TREATMENT OF DIABETES MELLITUS

Related Applications

This application claims the benefit of Indian Provisional Application No. 201821006582 filed on Feb 21, 2018; and Indian Provisional Application No. 201821046108 filed on Dec 6, 2018; which is hereby incorporated by reference in its entirety.

Technical Field of the Invention

The invention relates to an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

Background of the Invention

Diabetes is a metabolic syndrome characterized by hyperglycemia, which results from an absolute deficiency in insulin secretion (type 1 diabetes) or from resistance to insulin action combined with an inadequate compensatory increase in insulin secretion (type 2 diabetes). Type 1 diabetes is also called insulin-dependent diabetes. By far, the most common form of diabetes is type 2 diabetes, accounting for 95% of diabetes cases in adults. The chronic hyperglycemia in type 2 diabetes can cause major health complications, particularly in the smallest blood vessels in the body that nourish the kidneys, nerves, and eyes. The chronic hyperglycemia of diabetes is also associated with long term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Management of diabetes concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications. Oral therapeutic options for the treatment of type 2 diabetes mellitus include agents known as: biguanides (metformin), sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors.

SGLT2 is a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibitors lead to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type 2 diabetes.

Remogliflozin (base) has been disclosed in PCT publication W02001/016147 Al.

Remogliflozin etabonate is the pro-drug of remogliflozin. Remogliflozin etabonate also known as 5-methyl-4- [4-( 1 -methylethoxy)benzyl] - 1 -( 1 -methylethyl)- 1 H-pyrazol-3-yl-6-0- (ethoxycarbonyl)-P -D-glucopyranoside has the following formula

US Patent 7,084,123 discloses Remogliflozin etabonate and its salts. Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type 2 diabetes mellitus. Remogliflozin etabonate has the potential to be used as monotherapy for the treatment of type 2 diabetes in human subjects suffering from diabetes. Efforts have been made to develop oral formulations of remogliflozin for the treatment of type II diabetes.

PCT publication W02012/006398A2 relates to a biphasic composition comprising remogliflozin etabonate delayed release portions dispersed in remogliflozin immediate release portions. PCT publication W02009/022010A1 relates to a pharmaceutical composition comprising combination of SGLT2 inhibitor and DPP-IV inhibitor. The US patent 8,951,976 relates to a method of treatment for NAFL, NASH, hypernutritive fatty liver, alcoholic fatty liver disease, diabetic fatty liver and acute fatty liver using remogliflozin etabonate. PCT publication WO2010/092125 A 1 relates to a composition comprising (a) an SGLT2 inhibitor, and (b) a DPPIV inhibitor, and (c) a third anti-diabetic agent. PCT publication. However, there still exists a need for stable immediate release formulation of remogliflozin or pharmaceutically acceptable salt or ester thereof in combination with biguanide such as metformin used for treatment of type 2 diabetes mellitus.

Although several approaches have been reported in the art with respect to formulations comprising remogliflozin, there remains a substantial need in the art for new and improved pharmaceutical formulations of remogliflozin which exhibit advantageous effect on the treatment of type 2 diabetes mellitus. The present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

Summary of the Invention

In one embodiment, there is provided an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.

In another embodiment, there is provided an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

In another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and (B) an extra- granular portion comprising a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

In another embodiment, the pharmaceutically acceptable excipients are one or more of a diluent, a disintegrant, a binder, a glidant, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, or combinations thereof.

In still another embodiment, the remogliflozin or pharmaceutically acceptable salt or ester thereof is remogliflozin etabonate. In still another embodiment, the remogliflozin etabonate is present in an amount of about lOmg to about lOOOmg, preferably in an amount of about 50mg, or about lOOmg, or about 250mg.

In still another embodiment, the pharmaceutical composition comprises the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant in a weight ratio of about 1:0.01 to about 1: 10. Alternatively, the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disinetgrant is present in weight ratio of about 1:0.05 or about 1 :0.06.

In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) microcrystalline cellulose, (c) crosscarmellose sodium, and (d) polyvinylpyrrolidone, and (B) an extra-granular portion having (a) crosscarmellose sodium, (b) microcrystalline cellulose and (c) magnesium stearate, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 1 l00ng.hr/ml to about 6000ng.h/ml.

In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1 :0.0l to about 1 : 10 in either intra-granular portion or extra-granular portion.

In yet another embodiment, there is provided a kit comprising an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

In yet another embodiment, there is provided a method of treating a diabetes by administering to a subject in a need thereof an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml,

In yet another embodiment, the invention composition are provided as tablet, capsule, powder, mini-tablet, suspension, solution, pill and like. In yet another embodiment, the invention composition are administered as once a daily, or twice a daily, or thrice a daily administration by oral route.

In yet another embodiment, there is provided a process of preparing an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, said process comprises steps of: (i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable excipients to obtain granules, (ii) mixing said granules of step (i) with the pharmaceutically acceptable excipients and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form.

Detail Description of the Invention

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth in a non -provisional application claiming priority from the provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.

Remogliflozin etabonate (also referred as GSK189075) is a prodrug of remogliflozin that selectively inhibits SGLT2 and is shown to have a significantly short plasma half-life (ranging from 1.4 to 2.9 hrs) compared to other approved members (Dapagliflozin, Canagliflozin, Empagliflozin) of this class (half-life ranging from 10.6 to 13.1 hrs). Remogliflozin is being developed for use in the treatment of type 2 diabetes as monotherapy and in combination with existing anti-diabetic therapies. So far, a total of 26 clinical studies (Phase I, phase II and phase III) have been conducted in which 2050 subjects have been enrolled. A total of 434 healthy volunteers (including healthy obese subjects), 1152 subjects with type 2 diabetes, 10 subjects with type 1 diabetes and 19 special population subjects with mild or moderate renal impairment have been exposed to GSK189075 for up to 12 weeks, and at daily oral doses up to 4000 mg. Safety and efficacy of remogliflozin in patients with type 2 diabetes has been evaluated in separate dose ranging trials with BID (Bis a day) and QD (Once a day) dosing regimens of l2-weeks duration and it has shown significant reduction in HbAlc levels as well as fasting plasma glucose concentrations at the end of 12 weeks compared to placebo. Among these, the BID regimen showed better and more consistent efficacy and a discernible dose response effect compared to QD regimen, probably owing to its short half-life. Remogliflozin administered as BID regimen has also been well tolerated in the clinical studies at doses up to 1000 mg BID with low incidence of glycosuria related adverse events such as urinary tract infections (0-4%) and genital fungal infections (0-8.5%). There was no incidence of diabetic keto-acidosis across clinical studies. Efforts were made to modify the formulation (i.e. biphasic formulation with immediate and delayed release components) to achieve adequate efficacy and safety with once daily dosing regimen; however results for dose ranging 12-week study conducted with this formulation did not show comparable glycemic efficacy and dose response as compared to BID regimen with IR formulation. There was a statistically significant reduction of HbAlc with all the doses tested. The present inventors have found a novel and stable immediate release compositions of remogliflozin or pharmaceutical acceptable salt or ester thereof, where in the composition is efficacious and pose no toxicity in clinical studies. The present compositions are also proved non-inferior to dapagliflozin marketed composition for the treatment of type 2 diabetes.

