Pharmaceutical composition for treating autosomal dominant polycystic kidney disease

Abstract

The present disclosure addresses the problem of providing a dosage regimen for an orally administered pharmaceutical composition that is for treating and / or preventing autosomal dominant polycystic kidney disease and that contains, as an active ingredient, tamibarotene. The present disclosure provides a pharmaceutical composition that is for treating or preventing autosomal dominant polycystic kidney disease, that contains tamibarotene, and that is to be orally administered to an autosomal dominant polycystic kidney disease patient in an amount of 1.4-5.5 mg / day, particularly about 4 mg / day, in terms of the tamibarotene.

Description

Pharmaceutical composition for the treatment of autosomal dominant polycystic kidney disease

[0001] This disclosure relates to the dosage and administration of an orally administered pharmaceutical composition containing the active ingredient tamibarotene for the treatment and / or prophylaxis of autosomal dominant polycystic kidney disease.

[0002] Autosomal dominant polycystic kidney disease (ADPKD), a refractory genetic disorder, progressively forms numerous cysts in the kidneys and progresses to end-stage renal failure in middle age or later. The causative genes for ADPKD are PKD1 in 85% of cases and PKD2 in 15% of cases. Research has been conducted using disease model mice and experimental animals such as rats with modified genes, but a complete understanding of the disease mechanism has not been achieved, and no curative treatment has been developed.

[0003] Tolvaptan, the only vasopressin V2 receptor antagonist approved and used as a treatment for ADPKD, suppresses cyst formation and renal dysfunction, but its effects are limited and it cannot be considered a curative treatment. Furthermore, tolvaptan can cause serious side effects such as severe liver dysfunction, and its strong diuretic effect requires patients to take it with various behavioral restrictions, such as frequent fluid intake and urination, to prevent side effects like dehydration and hypernatremia. Therefore, there is a need to develop a curative drug that can improve patients' quality of life.

[0004] In recent years, there has been a surge in research aimed at creating disease models that reproduce the disease state by establishing disease-specific iPS cells by introducing causative gene mutations into somatic cells established from patients with intractable diseases or iPS cells derived from healthy individuals, and then differentiating them into affected cell types in vitro. This research is used for detailed disease analysis and drug discovery.

[0005] To develop therapeutic drugs for ADPKD, the inventors created a renal cyst model in which cysts spontaneously form in three-dimensional culture of renal collecting duct tissue, using a novel differentiation induction method developed by introducing a mutation into the PKD1 gene, one of the causative genes of ADPKD, into disease-specific iPS cells derived from healthy individuals. Using this disease model, they found that retinoic acid receptor agonists such as TTNPB and AM80 (tamibarotene) suppress cyst formation. They confirmed that retinoic acid receptor agonists suppress cyst formation in vivo in an ADPKD mouse model (Patent Document 1: WO 2024 / 090521).

[0006] Tamibarotene or AM80 (CAS number: 94497-51-5) is approved as a treatment for relapsed or refractory acute promyelocytic leukemia and is marketed as "Amnoleik® Tablets 2 mg" (Non-Patent Literature 1).

[0007] International Public Publication WO2024 / 090521

[0008] Amnoleik® Tablets 2 mg Package Insert (Revised October 2022 (1st Edition))

[0009] This disclosure aims to provide a pharmaceutical composition comprising tamibarotene for the treatment and / or prevention of autosomal dominant polycystic kidney disease (ADPKD) in humans. More specifically, this disclosure aims to provide a pharmaceutical composition for the treatment of ADPKD comprising a specific dose of tamibarotene.

[0010] This disclosure provides a pharmaceutical composition for the treatment or prevention of autosomal dominant polycystic kidney disease, comprising tamibarotene as an active ingredient, to be orally administered to human subjects at a dose of 1.4–5.5 mg / day.

[0011] This disclosure also provides a pharmaceutical composition for the treatment or prevention of autosomal dominant polycystic kidney disease, comprising tamibarotene as an active ingredient, to be orally administered to human subjects at approximately 4 mg / day as tamibarotene.

