The present invention relates to aleglitazar for use in the treatment or prevention of major adverse cardiac events, in particular in a Type 2 Diabetes patient having chronic kidney disease and dyslipidemia. Aleglitazar is (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy ]- benzo[b]thiophen-7-yl} -propionic acid. It belongs to the class of Peroxisome Proliferator Activated Receptors (PPAR) agonists. Aleglitazar is described in WO 02/092084.

Peroxisome Proliferator Activated Receptors (PPAR) are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Various subtypes thereof have been identified and cloned. These include PPAR alpha, PPAR beta (also known as PPAR delta) and PPAR gamma. There exist at least two major iso forms of PPAR gamma. While PPAR gamma 1 is ubiquitously expressed in most tissues, the longer isoform PPAR gamma2 is almost exclusively found in adipocytes. In contrast, PPAR alpha is predominantly expressed in the liver, kidney and heart. PPARs modulate a variety of body responses including glucose and lipid homeostasis, cell differentiation, inflammatory responses and cardiovascular events.

Aleglitazar is a potent, balanced dual PPAR alpha/gamma agonist. It combines the PPAR alpha with the PPAR gamma agonist effects.

In the randomized clinical trial AleCardio (Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus), although aleglitazar reduced hemoglobin AIC and improved serum HDL-C and triglyceride levels, consistently with other previous PPAR studies, it did not significantly decrease the incidence of cardiovascular death, myocardial infarction or stroke in the overall population. Additionally, aleglitazar treatment showed increased risks of heart failure, renal dysfunction, bone fracture, GI bleeding and hypoglycemia.

DP/31.01.19 However, aleglitazar surprisingly demonstrated in this study a positive effect on relative risk reduction of major adverse cardiac events (MACE) in the subgroup of patients who have chronic kidney disease and dyslipidemia. The safety profile was also balanced in this subgroup.

AleCardio was a randomized, double-blind, placebo controlled, multicenter study to evaluate the effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome (ACS) in patients with type 2 diabetes mellitus. The study design has previously been published in Lincoff et a , JAMA 2014; 311(15):1515-1525. and Lincoff et ah, Am Heart J. 2013;166(3):429-434. The study protocol was approved by the institutional review board of each center and all patients gave written informed consent. The study was overseen by steering and safety committees. The steering committee oversaw the study design, the study conduction and the study data analysis. A Data and Safety Monitoring Board (DSMB), consisting of independent physicians and statisticians with access to unblended data, monitored the safety of study. 7,226 patients who were hospitalized for ACS with either established or newly diagnosed type 2 diabetes were recruited between February 2010 and May 2012 from 722 centers in 26 countries. The study was planned to continue until patients were folio wed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. However, the trial was terminated in July 2013 following the DSMB’s recommendation and 704 primary end points events (74% of those projected) had been positively adjudicated by December 17, 2013.

The study enrolled patients with type 2 diabetes mellitus and acute coronary syndrome (ACS) requiring hospitalization. Acute coronary syndrome included myocardial infarction, with or without ST segment elevation on the electrocardiogram, or biomarker negative unstable angina. Exclusion criteria included symptomatic heart failure, hospitalization with heart failure within the previous 12 months, severe peripheral edema, estimated glomerular filtration rate of <45 mE/min/1 .73 m ² ) or fasting triglyceride level greater than 400 mg/dL. Patients could be randomized at hospital discharge following the qualifying ACS event or after a screening period of no longer than 12 weeks to allow stabilization of their clinical condition, completion of planned revascularization

procedures and achievement of steady-state renal function.

Patients were assigned in a double-blind fashion under a 1 : 1 ratio using a permuted block randomization without stratification through an interactive telephone and web system to receive aleglitazar, 150 ug daily or matching placebo, in addition to

contemporary and guideline-based care for ACS, diabetes, and coronary heart disease risk factors. Concomitant use of systemic corticosteroids for longer than 2 weeks,

thiazolidinediones or fibrates was not permitted. Patients returned for outpatient visits at 1 , 3, 6, 9, and 12 months following randomization, followed by alternating visits and phone contact every third month thereafter. The study drug was not interrupted until the repeated test of serum creatinine value was superior to 50% increase over the baseline visit.

