WO2018207099A1 - Treatment of polycystic ovary syndrome - Google Patents

Abstract

The invention concerns the use of LIK066 in the treatment, prevention or delay of polycystic ovary syndrome.

Description

TREATMENT OF POLYCYSTIC OVARY SYNDROME

Field of the Invention

The present invention relates to pharmaceutical uses of LIK066, their

pharmaceutically acceptable salts, and prodrugs thereof specifically for the treatment of polycystic ovary syndrome ("PCOS").

Background of the Invention

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women, affecting approximately 5-10% of women throughout their reproductive age. The various definitions of PCOS share common features of hyperandrogenism, clinical and/or biochemical and amenorrhea/oligomenorrhea.

About 28% of obese women have PCOS based on an obese population referred for weight loss interventions. Obesity is also a risk factor for PCOS, with weight gain reported prior to the diagnosis of PCOS. Weight loss is commonly used as a therapeutic approach for PCOS. In addition, insulin resistance affects 50%-70% of women with PCOS and occurs independently of obesity. However, the effect of obesity on insulin resistance is additive to that of PCOS. Clinical manifestations of PCOS can be heterogeneous and include features such as hirsutism, acne, obesity, menstrual dysfunction, infertility, and metabolic syndrome.

Insulin resistance is a common feature of PCOS across the weight spectrum, partly reflecting an intrinsic element of resistance with exacerbation by obesity. The insulin resistance appears to be tissue specific primarily affecting skeletal muscle and adipose tissue, but not ovarian and adrenal tissues. The compensatory hyperinsulinism has tissue- selective effects, which include aggravation of hyperandrogenism, primarily by stimulating activity of the cytochrome P450c 17a in the ovary. Hyperinsulinism also acts on the liver to decrease the production of sex hormone binding globulin (SHBG), thus leading to increased circulating levels of free androgens; and possibly at the level of the pituitary gonadotropes, by increasing production of luteinizing hormone (LH), which in turn stimulates ovarian steroidogenesis.

Interventions that reduce serum insulin levels such as metformin, insulin-sensitizing thiazolidinediones, and weight loss result in significant improvement of

hyperandrogenemia and ovulation in PCOS. Dapagliflozin, a sodium-glucose

cotransporter (SGLT) 2 inhibitor approved for T2D, is currently in a phase 3 clinical trial in PCOS, with and without metformin or exenatide to evaluate the relationship of insulin resistance, body weight and effects on hyperandrogenemia. There is a clear association between hyperinsulinism and hyperandrogenism in PCOS and clinical evidence that lowering insulin levels and/or increasing insulin sensitivity improve hyper androgenism and ovulation in these patients.

Over time, women with PCOS are at an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease. There is no cure for PCOS. Treatment involves management of symptoms by lifestyle modification such as weight loss, cosmetic interventions, pharmacotherapy for hirsutism, menstrual irregularities and infertility treatments.

Therefore, there is a need to provide treatments for PCOS in a subject in need of such treatment that can address the different aspects of this complex condition, in any patient in need of such treatment while demonstrating an acceptable safety and/or tolerability profile. The inhibition of both SGLT1 and SGLT2 might provide additional benefits for improving treatment efficacy and response rates. Summary of the Invention

Sodium-glucose cotransporters (SGLT) 1 and 2 play an important role in glucose homeostasis with SGLT1 being the primary transporter responsible for absorption of glucose and galactose in the intestine, and SGLT 2 being the primary transporter responsible for renal glucose reabsorption. SGLT2 inhibitors are approved for the treatment of type 2 diabetes, acting primarily by increasing urinary glucose excretion (UGE) and improving glycemic control. Blockade of enteric SGLT1 results in glucose and galactose malabsorption. There are no approved dual inhibitors of SGLT 1 and 2.

LIK066 is a highly selective, safe and potent dual SGLT1/2 inhibitor that is in development at Novartis for obesity. In humans, the pharmacodynamic effects of LIK066 include increased urinary glucose excretion (UGE), and inhibition of glucose absorption from the gut. Body weight loss has been demonstrated in a phase 2a trial in obesity.

LIK066 significantly reduces post-prandial glucose and insulin excursions in healthy volunteers, obese populations and T2D populations. This effect is observed with single dose and is acute, meaning that it is observed on the meal immediately following dosing and not 6 hours later, which suggests a direct lumenal effect on gut SGLT1 inhibition. This effect is also dose dependent, with maximal post-prandial insulin suppression at 50 mg or higher. Fasting insulin and glucose levels are not significantly affected by LIK066. To date, there are no data on the effect of LIK066 on androgen levels. In accordance with a first aspect of the invention, there is provided a method for the treatment or prevention of polycystic ovary syndrome (PCOS) in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an a inhibitor of SGLT1 and SGLT2, e.g., LIK066, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS.

In yet another embodiment, the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS.

In another embodiment the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of PCOS.

In accordance with another aspect of the invention, there is provided a method for the treatment or prevention of PCOS in a subject with Type 2 Diabetes and/or obesity, which comprises administering to said subject a therapeutically effective amount of LIK066, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS in a patient with Type 2 diabetes and/or obesity.

In yet another embodiment, the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS in a patient with Type 2 diabetes and/or obesity.

In another embodiment the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of PCOS in a patient with Type 2 Diabetes and/or obesity.

The foregoing brief summary broadly describes the features and technical advantages of certain embodiments of the present disclosure. Additional features and technical advantages will be described in the detailed description of the disclosure that follows.

The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

Brief Description of the Drawings

FIG. 1 depicts the study design.

FIG. 2 depicts the assessment schedule.

FIG. 3 depicts the assessment schedule.

FIG. 4 depicts the assessment schedule.

FIG. 5 depicts the assessment schedule.

Detailed Description of the Invention

In a first embodiment, the invention is a method for the treatment or prevention of

PCOS, which comprises administering to said subject a therapeutically effective amount of LIK066, or a pharmaceutically acceptable salt thereof.

In a second embodiment, the invention is the method according to the first embodiment, wherein about 50 mg of LIK066 is administered three times per day ("tid").

In a third embodiment, the invention is the method according to any one of the first or second embodiments, wherein LIK066 is administered just before a meal.

In a fourth embodiment, the invention is the method according to any one of the previous embodiments, wherein the subject is at least 18 years old.

