretin Amyloid Fibril Inhibitors”, Journal American Chemical Society, 2000, pp. 2178-2192, vol. 122. [cited by applicant]
Razavi, Hossein, et al., “Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation, and Medchanism of Action”, Angew. Chem, 2003, pp. 2864-2867, vol. 105. [cited by applicant]
Richards, Duncan B., et al.,“Repeat doses of anitbody to serum amyloid p. Component clear amyloid deposits in patients with systemic amyloidosis”, Science Translational Medicine Report, Jan. 3, 2018, pp. 1-8, 10(422). [cited by applicant]
Saelices, Lorena, et al., “Uncovering the Mechanism of Aggregation of Human Transthyretin”, Journal of Biological Chemistry, 2015, pp. 28932-28943, 290(48). [cited by applicant]
Verona, Gulielmo, et al., “Inhibition of the mechano-enzymatic amyloidogenssis of transthyretin: role of ligand affinty, binding cooperativity and occupancy of the inner channel”, Nature—Scientific Reports, 2017—pp. 1-7… [cited by applicant]
Onpattro—Annex—I thru IV—Summary of Product Characteristics, 34 pages. [cited by applicant]
Teqsedi—Annex—I thru IV—Summary of Product Characteristics, 39 pages. [cited by applicant]