We surprisingly found out in AleCardio that aleglitazar could stabilize the kidney function in diabetic kidney disease (DKD) patients who would have linear decrease of eGFR (estimated glomerular filtration rate). We also surprisingly found that aleglitazar could decrease the cardiovascular (CV) risk in Type 2 Diabetes patients with Chronic Kidney Disease (CKD) and dyslipidemia. This is of particular importance since the majority of DKD/CKD patients pass away due to CV events before they reach end stage renal disease (ESRD). The patients who had a higher CV risks (i.e. CKD patients with dyslipidemia) were selected for the analysis of the MACE outcome. Considering that low HDL-C is one of the unique dyslipidemia characters in CKD patients, this subset of higher risk patients was defined as eGFR<60 mL/min and HDL-C<40mg/dL. Both cutoffs are based on well accepted clinical criteria for CKD (Stage 3) or dyslipidemia (low HDL-C). The baseline charcteristics were balanced in both treatment arms in this subset population, as can be seen in Table 1.

Table 1. Baseline characteristics in the subset of AleCardio patients with CKD and dyslipidemia.

eGFR<60 ml/min and

HDL-C <40 mg/dL

Aleglitazar Placebo

n 317 295

Age (yr) 66 65

Weight (Kg) mean 82.2 85.3

BMI 28.9 29.8

Duration of T2DM (yr) 10.0 10.8

HA1C (%) 7.7 7.7

eGFR (ml/min/1.73m ² ) 50.3 50.3

UACR>300 mg/g (%) 9.46 13.9

HDL-C (mmol/1) 0.87 0.86

(mg/dL)

(33.59) (33.20)

LDL-C (mmol/1) 1.95 2.01

(mg/dL)

(75.29) (77.61)

TG (mmol/1) 2.0 2.1

NT-proBNP (ng/ml) 1536.6 1587.4

ACS Index Events

STEM (%) 44 44

NSTEM (%) 32 33

Unstable angina (%) 24 23

Diabetes Medications (%)

Metformin / Sulfonylureas / Insulin 60 / 41 / 28 59 / 38 / 37 Cardiac Medications (%)

Aspirin / ADP Inhibitor 92 / 88 94 / 87

Statins 92 93

RAS inhibitor 85 85

Surprisinlgy, the relative risk reduction of the MACE endpoint in aleglitazar treatment was 32% over the placebo group of AleCardio patients having CKD and dyslipidemia (HR 0.68, 95% Cl 0.44, 1.04, p=0.07). This was much higher than that in the overall AleCardio population. Interestingly, a significant MACE risk reduction was observed in Asian patients in general (Relative Risk Reduction 29%); moreover, the relativle risk reduction was much higher (up to 70%) in the subgroup of Asian patients having CKD with dyslipidemia. This is demonstrated by the data presented in Figures 1 and 2.

Figure 1 represents the time to first event of MACE endpoint in AleCardio patients with baseline eGFR<60mL/min and HDL-C<40mg/dL. Figure 2 shows the comparision of MACE endpoint in different subgroups. Major adverse cardiac events (MACE): composite of cardiovascular death, non-fatal MI or non- fatal stroke.

In a further analysis of AleCardio safety data, and in particular the PPAR agonist- related safety data, aleglitazar treatment showed a balanced safety profile in heart failure, serious renal dysfunction, and severe GI bleeding in the subset of patients with CKD and dyslipidemia, as shown in Table 2.

