Telmisartan for treatment of chronic kidney disease in dogs

Abstract

To provide a new therapeutic approach for the treatment of dogs against elevated UPC levels.SOLUTION: The present invention relates to telmisartan or a pharmaceutically acceptable salt thereof as a medicament for the treatment of elevated urinary protein-to-creatinine ratio (UPC) levels in dogs, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to telmisartan or a pharmaceutically acceptable salt thereof as a pharmaceutical agent for the treatment of elevated urinary protein creatinine ratio (UPC) levels in dogs, wherein a therapeutically effective amount of telmisartan is administered at various daily doses throughout the treatment period. [Background technology]

[0002] It is estimated that 300,000 to 1 million of the 70 million pet dogs in the United States suffer from chronic kidney disease (CKD), with over 10% of dogs of all breeds over the age of 15 years presenting to academic medical centers [1-3]. Of these, approximately 52% are affected by glomerular pathology, characterized by abnormal protein leakage in the urine (proteinuria) in CKD-affected animals [4]. Proteinuria is considered a risk factor for adverse outcomes, including renal morbidity and mortality, as well as all-cause mortality. In fact, dogs with a UPC greater than 1.0 are approximately three times more likely to experience uremic crisis and death than dogs with a UPC less than 1.0 [5]. Importantly, these risks increase with the degree of proteinuria and may apply even to patients with otherwise normal renal function [5, 6]. Several canine studies, both by evaluating clinical CKD patients [5] and by utilizing experimental models [7], have shown an association between the presence of proteinuria and the progression of CKD, as proteinuria can promote renal injury through several mechanisms [8].

[0003] For these reasons, intervention (in the form of dietary modification and pharmacological treatment to mitigate urinary protein leakage) is considered standard of care for dogs with proteinuric CKD [9-11]. Interventions that reduce the degree of proteinuria in affected dogs are associated with improved outcomes [10, 12, 13]. Angiotensin-converting enzyme inhibitors (ACEIs), such as enalapril, have been shown to reduce proteinuria in experimental [7] and spontaneous [12, 14] canine CKD models and are the most widely prescribed medications for this purpose. By reducing angiotensin II (ANGII) production, ACEIs' hemodynamic effects are primarily due to a reduction in glomerular transcapillary fluid pressure via a reduction in efferent glomerular arteriolar resistance, thereby reducing the degree of proteinuria

[15] . Despite their overall benefit in reducing proteinuria within the population, ACEIs are not universally successful, and the degree of antiproteinuric effect varies widely from patient to patient. For example, in a clinical trial designed to evaluate the effectiveness of enalapril as a treatment for spontaneous proteinuria, a clinically significant (i.e., 50%) reduction in proteinuria was noted in only 9 / 14 (64%) subjects, while 3 / 14 (22%) experienced an increase in proteinuria despite being treated with enalapril

[14] .

[0004] A case study reported that a 6-year-old female beagle dog was given telmisartan at an initial dose of 0.43 mg / kg body weight per day for 7 days, which was then increased to 0.86 mg / kg body weight per day to treat treatment-resistant proteinuria.

[16] Another case study described successful management of treatment-resistant proteinuria and systemic hypertension with telmisartan at 0.43 mg / kg and amlodipine at 0.3 mg / kg in an 11-year-old Yorkshire terrier undergoing surgery for renal cell carcinoma

[17] . International patent application WO2019 / 008077 teaches a dosing scheme for sartans for the prevention or treatment of hypertension in cats, with an initial dose of 1.0-5.0 mg / kg body weight, which is subsequently reduced over time. Protein-losing nephropathy (PLN) is commonly detected in dogs by the detection of protein in the urine, quantified using the urinary protein-to-creatinine ratio (UPC), and includes glomerulonephritis (GN), glomerulopathy, and amyloidosis. Normal glomeruli filter small molecules but restrict the passage of large or negatively charged molecules. Damage to the glomerulus allows large or negatively charged molecules to pass through, leading to leakage into the urine. PLN can lead to CKD if leakage is not controlled. Controlling proteinuria is the primary focus of PLN treatment. Therefore, there is an urgent need for more antiproteinuric medications and sustainable options for canine patients suffering from proteinuric CKD and / or PLN. Summary of the Invention [Problem to be solved by the invention]

[0005] One object of the present invention is to provide a new therapeutic approach for the treatment of dogs for elevated UPC levels. [Means for solving the problem]

[0006] It has now been found that dogs can be treated for elevated urinary protein creatinine ratio (UPC) levels by administering a therapeutically effective amount of telmisartan, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. Accordingly, the present invention relates to telmisartan or a pharmaceutically acceptable salt thereof for use in a method for treating elevated UPC levels in a dog in need of such treatment, the method comprising administering a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period and the daily dosage of telmisartan is increased during a second period following the first period during the treatment period.