In a fifth embodiment, the invention is the method according to any one of the first through third embodiments, wherein the subject is obese, defined as an individual having a Body Mass Index (BMI)≥ 22kg/m².

In a sixth embodiment, the invention is the compound LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS.

In a seventh embodiment, the invention is a pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of PCOS. In an eighth embodiment, the invention is the pharmaceutical composition according to the seventh embodiment, wherein the compositions comprises 50 mg of LIK066.

In a ninth embodiment, the invention is the pharmaceutical composition according to the seventh or eighth embodiment, wherein the pharmaceutical composition is administered three times per day.

In a tenth embodiment, the invention is the pharmaceutical composition according to any one of the seventh through ninth embodiments, wherein the subject has a BMI≥ 22kg/m².

In an eleventh embodiment, the invention is the use of LIK066, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of PCOS.

In twelfth embodiment, the invention is the medicament according to the eleventh embodiment, wherein the compositions comprises 50 mg of LIK066. In a thirteenth embodiment, the invention comprises LIK066 for use in the treatment of PCOS.

In a fourteenth embodiment, the invention comprises LIK066 for use in the treatment of PCOS in a subject with T2D, particularly to any individual with an HbA1c between 7.0% and 10.0%.

In a fifteenth embodiment, the invention comprises LIK066 for use in the treatment of

PCOS in a subject with a BMI≥ 22kg/m².

In sixteenth embodiment, the invention is a pharmaceutical unit dose comprising 50 mg of LIK066.

Definitions

A "pharmaceutically acceptable salt" is intended to mean a salt of a free base/free acid of a compound represented by formula (I) that is not toxic, biologically intolerable, or otherwise biologically undesirable. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Such salts are known in the field (e.g., S.M. Berge, et al, "Pharmaceutical Salts", J. Pharm. Sd., 1977, 66: 1-19; and "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", Stahl, RH., Wermuth, C.G., Eds.; Wiley- VCH and VHCA: Zurich, 2002). LIK066 is an inhibitor of the sodium-glucose co- transporter- 1 (SGLT1) and sodium- glucose co-transporter-2 (S chemical structure:

LIK066 has the following lUPAC name: (2S,3R,4R,5S,6R)-2-(3-((2,3- dihydrobenzo[b][1 ,4]dioxin-6-yl)methyl)-4-ethylphenyl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol.

LIK066 for use in the present invention is either obtained in the free form, as a salt thereof, a co-crystal or as prodrug derivatives thereof.

Furthermore, LIK066 including its salts, can also be obtained in the form of its hydrates, or include other solvents used for its crystallization. LIK066 may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.

The term "hydrate" refers to the complex where the solvent molecule is water. LIK066, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.

The higher oral bioavailability of LIK066 may give rise to the following beneficial effects relating to less bioavailable compounds: (i) an enhanced biological effect may be achieved after oral administration; (ii) an earlier onset of action may be observed following oral administration; (iii) a lower dose may be needed to achieve the same effect; (iv) a higher effect may be achieved by the same dose or (v) a prolonged action may be observed at the same dose.

The term "subject" as used herein typically refers to a human, especially to a human patient diagnosed with PCOS.

The term "treatment" as used herein refers to any type of treatment that imparts a benefit to a subject affected with PCOS.

PCOS is a common endocrine disorder among women of reproductive age. PCOS may result in enlarged ovaries, and physically manifest as excess hair growth, acne, obesity or infrequent or prolonged menstrual cycles. PCOS is typically diagnosed via one of two methods: clinical or biochemical hyperandrogenism. Clinical hyperandrogenism is defined as moderate to severe hirsutism with a Ferriman-Gallway score of > 9 AND a free

testosterone level that is equal to or > 50% above the ULN (defined below), while

biochemical hyperandrogenism is defined as free testosterone level that is equal to or > 75% above the ULN.

For the above-mentioned indications (the conditions and disorders) the appropriate dosage will vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in are indicated to be obtained at a daily dosage of from about 0.01 to about 100 mg/kg body weight, preferably from about 1 to about 30 mg/kg body weight, e.g., 10 mg/kg. An indicated daily dosage is in the range from about 0.1 to about 1000 mg, preferably from about 1 to about 150 mg, conveniently administered, for example, in an oral dose delivered 1-3 times per day. In one embodiment, about 50 of LIK066 is administered three times a day.

For use according to the invention, LIK066 may be administered in any usual manner, e.g., orally, for example in the form of tablets, capsules or drinking solutions; rectally, for example in the form of suppositories; intravenously, for example in the form of injection solutions or suspensions; or transdermal, for example in the form of a patch.

In one embodiment, the manner of administration is oral administration, for example in the form of a tablet, capsule or drinking solution. In one embodiment, the manner of administration is rectal administration, for example in the form of a suppository. In one embodiment, the manner of administration is transdermal administration, for example in the form of a patch. In one preferred embodiment, the manner of administration is oral administration.

Preferred pharmaceutical compositions comprise LIK066 in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in

conventional manner. Unit dosage forms may contain LIK066 in an amount greater than or equal to 2.5mg, for example greater than or equal to 10mg, such as for example greater than or equal to 50mg. Unit dosage forms may also contain LIK066 in an amount of greater than or equal to 2.5mg, 10mg, 40mg, 50mg, 75mg or 100mg or greater than or equal to 150mg or 200mg.

Unit dosage forms may contain LIK066 in an amount less than or equal to 100mg, for example less than or equal to 100mg, such as for example less than or equal to 50 mg or for example less than or equal to 10mg or for example less than or equal to 2.5mg. Unit dosage forms may also contain LIK066 in an amount in the range from 1 -100mg, e.g., 1-75mg or 1- 60mg such as 2-55mg.

The pharmaceutical compositions according to the invention are compositions for enteral administration, such as oral or rectal administration; or parenteral administration, such as intramuscular, intravenous, and nasal or transdermal administration, to warmblooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.

The pharmaceutical compositions comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.

Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules. Compositions for transdermal administration are described in Remington's Pharmaceutical Sciences 16^th Edition Mack; Sucker, Fuchs and Spieser, Pharmazeutische Technologie, 1^st Edition, Springer.

Example of PCOS treatment via a randomized, placebo controlled study

The following abbreviations and terms will be used throughout the following example, which is in reference to a clinical trial study.