There is provided an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.

The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.

As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" with regard to a certain therapeutically effective pharmaceutical dose indicates that values slightly outside the cited values, e.g., plus or minus 0.1% to 10%, which are also effective and safe.

As used herein, the terms "comprising", "including", "such as", and "for example" (or "e.g.") are used in their open, non-limiting sense.

"Subject" refers to an animal (especially mammal) or human being treated. The term "treating" and its grammatical variants (e.g. "to treat," "treating," and "treatment") refer to administration of remogliflozin etabonate to a patient with the purpose of ameliorating or reducing the incidence of one or more symptoms of a condition or disease state in the patient. Such symptoms may be chronic or acute; and such amelioration may be partial or complete.

Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

"Bioavailability" as used herein, refers to the amount of unchanged drug that reaches systemic circulation.

HbAlc: Glycated haemoglobin

“Cmax”: peak concentration during a dosing interval.

“Cmin”: minimum of trough concentration during a dosing interval

“T _m ax”: time of peak drug concentration during a dosing interval.

“AUC”: area under the concentration-time curve

“AUCo- _t au”: area under the concentration-time profile over a dosing interval

“AUCo- _t auss”: area under the concentration-time profile over a dosing interval at steady state.

QD: once daily

BID: twice in a day

There is provided an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

Particularly, there are provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, and (B) an extra-granular portion comprising a pharmaceutically acceptable excipient, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

The remogliflozin or pharmaceutically acceptable salt or ester thereof is remogliflozin etabonate. The remogliflozin etabonate is present in an amount of about lOmg to about lOOOmg. Alternatively, the remogliflozin etabonate is present in an amount of about 20mg, or about 30mg, or about 40mg, or about 50mg, or about 60mg, or about 70mg, or about 80mg, or about 90mg, or about lOOmg, about l50mg, or about 200mg, or about 250mg, or about 300mg, or about 400mg, or about 500mg, or about 600mg, or about 700mg, or about 800mg, or about 900mg. Alternatively, the invention composition comprises about 50mg, or about lOOmg or about 250mg of remogliflozin etabonate.

The remogliflozin or pharmaceutically acceptable salt or ester thereof is administered orally as once a day or twice a day or thrice a day. Preferred dosing is twice a day.

The pharmaceutical composition can be present in the form of a tablet, capsule, tablets in capsule, bilayer tablet, soft gelatin capsule, pill, oral suspension or solution. The compositions of the invention can be prepared by using known formulation methods such as direct compaction, wet granulation, dry granulation, hot melt granulation, granulation using spheronization etc.

The excipients are one or more of a diluent, a disintegrant, a binder, a glidant, a lubricant, a preservative, a buffering agent, a chelating agent, a polymer, an opacifier, a colorant, a gelling agent or viscosity modifying agent, an antioxidant, a solvent, a co-solvent, or combinations thereof.

The diluent is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, micro fine cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, sugars such as dextrose, mannitol, sorbitol, sucrose and combinations thereof. The diluent is present in a concentration of about 5-60% w/w by weight of composition. Alternatively, the diluent is present in a concentration of about 8-55% w/w, or about 12-30% w/w, or about 14- 18% w/w by weight of composition. In an embodiment, the intra-granular portion comprises diluent in about 5-30% w/w by weight of diluent or about 6% w/w by weight. In another embodiment, the extra-granular portion comprises diluent in about 5-60% w/w or about 55% w/w by weight.

The disintegrant is selected from the group consisting of crosscarmellose sodium, starch, potato starch, corn starch, crospovidone, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and combination thereof. The disintegrant is present in a concentration of about 1-30% w/w by weight of composition. Alternatively, the disintegrant is present in a concentration of about 1.5-25% w/w, or about 1.5-20% w/w, or about 1.5-15% w/w, or about 1.5-10% w/w, or about 1.5-5% w/w by weight of composition. In an embodiment, the intra-granular portion comprises disintegrant in about 1.5% w/w by weight of composition. In an embodiment, the extra-granular portion comprises disintegrant in about 2% w/w by weight of composition.

The glidant is selected from the group consisting of stearic acid, magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate and combination thereof. The glidant is present in a concentration of about 0.1-5% w/w by weight of composition. Alternatively, the glidant is present in a concentration of about 0.2-4% w/w, or about 0.5-3.5% w/w, or about 0.7-3% w/w, or about 0.9-2% w/w by weight of composition.

The binder is selected from the group consisting of starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, povidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols and combination thereof. The binder is present in a concentration of about 0.1-10% w/w by weight of composition. Alternatively, the binder is present in a concentration of about 0.5-8% w/w, or about 1-6% w/w, or about 1.2-4% w/w, or about 1.5-3% w/w, or about 2-3% w/w by weight of composition.

The preservative is selected from the group consisting of phenoxyethanol, parabens such as methyl paraben and propyl paraben and their sodium salts, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, and mixtures thereof. The preservative is present in a concentration of about 0.1-30% w/w by weight of composition. Alternatively, the preservative is present in a concentration of about 0.1-30% w/w, or about 0.5-25% w/w, or about 1-20% w/w, or about 2-15% w/w, or about 3-10% w/w by weight of composition.

The buffering agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide and mixtures thereof.

The chelating agent is selected from the group consisting of ethylene diamine tetraacetic acid (“EDTA”), and disodium edetate and EDTA derivatives.

The polymer is selected from the group consisting of gum arabic, sodium based lignosulfonate, methyl methacrylate, methacrylate copolymers, isobutyl methacrylate, ethylene glycol dimethacrylate and combination thereof.

The solvent is selected from the group consisting of water; tetrahydrofuran; alcohols, such as methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes such as pentane, hexane and heptane; ketones, such as acetone and methyl ethyl ketone; chlorinated hydrocarbons, such as chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride acetates, such as ethyl acetate and combination thereof.

In preferred embodiment, the diluent is microcrystalline cellulose. In preferred embodiment, the disintegrant is crosscarmellose sodium. In preferred embodiment, the glidant is magnesium stearate. In preferred embodiment, the binder is polyvinylpyrrolidone.

In an embodiment, there is provided a composition wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.01 to about 1 : 10. Alternatively, there is provided a composition wherein the remogliflozin or pharmaceutically acceptable salt or ester thereof and the disintegrant is present in weight ratio of about 1:0.05, or about 1 :0.06. In most preferred embodiment, the disintegrant is crosscarmellose sodium. In certain embodiments, the disintegrant is present only in intra-granular portion. In certain embodiments, the disintegrant is present only in extra-granular portion. In certain embodiments, the disintegrant is present in both intra-granular portion as well as extra-granular portion.

In certain embodiments, the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition. In an embodiment, the dose of lOOmg of remogliflozin etabonate provides the plasma concentration (Cmax) between about 350ng/ml to about lOOOng/ml, or about 400ng/ml to about 700ng/ml, or about 450ng/ml to about 600ng/ml, or preferably about 475ng/ml under fasted or fed condition.

In an embodiment, the dose of 250mg of remogliflozin etabonate provides the plasma concentration (Cmax) between about 400ng/ml to about l300ng/ml, or about 600ng/ml to about l350ng/ml, or about lOOOng/ml to about l200ng/ml, or preferably about 1 l56ng/ml under fasted or fed condition.