[0007] Furthermore, the present invention relates to telmisartan or a pharmaceutically acceptable salt thereof as a pharmaceutical agent for the treatment of elevated urinary protein creatinine ratio (UPC) levels in dogs that are non-refractory to treatment with ACE inhibitors. In a further embodiment of the present invention, there is provided a method for treating elevated urinary protein creatinine ratio (UPC) levels in a dog in need of such treatment, comprising administering to the dog a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period and the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. In a further embodiment, the present invention provides a method for the treatment of elevated urinary protein creatinine ratio (UPC) levels in a dog that are non-refractory to treatment with an ACE inhibitor, the method comprising administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to a dog in need of such treatment. Furthermore, the present invention relates to a pharmaceutical composition for use in a method for treating elevated urinary protein creatinine ratio (UPC) levels in chronic kidney disease in dogs in need of such treatment, the pharmaceutical composition comprising telmisartan according to the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 compares the percentage of dogs that experienced a 50% or greater reduction in UPC at day 30 between telmisartan-treated dogs and enalapril-treated dogs (see Example 1). [Figure 2] FIG. 1 compares mean change in UPC from baseline from Day 30 to Day 90 between telmisartan and enalapril treated dogs (see Example 2). [Figure 3] FIG. 1 shows the mean percent change in UPC from baseline from Day 30 to Day 120 for dogs treated with telmisartan compared to dogs treated with enalapril (see Example 2), where enalapril was added to the telmisartan group and telmisartan was added to the enalapril group at Day 90. [Figure 4] FIG. 1 shows the mean change from baseline in UPC from Day 30 to Day 120 for dogs treated with telmisartan compared to dogs treated with enalapril (see Example 2), where enalapril was added to the telmisartan group and telmisartan was added to the enalapril group at Day 90. [Figure 5] FIG. 1 shows the mean change from baseline in UPC from Day 30 to Day 120 for dogs treated with telmisartan compared to dogs treated with enalapril (see Example 2), where at Day 90, enalapril is not added to the telmisartan group and telmisartan is not added to the enalapril group. DETAILED DESCRIPTION OF THE INVENTION

[0009] Before describing the embodiments of the present invention, it should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a "preparation" includes a plurality of such preparations, and a reference to a "carrier" is a reference to one or more carriers and equivalents thereof known to those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values may vary by 1-5% unless otherwise indicated or known to those skilled in the art; therefore, the term "about" has been omitted from the description. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodologies reported in the publications as being capable of being used in connection with the present invention. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. The solution to the above technical problem is achieved by the description and embodiments characterized in the claims.

[0010] In accordance with the present invention, a method for treating elevated UPC levels (also referred to as proteinuria) in a dog in need of such treatment is described herein, the method comprising administering a therapeutically effective amount of telmisartan to the dog, the therapeutically effective amount of telmisartan being administered at various daily doses throughout a treatment period, starting with an initial dose of at least 1.0 mg / kg body weight. For example, during a first period during the treatment period, the daily dose of telmisartan may be 1.0 to 1.5 mg / kg body weight, and the daily dose of telmisartan is increased during a second period following the first period during the treatment period.

[0011] As used herein, the term "pharmaceutically acceptable salt" includes metal salts or addition salts that can be used in dosage forms.For example, the pharmaceutically acceptable salts of the compounds provided herein may be acid addition salts, base addition salts, or metal salts, and can be synthesized from parent compounds containing basic or acidic residues by conventional chemical methods.Such salts are generally prepared by reacting the non-acid or non-basic form of these compounds with an equivalent amount of an appropriate base or acid in water or an organic solvent or a mixture of both.Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as ammonium salts, and organic alkali salts such as diethylamine, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glutamine, and basic amino acid salts. Examples of metal salts include sodium, potassium, calcium, magnesium, aluminum, and lithium salts.