List of Abbreviations

ADR adverse drug reaction

AE adverse event

ALP alkaline phosphatase

ALT alanine aminotransferase

ANCOVA analysis of covariance

AST aspartate aminotransferase

BMI Body Mass Index

BUN blood urea nitrogen

CFR U.S. Code of Federal Regulation

CK creatinine kinase

CMO&PS Chief Medical Office and Patient Safety CQA Clinical Quality Assurance

Case Report/Record Form (paper or

CRF

electronic)

CRO Contract Research Organization

CTC Common Toxicity Criteria

CV coefficient of variation

DHEA dehydroepiandrosterone

DHEAS dehydroepiandrosterone sulfate

ECG electrocardiogram

EDxx effective dose xx%

EDC Electronic Data Capture

ELISA enzyme-linked immunosorbent assay

FAI free androgen index

FDA Food and Drug Administration

FSH follicle-stimulating hormone

GCP Good Clinical Practice

GGT gamma-glutamyl transferase

h hour

HBsAg hepatitis B surface antigen

HBV hepatitis B virus

HCV hepatitis C virus

HIV human immunodeficiency virus

homeostatic model assessment of insulin

HOMA-IR

resistance

ICF Informed Consent Form

International Conference on Harmonization

ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use

IEC Independent Ethics Committee

IRB Institutional Review Board

LDH lactate dehydrogenase

LFT liver function test

LH luteinizing hormone

LLN lower limit of normal

LLOQ lower limit of quantification MedDRA Medical Dictionary for Regulatory Activities mg milligram(s)

ml_ milliliter(s)

NCDS Novartis Clinical Data Standards

NOEL no observed effect level

p.o. oral

PCOS polycystic ovary syndrome

PD pharmacodynamic(s)

PK pharmacokinetic(s)

RBC red blood cell(s)

SAE serious adverse event

SD standard deviation

SGLT sodium glucose co-transporter

SGOT serum glutamic oxaloacetic transaminase

SGPT serum glutamic pyruvic transaminase

SHBG sex hormone-binding globulin

SOM Site Operations Manual

Suspected Unexpected Serious Adverse

SUSAR

Reactions

T testosterone

T2D type 2 diabetes mellitus

TBL total bilirubin

t.i.d. three times a day

ULN upper limit of normal

ULQ upper limit of quantification

UTI urinary tract infection

WBC white blood cell(s)

WHO World Health Organization

WoC Withdrawal of Consent

Terms

A procedure used to generate data required

Assessment

by the study

A specific group of subjects fulfilling certain

Cohort

criteria Any drug(s) (an active drug or an inactive drug, such as a placebo) which is used as a

Control drug

comparator to the investigational drug being tested in the trial

Dose of the study treatment given to the

Dosage subject in a time unit (e.g., 100 mg once a day, 75 mg twice a day)

Electronic data capture (EDC) is the electronic acquisition of clinical study data using data collection systems, such as Web- based applications, interactive voice response systems and clinical laboratory

Electronic Data Capture (EDC)

interfaces.

EDC includes the use of Electronic Case Report Forms (eCRFs) which are used to capture data transcribed from paper source forms used at the point of care.

Point/time of subject entry into the study at which informed consent must be obtained

Enrollment

(i.e. prior to starting any of the procedures described in the protocol)

Interval of time in the planned conduct of a study. An epoch is associated with a purpose

Epoch (e.g., screening, randomization, treatment, follow-up) which applies across all arms of a study.

The study drug whose properties are being tested in the study; this definition is consistent with US CFR 21 Section 312.3

Investigational drug and Directive 2001/20/EC and is

synonymous with "investigational new drug," "Investigational Medicinal Product," or "test substance"

A unique identifier assigned to each

Randomization number

randomized subject, corresponding to a specific treatment arm assignment

A subject who is screened but is not treated

Screen Failure

or randomized

Source data refers to the initial record, document, or primary location from where

Source Data/Document data comes. The data source can be a

database, a dataset, a spreadsheet or even hard-coded data, such as paper or eSource Any drug or combination of drugs

administered to the study participants as part

Study treatment of the required study procedures; includes investigational drug(s), control(s) or background therapy

When the subject permanently stops taking

Study treatment discontinuation study treatment prior to the defined study treatment completion date

A trial participant (can be a healthy volunteer

Subject

or a patient)

A unique number assigned to each subject upon signing the informed consent. This number is the definitive, unique identifier for

Subject number

the subject and should be used to identify the subject throughout the study for all data collected, sample labels, etc.

A measured value or assessed response that is determined in specific assessments

Variable

and used in data analysis to evaluate the drug being tested in the study

Withdrawal of consent from the study is defined as when a subject does not want to participate in the study any longer, and does not want any further visits or assessments,

Withdrawal of consent (WoC)

and does not want any further study related contact, and does not allow analysis of already obtained biologic material Pharmacokinetic definitions and symbols

The area under the plasma (or serum or blood) concentration-time curve from time

AUCIast

zero to the time of the last quantifiable concentration [mass x time / volume]

The observed maximum plasma (or serum or

Cmax

blood) concentration following drug administration [mass / volume]

Tmax The time to reach the maximum

concentration after drug administration [time]

STUDY DESIGN

Primary objective

Determine the efficacy of utilizing LIK066 in the treatment or prevention of PCOS in individuals, particularly obese individuals.

Secondary objectives

1. To assess the safety and tolerability of LIK066 in overweight and obese subjects with PCOS throughout the study. 2. To evaluate the treatment effect of LIK066 on gonadotropins and sex steroid levels on Day 15

Study design

This is a randomized, subject- and investigator-blinded, placebo-controlled, parallel group, non-confirmatory study in overweight and obese PCOS subjects.

Approximately 24 subjects are randomized in a 1 :1 ratio to LIK066 or placebo (12 subjects on LIK066; 12 on placebo). Discontinued subjects may be replaced. If more than 2 subjects experience menstrual bleeding during the study, additional subjects may be enrolled to account for those subjects in case they are excluded from the pharmacodynamic analysis set (if ovulation is confirmed based on progesterone assessment). The number of enrolled subjects; excluding replacements, should not exceed 30.

The treatment period is 2 weeks; dosing is oral, just before meals, 50 mg of LIK066 or matching placebo t.i.d. for 14 days and only one dose in the morning on Day 15.