Alternatively, the plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof is about 350ng/ml, or about 400ng/ml, or about 450ng/ml, or about 500ng/ml, or about 550ng/ml, or about 600ng/ml, or about 650ng/ml, or about 700ng/ml, or about 750ng/ml, or about 800ng/ml, or about 850ng/ml, or about 900ng/ml, or about 950ng/ml, or about lOOOng/ml, or about 1 lOOng/ml, or about l200ng/ml, or about l300ng/ml.

In certain embodiments, the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

In an embodiment, the dose of lOOmg of remogliflozin etabonate provides an AUC of in between about 800ng.hr/ml to about 5000ng.h/ml, or about 900ng.hr/ml to about 4000ng.h/ml, or about l000ng.hr/ml to about 3000ng.h/ml, or about H00ng.hr/ml to about 2000ng.h/ml, or about l200ng.hr/ml to about l500ng.h/ml or preferably about 1407 ng.hr/ml under fasted or fed condition.

In an embodiment, the dose of 250mg of remogliflozin etabonate provides an AUC of in between about l000ng.hr/ml to about 5000ng.h/ml, or about 2000ng.hr/ml to about 4500ng.h/ml, or about 3500ng.hr/ml to about 4000ng.h/ml, or preferably about 3737ng.hr/ml under fasted or fed condition.

Alternatively, the AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof is about 800ng.hr/ml or, about 900ng.hr/ml or, about l000ng.hr/ml or, about H00ng.hr/ml or, about l200ng.hr/ml or, about l300ng.hr/ml or, about l400ng.hr/ml or, about l500ng.hr/ml or, about l600ng.hr/ml or, about l700ng.hr/ml or, about l800ng.hr/ml or, about l900ng.hr/ml or, about 2000ng.hr/ml or, about 2l00ng.hr/ml or, about 2200ng.hr/ml or, about 2300ng.hr/ml or, about

2400ng.hr/ml or, about 2500ng.hr/ml or, about 2600ng.hr/ml or, about 2700ng.hr/ml or, about

2800ng.hr/ml or, about 2900ng.hr/ml or, about 3000ng.hr/ml or, about 4000ng.hr/ml or, about

5000ng.hr/ml.

In certain embodiments, there are provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml.

In one embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) microcrystalline cellulose, (c) crosscarmellose sodium, and (d) polyvinylpyrrolidone, and (B) an extra-granular portion having (a) crosscarmellose sodium,

(b) microcrystalline cellulose and (c) magnesium stearate, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 1 l00ng.hr/ml to about 6000ng.h/ml.

In another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) about 5-30% w/w by weight of microcrystalline cellulose,

(c) about 1-30% w/w by weight of crosscarmellose sodium, and (d) about 0.1-10% w/w by weight of polyvinylpyrrolidone, and (B) an extra-granular portion having (a) about 1-30% w/w by weight of crosscarmellose sodium, (b) about 5-60 % w/w by weight of microcrystalline cellulose and (c) about 0.1-5% w/w by weight of magnesium stearate, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about H00ng.hr/ml to about 6000ng.h/ml.

In still another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1 :0.0l to about 1 : 10 in either intra-granular portion or extra-granular portion.

In yet another embodiment, there is provided an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) about 50mg, or about lOOmg, or about 250mg of remogliflozin etabonate, (b) microcrystalline cellulose, (c) crosscarmellose sodium, and (d) polyvinylpyrrolidone, and (B) an extra-granular portion having (a) crosscarmellose sodium, (b) microcrystalline cellulose and (c) magnesium stearate, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 400ng/ml to about 600ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about H00ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and crosscarmellose sodium is present in weight ratio of about 1:0.01 to about 1: 10 in either intra- granular portion or extra-granular portion.

In further embodiments, there are provided a kits comprising an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml. In certain embodiments, there is provided a process of preparing an immediate release pharmaceutical composition comprising remogliflozin or pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, said process comprises steps of: (i) sifting and mixing the remogliflozin or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable excipients to obtain granules, (ii) mixing said granules of step (i) with the pharmaceutically acceptable excipients and compressing to obtain a tablet dosage form, and (iii) coating the said the tablet dosage form.

The present invention also provides a method of treating diabetes mellitus in a subject in need thereof by administering to the subject an immediate release composition comprising remogliflozin etabonate. Particularly in an embodiment, therapeutically effective amount of remogliflozin etabonate is administered in patients who have inadequate glycemic control with stable dose of metformin as monotherapy

In certain embodiments, there is provided a method of treating a diabetes by administering orally to a subject in a need thereof an immediate release pharmaceutical composition comprising: (A) an intra-granular portion comprising (a) remogliflozin etabonate, (b) a diluent, (c) a disintegrant, and (d) a binder, and (B) an extra-granular portion having (a) a disintegrant, (b) a diluent, and (c) a lubricant, and wherein the composition provides a plasma concentration (Cmax) of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 300ng/ml to about l400ng/ml under fed or fasted condition or the composition provides an AUC of remogliflozin or pharmaceutically acceptable salt or ester thereof between about 700ng.hr/ml to about 6000ng.h/ml, and wherein the remogliflozin etabonate and the disintegrant is present in weight ratio of about 1:0.01 to about 1: 10 in either intra-granular portion or extra-granular portion.

In an embodiment, subjects have HbAlc > 7% but < 10%. Preferably the subjects are in age group of >18 and < 65 years of age, diagnosed with type 2 diabetes. In another embodiment, subjects receive stable dose of metformin > 1500 mg/day (> 1000 mg/day for subjects not tolerating) as monotherapy for at least 8 weeks prior to screening and having inadequate glycemic control at screening defined as HbAlc levels of >7% to <10%.

In another embodiment, remogliflozin etabonate immediate release tablet is administered once or twice in a day with or without food. Particularly, the composition is administered twice daily with food preferably at the same time.

In another embodiment, the composition is administered twice daily for the period of 24 weeks.

Present invention relates to a method of treating type 2 diabetes mellitus in a subject in need thereof who is 18 to 65 years of age and received stable dose of metformin > 1500 mg/day (> 1000 mg/day for subjects not tolerating) as monotherapy for at least 8 weeks prior to screening and having inadequate glycemic control at screening defined as HbAlc levels of >7% to <10%; comprising administering to a subject twice daily immediate release tablet comprising remogliflozin etabonate in an about 50mg, or about lOOmg, or about 250mg.