[0012] As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically acceptable and do not typically cause allergic reactions or similar side effects such as stomach discomfort, dizziness, etc. when administered to humans. As used herein, the term "pharmaceutically acceptable" preferably means approved by a federal or state regulatory agency, listed in the United States Pharmacopoeia or another pharmacopoeia, or generally recognized for its use in animals, preferably mammals, more particularly canines. The term "proteinuria" as used herein encompasses any elevated pathological UPC level, which may be preglomerular, glomerular, or postglomerular in origin. Pathological proteinuria is a persistent problem due to glomerular damage, while functional proteinuria is generally a transient problem. Lower urinary tract infection or inflammation (including tumors) can induce significant proteinuria, and urinary protein should always be evaluated in terms of urine sediment, culture results, and current clinical signs. Nonglomerular kidney diseases such as pyelonephritis, severe chronic renal failure, or acute renal tubular necrosis can also cause proteinuria. Excessive protein supply to the kidney ("preglomerular proteinuria") can lead to proteinuria in conditions such as hemoglobinuria or multiple myeloma. Proteinuria with elevated or pathological UPC levels may be associated with chronic kidney disease (CKD) and / or protein-losing nephropathy (PLN).

[0013] As used herein, the term "non-resistant to ACE inhibitor treatment" refers to dogs suffering from proteinuria that can be treated with an ACE inhibitor, but with lower efficacy than telmisartan. Conversely, the elevated UPC levels of dogs resistant to ACE inhibitor treatment cannot be reduced with the help of an ACE inhibitor. In non-treatment-resistant subpopulations of dogs, the effectiveness of treatment with ACE inhibitors is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, greater than 50%, greater than 60%, or greater than 70% less effective than telmisartan for reducing UPC levels. In a preferred embodiment, telmisartan and / or methods according to the invention relate to the treatment of non-treatment-resistant subpopulations of dogs, although the administration scheme according to the invention can advantageously be administered to both non-treatment-resistant and treatment-resistant subpopulations of dogs.

[0014] The dogs treated with telmisartan according to the present invention are preferably pet dogs of any breed, including any type of mixed breed. Depending on the breed or size of the mixed breed, they will develop proteinuria with elevated UPC levels at 7 years of age or older, preferably 7 to 18 years of age, particularly 8 to 16 years of age. Small breeds generally develop this disease at a later age than large breeds, preferably 8 to 18 years of age, which may be affected at 7 to 16 years of age. As used herein, the term "together with" or "in combination with" covers both separate and sequential administration of telmisartan and another drug. For example, when drugs are administered sequentially, either telmisartan or the other drug may be administered first. When drugs are administered simultaneously, the drugs may be administered in the same or different pharmaceutical compositions. Adjunctive therapy, i.e., when one drug is used as a primary treatment and the other drug is used to support the primary treatment, is also an embodiment of the present invention. In one embodiment of the present invention, the adjunctive therapy includes adding another drug to telmisartan after 30 days, 40 days, 60 days, 70, 80, 90 days, 100 days, 110 days, 120 days, or 1, 2, 3, 4, 5, 6, or 12 months, or any period between 30 and 120 days, or any period between 1 and 12 months. In one embodiment, the adjunctive therapy begins on day 90. In one embodiment, the other drug is enalapril. In one embodiment, the primary drug is telmisartan and the other drug is enalapril, and the other drug is added on or after day 90 of telmisartan treatment.

[0015] In yet another embodiment, the primary drug is telmisartan and the other drug is selected from the group consisting of amlodipine, pimobendan, levosimendan, ramipril, benazepril, and enalapril, and the other drug is added to the telmisartan treatment on day 90, day 120, day 180, day 360, or any time between day 90 and day 360. The active ingredient(s) may be used as separate formulations or as a single combined formulation. If combined in the same formulation, it will be understood that the two compounds must be stable and compatible with each other and the other ingredients of the formulation. Formulations of the present invention include those suitable for oral, parenteral (e.g., subcutaneous, intradermal, intrathecal, e.g., by injection or depot, including intramuscular and intravenous, e.g., by depot), rectal, topical (including cutaneous, buccal, and sublingual), or inhalation or insufflation administration. The optimal route of administration may depend on the patient's condition and disorder. Preferably, the compositions of the present invention are formulated for oral administration.