The study design is set forth in Figure 1. Each subject participates in a screening period of up to 6 weeks, a baseline period (including an optional overnight stay at the study site), a treatment period of 2 weeks (outpatient visits and one optional overnight stay at end of treatment), and a follow-up period of about 1 week with an end of study visit on

approximately Day 22. A subject's duration of participation in the study is up to a total of 9 weeks inclusive of the 6-week screening window.

At screening, subjects should report to the study site after an overnight fast of at least 8 hrs. Blood samples for eligibility criteria must be collected during fasting between 6 am and 8 am. Subjects who meet all eligibility criteria at screening will be admitted for baseline evaluations.

The baseline visit (Day -1) includes an optional overnight stay (starting Day -2) and an 8- 10 hour overnight fast. Serial blood samples for hormone levels is collected between 6 am and 8 am the following morning (Day -1), followed by the test meal for breakfast (without drug administration) and serial post-prandial blood sampling over a 4 hour period.

If the time interval between the screening and baseline visits is more than 10 days, then baseline safety labs must be reviewed by the investigator to ensure eligibility criteria continue to be met and to then enable randomization.

The investigator must randomize eligible subjects on, or prior to, Day 1. The site staff must provide subjects with study drug and instructions on drug administration immediately before meals, three times a day. The site staff should inform subjects that they are to avoid high carbohydrate meals in order to minimize Gl discomfort with dosing.

During the treatment period, a follow-up visit is conducted on Day 8 to check tolerability, safety and compliance. This visit may be conducted either by phone or in person at the site, at the discretion of the investigator.

On Day 14, subjects return to the site for an optional overnight stay. The end of treatment assessment takes place on Day 15 after an overnight fast of at least 8 hours. On Day 15 morning, serial blood samples are collected during fasting between approximately 6 am and 8 am. This is followed by last dose administration and by a repeat breakfast test meal, similar in composition to the baseline test meal. Serial blood samples will be collected over the 4 hour post-prandial period. The investigator discharges subjects after completing Day 15 assessments.

The End-of-Study visit will occur on approximately Day 22, for study completion evaluations. This visit may be performed earlier in the case of early termination.

At baseline, the physical examination includes cutaneous manifestations of hyperandrogenism, e.g., hirsutism, acne, androgenic alopecia, as well as acanthosis nigricans and skin tags; baseline measures of body weight, waist circumference, hip circumference and waist/hip ratio. The medical history includes the approximate onset of the last menstrual period and prior history of gestational diabetes.

In this study, endocrine assessments include total testosterone, free testosterone, LH,

FSH, SHBG, estradiol, progesterone, DHEAS, DHEA, androstenedione, insulin and glucose. Safety assessments throughout the study include vital signs, physical examinations, ECGs, standard clinical laboratory evaluations (blood chemistry, hematology, urinalysis), adverse events and serious adverse events.

Rationale for study design

• Randomization reduces the risk of imbalances in baseline subject characteristics

between groups, and reduces the risk of bias in the interpretation of pharmacodynamic, safety and tolerability endpoints.

· Subject- and investigator-blinding minimizes bias in adverse event reporting by

subjects and investigators and in causality assessments by investigators.

• Parallel treatment arms: A crossover design would be impractically long due to the

need of a prolonged wash-out period to enable the pituitary-gonadal function to get back to baseline.

· Placebo comparator supports the analysis of the treatment effect of LIK066 on

pharmacodynamic markers, especially given the risk of confounding effects due to biologic and analytic variability of androgen levels in women. Including a placebo arm also helps for causality evaluation of adverse events in relation to study drug, study procedures and/or underlying disease.

· Domiciling controls for confounders that influence the circadian rise in testosterone

levels, such as overnight fast; enables serial sampling of fasting testosterone over the time period of peak secretion (between about 6 am and 8 am); and ensures an adequate fasting period prior to the breakfast meal, which is important for assessing the treatment effect of LIK066 on insulin secretion.

• Free testosterone (T) as primary end-point: Free T and not total T, is considered to be more sensitive as a diagnostic marker of hyperandrogenism in women with PCOS. Total testosterone has inadequate sensitivity to differentiate between normal and PCOS women. Free T is also the biologically active form of testosterone and, unlike total T, free T may significantly change in response to treatment effects on SHBG.

• Test meal: A standardized breakfast test meal is used to evaluate the post-prandial effect of LIK066 on insulin excursion and enable evaluation of the relationship between effects of LIK066 on insulin and those on androgen levels, in support of the primary hypothesis of this study. The test meal is enriched for carbohydrate in order to stimulate insulin release. The test meal is benchmarked to tests used in other clinical studies with LIK066 in order to enable comparison of treatment effects across studies and

populations.

· PK sampling: Limited number of PK samples are collected on Day 15 at the time of test meal, in order to evaluate the steady-state PK of LIK066 in subjects with PCOS, and to assist with PKPD analyses or modeling activities.

Rationale for dose/regimen, route of administration and duration of treatment

The dosing regimen for LIK066 in this study is 50 mg orally (or matching placebo), t.i.d. before each main meal (Quaque ante cibum, q.a.c.) (before breakfast, lunch and dinner) for 14 days. The last dose is administered on Day 15 morning before the test meal.

LIK066 regimens of either 50 mg or 150 mg once a day are approximately≥ ED₈o for maximal urine glucose excretion (UGE), and are predicted to be≥ ED₉₀ for body weight loss, reflecting dual SGLT1 and SGLT2 inhibition At these doses, LIK066 has been shown to reduce post-prandial incremental insulin and plasma glucose in a dose-dependent manner in clinical studies in healthy, obese and T2D subjects.

Dose level: Gut inhibition of SGLT1 by LIK066 is expected to inhibit absorption of prandial glucose, resulting in lower post-prandial serum glucose excursions and lower post-prandial insulin release. A single dose of LIK066 of 50 mg and 150 mg has been shown to acutely reduce post-prandial incremental insulin by 59% and 81 %, respectively and post-prandial incremental plasma glucose by 72% and 91 %, respectively, when compared to placebo in patients with T2D (test meal). In patients with PCOS, reduction of insulin levels by about 25 %, e.g., with metformin, has been associated with improved hyperandrogenism and subsequent ovulation. The magnitude of reduction in the incremental insulin levels with 50 mg of LIK066 over 2 weeks before three main meals is expected to result in a clinically relevant effect size on androgen levels in PCOS.