In certain embodiments, the invention composition when administered orally produces characteristic pharmacokinetic profile for remogliflozin etabonate (GSK 189075), remogliflozin (GSK 189074), and metabolite of remogliflozin (GSK 279782), which has a similar potency to remogliflozin, wherein the maximum plasma concentrations (T _max ) were achieved rapidly for all three analytes with median T _max ranging from 0.5 to 1.5 hours. In one embodiment, under fed state, there is a slight delay in T _max with the medians ranging from 1.5 to 3 hours. In another embodiment, C _max is comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 0.77 to 1.44 and 0.81 to 1.12, respectively. In another embodiment, the AUC of the active moiety, is comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 1.22 to 2.01 and 1.35 to 1.56, respectively. In another embodiment, the metabolite’s and prodrug’s AUCs are slightly higher under fed state. In another embodiment, an elimination half-lives (ti _/2 ) for the active moieties (Remogliflozin and GSK279782) ranges from l.55hrs to 2.8hrs in the fasting and fed state for lOOmg and from l.8hr to 3.7 hr respectively for 250mg. In another embodiment, across dose levels and diet conditions, the active moiety (Remogliflozin) shows the highest exposures, followed by metabolite (GSK 279782), (~ 25 to 42% of active moiety), whereas the inactive prodrug (GSK 189075), shows the lowest exposure (<3% of active moiety). In certain embodiments, invention composition comprising about lOOmg or 250mg of remogliflozin or pharmaceutically acceptable salt or ester thereof when administered to diabetic subjects reduces HbAlc levels and hyperglycemia and are comparable with dapagliflozin 10 mg. In another embodiment, the treatment is for 4 weeks, or for 8 weeks, or 12 weeks, or for 24 weeks, or 36 weeks or up to a period until the disease symptoms ceased to show. In certain embodiments, remogliflozin or pharmaceutically acceptable salt or ester thereof at lOOmg and 250 mg doses is non inferior to dapagliflozin 10 mg.

The embodiments of the invention have been described with help of below examples and but are not limited to specific examples.

Examples

Example 1: Immediate release formulation of remogliflozin etabonate.

Table 1

1. Remogliflozin etabonate, crosscarmellose sodium and microcrystalline cellulose were sifted.

2. Povidone was dissolved in water to make clear binder solution.

3. Co-sifted material was granulated using binder solution.

4. Wet mass of step 3 was passed through mesh no # 12 and granules were dried.

5. Granules were lubricated with magnesium stearate along with crosscarmellose sodium and microcrystalline cellulose.

6. Lubricated granules were compressed to form tablets.

7. Final tablets were either coated or non-coated.

EXAMPLE 2: Single dose pharmacokinetic (PK) study results of remogliflozin etabonate immediate release formulation.

Inventors previously conducted a single dose PK study- 0355-17 with 250 mg immediate release tablet formulation in 30 healthy adult male subjects. In this study, remogliflozin was found to be safe and well tolerated with no serious or significant adverse events. In this study, as a precautionary measure to avoid any hypoglycemic event, remogliflozin etabonate tablet was administered along with glucose solution; whereas in the historical studies, subjects received remogliflozin tablet along with only water. Influence of glucose solution on the PK of remogliflozin precluded a comparison with historical PK profiles.

Therefore, in order to perform a like-to-like comparison and to understand the PK characteristics, inventors conducted a study - 0637-17 in 65 healthy male volunteers (Study Protocol 0637-17) following single dose of remogliflozin etabonate, administered with water under fasted state (N=30) as well as under fed state (N=30). Both 100 and 250 mg dose levels were tested in this study. In order to confirm the impact of glucose solution on the PK profile of remogliflozin etabonate, a small subset of subjects (N=5) were administered with 250 mg of remogliflozin etabonate tablet along with 20% glucose solution.

Plasma concentration profiles:

Following oral administration of remogliflozin etabonate, three analytes (GSK 189075, GSK 189074 and GSK 279782) were quantified in plasma samples collected over a period of 24 hours, using a validated LC/MS/MS method. Remogliflozin etabonate (GSK 189075) is inactive and is a prodrug that rapidly gets converted to the active moiety remogliflozin (GSK 189074), which then further metabolize to GSK 279782. The remogliflozin (GSK 189074) showed the highest plasma exposure and is most important from safety and efficacy perspective, followed by GSK 279782 which showed relatively lower plasma exposure and less important from safety and efficacy perspective. The inactive prodrug (GSK 189074) has very low serum exposure and is not anticipated to contribute towards efficacy or safety. Following oral administration of remogliflozin etabonate under fasted state, maximum plasma concentrations were achieved rapidly for all three analytes with median Tmax ranging from 0.5 to 1.5 hours. Under fed state, there was a slight delay in T _max with the medians ranging from 1.5 to 3 hours. When remogliflozin etabonate was administered with plain water an early T _max was observed, and the plasma concentration profiles did not show prominent multiple peaks as seen in the previous study which was a single dose PK study with 250 mg immediate release tablet formulation in 30 healthy adult male subjects. While when remogliflozin etabonate was administered with glucose solution, there was a prolonged absorption with multiple peaks leading to a considerable delay in T _max (5.5 to 6 hours).

This confirmed that the glucose solution administered along and/or during the study could be impacting the absorption, probably by interfering with the solubility of the prodrug (remogliflozin etabonate). Therefore for a like-to-like comparison of PK of remogliflozin etabonate with the historical data, the data from the current study is more appropriate.

Pharmacokinetic Parameters:

The PK parameters were estimated for all the 3 analytes at both dose levels (100 and 250 mg). Both the Cmax and AUC of all the 3 analytes were largely dose proportional between 100 mg to 250 mg. Across dose levels and diet conditions, the active moiety (GSK 189074) showed highest exposures, followed by metabolite (GSK 279782) (~ 25 to 42% of active moiety). The inactive prodrug (GSK 189075) had the lowest exposure (<3% of active moiety), across the treatments. The elimination half-lives remained consistent for each analyte between the doses and diet conditions, with shortest half-life for the prodrug (~ 0.5 hours) and the longest for the metabolite (~ 3.8 hours).

The Cmax were generally comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 0.77 to 1.44 and 0.80 to 1.12, respectively. The AUC of the active moiety also were generally comparable between fasted and fed state at 100 mg and 250 mg with fed/fasted ratio ranging from 1.22 to 1.35, respectively. The metabolite and prodrug AUCs were slightly higher under fed state, with fed/fasted ratio ranging from 1.6 to 2.0 and 2.0 to 2.5, respectively.

The summary PK parameters of all the three analytes at 100 and 250 mg, under fasted and fed state are provided in table 2.

Table 2: Study 0637-17; summary PK Parameters of Remogliflozin etabonate (GSK 189075), Remogliflozin (GSK 189074) and metabolite (GSK 279782)

a: Median (Min-Max)

EXAMPLE 3: Comparison of PK data from study 0637-17 with Historical PK data

Historically, the PK of remogliflozin etabonate was evaluated in healthy volunteers in a number of clinical studies, following single oral dose of immediate release tablets with plain water. The PK data after a single dose of 100 and 250 mg from the following historical studies was available for comparison (Table 3).

Table 3: Details of historical studies used for comparison of remogliflozin etabonate PK data.

*: Extrapolated to 250 mg assuming proportionality for comparison

The comparison of PK data between the current study (0637-17) vs historical studies were performed descriptively as well as graphically using the exposure parameters (Cmax and AUC). The geometric mean Cmax and AUC estimates in the historical clinical studies has shown considerable between study variability. Therefore instead of a descriptive comparison of Cmax and AUC of the current study with individual historical studies, a grand mean of Cmax and AUC for each analyte was calculated across the historical studies and was compared with grand mean (fasted and fed) of the current study. The comparison of the PK data are presented below for each analyte separately.