[0016] The formulations may be conveniently presented in unit dosage form, e.g., as described in "Remington: The Science and Practice of Pharmacy," Lippincott Williams and Wilkins, 21 st It may be prepared by any method well known in the field of pharmacy, such as described in "The Journal of Pharmaceutical Sciences, Vol. 1, No. 1, pp. 2005-2009." Suitable methods include the step of bringing into association the active ingredient with a carrier that constitutes one or more excipients. Generally, the formulation is prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. It will be understood that when two active ingredients are administered independently, each active ingredient may be administered by a different means. Formulations suitable for oral administration may be presented as discrete units such as capsules, wafers, tablets, etc., each containing a predetermined amount of the active ingredient, particularly as chewable tablets; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0017] Alternatively, the active ingredient may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Formulations containing the active ingredient may be presented as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, and / or hydrogenated edible fats and oils), emulsifiers (e.g., lecithin, sorbitan monooleate, and / or acacia gum), non-aqueous vehicles (e.g., edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and / or ethyl alcohol), preservatives (e.g., methyl or propyl p-hydroxybenzoates and / or sorbic acid). Additionally, the oral dosage form may contain one or more flavoring agents, which may increase compliance in dogs treated by chewing and swallowing the medication. Most preferably, telmisartan is administered orally in the form of a chewable tablet or in the form of an aqueous solution containing benzalkonium chloride, such as the product Semintra® available from Boehringer Ingelheim Vetmedica GmbH, Ingelheim, Germany.

[0018] Specifically, the following items are disclosed herein: a) Telmisartan or a pharmaceutically acceptable salt thereof for use in a method for treating elevated urinary protein creatinine ratio (UPC) levels in a dog in need of such treatment, the method comprising administering a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. b) Telmisartan according to item a), wherein elevated UPC levels are associated with chronic kidney disease (CKD), protein-losing nephropathy (PLN) and / or systemic hypertension. c) Telmisartan according to item a) or b), which is a sodium salt or a potassium salt. d) Telmisartan according to any one of items a) to c), wherein the daily therapeutically effective amount is in the range of 1.0 to 4.0 mg / kg body weight, preferably 1.0 to 3.5 mg / kg body weight, particularly 1.0 to 3.0 mg / kg body weight.

[0019] e) Telmisartan according to any one of items a) to d), wherein the daily dose of telmisartan is increased in the second period by an increment in the range of 0.25 to 2.50 mg / kg body weight. f) Telmisartan according to any one of items a) to e), wherein the daily dose of telmisartan during the first period of the treatment period is 1.0 to 1.5 mg / kg of body weight and the daily dose of telmisartan during the second period is 1.75 to 3.50 mg / kg of body weight. g) Telmisartan according to any one of items a) to f), wherein the daily dose of telmisartan is reduced after the second period by an incremental amount in the range of 0.25 to 2.50 mg / kg body weight. h) Telmisartan according to any one of items a) to g), wherein the daily dose of telmisartan is reduced if, after the second period, the urinary protein creatinine ratio (UPC) level measured in the dog has decreased by at least 70% compared to the baseline UPC value measured in the dog before the first period. i) Telmisartan according to any one of items a) to h), administered together with at least one other drug to a dog in need of such treatment.

[0020] j) Telmisartan according to item i), wherein the other drug is selected from the group consisting of calcium channel blockers, preferably amlodipine, cardiac calcium sensitizers, preferably pimobendan or levosimendan, ACE inhibitors, preferably ramipril, benazepril or enalapril. k) Telmisartan according to any one of items a) to j), wherein UPC levels are reduced by at least 50% compared to baseline within the first period of treatment. l) Telmisartan or a pharmaceutically acceptable salt thereof as a pharmaceutical for the treatment of a disease or disorder in dogs associated with elevated urinary protein creatinine ratio (UPC) levels that is non-resistant to treatment with ACE inhibitors. As shown in Figure 1 , the majority of dogs treated with telmisartan showed at least a 50% reduction in UPC at day 30 compared with dogs treated with enalapril (16 / 20 (80%) vs. 5 / 17 (29.4%), respectively). As shown in Figure 2, the mean change in UPC was greater in telmisartan-treated dogs compared to enalapril-treated dogs from Day 30 to Day 90, with telmisartan-treated dogs achieving a greater change at Day 90. Additionally, as shown in Figure 3, the mean percent change in UPC from Day 30 to Day 90 was greater in telmisartan-treated dogs compared to enalapril-treated dogs. The mean UPC decreased by more than 70 with the combination of telmisartan and enalapril from Day 90 to Day 120.

[0021] m) A method for treating elevated urinary protein creatinine ratio (UPC) levels in a dog in need of such treatment, comprising administering to the dog a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period. n) The method according to item m), wherein elevated UPC levels are associated with chronic kidney disease (CKD), protein-losing nephropathy (PLN) and / or systemic hypertension. o) The method according to item m), which comprises administering an effective amount of the sodium or potassium salt of telmisartan. p) The method according to item m), wherein the daily therapeutically effective amount of telmisartan is in the range of 1.0 to 4.0 mg / kg body weight, preferably 1.0 to 3.5 mg / kg body weight, in particular 1.0 to 3.0 mg / kg body weight.

