Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/401—Proline; Derivatives thereof, e.g. captopril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• 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.
• UPC urinary protein-to-creatinine ratio
• Intervention in the form of dietary modification and treatment with pharmacologic agents designed to mitigate urinary protein loss
• intervention is considered standard-of-care for dogs with proteinuric CKD
• Interventions that reduce the magnitude of proteinuria in affected dogs are associated with improved outcomes
• Angiotensin-converting enzyme inhibitors (ACEI) such as enalapril
• ACEI Angiotensin-converting enzyme inhibitors
• enalapril have been shown to decrease proteinuria in experimental [7] and naturally occurring [12, 14] models of canine CKD and are the drugs most widely prescribed for this purpose.
• ACEI angiotensin II
• the International patent application WO 2019/008077 teaches an administration scheme of sartans for prophylaxis or treatment of hypertension in a cat, where the initial dosage is 1.0 to 5.0 mg/kg of bodyweight and is decreased in a subsequent period.
• PPN Protein Losing Nephropathies
• UPC urine protein-creatinine ratio
• diseases such as glomerulonephritis (GN), glomerulopathy, and amyloidosis.
• GN glomerulonephritis
• glomerulopathy glomerulopathy
• amyloidosis The normal glomerulus acts to allow filtration of small molecules but restricts passage of larger or negatively charged molecules. If the glomerulus is damaged, large or negatively charged molecules can pass through resulting in leakage into the urine.
• PLN may lead to CKD if the losses are not controlled. Controlling proteinuria is the primary focus for the treatment of PLN.
• dogs can be treated against elevated urinary protein-to-creatinine ratio (UPC) levels by administering therapeutically effective amounts of telmisartan, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• UPC urinary protein-to-creatinine ratio
• the invention relates to telmisartan or a pharmaceutically acceptable salt thereof for use in a method for the treatment of elevated UPC levels in a dog in need of such treatment, wherein the method comprises administration of a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• the 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, which are non-refractory to the treatment with ACE inhibitors in dogs.
• UPC urinary protein-to-creatinine ratio
• a method for the treatment of elevated urinary protein-to-creatinine ratio (UPC) levels in a dog in need of such treatment comprises administration of a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• UPC urinary protein-to-creatinine ratio
• the invention provides a method for the treatment of elevated urinary protein-to-creatinine ratio (UPC) levels, which are non-refractory to the treatment with ACE inhibitors in dogs, which method comprises administration of a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to a dog in need of such a treatment.
• UPC urinary protein-to-creatinine ratio
• the invention relates to a pharmaceutical composition for use in a method for the treatment of chronic kidney disease of elevated urinary protein-to-creatinine ratio (UPC) levels, in a dog in need of such treatment, which comprises telmisartan or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier.
• UPC urinary protein-to-creatinine ratio
• FIG. 1 is a plot of the proportion of telmisartan-treated dogs compared to enalapril-treated dogs, which experienced a reduction of UPC > 50% at day 30 (cp. Example 1).
• FIG. 2 is a plot of the average change from baseline in UPC from day 30 to day 90 for telmisartan treated dogs compared to enalapril treated dogs (cp. Example 2).
• FIG. 3 depicts the average percent change from baseline of UPC in telmisartan treated dogs compared to enalapril treated dogs from day 30 to day 120 (cp. Example 2), where at day 90 enalapril has been added to the telmisartan group and telmisartan has been added to the enalapril group.
• FIG. 4 depicts the average change from baseline of UPC in telmisartan dogs compared to enalapril treated dogs from day 30 to day 120 (cp. Example 2), where at day 90 enalapril has been added to the telmisartan group and telmisartan has been added to the enalapril group..
• FIG. 5 depicts the average change from baseline of UPC in telmisartan dogs compared to enalapril treated dogs from day 30 to day 120 (cp. Example 2), where at day 90 no enalapril has been added to the telmisartan group and vice versa.