Dosing regimen of t.i.d. and q.a.c (before each meal): The post-prandial effect of

LIK066 on glucose and insulin is observed on the meal that immediately follows dosing, and not significantly with later meals, possibly due to limited lumenal exposure time to LIK066. For example, an LIK066 dose of 150 mg induced acute reduction of post-prandial glucose and insulin but had no apparent effect on a test meal given approximately 6 hours post- dose as reported in the IB. For this reason, LIK066 will be administered immediately before each of the main meals; breakfast, lunch and dinner, i.e. t.i.d. and q.a.c. to ensure repeated pharmacologic reduction in insulin response per meal. This regimen is expected to induce a more sustained reduction in cumulative insulin levels at least during the daytime.

Safety and tolerability: The local gut lumenal exposure to LIK066 has been associated with Gl symptoms, notably diarrhea and flatulence that are temporally related to meal intake with dosing. The daily systemic exposure from the 50 mg t.i.d. regimen in the PCOS population is expected to maintain a≥ 10-fold exposure multiple relative to the NOEL AUC threshold for aneugenicity.

Rationale for treatment duration: A 14 day treatment period is expected to support an effect of LIK066 on androgen levels in this population given the expected magnitude of reduction in overall insulin levels with t.i.d. dosing. A similar treatment duration with insulin inhibitors, such as diazoxide, were shown to reduce hyperandrogenism.

Overall, a dosing regimen of LIK066 at 50 mg p.o. t.i.d. and q.a.c. x 14 days is safe and effective for pharmacodynamic evaluation of treatment effect on the androgen and insulin profile in this population.

Rationale for choice of comparator

A placebo group is included to ensure blinding and to determine the study effect.

Population

The study population consists of female patients (≥18 years old) with PCOS.

Inclusion criteria 1. Patients eligible for inclusion in this study must fulfill all of the following criteria: Written informed consent must be obtained before any assessment is performed.

2. Overweight/obese women with PCOS aged 18 to 40 years, inclusive

3. PCOS diagnosed as

· Hyperandrogenism, clinical OR biochemical, AND

• Amenorrhea or oligomenorrhea (less than 8 menses within the last 12 months), AND

• Exclusion of other causes of hyperandrogenism (see exclusion criteria)

Clinical hyperandrogenism is defined as moderate to severe hirsutism with a Ferriman- Gallway score of > 9 AND a free testosterone level that is equal to or > 50% above the ULN.

Biochemical hyperandrogenism is defined as free testosterone level that is equal to or > 75% above the ULN.

The screening labs for free T can be repeated once for borderline levels; the highest level of free T must be considered for eligibility.

4. Indicators of insulin resistance at screening defined as:

• Sex hormone binding globulin, SHBG < LLN OR

• Fasting insulin above the median of normal range of assay used

5. Overweight/obese subjects with BMI of 28 - 45 kg/m², inclusive, and stable weight +/- 3 kg over previous 3 month (by history)

6. At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position and again in the standing position as outlined in the SOM. Subjects with mild hypertension and those with treated hypertension are allowed. Sitting vital signs should be within the following ranges:

• oral body temperature between 35.0-37.5 °C

· systolic blood pressure, 90-150 mmHg

• diastolic blood pressure, 50-90 mmHg

• pulse rate, 40-90 bpm

If vital signs are outside these ranges, the Investigator should obtain two additional readings, so that up to three consecutive assessments are made, following the procedure in the SOM. At least the last reading must be within the ranges provided above in order for the subject to qualify.

Subjects should be excluded if their standing vital signs (relative to sitting) show findings which, in the opinion of the Investigator, are associated with clinical manifestations (such as lightheadness or palpitations) of postural hypotension (i.e. absence of any other cause). Postural hypotension is defined as either a > 20 mmHg decrease in systolic or a >10 mmHg decrease in diastolic blood pressure, accompanied by a > 20 bpm increase in heart-rate (from sitting to standing).

7. Subjects must use non-hormonal methods of contraception from enrollment until one week after last dose. Non-hormonal contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (i.e., calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are NOT acceptable methods of contraception.

• Hysterectomy or tubal ligation at least six weeks before the treatment period.

· Placement of a non-hormonal intrauterine device (IUD).

• Male partner sterilization (at least 6 months prior to screening). The vasectomized partner should be the sole partner for that subject.

• Barrier methods of contraception: Condom or Occlusive cap. For UK: with

spermicidal foam/gel/film/cream/vaginal suppository.

8. Able to communicate well with the Investigator, to understand and comply with the

requirements of the study.

Exclusion criteria

Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions are applied by the investigator, in order to ensure that the study population is representative of all eligible patients.

1. Subjects with pre-existing type 1 or type 2 diabetes mellitus, Cushing's syndrome,

congenital adrenal hyperplasia, ovarian or adrenal androgen-secreting tumor, uncontrolled thyroid disease, untreated obstructive sleep apnea.

2. Oophorectomy.

3. Exogenous causes of hirsutism (such as drug-induced). 4. Menstruation in the 30 days prior to screening or prior to the initiation of treatment (Day 1).

5. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test

6. Abnormal screening labs defined as:

• Early morning total testosterone levels => 2.5x ULN or => 200 ng/dl

• DHEAS > 2x ULN or > 700 mcg/dl

• Prolactin > ULN on early AM sample (allow repeat x 1 for borderline levels, enroll based on 1 normal level)

• 17-OHP levels (early AM sample) > 200 ng/dl

• Clinically significant abnormalities in TSH

7. Symptomatic genital or urinary tract infection (UTI) in the 4 weeks prior to screening or the presence of active UTI at screening

8. Ongoing participation in a weight loss program such as with exercise, diet or drugs.

9. History of significant gastrointestinal surgery that could affect intestinal glucose

absorption (e.g., bariatric surgeries including, Roux-en-Y gastric bypass, sleeve gastrectomy, Nissen fundoplication); active gastrointestinal disorders such as irritable bowel syndrome and inflammatory bowel disease.

10. Clinically significant Gl disorder related to malabsorption or that may affect drug or glucose absorption (e.g., swallowing disorder, severe Gl motility disorder, chronic diarrhea, glucose/galactose/lactose intolerance)

11. History of hypersensitivity to the study drug, or to drugs of similar chemical classes.

12. Use of prohibited medications, including: · antidiabetic medications or weight loss drugs within 3 months of screening.