[0022] q) The method according to item m), wherein the daily dose of telmisartan is increased in a second period by an incremental amount in the range of 0.25 to 2.50 mg / kg body weight. r) The method according to item m), wherein the daily dose of telmisartan is reduced after the second period by an incremental amount in the range of 0.25 to 2.50 mg / kg body weight. s) The method according to item r), wherein the daily dose of telmisartan is reduced if, after the second time period, the urinary protein creatinine ratio (UPC) level measured in the dog is reduced by at least 70% compared to the baseline UPC value measured in the dog before the first time period. t) The method according to item m), further comprising administering at least one other drug to the dog in need of such treatment. u) The method according to item t), wherein the other drug is selected from the group consisting of calcium channel blockers, cardiac calcium sensitizers, and ACE inhibitors.

[0023] v) The method according to item u), wherein the other drug is selected from the group consisting of amlodipine, pimobendan, levosimendan, ramipril, benazepril, and enalapril. w) The method according to item m), wherein the UPC level is reduced by at least 50% compared to baseline within the first period of treatment. x) A method for the treatment of a disease or disorder in a dog associated with elevated urinary protein creatinine ratio (UPC) levels that is non-resistant to treatment with an ACE inhibitor, said method comprising administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to a dog in need of such treatment. Having generally described the invention, it will be better understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0024] Example Experimental methods and design A prospective, block-randomized, double-blind clinical trial was conducted. Fifty-four client-owned dogs with persistent pathological renal proteinuria were recruited over a 2-year period. [Example]

[0025] animal Asphyxiated and non-asphyxiated dogs with hypertensive and non-hypertensive CKD (N = 54) were prospectively recruited from patients presenting to the hospital. Dogs included as cases had confirmed persistent pathological renal proteinuria due to CKD and met the following criteria to be classified as such: Inclusion criteria for patients Subjects were randomly assigned to study animals with UPC levels of approximately 2.0 (non-asphyxiated patients; IRIS stage 1) or approximately 0.5 (asphyxiated patients; IRIS stages 2-4) in two urine samples collected two weeks apart. Abdominal ultrasound examination demonstrated findings consistent with CKD (both kidneys small and irregular) and the absence of renal tumors.

[0026] Exclusion criteria Animals will be excluded if one or more of the following are identified: evidence of hemorrhage, inflammation, or bacteria on urine sediment analysis; a positive urine culture at the time of proteinuria identification; a positive heartworm antigen test within 3 months of proteinuria identification and / or not currently receiving regular monthly heartworm prophylaxis; historical, physical examination, or clinical pathology findings suggestive of acute kidney injury, infectious nephropathy, or lower urinary tract infection; systolic hypotension (SBP <120 mmHg); moderate to severe hyperkalemia (serum potassium >6.5 mmol / L); history of oral ACEi and / or corticosteroids within 1 month (ACEi) or 2 weeks (corticosteroids) prior to the study; or an intercurrent illness associated with proteinuria, the treatment of which may alleviate proteinuria (e.g., systemic lupus erythematosus, ehrlichiosis, tumor). Dogs with suspected or confirmed hyperadrenocorticism and diabetes are included if the disease is considered adequately controlled by medical therapy.

[0027] Grouping of patients for block randomization Once included in the study, dogs were grouped according to the International Renal Institutions Research Association (IRIS) classification scheme for CKD based on the presence / severity of azotemia. Dogs classified as IRIS stages 2–4 (serum creatinine ≥ 1.4 mg / dL with inadequately diluted urine [USG < 1.030]) were considered azotemic (AZ), whereas dogs classified as IRIS stage 1 (creatinine < 1.4 mg / dL) were considered non-azotemic (non-AZ). Within each of these two groups, dogs were stratified based on the IRIS recommendations for arterial pressure (AP) substaging. According to this scheme, dogs with a sustained mean indirect arterial systolic pressure < 150 mmHg were classified as AP0 (minimal risk of target organ damage). Dogs with a sustained mean indirect arterial systolic pressure ≥ 150 mmHg were classified as AP1–3 (at risk of target organ damage). Therefore, four groups were identified: 1.AZ (IRIS stages 2-4), IRIS substages AP1-3 2.AZ (IRIS stages 2-4), IRIS substage AP0 3. Non-AZ (IRIS stage 1), IRIS substage AP1-3 4. Non-AZ (IRIS stage 1), IRIS substage AP0 After being assigned to one of these four groups, each patient was assigned based on a randomized block scheme to receive either enalapril (n=27) or telmisartan (n=27), as described below. The purpose of the grouping was to ensure that the two treatment groups contained equal numbers of patients.