• the daily dosage amount of telmisartan for a first period of time during the treatment period can be 1.0 to 1.5 mg/kg of body weight, where the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• the term“pharmaceutically acceptable salts” includes the metal salts or the addition salts which can be used in dosage forms.
• the pharmaceutically acceptable salts of the compounds provided herein can be acid addition salts, base addition salts or metal salts, and can be synthesized from parent compounds containing a basic or acid residue by means of conventional chemical processes.
• Such salts are generally prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of both.
• Non-aqueous media are generally preferred, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
• acid addition salts include mineral acid additions salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
• mineral acid additions salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
• organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
• alkali addition salts include inorganic salts such as, for example, ammonium salts and organic alkaline salts such as, for example, diethylamine, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine and basic amino acid salts.
• organic alkaline salts such as, for example, diethylamine, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine and basic amino acid salts.
• metal salts include, for example, sodium, potassium, calcium, magnesium, aluminium and lithium salts.
• the term “pharmaceutically acceptable” relates to molecular entities and compositions that are physiologically tolerable and do not normally cause an allergic reaction or a similar adverse reaction, such as gastric discomfort, dizziness and the like, when administered to humans.
• the term“pharmaceutically acceptable” preferably means that it is approved by a regulatory agency of the federal or state government or listed in the US pharmacopoeia or another pharmacopoeia, generally recognized for its use in animals, preferably in mammals and more particularly in dogs.
• proteinuria as used herein embraces any kind of elevated, pathologic UPC levels, which can be pre-glomerular, glomerular, or post-glomerular in origin.
• Pathologic proteinuria is a persistent problem from glomerular damage, whereas functional proteinuria is generally transient. Infection or inflammation (including neoplasia) of the lower urinary tract can induce significant proteinuria, and urinary protein should always be evaluated in light of the urinary sediment and culture results and the clinical signs present.
• Non-glomerular renal diseases such as pyelonephritis, severe chronic renal failure, or acute tubular necrosis may also cause proteinuria.
• pre-glomerular proteinuria Excessive protein delivery to the kidney (“pre-glomerular proteinuria”) may lead to proteinuria, in conditions such as hemoglobinuria or multiple myeloma. Proteinuria with elevated or pathologic UPC levels may be associated with chronic kidney disease (CKD) and/or protein losing nephropathy (PLN).
• CKD chronic kidney disease
• PPN protein losing nephropathy
• non-refractory to the treatment with ACE inhibitors refers to dogs suffering from proteinuria, which can be treated with an ACE inhibitor, but with less efficacy than telmisartan. To the contrary the elevated level of UPC of dogs that are refractory to ACE inhibitors cannot be lowered with the aid of ACE inhibitors.
• the efficacy of treatment with an ACE inhibitor is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, more than 50%, more than 60%, or more than 70% less effective than telmisartan for lowering their UPC levels.
• the telmisartan and/or the method according to the invention relates to the treatment of the non-refractory subpopulation of dogs.
• the administration scheme according to the invention may advantageously be administered to both the subpopulations, the non-refractory as well as to refractory dogs.
• the dogs to be treated with telmisartan according to the invention are preferably pet dogs of any breed including any kind of mongrel. Depending on the size of the breed or mongrel they will suffer from proteinuria with elevated UPC levels at an age of 7 years or more, preferably from 7 to 18 years, in particular from 8 to 16 years. Small breeds will as a rule suffer at a later age, preferably from 8 to 18, from this disease than big ones, which may be affected at an age of 7 to 16 years.
• telmisartan covers both separate and sequential administration of telmisartan and another drug.
• the agents when the agents are administered sequentially, either the telmisartan or the other drug may be administered first.
• administration is simultaneous, the agents may be administered either in the same or a different pharmaceutical composition.
• Adjunctive therapy i.e. where one agent is used as a primary treatment and the other agent is used to assist that primary treatment, is also an embodiment of the present invention.