• hormonal therapy including but not limited to estrogen/progesterone contraceptives, estrogens, androgens, gonadotropin-releasing hormone within 3 months of screening, or progesterone contraceptives within 1 month of screening. Thyroid replacement therapy is allowed; subjects must be on a stable dose for at least 3 months prior to screening. • Infertility treatment e.g., letrozole and clomiphene citrate within 1 month of screening

• muscle anabolic agents/drugs within 3 months of screening.

• Systemic glucocorticosteroid treatment for > 7 consecutive days for worsening of an underlying condition within 4 weeks of screening. Use of topical or inhaled glucocorticosteroids is permitted.

• Strong inhibitors of CYP3A4/5 including boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole at least 7 days prior to the study treatment.

• Strong CYP3A inducers including avasimibe, carbamazepine, phenytoin, rifampin, St. John's wort at least 7 days prior to the study treatment,

• General UGT inhibitors including probenecid, valproic acid at least 7 days prior to the study treatment.

· other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, or longer if required by local regulations. Any other limitation of participation in an investigational trial based on local regulations.

• any drugs with known toxicity to a major organ system within the past 3 months (i.e., cytostatic drugs).

· Unless allowed by the study protocol, any other prescription drugs, new herbal

supplements, within four (4) weeks prior to initial dosing, and/or over-the-counter (OTC) medication, new dietary supplements (vitamins included), within 3 days prior to initial dosing. If needed, acetaminophen or ibuprofen is acceptable for incidental and limited use.

13. Malignancy including leukemia and lymphoma (not including basal cell skin cancer

which has been adequately treated) within 1 year prior to screening.

14. History of autonomic dysfunction (e.g., history of fainting, clinically significant orthostatic hypotension, clinically significant sinus arrhythmia).

15. Significant cardiovascular disease, active or within 6 months of screening such as

myocardial infarct (Ml), unstable angina, or clinically significant ECG abnormalities at screening 16. Evidence of clinically significant abnormal liver function tests for any of the labs at screening, confirmed by a repeat assessment:

• ALT, AST, GGT, alkaline phosphatase > 3 x ULN.

• serum bilirubin > 1.5 x ULN.

17. Ketoacidosis, lactic acidosis, or hyperosmolar coma within 6 months of screening.

18. Significant blood loss equaling at least one unit of blood (500 ml) or a blood transfusion within 3 months prior to screening.

19. History of drug or alcohol abuse within the 12 months prior to screening or evidence of such abuse as indicated by the laboratory assays conducted at screening.

20. Evidence of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result at screening.

21. Any finding during screening assessments (vital signs, physical examination, ECG or clinical lab assessments), surgical or medical condition which may significantly alter the absorption, distribution, metabolism, or excretion of drugs, or in the investigator's judgment, which may jeopardize the subject in case of participation in the study, or would interfere with interpretation of the study results.

Treatment arms

Subjects will be assigned to one of the following 2 treatment arms in a ratio of 1 :1

• LIK066 50 mg three times daily; before breakfast, lunch and dinner (12 subjects).

• Matching placebo tablets three times daily; before breakfast, lunch and dinner (12 subjects).

Treatment assignment and randomization

Randomized treatment is assigned to individual subjects by way of a randomization number, which will be in the range of 5101-5130. The randomization number is only used to identify which treatment the subjects have been randomized to receive. The Subject number assigned to a subject at screening remains the unique identifier for the subject throughout the study.

Replacement randomization numbers will be in the range of 6101-6130. If a subject requires a replacement, the replacement subject will be assigned a randomization number corresponding to the original subject (e.g. , Subject 6103 would replace Subject 5103). Any additional subjects enrolled will use sequential subject numbering. The randomization numbers are generated using the following procedure to ensure that treatment assignment is unbiased and concealed from subjects and investigator staff. Treatment allocation cards (noting the randomization numbers) will be produced by or under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of treatment arms to randomization numbers in the specified ratio.

The randomization scheme for subjects will be reviewed and approved by a member of the Randomization Office. The investigator will enter the randomization number on the CRF (eCRF). If more than one study center recruits subjects simultaneously, the CTL or designee will coordinate assigning randomization numbers across sites as described in the SOM.

Treatment blinding

This is a subject and investigator-blinded study. Subjects and investigators will remain blinded to study treatment throughout the study, except where indicated below.

The identity of the treatments will be concealed by the use of study drugs that are all identical in packaging, labeling, and schedule of administration, appearance, and odor.

Site staff

With the exception of any unblinded site staff identified below, all site staff (including study investigator and study nurse) will be blinded to study treatment throughout the study. Unblinding a single subject at site for safety reasons (necessary for subject management) will occur via an emergency system in place at the site.

Drug product will be supplied in bulk, so an unblinded pharmacist who is

independent of the study team will be required in order to maintain the blind. This unblinded pharmacist (or delegate) will receive treatment allocation cards from Drug Supply

Management with the appropriate treatment allocation numbers. Appropriate measures must be taken by the unblinded pharmacist to ensure that the treatment assignments are concealed from the rest of the site staff. Sponsor staff

The following unblinded sponsor roles are required for this study:

Unblinded field monitor(s);

Unblinded clinical staff managing drug re-supply to site; and Unblinded sample analyst(s).

The unblinded field monitors are required to review drug accountability and allocation at site. The unblinded monitors are not provided with a randomization list directly but will be unblinded through review of source documentation compiled by the unblinded pharmacist, which details treatment allocation to individual subjects. The unblinded monitors will also be able to review the treatment allocation cards provided to the unblinded pharmacist.

Sponsor clinical staff are required to assist in the management and re-supply of investigational drug product. These individuals are not provided with randomization lists directly, but may be unblinded through communication of drug re-supply needs via the unblinded site pharmacists.

The sample analysts will receive a copy of the randomization schedule (via request to the Randomization Office), to facilitate analysis of the samples. The sample analysts will provide the sample data to the study team under blinded conditions unless otherwise allowed.

The study statistician will be able to access the randomization list for interim analyses and is allowed to share unblinded information with the rest of the clinical team as appropriate for internal decision purposes. For example, unblinded summaries and unblinded individual data can be shared with the team for interim analyses. Study programmers and other personnel involved in study data analysis (e.g., biomarker expert) are allowed to access treatment assignment information for the purpose of conducting interim analyses.