[0028] Baseline At enrollment (day 0), all owners were asked to read and sign a document consenting to their pet's participation in the study. The following baseline data were collected for each case: complete physical examination (performed by one of the investigators), fundus examination, blood pressure measurement, blood chemistry panel, urinalysis, abdominal ultrasound, UPC, and urine culture. Screening test results could be used as baseline information if performed within 2 weeks of study enrollment. Baseline UPC was defined as the mean of two measurements taken 2 weeks apart prior to enrollment.

[0029] ARB / ACEi therapy On day 0, dogs were randomly assigned in a double-blind manner to receive either telmisartan (group TEL, n=27) or enalapril (group ENAL, n=27) orally every 24 hours at 1 mg / kg. Randomization and distribution of telmisartan or enalapril was performed at the appropriate dose. Owners were provided with appropriate emergency contact telephone numbers. Enalapril is readily available, and telmisartan is supplied in aqueous solution by Boehringer Ingelheim Vetmedica Inc., St. Joseph, Missouri, and is marketed as Semintra®. Antihypertensives / Other Therapies Dogs classified as AP3 (SBP ≥ 180 mmHg; ≥ 200 mmHg in sight hounds) are concurrently administered a calcium channel blocker (CCB; amlodipine; 0.1 mg / kg orally every 24 hours). The concomitant administration of RAAS inhibitors and CCBs is common in human patients and has been recommended by a veterinary expert committee. 22 It is recommended by and has been shown to be effective in experimental models of proteinuria. All dogs were started on or continued on a commercially formulated diet low in phosphorus and protein for at least 1 month before enrollment. Dietary composition remained stable throughout the study. Fish oil treatment was permitted, provided dogs had been receiving this supplement for more than 1 month at the time of enrollment.

[0030] monitoring Monitoring procedures followed the recommendations of the Standard Therapy Subgroup of the IRIS Canine GN Study Group. All dogs were reexamined on day 7, during which physical examination, SBP, serum creatinine (sCr), and serum potassium (K) were assessed. A greater than 30% increase in sCr compared to baseline or identification of moderate / severe hyperkalemia (serum potassium greater than 6.5 mmol / L) or systolic hypotension (SBP less than 120) prompted investigators to unmask the patient and remove them from the study. For dogs with a reliably identified mean SBP of approximately 180 mmHg (i.e., if the dog was classified as AP3), amlodipine was titrated to 0.1 mg / kg twice daily. Dogs classified as AP3 were subsequently reexamined at 7-day intervals to ensure therapy effectiveness, with adjustments to antihypertensive therapy. At each study visit, assuming the mean SBP measurement remained approximately 180 mmHg, the dog's amlodipine dose was increased in increments of 0.05 mg / kg twice daily to a maximum dose of 0.3 mg / kg twice daily. SBP and sCr were retested 7 days later after any adjustments had been made.

[0031] Final Phase 1 Study Visit On day 30, all dogs underwent a physical examination, SBP, serum biochemistry, urinalysis, and UPC measurement. At this and subsequent time points, urine for UPC measurement consisted of a pooled sample made by combining three free-collected specimens collected by the owner the previous day and stored refrigerated. Main objective endpoints The primary objective endpoints for Phase 1 are the percent change in UPC (ΔUPC) and the proportion of patients achieving a 50% reduction in UPC or a reduction in UPC to <0.5 after 30 days of treatment. conclusion As shown in Figure 1 , a greater proportion of dogs treated with telmisartan experienced a 50% or greater decrease in UPC at day 30 compared with dogs treated with enalapril (16 / 20 (80%) vs. 5 / 17 (29.4%), respectively; P = 0.003). [Example]

[0032] Specific Objectives No. 2 and No. 3 (Phase 2 and Phase 3, Interim Phase) Phase 2 of this study compared the efficacy of enalapril and telmisartan when used as part of a protocol allowing titration of enalapril and telmisartan. Phase 3 evaluated the combination in dogs whose proteinuria persisted despite the highest dose of each drug alone. Each of the 54 dogs remained in the treatment group to which they were assigned in Phase 1. Within these groups, if the proteinuria UPC remained at approximately 0.5 on monthly retests, titration of the study drug followed by combination therapy was implemented.