• adjunctive therapy includes adding the other agent to telmisartan after a period of time such as after 30 days, after 40 days, after 60 days, after 70, 80, 90 days, 100 days, 1 10 days, 120 days, or after 1 , 2, 3, 4, 5, 6, or 12 months, or after any period of time between 30 and 120 days, or after any period of time between 1 and 12 months.
• the adjunctive therapy is started at day 90.
• the other agent is enalapril.
• the primary agent is telmisartan
• the other agent is enalapril
• the other agent is added to the telmisartan treatment at 90 days, or after 90 days.
• the primary agent is telmisartan
• the other agent is selected from the group consisting of amlodipine, pimobendan, levosimendan, ramipril, benazepril and enalapril
• the other agent is added to treatment with telmisartan at 90 days, 120 days, 180 days, 360 days, or at any time between 90 days and 360 days.
• the one or more active ingredients may be used either as separate formulations or as a single combined formulation. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
• Formulations of the invention include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) or in a form suitable for administration by inhalation or insufflation administration.
• parenteral including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous
• rectal and topical including dermal, buccal and sublingual
• the most suitable route of administration may depend upon the condition and disorder of the patient.
• the compositions of the invention are formulated for oral administration.
• formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy e.g. as described in“Remington: The Science and Practice of Pharmacy”, Lippincott Williams and Wilkins, 21 st Edition, (2005). Suitable methods include the step of bringing into association to active ingredients with a carrier which constitutes one or more excipients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. It will be appreciated that when the two active ingredients are administered independently, each may be administered by a different means.
• Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, in particular chewable tablets, each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or water-in-oil liquid emulsion.
• the active ingredients may also be presented a bolus, electuary or paste.
• the active ingredients may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs.
• Formulations containing the active ingredients may also 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, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats), emulsifying agents (e.g. lecithin, sorbitan mono-oleate and/or acacia), non-aqueous vehicles (e.g.
• suspending agents e.g. sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats
• emulsifying agents
• edible oils such as almond oil, fractionated coconut oil, oily esters, propylene glycol and/or ethyl alcohol
• preservatives e.g. methyl or propyl p- hydroxy benzoates and/or sorbic acid
• the oral formulation may contain one or more flavoring agents, which enhance the compliance of the dog to be treated to chew and swallow the medication.
• telmisartan is administered orally in form of a chewable tablet or as an aqueous solution containing benzalkonium chloride as in the product Semintra®, which is commercially available from Boehringer Ingelheim Vetmedica GmbH, Ingelheim Germany.
• telmisartan or a pharmaceutically acceptable salt thereof for use in a method for the treatment of elevated urinary protein-to-creatinine ratio (UPC) levels in a dog in need of such treatment, wherein the method comprises administration of a therapeutically effective amount of telmisartan to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• UPC urinary protein-to-creatinine ratio
• telmisartan according to any one of items a) to d), wherein the daily dosage amount of telmisartan is increased for the second period of time by an incremental amount ranging from 0.25 to 2.50 mg/kg of body weight.
• telmisartan according to any one of items a) to f), wherein the daily dosage amount of telmisartan is decreased after the second period of time by an incremental amount ranging from 0.25 to 2.50 mg/kg of body weight.
• telmisartan according to any one of items a) to g), wherein the daily dosage amount of telmisartan is decreased after the second period of time when the urinary protein-to- creatinine ratio (UPC) level measured for the dog decreases by at least 70 % in relation to a baseline UPC value measured for the dog prior to the first period of time.
• UPC urinary protein-to- creatinine ratio
• i) Telmisartan according to item i), wherein the other drug is selected from the group consisting of calcium channel blockers, preferably amlodipine, cardiotonic- calcium sensitizing agents, preferably pimobendan or levosimendan, ACE inhibitors, preferably ramipril, benazepril or enalapril.
• the other drug is selected from the group consisting of calcium channel blockers, preferably amlodipine, cardiotonic- calcium sensitizing agents, preferably pimobendan or levosimendan, ACE inhibitors, preferably ramipril, benazepril or enalapril.