The clinical trial team is allowed to share unblinded results with other sponsor staff (e.g., decision boards) as required for internal decision making on the study or the project at the time of interim analyses while the study is ongoing.

All unblinded personnel will otherwise keep randomization lists and data or information that could unblind other study team members confidential and secure except as described above. Following final database lock all roles may be considered unblinded.

Dispensing the study drug

Each study site is supplied with study drug in packaging of identical appearance.

The study drug packaging has a 2-part label. A unique randomization number is printed on each part of this label which corresponds to one of the treatment arms. Investigator staff identify the study drug package(s) to dispense to the patient by contacting the IRT and obtaining the medication number(s). Immediately before dispensing the package to the patient, investigator staff detach the outer part of the label from the packaging and affix it to the source document (Drug Label Form) for that patient's unique patient number.

Concomitant medication

The investigator must instruct the patient to notify the study site about any new medications he/she takes after the patient was enrolled into the study. All medications, procedures and significant non-drug therapies (including physical therapy and blood transfusions) administered after the patient was enrolled into the study must be recorded in the Concomitant Medications/Surgical and Medical Procedures eCRF. Every effort should be made by the Investigator to keep the dose level of each patient's allowed background heart failure medications stable throughout the entire study duration. However; if the clinical condition of the patient warrants a change in any of these medications, it is allowed at the discretion of the study Investigator. Each concomitant drug must be individually assessed against all exclusion criteria/prohibited medication. If in doubt the investigator should contact the Novartis medical monitor before randomizing a patient or allowing a new medication to be started.

Emergency breaking of assigned treatment code

Emergency code breaks are only undertaken when it is required to in order to treat the patient safely. Most often, study treatment discontinuation and knowledge of the possible treatment assignments are sufficient to treat a study patient who presents with an emergency condition. Emergency treatment code breaks are performed using the IRT. When the investigator contacts the system to break a treatment code for a patient, he/she must provide the requested patient identifying information and confirm the necessity to break the treatment code for the patient. The investigator then receives receive details of the investigational drug treatment for the specified patient and communication confirming this information. The system automatically informs the Novartis monitor for the site and the Study Team that the code has been broken.

It is the investigator's responsibility to ensure that there is a dependable procedure in place to allow access to the IRT system at any time in case of emergency. The investigator provides the protocol number, the study drug name (if available) and the patient number.

In addition, oral and written information to the patient is provided on how to contact the investigator^'s backup in cases of emergency, or when the investigator is unavailable, to ensure that un-blinding can be performed at any time. Patients whose treatment has been unmasked must be discontinued from study treatment. Study completion and post-study treatment

A patient is considered to have completed the study when the patient has completed the last planned visit (see FIGs 2-5). The study as a whole is considered completed when all randomized subjects have completed the last visit planned in the protocol or have discontinued the study prematurely. The investigator must provide follow-up medical care for all subjects who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.

Visit schedule and assessments

Figures 2-5 list all of the study visits and assessments and indicates with an "X" when the assessments are performed. Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely discontinue the study for any reason should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed. At this final visit, all dispensed investigational product should be reconciled and the adverse event and concomitant medications reconciled on the eCRF. Patients will be contacted for safety evaluations during the 30 days following the last administration of study treatment.

Patient demographics/other BL characteristics

Demographic and BL characteristics data collected on all randomized patients include: year of birth, age, sex, race, ethnicity, relevant medical history/current medical conditions present before signing informed consent including smoking and alcohol history. Where possible, diagnoses and notable symptoms are recorded. Investigators have the discretion to record abnormal test findings on the medical history eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent form (ICF) signature. Treatment exposure and compliance

Compliance is assessed by the investigator and/or study personnel at each visit using pill counts and information provided by the patient. This information is captured in the source documents at each visit. All study treatment dispensed and returned must be recorded in the Drug Accountability Log. The site is also required to complete the

appropriate Dosage Administration Record eCRF to record any study drug regimen changes or interruptions.

Efficacy Pharmacodynamic (PD) samples will be collected at the timepoints defined in the Assessment schedule as set forth in Figs. 2-5. PD samples will be obtained and evaluated in all subjects, including the placebo group. Pharmacodynamic assessments include :

• Early morning fasting testosterone, free and total; SHBG, androstenedione, DHEA, DHEAS, LH, FSH and free androgen index (FAI)

Data collection

Designated investigator staff will enter the data required by the protocol into the Electronic Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. Designated investigator site staff will not be given access to the EDC system until they have been trained. Validation checks for data discrepancies and, by generating appropriate error messages, allow the data to be confirmed or corrected before transfer of the data to Novartis or the CRO working on behalf of Novartis. The Investigator must certify that the data entered into the Electronic Case Report Forms are complete and accurate. After database lock, the investigator will receive copies of the subject data for archiving at the investigational site.

Data not requiring a separate written record will be defined in the SOM and

Assessment schedule and can be recorded directly on the CRFs. All other data captured for this study will have an external originating source (either written or electronic) with the CRF not being considered as source. All data should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification.

Database management and quality control

Novartis or designated CRO staff review the data entered into the CRFs by investigational staff for completeness and accuracy and instruct the site personnel to make any required corrections or additions. Queries are sent to the investigational site via the EDC system. Designated investigator site staff is required to respond to the query and confirm or correct the data. If the electronic query system is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff who will make the correction to the database. The signed copy of the Data Query Form is kept at the investigator site. Concomitant medications entered into the database will be coded using the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification system. Medical history/current medical conditions and adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology. Laboratory results will be sent electronically to Novartis (or a designated CRO).

The occurrence of relevant protocol deviations will be determined. After these actions have been completed and the database has been declared to be complete and accurate, it will be locked and made available for data analysis.

Data analysis

The analysis will be conducted on all subject data at the time the trial ends. Any data analysis carried out independently by the investigator should be submitted to Novartis before publication or presentation.

Analysis sets

For all analysis sets, subjects will be analyzed according to the study treatment(s) received. The safety analysis set will include all subjects that received any study drug. The PK analysis set will include all subjects with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and with no protocol deviations that impact on PK data. The PD analysis set will include all subjects with available PD data and no protocol deviations with relevant impact on PD data.