Table 2

Safety Data GFR<60 + HDL-C <40 Overall Population

Aleglitazar Placebo Aleglitazar Placebo

n 317 295 3,587 3,587

Hypoglycemia 20.2% ² 15.6% 16.9% ² 11.0%

Heart Failure 8.8% / 5.0% ¹ 8.8% / 7.1% 6.9% /4.6% ³ 5.0% /3.8%

(any/Serious)

Serious Renal AE 3.2% ² 2.7% 1.4% ² 0.9%

Bone fracture 2.2% ² 1.4% 2.3% ² 1.8%

Severe Gl Bleeding 1.6% ¹ 1.7% 1.5% ² 0.9% 1 Optimistic; ² On Target; ³ Minimal or killing for safety

(based on aleglitazar Target Product Profile)

The invention thus relates to aleglitazar for use in treatment or prevention of major adverse cardiac events in a Type 2 Diabetes patient having chronic kidney disease and dyslipidemia. The invention also relates to aleglitazar for use in the treatment or prevention of major adverse cardiac events in a Type 2 Diabetes patient having a GFR inferior to 60 mL/min and a HDL-C level inferior to 40 mg/dL.

The invention further relates to aleglitazar for use as defined above, wherein chronic kidney disease is diabetic kidney disease. The invention further relates to aleglitazar for use as defined above, wherein major adverse cardiac events are cardiovascular death, non-fatal myocardial infarction or non- fatal stroke. The invention also relates to aleglitazar for use as defined above, wherein the patient is of Asian ethnicity.

“Asian ethnicity” refers to a person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, including, for example,

Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. Reference: FDA 2005 Guidance for Industry - Collection of Race and Ethnicity Data in Clinical Trials.

CKD is generally defined as kidney damage for at least 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR; or GFR <60 mL/min/1 73m2 for at least 3 months, with or without kidney damage.

DKD is a subset of CKD, wherein the patient has diabetes induced kidney injury and albuminuria.

Type 2 Diabetes, like CKD and DKD, is a well characterized disease and its diagnosis criteria are established by the World Health Organization.

The invention also relates to aleglitazar for use in the treatment or prevention of major adverse cardiac events in a Type 2 Diabetes patient of Asian ethnicity.

The invention relates in particular to aleglitazar for use as defined above wherein aleglitazar is for oral use at a dose of 150 ug once a day.

The invention further relates to:

The use of aleglitazar in the manufacture of a medicament for treating or preventing major adverse cardiac events in a Type 2 Diabetes patient having chronic kidney disease and dyslipidemia;

The use of aleglitazar in the manufacture of a medicament for treating or preventing major adverse cardiac events in a Type 2 Diabetes patient having a GFR inferior to 60 mF/min and a HDF-C level inferior to 40 mg/dF;

The use as defined above, wherein chronic kidney disease is diabetic kidney disease;

The use as defined above, wherein major adverse cardiac events are cardiovascular death, non-fatal myocardial infarction or non-fatal stroke; and

The use as defined above, wherein the patient is of Asian ethnicity. The invention also relates to the use of aleglitazar in the manufacture of a medicament for treating or preventing major adverse cardiac events in a Type 2 Diabetes patient of Asian ethnicity.

The invention relates in particular to a use as defined above wherein aleglitazar is for oral use at a dose of 150 ug once a day.

The invention further relates to:

A method for the treatment or prevention of major adverse cardiac events in a Type 2 Diabetes patient having chronic kidney disease and dyslipidemia comprising the administration of aleglitazar to a patient in need thereof; A method for the treatment or prevention of major adverse cardiac events in a Type

2 Diabetes patient having a GFR inferior to 60 mL/min and a HDL-C level inferior to 40 mg/dL comprising the administration of aleglitazar to a patient in need thereof;

A method as defined above, wherein chronic kidney disease is diabetic kidney disease; A method as defined above, wherein major adverse cardiac events are cardiovascular death, non-fatal myocardial infarction or non-fatal stroke; and

A method as defined above, wherein the patient is of Asian ethnicity.

The invention aslo relates to a method for the treatment or prevention of major adverse cardiac events in a Type 2 Diabetes patient of Asian ethnicity comprising the administration of aleglitazar to a patient in need thereof.

The invention relates in particular to method as defined above wherein aleglitazar is orally administered at a dose of 150 ug once a day.

In the present invention, the patient can in particular be a patient suffering from acute coronary syndrome.