GSK 189074 (Remogliflozin)

GSK 189074 is the active moiety, showed the highest exposure among the 3 analytes in this study as well as in historical studies. GSK 189074 is the major contributor to efficacy and is the most important analyte for comparison in terms of efficacy and safety. In the historical studies at 250 mg, the geometric mean Cmax of GSK 189074 ranged from 805 ng/mL to 1563 ng/mL indicating considerable between study variability (1.9-fold difference). The grand mean of Cmax from historical studies was estimated to be 1013 ng/mL. The average Cmax (fasted and fed) of the current study was estimated to be 1156 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical studies is around 1.14, indicating at 250 mg the GSK 189074 Cmax in the current study is comparable with that of the historical studies. Similarly, in the historical studies at 250 mg, the geometric mean AUCo-i _nf of GSK 189074 ranged from 1743 ng.h/mL to 3243 ng.h/mL indicating considerable between study variability (1.9-fold difference). The grand mean of AUCo-i _nf from historical studies was estimated to be 2250 ng.h/mL. The average AUCo-i _nf (fasted and fed) of the current study was estimated to be 3737 ng.h/mL. The ratio of the grand mean AUCo- i _nf of the current study to that of the historical studies is around 1.66, indicating at 250 mg the GSK 189074 AUCo-i _nf estimated in the current study is within 2-fold to that of the historical studies and this difference is not anticipated to be of clinical significance. In the historical studies at 100 mg, the geometric mean C _max of GSK 189074 ranged from 230 ng/mL to 753 ng/mL indicating considerable between study variability (3.3-fold difference). The grand mean of C _max from historical studies was estimated to be 389 ng/mL. The average C _max (fasted and fed) of the current study was estimated to be 475 ng/mL. The ratio of the grand mean C _max of the current study to that of the historical studies is around 1.22, indicating at 100 mg the GSK 189074 C _max in the current study is comparable with that of the historical studies. Similarly, in the historical studies at 100 mg, the geometric mean AUCo-i _nf of GSK 189074 ranged from 471 ng.h/mL to 1242 ng.h/mL indicating considerable between study variability (2.6-fold difference). The grand mean of AUCo- i _nf from historical studies was estimated to be 706 ng.h/mL. The average AUCo-i _nf (fasted and fed) of the current study was estimated to be 1407 ng.h/mL. The ratio of the grand mean AUCo-i _nf of the current study to that of the historical studies is around 1.99, indicating the GSK 189074 AUC0- inf estimated in the current study is within 2-fold to that of the historical studies. A 2-fold difference in exposure at 100 mg dose level is not anticipated to be of clinical significance. This is shown in Table 4 as below.

Table 4: Summary of exposure parameters (C _max and AUC) of GSK 189074 from individual studies and comparison with study 0637-17.

GSK189074 Geometric mean Cmax Mean SD Min Max Ratio

Dose: 100 mg ng/mL ng/mL ng/mL ng/mL ng/mL

0637-17 (N=15); Fasted 536 555.0 142.0 281.0 580.0

0637-17 (N=15); Fed 414 436.0 158.0 271.0 796.0

Grand Mean 475 *86 KG2105259 (N=8); Fasted 317 335.0 131.0 195.0 632.0 1.7

KG2105217 (N=12); Fasted 255 310.0 187.0 75.0 605.0 2.1

KG2105217 (N=l l); Fed 230 265.0 131.0 53.0 507.0 1.8

KGT1101 (N=6); Fasted 753 782.0 248.0 594.0 1212.0 0.7

Grand Mean 389 ^# 246 1.22

GSK189074 Geometric Mean AUCo-inf Mean SD Min Max Ratio

Dose: 100 mg ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL

0637-17 (N=15); Fasted 1267 1304 318 791 1869

0637-17 (N=15); Fed 1547 1574 315 1209 2351

Grand Mean 1407 ^# 198

KG2105259 (N=8); Fasted 471 504 230 295 1046 2.69

KG2105217 (N=12); Fasted 504 566 287 210 1165 2.51

KG2105217 (N=l l); Fed 606 676 315 183 1354 2.55

KGT1101 (N=6); Fasted 1242 1259 222 916 1598 1.02

Grand Mean 706 ^# 362 1.99

GSK189074 Geometric mean Cmax Mean SD Min Max Ratio

Dose: 250 mg ng/mL ng/mL ng/mL ng/mL ng/mL

0637-17 (N=15); Fasted 1275 1419 679 543 2702

0637-17 (N=15); Fed 1037 1049 167 775 1338

Grand Mean 1156 ^# 168

KG2108197 (N=20); Fasted 805 882 411 374 2036 1.58 ^a KG2105253 (N=8) ; Fasted 807 1014 722 292 2500 1.58 ^b KG2105253 (N=7) ; Fasted 1000 1043 344 748 1537 1.28

*KGT1102 (N=6); Fasted 1563 1789 944 653 3231 0.82

KGW111057 (N=27); Fed 892 927 276 572 1656 1.16

Grand Mean 1013 ^# 317 1.14

GSK189074 Geometric Mean AUCo-inf Mean SD Min Max Ratio

Dose: 250 mg ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL

0637-17 (N=15); Fasted 3178 3341 1049 1760 4976

0637-17 (N=15); Fed 4295 4392 943 2555 6328 Grand Mean 3737 ^# 790

KG2108197 (N=20) ; Fasted 1743 1859 698 994 3364 1.82 aKG2105253 (N=8) ; Fasted 1973 2096 815 1224 3596 1.61 bKG2105253 (N=7) ; Fasted 2262 2392 844 1398 3596 1.40

*KGT1102 (N=6); Fasted 3243 3379 1005 2109 4666 0.98

KGW1 11057 (N=27); Fed 2028 2120 656 1243 3502 2.12

Grand Mean 2250 *585 1.66

*: Extrapolated to 250 mg from the data at 200 mg, assuming linearity; a and b: Data from control subjects with normal renal function in the renal impairment study; #: standard deviation of the individual study geometric mean C _ra „ and AUCs

GSK 279782 (metabolite)