[0033] ARB / ACEi therapy Phase 2 (Days 31–90): For dogs identified with a UPC of less than 0.5 on Day 30, treatment continued with telmisartan at a dose of 1 mg / kg orally every 24 hours or enalapril at a dose of 0.5 mg / kg orally twice daily until the end of the study (Day 120). For dogs identified with a UPC of approximately 0.5 on Day 30, the dose of study drug was titrated monthly in increments of 1 mg / kg orally every 24 hours (TEL group) or 0.5 mg / kg orally twice daily (ENAL group) until the target UPC of less than 0.5 was reached or until the "ceiling dose" of either drug was reached (3 mg / kg orally every 24 hours for telmisartan or 1.5 mg / kg orally twice daily for enalapril), whichever occurred first. Phase 3 (Days 91-120): For dogs identified with a UPC of less than 0.5 before Day 90, treatment continued with telmisartan or enalapril at a dose sufficient to cause control of proteinuria until the end of the study. For dogs identified with a UPC of approximately 0.5 at Day 90, enalapril at a dose of 0.5 mg / kg twice daily or telmisartan at a dose of 1 mg / kg every 24 hours was added to dogs in the TEL and ENAL groups, respectively. Combination therapy continued for one month until the end of the study. monitoring If an individual dog's treatment regimen was changed on day 30, he / she was reexamined 1 week later (day 37), at which time SBP, sCr, and serum potassium levels were assessed. A greater than 30% increase in creatinine or moderate / severe hyperkalemia (serum potassium greater than 6.5 mmol / L) prompted the investigator to unmask the patient and remove them from the study. If mild hyperkalemia (serum potassium 6.1–6.5 mmol / L) was identified, no escalation to the next dose was performed, regardless of UPC.

[0034] Thereafter, dogs with persistent proteinuria were monitored monthly (i.e., on days 60 and 90) by SBP, UPC, and urinalysis. If an active urinary sediment was identified, a urine culture was performed. For dogs with persistent proteinuria requiring drug titration, SBP, sCr, and serum potassium were retested 1 week after adjustment (days 67 and 97) and unmasked according to the criteria outlined above, followed by further dose titration. Dogs with a confirmed UPC of less than 0.5 at any time point had their monitoring parameters retested only at the end of the study (day 120). Final Study Visit: On day 120, all dogs undergo a complete physical examination, measurement of SBP, serum renal biochemistry, urinalysis (cystocentesis) and UPC.

[0035] Main objective endpoints The primary objective endpoints for Phase 2 included ΔUPC from baseline, the proportion of patients achieving a 50% reduction in UPC or a reduction in UPC to <0.5 after a total of 3 months of treatment, and time to a 50% reduction in UPC or a reduction in UPC to <0.5. The primary objective endpoints for Phase 3 included ΔUPC from baseline, ΔUPC through the treatment month (UPC at day 90 minus UPC at day 120), and the proportion of patients achieving a 50% reduction in UPC or a reduction in UPC to <0.5 with combination therapy. conclusion As shown in Figure 2, the mean change from baseline in UPC between days 30 and 90 was greater in telmisartan-treated dogs compared to enalapril-treated dogs, with telmisartan-treated dogs achieving a greater change at day 90. The mean UPC changes are shown in Table I below.

[0036] TIFF2025120167000001.tif29156 Additionally, as shown in Figure 3, the mean percent change from baseline in UPC was greater in telmisartan-treated dogs compared to enalapril-treated dogs from Day 30 to Day 90. The combination of telmisartan and enalapril from Day 90 to Day 120 achieved a mean UPC reduction of more than 70%. The mean percent change in UPC is shown in Table II below.

[0037] TIFF2025120167000002.tif46164Furthermore, as shown in Figure 4, the mean change in UPC for dogs receiving additional medication at day 90 was significantly greater for dogs initially treated with telmisartan than for dogs in the enalapril treatment group. The mean UPC changes are shown in Table III below.

[0038] Additionally, as shown in Figure 5, the mean change in UPC from day 90 to day 120 without additional drug administration was greater in telmisartan-treated dogs than in enalapril-treated dogs. The mean UPC changes are shown in Table IV below.

[0039] TIFF2025120167000004.tif34156

[0040] Cited literature The following publications are incorporated herein by reference in their entireties as if each individual publication were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. TIFF2025120167000005.tif214158 TIFF2025120167000006.tif76154

Claims

1. 1. A method for treating elevated urinary protein creatinine ratio (UPC) levels in a dog in need of such treatment, comprising administering a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period.

2. 2. The telmisartan of claim 1, wherein elevated UPC levels are associated with chronic kidney disease (CKD).

3. 3. Telmisartan according to claim 1 or 2, wherein elevated UPC levels are associated with leaky nephropathy (PLN).

4. Telmisartan according to any one of claims 1 to 3, wherein elevated CKD and UPC levels are associated with systemic hypertension.

