US-20260124164-A1 - PHARMACEUTICAL COMPOSITION FOR TREATING AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

US20260124164A1US 20260124164 A1US20260124164 A1US 20260124164A1US-20260124164-A1

Abstract

A new dosage regimen of a pharmaceutical composition comprising tamibarotene as the active ingredient for treating autosomal dominant polycystic kidney disease. A pharmaceutical composition comprising tamibarotene for the treatment or prevention of autosomal dominant polycystic kidney disease (ADPKD), wherein the composition is administered orally to a patient with ADPKD in an amount of 1.4-5.5 mg/day, particularly 4.0 mg/day of tamibarotene.

Inventors

Kenji Osafune
Shinichi MAE
Saori NISHIO
Fumihiko HATTANDA
Tsuyoshi Nakano
Ryuichiro HIRAYAMA
Tomoko Suzuki
Ayuto HAYASHI

Assignees

KYOTO UNIVERSITY
NATIONAL UNIVERSITY CORPORATION HOKKAIDO UNIVERSITY
REGE NEPHRO CO., LTD.

Dates

Publication Date: 20260507
Application Date: 20250618
Priority Date: 20241106

Claims (2)

1 . A method for treating autosomal dominant polycystic kidney disease (ADPKD) in a subject, the method comprising administering 1.4-5.5 mg/day of tamibarotene orally to the subject.
2 . A method for treating autosomal dominant polycystic kidney disease (ADPKD) in a subject, the method comprising administering about 4 mg/day of tamibarotene orally to the subject.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application No. PCT/JP2024/046002 filed Dec. 25, 2024, which claims priority to Japan Patent Application No. 2024-194582 filed Nov. 6, 2024, each of which is incorporated by reference herein in its entirety. TECHNICAL FIELD This disclosure relates to a new dosage regimen of an oral pharmaceutical composition comprising tamibarotene as an active ingredient for treating and/or preventing autosomal dominant polycystic kidney disease. BACKGROUND ART Autosomal dominant polycystic kidney disease (ADPKD) is a difficult-to-treat inherited disorder that progressively forms numerous cysts in the kidneys and progresses to end-stage renal disease after middle age. About 85% of cases are caused by the PKD1 gene and about 15% are caused by the PKD2 gene. Research has been conducted using various experimental animal models such as mice and rats with modified genes; however, a complete understanding of the disease pathology has not been achieved and no radical treatment methods have been developed. Tolvaptan, a vasopressin V2 receptor antagonist, is the only approved drug for treating ADPKD. It suppresses cyst formation and renal function decline. However, its effects are limited, and it cannot provide a cure. Tolvaptan can cause serious side effects, such as severe liver dysfunction. patients who take tolvaptan are subject to various behavioral restrictions, such as the need for frequent water intake and urination to prevent the development of side effects such as dehydration and hypernatremia due to its strong diuretic effect, so there is a need to develop a novel therapeutic agent that improves patients' quality of life. In recent years, research has been actively conducted to analyze the detailed pathology and search for therapeutic agents by generating iPS cells from the somatic cells of patients with intractable diseases or disease-specific iPS cells by introducing mutations into the causative genes of iPS cells derived from healthy individuals, and inducing the differentiation of these cells into the affected cell types in vitro, so as to prepare disease models that reproduce the pathology. To develop a therapeutic agent for the treatment of ADPKD, the inventors created a three-dimensional culture of renal collecting duct tissue that can be used as a renal cyst model in which cysts spontaneously form. The renal cyst model was created by introducing mutations into the PKD1 gene, one of the causative genes of ADPKD, in iPS cells derived from a healthy individual, and then, the iPS cells were differentiated into renal collecting duct tissue by using our unique novel differentiation induction method. Using this disease model, we found that retinoic acid receptor agonists such as TTNPB and AM80 (tamibarotene) suppress cyst formation. We also confirmed that retinoic acid receptor agonists inhibit cyst formation in vivo in an ADPKD model mouse (Patent Document 1: WO 2024/090521). Tamibarotene, or AM80 (CAS number: 94497-51-5), is approved for the treatment of relapsed and refractory acute promyelocytic leukemia and is marketed as “Amnolake® tablet 2 mg” (non-patent literature 1). CITATION LIST Patent Literature Patent Literature 1: WO2024/090521 Non-Patent Literature Non-Patent Literature 1: Amnolake® Tablet 2 mg Package Insert (October 2022 Revision, 1st Edition) SUMMARY OF THE INVENTION Technical Problem An object of the present disclosure is to provide a pharmaceutical composition comprising tamibarotene for treating and/or preventing autosomal dominant polycystic kidney disease (ADPKD) in humans. Specifically, this disclosure aims to provide a pharmaceutical composition for the treatment of ADPKD that comprises a specific dosage of tamibarotene. Solution to Problem This disclosure provides a pharmaceutical composition for treating or preventing autosomal dominant polycystic kidney disease, comprising tamibarotene as the active ingredient, which is administered orally to a human subject at 1.4 to 5.5 mg/day of tamibarotene. This disclosure also provides a pharmaceutical composition for treating or preventing autosomal dominant polycystic kidney disease, comprising tamibarotene as the active ingredient, which is administered orally to a human subject at about 4 mg/day of tamibarotene. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows the results of Reference Example 1. Artificial collecting duct organoids with cystic structures were generated from human PKD1 knocked out iPS cell line 1383D2, and used as an in vitro kidney cyst model of ADPKD. The in vitro model was treated with tamibarotene at concentrations of 0.01 UM and 0.1 μM for three days. Suppression of cyst enlargement was observed. The data from three independent experiments are presented as mean±S.D. (n=3). A Student's t-test was performed. FIG. 2 The results of Example 1 are shown. Tamibarotene was administered orally to the adult-onset ADPKD model mice once daily for 28 days