As observed in historical studies, GSK 279782 is an active metabolite formed from GSK 189074 and the plasma exposures were around 24 to 43% of the GSK 189074 exposure. Hence though GSK 279782 is active, the contribution of GSK 279782 towards the efficacy is expected to be lower than that of GSK 189074. The GSK 279782 exposures in the current study (0637-17) was also lower, around 24 to 42% of GSK 189074 exposure indicating comparable extent of metabolite formation. In the historical studies at 250 mg, the geometric mean Cmax of GSK 279782 ranged from 129 ng/mL to 240 ng/mL indicating considerable between study variability (1.9 -fold difference). The grand mean of Cmax from historical studies was estimated to be 203 ng/mL. There were no historical PK data of GSK 279782 under fed state at the 250 mg dose level. Hence for the comparison, Cmax under fasted state from the current study was used. The geometric mean Cmax in the current study was 286 ng/mL. The ratio of the geometric mean Cmax of the current study to that of the historical studies is around 1.42, indicating GSK 189074 Cmax in the current study is largely comparable with that of the historical studies. Similarly, in the historical studies at 250 mg, the geometric mean AUCo-inf of GSK 279782 ranged from 468 ng.h/mL to 801 ng.h/mL indicating considerable between study variability (1.7-fold difference). The grand mean of AUCo-inf from historical studies was estimated to be 658 ng.h/mL. There were no historical PK data of GSK 279782 under fed state at the 250 mg dose level. Hence for the comparison, AUCo-inf under fasted state from the current study was used. The geometric mean AUCo-inf of the current study was estimated to be 1037 ng.h/mL. The ratio of the geometric mean AUCo-inf of the current study to that of the historical studies is around 1.58, indicating the GSK 279782 AUCo-inf, estimated in the current study is within 2-fold to that of the historical studies, which is not anticipated to be of clinical significance. In the historical studies at 100 mg, the geometric mean Cmax of GSK 279782 ranged from 70 ng/mL to 150 ng/mL indicating considerable between study variability (2.1 -fold difference). The grand mean of Cmax from historical studies was estimated to be 93 ng/mL. The average Cmax (fasted and fed) from the current study was estimated to be 118 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical studies is around 1.26, indicating GSK 279782 Cmax in the current study is comparable with that of the historical studies. Similarly, in the historical studies at 100 mg, the geometric mean AUCo-inf of GSK 279782 ranged from 177 ng.h/mL to 393 ng.h/mL indicating considerable between study variability (2.2-fold difference). The grand mean of AUCo-inf from historical studies was estimated to be 257 ng.h/mL. The average AUCo-inf (fasted and fed) of the current study was estimated to be 488 ng.h/mL. The ratio of the grand mean AUCo-inf of the current study to that of the historical studies is around 1.89, indicating the GSK 279782 AUCo-inf _, estimated in the current study is within 2-fold to that of the historical studies. However, a less than 2-fold difference in exposure of the metabolite at 100 mg dose is not anticipated to be of clinical significance. This is shown in Table 5 as below.

Table 5: Summary of exposure parameters (Cmax and AUC) of GSK 279782 from individual studies and comparison with study 0637-17

GSK279782 Geometric mean Cmax Mean SD Min Max Ratio

Dose: 100 mg ng/mL ng/mL ng/mL ng/mL ng/mL

0637-17 (N=15); Fasted 97 Ϊ08 59 48 262

0637-17 (N=15); Fed 139 145 42 79 206

Grand Mean ΪΪ8 *30

KG2105259 (N=8); Fasted 74 83 40 33 138 1.31

KG2105217 (N=12); Fasted 79 95 55 21 190 1.23

KG2105217 (N=l l); Fed 70 80 40 18 152 1.99

KGT1101 (N=6); Fasted 150 162 74 85 301 0.65

Grand Mean 93 *38 1.27

GSK279782 Geometric Mean AUCo-inf Mean SD Min Max Ratio

Dose: 100 mg ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL 0637-17 (N=15); Fasted 324 359 180 172 801

0637-17 (N=15); Fed 651 687 231 368 1062

Grand Mean 488 *231

KG2105259 (N=8); Fasted 177 Ϊ92 tG 70 294 1.83

KG2105217 (N=12); Fasted 218 246 123 85 483 1.49

KG2105217 (N=l l); Fed 240 266 115 78 467 2.71

KGT1101 (N=6); Fasted 393 408 125 267 642 0.82

Grand Mean 257 *94 ^” L90

GSK279782 Geometric mean Cmax Mean SD Min Max Ratio

Dose: 250 mg ng/mL ng/mL ng/mL ng/mL ng/mL

0637-17 (N=15); Fasted 286 318 165 128 820

0637-17 (N=15); Fed 320 342 123 130 592

Grand Mean 286 *24

KG2108197 (N=20); Fasted 203 222 86 71 344 1.41 aKG2105253 (N=8) ; Fasted 129 151 84 46 267 2.22 bKG2105253 (N=7) ; Fasted 238 259 113 136 443 1.20 *KGT1102 (N=6); Fasted 240 253 93 155 425 1.19 KGW111057 (N=27); Fed

Grand Mean 203 *52 1.41

GSK279782 Geometric Mean AUCo-mt Mean SD Min Max Ratio Dose: 250 mg ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL

0637-17 (N=15); Fasted 1037 1120 485 554 2180

0637-17 (N=15); Fed 1617 1705 538 773 2594

Grand Mean 1327 *410

KG2108197 (N=20); Fasted 617 677 298 285 1365 1.68 aKG2105253 (N=8) ; Fasted 468 500 188 277 794 2.22 bKG2105253 (N=7) ; Fasted 744 789 315 470 1429 1.39 *KGT1102 (N=6); Fasted 801 823 218 639 1206 1.29 KGW111057 (N=27); Fed

Grand Mean 658 *148 1.58

*: Extrapolated to 250 mg from the data at 200 mg, assuming linearity; a& b: Data from control subjects with normal renal function in the renal impairment study; #: standard deviation of the individual study geometric mean Cmax and AUCs GSK 189075 (Prodrug)

GSK 189075 (remogliflozin etabonate) is the prodrug of GSK 189074 and is inactive. As observed in historical studies, GSK 189074 had the lowest plasma exposure among the 3 analytes, only about 1 to 3 % of the plasma exposures of active moiety (GSK 189074). GSK 189075 is also rapidly cleared and has the shortest half-life (around 0.5 hours) among the 3 analytes. As observed in the historical studies, the prodrug showed a rapid conversion to the active moiety in the current study as well with similar extent of conversion. The plasma exposures of GSK 279782 was 1 to 3% of that of active moiety and showed shortest half-life of around 0.5 hours, similar to what was reported in the historical studies. In the historical studies, at 250 mg dose the GSK 189075 geometric mean Cmax ranged from 31 ng/mL to 57 ng/mL indicating considerable between study variability (1.8-fold difference). The grand mean Cmax of the historical studies were about 46 ng/mL and the average Cmax (fasted and fed) from the current study is 45 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical study is 0.97, indicating GSK 189075 Cmax is comparable to that of the historical studies. Similarly in the historical studies, at 250 mg dose the GSK 189075 geometric mean AUCo-inf ranged from 27 ng.h/mL to 61 ng.h/mL, indicating considerable between study variability (2.3-fold difference). The grand mean AUCO-inf of the historical studies were about 43 ng.h/mL and the average AUCo-inf (fasted and fed) from the current study is 70 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical study is 1.6, indicating GSK 189075 AUCO-inf is within 2-fold to that of the historical studies. Considering the minimal exposure and no contribution to efficacy, this difference is not anticipated to be clinically significant. In the historical studies, at 100 mg dose the GSK 189075 geometric mean Cmax ranged from 7 ng/mL to 30 ng/mL indicating considerable between study variability (4.3-fold difference). The grand mean Cmax of the historical studies were about 15 ng/mL and the average Cmax (fasted and fed) from the current study is 21 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical study is 1.4, indicating GSK 189075 Cmax is generally comparable to that of the historical studies. In the historical studies, at 100 mg dose the GSK 189075 geometric mean AUCO-inf ranged from 11 ng.h/mL to 16 ng.h/mL (l.5-fold difference). The grand mean AUCO-inf of the historical studies were about 13 ng.h/mL and the average AUC0- inf (fasted and fed) from the current study is 30 ng/mL. The ratio of the grand mean Cmax of the current study to that of the historical study is 2.2, indicating GSK 189075 AUCO-inf is higher to that of the historical studies. However, considering the minimal exposure and no contribution to efficacy, this difference is not anticipated to be clinically significant. This is shown in Table 6 as below.