[0012] Figure showing the results of Reference Example 1. When artificial collecting tubule organoids with cystic structures, i.e., an in vitro renal cyst model of ADPKD, were produced from human iPS cell line 1383D2 with PKD1 knockout, and treated with tamibarotene 0.01 μM and 0.1 μM for 3 days, an inhibitory effect on cyst growth was observed. Data from three independent experiments are shown as mean ± SD (n=3). Student's t-test was performed. Results of Example 1. Adult-onset ADPKD mouse models were orally administered tamibarotene once daily for 28 days at doses of 0.2 mg / kg and 1.0 mg / kg. Figure showing the difference in body weight between mice that received tamibarotene and those that did not. Figure showing the difference in urea nitrogen (UN) between mice that received tamibarotene and those that did not in Example 1. Cross-sectional images of polycystic kidneys in model mice that received tamibarotene and those that did not in Example 1. Kidney weight-to-body weight ratio (2KW / BW) and renal cystic index of model mice administered with and without tamibarotene in Example 1. Cross-sectional view of the liver of model mice administered with and without tamibarotene in Example 1. Changes in liver weight-to-body weight ratio (LW / BW) and liver cystic index of model mice administered with and without tamibarotene in Example 1. Tamibarotene dose and C max Correlation between tamibarotene dose and AUC in mice. 0-inf Correlation. This graph shows the results up to week 28 after the start of a clinical trial in which tamibarotene 4 mg / day was administered daily to patients with autosomal dominant polycystic kidney disease.

[0013] In this disclosure, when a number is accompanied by the term "approximately," it is intended to include a range of ±10% of that value. For example, "approximately 20" includes "18 to 22." A range of numbers includes all numbers between the two endpoints and the numbers at both endpoints. The "approximately" in relation to a range applies to both endpoints of that range. Therefore, for example, "approximately 20 to 30" includes "18 to 33."

[0014] In this disclosure, “treatment” means, in a person having the disease, reducing or eliminating the cause of the disease, delaying or halting the progression of the disease, reducing, alleviating, improving or eliminating its symptoms, and / or suppressing the worsening of its symptoms.

[0015] In this disclosure, “prevention” means preventing the onset of the disease in a subject, reducing the likelihood of developing the disease, or reducing or alleviating symptoms if the disease does develop. Here, the onset of the disease includes relapse after cure or remission. Subjects include, for example, subjects who are at high risk of developing the disease but have not yet developed or relapsed. Subjects with a genetic predisposition to ADPKD include genetic mutations in the causative genes of ADPKD (such as PKD1 and PKD2).

[0016] The inventors investigated the effective dose of tamibarotene when administered orally using ADPKD model mice. By obtaining pharmacokinetic parameters at the dose in which efficacy was confirmed in the model mice, and calculating the dose that would yield equivalent pharmacokinetic parameters in humans, they determined the dosage and administration method that would be expected to be effective in humans. A clinical trial was then conducted in ADPKD patients based on this dosage and administration method to confirm its effectiveness.

[0017] Based on studies using a mouse model, it was found that an oral dose of 1.4–5.5 mg / day of tamibarotene is suitable for efficacy in humans. Based on this information, a Phase II clinical trial is being conducted with a dose of 4.0 mg / day of tamibarotene. As a result, cases have been reported in which the administration of 4.0 mg / day of tamibarotene showed improvement in subjective symptoms of renal pain. Furthermore, as an interim result of the clinical trial, a clear decrease in the rate of increase in bilateral kidney volume (TKV) was observed with tamibarotene administration up to 28 weeks.

[0018] The pharmaceutical composition containing tamibarotene of this application may contain pharmaceutically acceptable carriers or additives. Examples of such carriers or additives include isotonic agents, thickeners, sugars, sugar alcohols, preservatives, bactericides, antibacterial agents, pH adjusters, stabilizers, chelating agents, oily bases, gel bases, wetting agents, surfactants, suspending agents, binders, excipients, lubricants, disintegrants, foaming agents, fluidizing agents, dispersants, emulsifiers, buffers, solubilizers, and antioxidants. A single pharmaceutically acceptable carrier or additive may be used, or two or more may be used in combination.