5. Telmisartan according to any one of claims 1 to 4, which is a sodium or potassium salt.

6. 6. The telmisartan according to any one of claims 1 to 5, wherein the daily therapeutically effective amount is in the range of 1.0 to 4.0 mg / kg body weight.

7. The method of any one of claims 1 to 6, wherein the daily dosage of telmisartan is increased in the second period by an increment in the range of 0.25 to 2.50 mg / kg body weight.

8. 8. The method of claim 1, wherein the daily dose of telmisartan is 1.0 to 1.5 mg / kg body weight during a first period of the treatment period and 1.75 to 3.50 mg / kg body weight during a second period of the treatment period.

9. Telmisartan according to any one of claims 1 to 8, wherein the daily dosage of telmisartan is reduced after the second period by an increment in the range of 0.25 to 2.50 mg / kg body weight.

10. 10. The method of claim 1, wherein the daily dose of telmisartan is reduced if the level of urinary protein creatinine ratio (UPC) measured in the dog after the second period is reduced by at least 70% compared to the baseline UPC value measured in the dog before the first period.

11. Telmisartan according to any one of claims 1 to 8, administered together with at least one other drug to a dog in need of such treatment.

12. 10. Telmisartan according to claim 9, wherein the other drug is selected from the group consisting of calcium channel blockers, preferably amlodipine, cardiac calcium sensitizers, preferably pimobendan or levosimendan, ACE inhibitors, preferably ramipril, benazepril or enalapril.

13. Telmisartan according to any one of claims 1 to 9, wherein UPC levels are reduced by at least 50% compared to baseline within the first period of treatment.

14. Telmisartan or a pharmaceutically acceptable salt thereof as a pharmaceutical for the treatment of a disease or disorder associated with elevated urinary protein creatinine ratio (UPC) levels in dogs that is non-refractory to treatment with ACE inhibitors.

15. 1. A pharmaceutical composition comprising telmisartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for use in a method for treating elevated urinary protein creatinine ratio (UPC) levels in a dog in need of such treatment, said method comprising administering a therapeutically effective amount of telmisartan to the dog, said therapeutically effective amount of telmisartan being administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period.

16. A method for treating elevated urinary protein creatinine ratio (UPC) levels in a dog in need of such treatment, comprising administering to the dog a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of telmisartan is administered at various daily dosages throughout a treatment period, wherein the daily dosage of telmisartan is at least 1.0 mg / kg body weight during a first period during the treatment period, and wherein the daily dosage of telmisartan is increased during a second period following the first period during the treatment period.

17. 17. The method of claim 16, wherein elevated UPC levels are associated with chronic kidney disease (CKD).

18. 17. The method of claim 16, wherein elevated UPC levels are associated with protein-losing nephropathy (PLN).

19. 17. The method of claim 16, wherein elevated UPC levels are associated with CKD and PLN.

20. 17. The method of claim 16, wherein elevated UPC levels are associated with systemic hypertension.

21. 17. The method of claim 16, comprising administering an effective amount of the sodium or potassium salt of telmisartan.

22. 17. The method of claim 16, wherein the daily therapeutically effective amount of telmisartan is in the range of 1.0 to 4.0 mg / kg body weight.

23. 17. The method of claim 16, wherein the daily dosage of telmisartan is increased during the second period by an increment ranging from 0.25 to 2.50 mg / kg body weight.

24. 17. The method of claim 16, wherein the daily dosage of telmisartan is reduced after the second period by an incremental amount in the range of 0.25 to 2.50 mg / kg body weight.

25. 25. The method of claim 24, wherein the daily dose of telmisartan is reduced if the level of urinary protein creatinine ratio (UPC) measured for the dog after the second period is reduced by at least 70% compared to the baseline UPC value measured for the dog before the first period.

26. 17. The method of claim 16, further comprising administering at least one other drug to a dog in need of such treatment.

27. 27. The method of claim 26, wherein the other drug is selected from the group consisting of calcium channel blockers, cardiac calcium sensitizers, and ACE inhibitors.

28. 28. The method of claim 27, wherein the other drug is selected from the group consisting of amlodipine, pimobendan, levosimendan, ramipril, benazepril, and enalapril.

29. 17. The method of claim 16, wherein UPC levels are reduced by at least 50% compared to baseline within the first period of treatment.

30. A method for treating a disease or disorder in a dog associated with elevated urinary protein creatinine ratio (UPC) levels that is non-resistant to treatment with an ACE inhibitor, the method comprising administering a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to a dog in need of such treatment.

Images