Table 6: Summary of exposure parameters (Cmax and AUC) of GSK 189075 from individual studies and comparison with study 0637-17.

GSK 189075 Geometric mean Cmax Mean SD Min Max Ratio

Dose: 100 mg ng/mL ng/mL ng/mL ng/mL ng/mL

0637-17 (N=15); Fasted 21 26 19 7 70

0637-17 (N=15); Fed 21 24 15 8 66

Grand Mean 21 *0

KG2105259 (N=8); Fasted 13 15 9 7 36 1.62 KG2105217 (N=12); Fasted 10 13 11 3 39 2.10 KG2105217 (N=l l); Fed 7 10 7 2 25 3.00 KGT1101 (N=6); Fasted 30 32 9 18 44 0.70

Grand Mean is ^# 10 1.40

GSK 189075 Geometric Mean AUCo-mt Mean SD Min Max Ratio Dose: 100 mg ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL

0637-17 (N=15); Fasted 17 20 P 6 38

0637-17 (N=15); Fed 42 46 19 24 82

Grand Mean 30 *18

KG2105259 (N=8); Fasted 13 13 13 13 1.31 KG2105217 (N=12); Fasted 11 11 5 6 19 1.55 KG2105217 (N=l l); Fed 13 14 7 6 24 3.23 KGT1101 (N=6); Fasted 16 16 4 12 20 1.06 Grand Mean 13 *2 2.23

GSK 189075 Geometric mean Cmax Mean SD Min Max Ratio

Dose: 250 mg ng/mL ng/mL ng/mL ng/mL ng/mL

0637-17 (N=15); Fasted 50 64 46 17 174

0637-17 (N=15); Fed 39 43 18 13 77 Grand Mean 45 *8

KG2108197 (N=20) ; Fasted 31 43 33 6.3 116 1.61 aKG2105253 (N=8) ; Fasted 42 59 45 11 135 1.19 bKG2105253 (N=7) ; Fasted 53 66 42 13 135 0.94

*KGT1102 (N=6); Fasted 46 54 30 18 100 1.08

KGW111057 (N=27); Fed 57 67 39 22 184 0.68

Grand Mean 46 ^# 10 0.97

GSK 189075 Geometric Mean AUCo-mt Mean SD Min Max Ratio Dose: 250 mg ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL ng.hr/mL

0637-17 (N=15); Fasted 50 61 48 21 196

0637-17 (N=15); Fed 89 97 40 47 169

Grand Mean 70 *28

KG2108197 (N=20); Fasted 27 31 16 12 64 L85 aKG2105253 (N=8) ; Fasted 44 49 25 23 91 1.14 bKG2105253 (N=7) ; Fasted 42 53 32 10 91 1.19 *KGT1102 (N=6); Fasted 41 48 25 20 76 1.21 KGW111057 (N=27); Fed 61 68 36 27 188 1.46 Grand Mean 43 *12 1.61

*: Extrapolated to 250 mg from the data at 200 mg, assuming linearity; a & b: Data from control subjects with normal renal function in the renal impairment study; #: standard deviation of the individual study geometric mean Cmax and AUCs

EXAMPLE 4: Safety margins for all the 3 analytes in comparison to the plasma exposures in long term toxicology studies.

Table 7 shows anticipated safety margins in humans with 250 mg bid relative to plasma exposures at NOAEL doses in long term toxicology studies.

Species Dose (mg/kg) Gender Analyte Safety Margins

Mouse 2000 M GSK 189075 207

13 week NOAEL GSK 189074 21.5

GSK 279782 23.5

F GSK 189075 36.9 Species Dose (mg/kg) Gender Analyte Safety Margins

GSK 189074 29

GSK 279782 21.3

Rat 1200 M GSK 189075 74 ^~ 4

26 week NOAEL GSK 189074 17.2

GSK 279782 21.5

F GSK 189075 44.9

GSK 189074 19.3

GSK 279782 32.9

Dog 650 M GSK 189075 450.0

52 week NOAEL GSK 189074 16.9

GSK 279782 2.9

F GSK 189075 523.1

GSK 189074 21.4

GSK 279782 4.0

GSK 189075 Ϊ40

GSK 189074 7474

* Human 250 mg, BID M GSK 279782 2654

Steady state human AUC with 250 mg BID is calculated by doubling the single dose AUCo _m f ( average of fasted and fed state)

Below is the summary of the above PK studies:

• When remogliflozin etabonate was administered with plain water under fasted state, an early T _max was observed (Median: 0.5 hour to 1.5 hour) for all three analytes. Under fed state, there was a slight delay in T _max in comparison to fasted state with the medians ranging from 1.5 to 3 hours, similar to that in the historical studies.

• Similar to the historical studies, in study 0637-17 the active moiety (GSK 189074) showed the highest C _max and AUC, followed by metabolite GSK 279782. The metabolite exposure was 24 to 43% of active moiety, similar to that observed in the historical studies indicating comparable extent of metabolite formation. • The inactive prodrug (GSK 189075) had the lowest Cmax and AUC (around 1 to 3% of that of active moiety), similar to that observed in the historical studies. The elimination half- lives of all 3 analytes were also comparable with that of the historical data.

• The exposure parameters (Cmax and AUC) generated in current study (0637-17) were compared with that of historical studies both descriptively and graphically. The Cmax of all the 3 analytes from study 0637-17 was found to be generally comparable with ratios ranging from (GSK 189074: 1.14 to 1.22; GSK 279782: 1.27 to 1.41; and GSK 189075: 0.97 to 1.40). The AUCo-inf of all the analytes were generally within 2-fold (GSK 189074: 1.66 to 1.99; GSK 279782: 1.58 to 1.90); and within 2.3-fold for inactive GSK 189075 (1.61 to 2.23).

• Based on the systemic exposures and the in-vitro SGLT-2 inhibition rate constant (Ki), GSK 189074 is the major contributor of efficacy, followed by GSK 279782, whereas GSK 189075 does not contribute to efficacy. Hence the slight differences in the exposures are not anticipated to be clinically significant.

• In addition, there are adequate safety margins for all the 3 analytes in comparison to the plasma exposures in long term toxicology studies conducted in mouse, rat, and dogs. The anticipated safety margins with a 250 mg BID regimen for GSK 189075: 21 to 523-fold, for GSK 189074: 17 to 29-fold, and for GSK 279782: 3 to 33-fold.

Overall, in comparison to historical studies, there were no clinically relevant differences in the pharmacokinetics after a single dose of Remogliflozin etabonate formulation at 100 and 250 mg in Indian subjects. Further, there were no safety concerns and no hypoglycemic events are reported in the study. The plasma exposure in clinic at 250 mg BID are anticipated to be many fold lower than the plasma exposure at NOAEL doses in long term toxicology studies indicating adequate safety margins even at 250 mg dose.

EXAMPLE 5: A 24-week randomised, double -blind, double-dummy, parallel-group, multi-centre, active controlled study to evaluate efficacy and safety of remogliflozin etabonate in subjects with Type 2 diabetes mellitus.