[0019] The pharmaceutical composition of this application is administered orally. Dosage forms of the pharmaceutical composition include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, capsules, microcapsules, chewable tablets, liquids, suspensions, emulsions, and the like.

[0020] Preferably, the pharmaceutical composition of this application is a tablet containing tamibarotene as the active ingredient. Excipients and additives for the tablet, though not limited to these, include lactose monohydrate, corn starch, hydroxypropyl cellulose, and magnesium stearate. As a pharmaceutical composition containing tamibarotene, commercially available Amnoleik tablets can be used.

[0021] The amount of tamibarotene in a single tablet is not limited, but examples include tablets containing 1 mg, 2 mg, or 4 mg of tamibarotene.

[0022] Tamibarotene should be administered orally once daily at a dose of approximately 4.0 mg / day, and the duration of administration can be continued as long as there are no tolerable issues. Reference example 1

[0023] Artificial collecting duct organoids with cystic structures were induced using PKD1 knockout iPS cells of strain 1383D2 by the method described above. The inhibitory effect of tamibarotene on renal collecting duct cyst enlargement was confirmed using the following protocol: 1. Organoids with cyst formation were collected in a tube. 2. The culture medium was removed and 2 mL of Cell Recovery Solution was added (4°C, 30 min). 3. The gel was dissolved by gently pipetting with a P-1000 pipettor and centrifuged (500 g, 2 min). 4. The supernatant from step 3 was removed, 5 mL of FBS-containing medium (STO medium) was added, and the cysts were separated from the organoids by pipetting. 5. The cysts were collected in a 15 mL tube using a stereomicroscope. 6. The supernatant was removed, 2 mL of Accutase was added, and the tubes were treated at 37°C for 5 min. 7. Dissociated into single cells by pipetting with a P-1000 pipettor. 8. After filtering, the cell count was measured. 9. After measuring the cell count, the cell suspension containing the required number of cells was transferred to a tube, and 5 mL of FBS-containing medium (STO medium) was added to stop the Accutase reaction. 5x10 4 The required amount of cell suspension was calculated for seeding at cells / well. 10. Centrifugation (200g, 5 minutes) was performed to prepare pellets. 11. The supernatant was carefully removed, and DMEM / F12 + B27 w / o VA medium (10% Afamin / Wnt3a CM, 200ng / mL R-Spondin 1, 200ng / mL FGF1, 10μM Forskolin, 2.5μM AVP, 10μM Y27632) was added and the cells were suspended. 5x10 4 To seed cells at a rate of cells / well, the required amount of culture medium was calculated. 12. Place the cell suspension from step 11 into a pre-prepared 50% Matrigel plate in 5x10 cells. 4Cells were seeded at / well. To prevent Matrigel from collapsing, the cell suspension was added slowly. 13. By culturing at 37°C and 5% CO2 for 2 days, a cyst structure was created. 14. The medium was removed, 200 ng / mL FGF1 and 2.5 μM AVP were added to DMEM / F12 + B27 w / o V.A. medium, and tamibarotene was further added to 0.01 μM or 0.1 μM, followed by culturing at 37°C and 5% CO2 for 3 days. DMSO was added to the control. 15. Nine images were taken at 4x magnification within the well using a fluorescence microscope (Keyence, BZ-X700), the cyst area was measured with BZ-X Analyzer, and the average value was calculated. The results are shown in Figure 1. An inhibitory effect on cyst enlargement was observed at both concentrations of 0.01 μM and 0.1 μM of tamibarotene.

[0024] Generation of ADPKD model mice. Pkd1 established by Shibazaki et al. flox / flox mice (Shibazaki S., Hum Mol Genet. 2008, 1505-1516) were crossed with Mx1-Cre mice (The Jackson Laboratory, Maine, USA) to generate Pkd1 flox / + : Mx1-Cre mice. Furthermore, Pkd1 flox / + : Mx1-Cre mice were crossed with Pkd1 flox / flox mice to generate Pkd1 flox / flox : Mx1-Cre mice. Pkd1 flox / flox : Mx1-Cre mice can delete Pkd1 at any time (Cre-loxP site-specific recombination) by expressing the Cre gene under the control of the promoter of the interferon-responsive Mx1 gene using polyinosinic-polycytidylic acid (pI-pC) that induces the production of interferon. Pkd1 flox / flox : An adult-onset ADPKD mouse model was generated by deleting Pkd1 by intraperitoneally injecting 10 μg / g (BW) of pI-pC into Mx1-Cre mice continuously for 6 days starting from day 10 after birth.