• telmisartan-treated dogs shows at least a 50% reduction in UPC at day 30 (16/20 (80%) versus 5/17 (29.4%), respectively) as shown in FIG. 1.
• the average change in UPC is greater from day 30 to day 90 for telmisartan treated dogs compared to enalapril treated dogs with a greater change realized at day 90 for telmisartan treated dogs.
• the average percent change from baseline in UPC is greater in telmisartan treated dogs compared to enalapril treated dogs from day 30 to day 90 as shown in FIG. 3.
• the combination of telmisartan and enalapril from day 90 to day 120 achieves a reduction of more than 70 of the average UPC.
• a method for the treatment of elevated urinary protein-to-creatinine ratio (UPC) levels, in a dog in need of such treatment comprises administration of a therapeutically effective amount of telmisartan or a pharmaceutically acceptable salt thereof to the dog, wherein the therapeutically effective amount of telmisartan is administered in a daily dosage amount that is varied over a treatment period, the daily dosage amount of telmisartan for a first period of time during the treatment period is at least 1.0 mg/kg of body weight, and the daily dosage amount of telmisartan is increased for a second period of time subsequent the first period of time during the treatment period.
• the elevated UPC levels are associated with chronic kidney disease (CKD), protein losing nephropathy (PLN) and/or systemic hypertension.
• telmisartan ranges from 1.0 to 4.0 mg/kg, preferably 1.0 to 3.5 mg/kg, in particular 1.0 to 3.0 mg/kg of body weight.
• UPC urinary protein-to-creatinine ratio
• Inclusion criteria Included animals had an UPC level of approximately 2.0 (for non-azotemic patients; IRIS stage 1) or approximately 0.5 (for azotemic patients; IRIS stages 2-4), documented in each of two urine samples collected 2 weeks apart. Abdominal ultrasound findings consistent with CKD (bilaterally small, irregular kidneys) and absence of renal neoplasia have also been documented.
• Exclusion criteria Animals have been excluded if one or more of the following are identified: evidence of hemorrhage, inflammation or bacteria on urine sediment analysis; positive urine culture at the time of identification of proteinuria; positive heartworm antigen test within 3 months of identification of proteinuria and/or not currently receiving regular monthly heartworm preventive; historical, physical examination or clinical pathologic findings suggestive of acute kidney injury, infectious nephropathy or lower urinary tract infection; systolic hypotension (SBP ⁇ 120 mm Hg); moderate-to-severe hyperkalemia (serum K >6.5 mmol/L); history of having received oral ACEi and/or corticosteroids in the month (ACEi) or 2 weeks (corticosteroids) preceding examination; concurrent illness associated with proteinuria, the treatment of which might result in mitigation of proteinuria (e.g, systemic lupus erythematosis, ehrlichiosis, neoplasia). Dogs with suspected or confirmed hyper-adrenocorticism and diabetes me
• IRIS International Renal Interest Society
• dogs with persistent average indirect arterial systolic BP ⁇ 150 mm Hg will be classified as AP0 (minimal risk for target organ damage).
• Those with persistent average indirect arterial systolic BP>150 mm Hg have been classified as AP1-3 (at risk for target organ damage).
• Four groups will thus be identified:
• IRIS Stages 2-4 IRIS substage AP1-3 3. non-AZ (IRIS Stage 1), IRIS substage AP1 -3
• IRIS Stages 2-4 IRIS substage AP0 4. non-AZ (IRIS Stage 1), IRIS substage AP0
• Baseline On inclusion (day 0), all owners have been required to read/sign a form consenting to their pets’ participation in the study.
• the following baseline data have been collected for each case: full physical examination (performed by one of the study investigators), fundic examination, blood pressure measurement, serum chemistry panel, urinalysis, abdominal ultrasound, UPC and urine culture.