Objective: The proposed phase 3 clinical study evaluated the efficacy and safety of remogliflozin etabonate administered as 100 mg or 250 mg BID in comparison to dapagliflozin 10 mg QD in the subjects who have inadequately controlled type 2 diabetes with stable dose of metformin. Dapagliflozin was selected as an active comparator as it is approved as both monotherapy and as adjunct to other anti-diabetic agents and has shown significant glycemic efficacy in clinical trials. A dose of 10 mg of Dapagliflozin once a day was selected based on approval and clinical usage. HbAlc is an accepted surrogate for assessment of short-term clinical consequences of hyperglycemia, as well as the long-term microvascular complications of diabetes mellitus and were be evaluated as the primary efficacy endpoint in this study.

Study population: Subjects with T2DM receiving stable doses of metformin as monotherapy for at least 8 weeks prior to screening at a dose of > 1500 mg per day (>1000 mg per day in subjects not tolerating) and have inadequate glycemic control (i.e. HbAlc > 7% but < 10% at screening).

Design: This was a 24-week randomized, double -blind, double-dummy, active-controlled, three- arm, parallel-group, multi-center study to evaluate the efficacy and safety of remogliflozin etabonate in comparison to dapagliflozin in subjects with type 2 diabetes who have inadequate glycemic control with stable dose of metformin as monotherapy. Subjects with HbAlc > 7% but < 10% at Screening (Visit 1) were considered eligible for randomization, on fulfilling other study inclusion criteria. For each subject, the study began when signed informal consent form (ICF) was provided. Eligible subjects were randomized to receive one of the following treatments in a double blind, double dummy design. Matching placebo(s) were used to blind the three treatment arms and every subject received a total of 3 tablets twice daily including one of the following active study drugs along with matching placebo(s) for the other two study drugs.

Arm 1: Remogliflozin etabonate 100 mg, administered as 1 tablet BID for 24 weeks

Arm 2: Remogliflozin etabonate 250 mg, administered as 1 tablet BID for 24 weeks.

Arm 3: Dapagliflozin 10 mg, administered as 1 tablet QD in morning + Placebo administered as 1 tablet QD in evening, for 24 weeks.

In addition, subjects were continued to receive metformin at stable doses of > 1500 mg per day (> 1000 mg per day in subjects not tolerating), throughout the study period in an open label manner. Balanced randomization was ensured in the Arm 1 and Arm 2 (i.e. remogliflozin etabonate 100 mg and remogliflozin etabonate 250 mg Tablets) and randomization was stratified for baseline HbAlc level (HbAlc 7-7.9%, 8-8.9% and 9-10%) at randomization visit. The end of the study was the date of the last study visit for the last subject in the study. An overview of the study design is shown figure 1.

Each subject underwent screening assessments on Visit 1 (Screening). The screening period was for a total of 3 weeks duration and included at least 2 weeks of open label, lead-in period in which standard consultation for dietary and exercise modification was provided to all subjects in accordance with the applicable national/international guidelines (eg. American Diabetes Association. Standards of medical care in diabetes - 2016, ICMR guidelines for management of type 2 diabetes - 2005). Assessments performed at the screening visit was considered for determining eligibility of the subject. However key assessments (eg. HbAlc, FPG, total body weight) were repeated at the Randomization visit (Visit 2) before study drug administration for obtaining most accurate baseline values to be used for efficacy analysis. Double-blind study treatment was administered daily in randomized subjects for 24 weeks. Subjects were required to visit at weeks 1 and 4 after randomization, followed by visits every 4 weeks until Week-24. An additional visit for a safety follow up was required 2 weeks after successful completion of the double -blind study treatment. Subjects were provided with diary at the time of randomization along with glucometer to record details about study drug administration, adverse events and self- monitored fasting plasma glucose levels. Subject were required to bring completed diary at each visit. Additionally a periodic telephonic follow up (at least once every fortnight) by study team was advised to ensure compliance. Pharmacokinetic sampling (PK) was performed at specified time points in a subset of study population. Subjects consenting for the PK study were admitted for 24 hours on Day 1 and Day 8 for serial PK sampling.

The results from this study are summarized below in table 1, 2 and 3.

Table 8: Analysis of Mean Change in Glycosylated Haemoglobin (HbAlc%) Levels (PP Population): MMRM

Cl = confidence interval; HbAlc = glycosylated haemoglobin; LSM = least squares mean; PP = per protocol; MMRM = mixed model repeated measures; SE = standard error

Difference: LSM (SE) between arms is calculated for remogliflozin etabonate 100 mg or

remogliflozin etabonate 250 mg vs dapagliflozin 10 mg (remogliflozin etabonate - dapagliflozin).

The 90% Cl and 95% Cl for the LSM difference in HbAlc% levels between arms are calculated for

remogiflozin etabonate 100 mg or remogliflozin etabonate 250 mg minus dapagliflozin 10 mg.

P value ¹ is calculated for the 1-sided non-inferior test with non-inferiority margin 0.35, P value ² for 2-sided superior test.

P values are calculated for the comparison of treatment arms with treatment as main effect and by considering the baseline HbAlc% value, centre, visit and treatment as covariates.

Exclude rescue medication subjects at each visit.

Table 9: Analysis of Mean Change in Fasting Plasma Glucose (FPG) Concentrations, mg/dL (PP Population): MMRM

Cl = confidence interval; LSM = least squares mean; MMRM = mixed model repeated measures;

PP = per protocol; SE = standard error

Difference: LSM (SE) between treatment arms is calculated for remogliflozin etabonate 100 mg or

remogliflozin etabonate 250 mg vs dapagliflozin 10 mg (remogliflozin etabonate - dapagliflozin).

The 95% Cl for the LSM difference in FPG, mg/dL between treatment arms is calculated for

remogliflozin etabonate 100 mg or remogliflozin etabonate 250 mg vs dapagliflozin 10 mg.

P value ¹ is calculated for the comparison of treatment arms using MMRM with treatment as main effect and by considering the baseline FPG, mg/dL value, centre, visit, and treatment as covariates.

Conclusions

• Both 100 mg and 250 mg doses of remogliflozin etabonate reduced HbAlc levels at 24 weeks and met the target when compared with dapagliflozin 10 mg. Remogliflozin etabonate lOOmg and 250 mg doses were found to be non inferior to dapagliflozin 10 mg (means: 0.14%, 0.19%; 90% CIs: [0.38%, 0.10%], [0.42%, 0.05%], respectively) with high statistical significance (P values for both comparisons: <0.001; PP population), in subjects with T2DM. The primary efficacy endpoint was achieved with both 100 mg and 250 mg doses of remogliflozin etabonate.

• Results were confirmed by secondary analysis in the Modified Intention To Treat (mITT) population and all sensitivity analyses in both PP and mITT populations by the methods of MMRM, and ANCOVA with OC, ANCOVA with LOCF, and ANCOVA with IR on the primary efficacy endpoint

• Overall, all the secondary endpoints showed no significant differences between 100 mg or 250 mg dose of remogliflozin etabonate and dapagliflozin 10 mg (P>0.05).

• No effect of HbAlc level strata at baseline was observed on the difference between 100 mg and 250 mg doses of remogliflozin etabonate in HbAlc level reduction.