[0025] Tamibarotene was diluted with 100% DMSO, and then further diluted 250-fold with methylcellulose to prepare the tamibarotene solution. Adult-onset ADPKD mouse models were orally administered the tamibarotene solution once daily at a dose of 0.2 mg / kg or 1.0 mg / kg starting at 28 days postnatal. A methylcellulose solution in 0.4% DMSO was administered as a control.

[0026] Urine samples were obtained by collecting urine over a 24-hour period 22 days after the start of administration (50 days after birth). Body weight was measured 28 days after the start of administration (56 days after birth), and all animals were euthanized. The kidneys and livers were removed and their respective weights were measured.

[0027] Measurement of UN (urea nitrogen): Mouse UN was measured using the UN-L kit (A666-00, Cerotec Corporation).

[0028] Hematoxylin-eosin (HE) staining and cystic index measurement: Kidney and liver tissue were fixed with 4% paraformaldehyde solution, and 4 μm thick paraffin sections were prepared. After deparaffinization, HE staining was performed, and the tissue was photographed with a light microscope. The cystic index was calculated using image analysis and measurement software (WinROOF, Mitani Corporation) as a multiplier of 100 for the entire cystic area / entire kidney tissue area or the entire cystic area / entire liver area. Statistical analysis was performed using the maximum comparison method. The results are shown in Figures 2 to 5.

[0029] There was no difference in body weight between the control (solvent only) and the tamibarotene-administered group (Figure 2), but urea nitrogen (UN) and kidney weight-to-body weight ratio (2KW / BW) were significantly reduced with tamibarotene administration (Figures 3 and 4). There was no difference in renal cystic index with tamibarotene administration (Figure 4), but both liver weight-to-body weight ratio (LW / BW) and liver cystic index were significantly reduced with tamibarotene administration (Figure 5).

[0030] The results from Example 1 confirmed that doses of 0.2 and 1.0 mg / kg / day were effective in suppressing cyst formation in the ADPKD mouse model.

[0031] Pharmacokinetics in mice: Using C57BL / 6J mice, the pharmacokinetics of tamibarotene upon oral administration were measured. Table 1 and Figure 6 show the pharmacokinetic parameters in mice administered tamibarotene orally. Also, the correlation between the dose of tamibarotene and AUC 0-inf is shown in Figure 7.

[0032] In Example 1, in the mice in which the inhibitory effect on cyst formation was confirmed in the ADPKD mouse model, the Cmax at a dose of 0.2 mg / kg was approximately 67 ng / mL, which was approximately 20 times higher than the concentration of 0.01 μM (3.5 ng / mL) at which the inhibitory effect on cyst enlargement was observed in the in vitro renal cyst model.

[0033]

[0034] Calculation of human dose: Since it was confirmed that doses of 0.2 and 1.0 mg / day in the ADPKD mouse model were effective in inhibiting cyst formation, based on the AUC in Table 1 and Figure 7 0-inf and the AUC in APL patients 0-inf (128.37 ng·h / mL when administering 2.0 mg / day of tamibarotene, 320.41 ng·h / mL when administering 4.0 mg, 430.26 ng·h / mL when administering 6.0 mg, from the interview form of 2 mg Amnorex tablets), the human dose corresponding to the mouse dose was calculated, and it was estimated that the dose expected to have an effect in the clinical trial in humans was 1.4 - 5.5 mg / body (Table 2).