Statistical model, hypothesis, and method of analysis

The primary analysis will assess the treatment effect of LIK066 on free T at Day 15. The ratio of Day 15 to baseline free T will be analyzed in an analysis of covariance model with treatment as a categorical factor and baseline free T as a covariate. Additional baseline characteristics that may be predictive of free T may be added to the model as covariates. The logarithm of the ratio and of baseline free T will be applied prior to the analysis.

The geometric mean of the ratio to baseline for free T will be estimated from the model for LIK066 and placebo, along with the treatment ratio and the associated p-value and two- sided 90% confidence interval (CI). From these quantities, the following criteria will be assessed:

• the upper confidence limit of the 90% CI is less than 1 , and

• the estimated treatment ratio is less than 0.75.

The first criterion addresses with high certainty whether the effect of LIK066 on free T reduction is superior to placebo. The second criterion addresses whether the observed treatment effect of LIK066 on free T reduction is at least 25%. An effect size of 20-25% on hyperandrogenism is considered to be clinically meaningful in PCOS as it correlates with improved ovulation and fertility. Subjects who are deemed to have hormonal evidence of ovulation during the study may be excluded from the primary analysis. Handling of missing values/censoring/discontinuations

The primary efficacy analysis will be based on all subjects with an evaluable baseline and Day 15 free T profile and that have no hormonal evidence of ovulation during the study.

Sensitivity analyses

As a sensitivity analysis, the change from baseline in free T at Day 15 will be analyzed in an analysis of covariance model of the same form as the one specified for the primary analysis, except no logarithmic transformation will be applied. The least-squares mean change from baseline will be estimated from the model for LIK066 and placebo, along with the treatment difference and the associated p-value and two-sided 90% confidence interval.

Analysis of secondary vahable(s)

The secondary variables will be the gonadotropins (LH and FSH), the sex steroids (total testosterone, estradiol, progesterone, DHEAS, DHEA, androstenedione), SHBG, and free androgen index. For LH, FSH, and total testosterone, the average of the three morning fasting concentrations will be additional secondary variables.

Efficacy / Pharmacodynamics

Each of the secondary variables will be listed by treatment group, subject, and visit/time and summarized by treatment and visit/time. The change from baseline and % change from baseline will also be listed and summarized.

For biomarkers whose concentrations are measured using an assay with a working range defined by a lower limit of quantification (LLOQ) and upper limit of quantification (ULOQ), values < LLOQ and values > ULOQ will be shown as such in the listings, but will be imputed as LLOQ/2 and ULOQ, respectively, for summaries, analyses, and plots. In the summary tables, the frequency (n, %) of values below the LLOQ and above the ULOQ, respectively, will be included.

For each variable, the ratio of Day 15 to baseline will be analyzed in an analysis of covariance model with treatment as a categorical factor and baseline as a covariate. The logarithm of the ratio and of baseline will be applied prior to the analysis. The geometric mean of the ratio to baseline will be estimated from the model for LIK066 and placebo, along with the treatment ratio and the associated p-value and two-sided 90% confidence interval.

Safety

Vital signs All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be provided by treatment and visit/time.

ECG evaluations

All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time.

Clinical laboratory evaluations

All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges are available abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time.

Adverse events

All information obtained on adverse events will be displayed by treatment group and subject.

The number and percentage of subjects with adverse events will be tabulated by body system and preferred term with a breakdown by treatment. A subject with multiple adverse events within a body system is only counted once towards the total of this body system.

Pharmacokinetics

LIK066 plasma concentration data will be listed by treatment, subject, and visit/sampling time point. Descriptive statistics will be provided by treatment and visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero. Concentrations below LLOQ will be treated as zero in summary statistics and for PK parameter calculations. A geometric mean will not be reported if the dataset includes zero values.

Each of the PK parameters will be listed by treatment and subject and summarized by treatment. Descriptive statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, and maximum. An exception to this is Tmax where median, minimum, and maximum will be presented.

Pharmacokinetic / pharmacodynamic interactions

The relationship between PK and key PD parameters on Day 15 may be explored using a graphical approach.

Sample size calculation The sample size for this study has been based on a relevant interventional study in a similar population of adults with PCOS. The mean and standard deviation of free T by LC- MS/MS in this study, as a pooled estimate across all treatment arms at baseline, is 79 pmol/L and 40 pmol/L, respectively. The study reported a decrease in free T of 19% after 7 days of treatment with AZD4901 , a neurokinin B receptor antagonist.

The sample size calculation assumes similar baseline characteristics of free T, a 2% reduction in free T in the placebo arm, and a correlation between baseline and Day 14 free T of 0.5. The assumption also is that the true treatment effect of LIK066 is 35% over placebo. We choose to assume a correlation between baseline and Day 15 of 0.5 because, based on results of free T in a published study of metformin in women with PCOS, we believe it to be smaller than the true correlation, and hence it is likely that the power for achieving the primary study criteria is conservative.

Based on these assumptions, a sample size of 24 subjects in a 1 :1 treatment allocation (12 on LIK066; 12 on placebo) will provide 80% probability of achieving the dual criteria specified in the previous section. The probability of a type I error (achieving the criteria when in fact there is no true treatment effect on free T) is 5%. These results are based on 10,000 simulations of the primary analysis.

Regulatory and ethical compliance

This clinical study is designed and shall be implemented, executed and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, US CFR 21 , and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki.

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

What is claimed is:

A method for the treatment or prevention of polycystic ovary syndrome in a subject in need of such treatment, which comprises administering to said subject a

therapeutically effective amount of LIK066, or a pharmaceutically acceptable salt or co-crystal thereof.

The method of claim 1 , wherein 50 mg of LIK066 is administered.

The method according to any one of claims 1 -2, wherein LIK066 is administered three times a day.

The method according to any one of claims 1 -3, wherein LIK066 is administered immediately before a meal.

The compound LIK066, or a pharmaceutically acceptable salt, co-crystal or prodrug thereof, for use in the treatment or prevention of polycystic ovary syndrome.

A pharmaceutical composition comprising LIK066, or a pharmaceutically acceptable salt, co-crystal or prodrug thereof, for use in the treatment or prevention of polycystic ovary syndrome.

Use of LIK066, or a pharmaceutically acceptable salt, co-crystal or prodrug thereof, the treatment or prevention of polycystic ovary syndrome.

Use of LIK066, or a pharmaceutically acceptable salt, co-crystal or prodrug thereof, in the manufacture of a medicament for use in the treatment or prevention of polycystic ovary syndrome.