• the results of screening tests, if performed within 2 weeks of inclusion in the study, may be used as baseline information.
• Baseline UPC has been defined as the average of two measurements, taken 2 weeks apart, prior to enrollment.
• a calcium channel blocker (CCB; amlodipine, 0.1 mg/kg PO q 24 hours) has been administered contemporaneously.
• Co-administration of RAAS-inhibitors and CCB is common in human patients, recommended by a panel of veterinary experts 22 and shown to be efficacious in a laboratory model of proteinuria. All dogs have been started or maintained on a commercially available diet formulated to be low in phosphorus and protein, for at least 1 month prior to enrollment. During the study period, diet remained constant. T reatment with fish oil has been allowed, provided that the dog has been receiving this supplement for >1 month at the time of enrollment.
• dogs classified as AP3 have been rechecked at 7-day intervals to ensure efficacy of therapy with adjustment of antihypertensive therapy.
• SBP measurements remained at about 180 mm Hg, then the dog’s amlodipine dose have been increased in increments of 0.05 mg/kg BID to a maximum dose of 0.3 mg/kg BID.
• SBP and sCr have been rechecked 7 d following any adjustments.
• the major objective endpoints of phase I are percentage change in UPC (AUPC) and percentage of patients achieving 50% reduction or decrease to ⁇ 0.5 of UPC after 30 d of therapy.
• Phase II of this study compared the efficacy of enalapril and telmisartan when these drugs were used as part of protocols that allow their up-titration, and phase III will evaluate their combination in dogs whose proteinuria persisted in the face of the highest doses of each drug alone. Each of the 54 dogs will remain in the treatment group to which he/she was assigned in phase I. Within these groups, up-titration of study drugs, followed by combination therapy have been performed if proteinuria persisted with UPC at about 0.5 on monthly rechecks.
• Phase II (days 31-90 ' ): For those dogs in which UPC ⁇ 0.5 was identified on day 30, treatment continued with telmisartan at a dose of 1 mg/kg PO q 24 h or enalapril at a dose of 0.5 mg/kg PO BID until the end of the study (day 120).
• the dose of study drug has been up-titrated monthly in increments of 1 mg/kg PO q 24 h (TEL group) or 0.5 mg/kg BID (ENAL group) until a target UPC ⁇ 0.5 was attained OR a“ceiling dose” (3 mg/kg PO q 24 h for telmisartan or 1.5 mg/kg PO BID for enalapril) of either drug is reached, whichever occurs first.
• Phase III (days 91-1201: For those dogs in which UPC ⁇ 0.5 was identified on or before day 90, treatment continued with telmisartan or enalapril at the dose producing proteinuria control until the end of the study. For those in which UPC approximately 0.5 was identified on day 90, enalapril at a dose of 0.5 mg/kg BID or telmisartan at a dose of 1 mg/kg q 24 h has been added for dogs in the TEL and ENAL groups, respectively. Combination therapy continued for 1 month, until the end of the study.
• the major objective endpoints for phase II included AUPC from baseline and percentage of patients achieving 50% reduction or decrease to ⁇ 0.5 of UPC following a total of 3 months of therapy, as well as time to 50% reduction or decrease to ⁇ 0.5 of UPC.
• Phase Ill’s major objective endpoints included AUPC from baseline, AUPC over the month of therapy (UPCday90 - UPCday120) and percentage of patients achieving 50% reduction or decrease to ⁇ 0.5 of UPC with combination therapy.
• the average percent change from baseline in UPC is greater in Telmisartan treated dogs compared to Enalapril treated dogs from day 30 to day 90 as shown in FIG. 3.
• the combination of Telmisartan and Enalapril from day 90 to day 120 achieves a > 70 % reduction of the average UPC.
• the average of UPC percent change is shown in the following table II
• telmisartan has been administered between day 90 and day 120
• additional enalapril has been administered between day 90 and day 120
• FIG. 5 The average of UPC change is shown in the following table IV.

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