[0035]

[0036] Pharmacokinetics upon administration to human ADPKD patients: The pharmacokinetics of tamibarotene in ADPKD patients were investigated in the Phase II clinical trial. For 7 ADPKD patients, the average of AUC 0-inf upon single administration of 4 mg / body of tamibarotene was 282.1 ng h / mL, and the AUC 0-infThe average was 270.6 ng h / mL. When converted to the dosage for mice, these were 0.57 mg / body and 0.54 mg / body respectively (Table 3). Therefore, it is almost the same as the human dosage of 3.3 - 5.5 mg / body corresponding to the mouse dosage of 0.365 - 0.905 mg / kg in Table 2 of Example 2, and it was confirmed that the clinical dosage predicted from the PK results of tamibarotene in APL patients is also appropriate in ADPKD patients.

[0037]

[0038] Purpose of the Phase 2 Clinical Trial: To evaluate the efficacy, safety, and pharmacokinetics of tamibarotene when administered to patients with autosomal dominant polycystic kidney disease (ADPKD)

[0039] Subjects: A Phase II clinical trial was conducted on patients diagnosed with ADPKD according to the following modified Pei-Ravine criteria. - Corresponding to Class 1C, 1D, and 1E according to the Mayo classification - Estimated glomerular filtration rate (eGFR) value [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cr-cys] of ≥ 60 mL / min / 1.73m 2 As above - At the time of informed consent, it was determined that treatment with tolvaptan was difficult or the patient did not wish to receive treatment with tolvaptan - Systolic blood pressure of ≤ 140 mmHg and diastolic blood pressure of ≤ 90 mmHg For patients receiving administration of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist, the dosage has been constant for ≥ 6 weeks before obtaining informed consent

[0040] Patient Exclusion Criteria: • Pregnant women or those who may be pregnant • Breastfeeding patients • Female subjects of childbearing potential or male subjects with a childbearing partner who are unable to use contraception for the following periods: 1) Females: From obtaining consent to 2 years after the last dose of the investigational drug 2) Males: From obtaining consent to 6 months after the last dose of the investigational drug • Patients who have used medications that affect renal cysts (tolvaptan, immunosuppressants, somatostatin analogs, sodium glucose cotransporter 2 (SGLT2) inhibitors, biguanide antidiabetic drugs, pioglitazone-containing preparations) and the period from the last dose to the first dose of the investigational drug is within 12 weeks • Patients with complications of intracranial aneurysms requiring treatment • Patients with malignant tumors • Patients with hemoglobin A1c (HbA1c) levels of 7.0% or higher despite being diagnosed with diabetes and receiving treatment • Lumbar spine bone mineral density < Patients with fragility fractures in 70% of the body or in any part of the body; patients with low-density lipoprotein (LDL) cholesterol levels of 160 mg / dL or higher, or triglycerides (TG) levels of 175 mg / dL or higher, despite treatment for dyslipidemia; patients with either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding the upper limit of normal.

[0041] Dosage and Administration: Administer tamibarotene 4.0 mg (tablet) or placebo tablet orally once daily for 52 weeks.

[0042] To confirm the efficacy, CT images of the kidney region of the trial patients were obtained at the time of obtaining informed consent to participate in the clinical trial, at the start of tamibarotene administration, and 28 weeks after the start of administration. The period from obtaining informed consent to the start of administration was within one year. Using the image analysis software SYNAPSE VINCENT (Fujifilm Corporation), a radiologist obtained bilateral kidney volume (TKV) from the CT image data in accordance with standard procedures.

[0043] Table 4 and Figure 8 show the changes (slope) in bilateral kidney volume (TKV) in 7 patients who received tamibarotene 4.0 mg (tablets) orally once daily for 28 weeks (6 months) during the interim clinical trial.

[0044]

[0045] As is clear from Figure 8, in 5 out of 7 cases, administration of tamibarotene clearly reduced the rate of increase in TKV kidney volume.

Claims

1. A pharmaceutical composition containing tamibarotene for the treatment or prevention of autosomal dominant polycystic kidney disease, to be orally administered to patients with autosomal dominant polycystic kidney disease at a dose of 1.4–5.5 mg / day.

2. A pharmaceutical composition containing tamibarotene for the treatment or prevention of autosomal dominant polycystic kidney disease, administered orally at approximately 4 mg / day to patients with autosomal dominant polycystic kidney disease.

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