POLYPILL FOR PRIMARY AND SECONDARY PREVENTIONS OF CARDIOVASCULAR MORBIDITY AND MORTALITY

1Dr. Bhaswat S. Chakraborty

Sr. VP & Chair, R&D Core Committee

Cadila Pharmaceuticals Ltd.

Presented at the IACS Conference 'Translational Research in Cardiovascular Sciences”

Anand, Gujarat, February 5-6, 2016

CVDS: CURRENT GLOBAL BURDEN

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CVD RISK FACTORS Cardiovascular risk factors 

Non-modifiable: Family history, ethnicity and age Modifiable: Hypertension, high cholesterol, obesity, physical

inactivity, diabetes, unhealthy diets, tobacco, and harmful use of alcohol

Modifiable risk factors Hypertension – biggest risk factor for stroke; significant role in

heart attacks; preventable & treatable Physical inactivity & obesity increases heart disease and stroke

risk by 50%.  Type2 diabetes doubles coronary heart disease and stroke risk A diet high in saturated fat increases the risk of heart disease

and stroke Chronically stressful life, social isolation, anxiety and depression Up to 1 or 2 alcohol drinks OK but above this will damage the heart

muscle Certain medicines e.g., contraceptive pill and hormone

replacement therapy (HRT). Left ventricular hypertrophy (LVH)

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WHAT ARE CVDS? Cardiovascular diseases (CVDs) are a group of disorders

of the heart and blood vessels and they include: Coronary heart disease – disease of the blood vessels

supplying the heart muscle Cerebrovascular disease – disease of the blood vessels

supplying the brain Peripheral arterial disease – disease of blood vessels supplying

the arms and legs Rheumatic heart disease – damage to the heart muscle and

heart valves from rheumatic fever, caused by streptococcal bacteria;

Congenital heart disease – malformations of heart structure existing at birth

Deep vein thrombosis and pulmonary embolism – blood clots in the leg veins, which can dislodge and move to the heart and lungs 5

COMMON SYMPTOMS OF CVDS Symptoms of heart attacks and strokes

Pain or discomfort in the centre of the chest Pain or discomfort in the arms, the left shoulder, elbows, jaw, or back Difficulty or shortness of breath; feeling sick or vomiting; feeling

light-headed or faint; breaking into a cold sweat; and becoming pale Women are more likely to have the above

Symptoms of stroke Sudden weakness of the face, arm, or leg, most often on one side of

the body Numbness of the face, arm, or leg, especially on one side of the body Confusion, difficulty speaking or understanding speech Difficulty seeing with one or both eyes Difficulty walking, dizziness, loss of balance or coordination Severe headache with no known cause Fainting or unconsciousness

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PRIMARY PREVENTION OF CVDS Population level primary prevention:

Lowering the average risk factors like BP, LDL cholesterol, smoking and obesity in the entire population

Examples of population-wide interventions comprehensive tobacco control policies taxation to reduce the intake of foods that are high in fat,

sugar and salt building walking and cycle paths to increase physical activity strategies to reduce harmful use of alcohol providing healthy school meals to children.

Individual level 1o prevention: targeted those at high total cardiovascular risk or those with single risk factor levels above traditional

thresholds, e.g., hypertension and hypercholesterolemia7

PRIMARY PREVENTION OF CVDS

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• Statin: simvastatin• CCB: amlodipine

low dose• ARB: losartan

low dose • Thiazide: hydrochlorothiazide low dose • No Aspirin

Wald NJ, Morris JK. Eur J Epidemiol 2014. DOI 10.1007/s10654-014-9932-1

Age of starting preventive treatment: 50 years Among these, % who benefit: 33% Their average benefit: 8 years (Years of life gained without an IHD event or stroke.)

PRIMARY PREVENTION: POLYPILL EFFICACY

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Wald N. (2014). FDA Presentation

SECONDARY PREVENTION OF CVDS For secondary prevention of CVDs in those with established

disease, including diabetes, treatment with the following medications are necessary: Aspirin, beta-blockers, ACE inhibitors & statins

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Yusuf S. (2002). THE LANCET , 360: 2-3

5-COMPONENT POLYPILL EFFICACY FOR SECONDARY PREVENTION

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Wald NJ, Law MR. (2003) BMJ 326:1419-24

THE CADILA POLYCAPTM USED IN TIPS1 & PK STUDY Hydrochlorothiazide (12.5mg) Atenolol (50mg) Ramipril (5mg) Simvastatin (20mg) Acetyl Salicylic Acid (ASA)

(100mg, Enteric Coated)

In a 00 hard gelatin capsule 12

Reduction in

Heart Rate

Polycap -7.0

Other Atenolol arms

-7.0

Non Atenolol arms 0.0

THE INDIAN POLYCAPTM STUDY (TIPS 1) POLYCAP: MEAN CHANGES IN BP, HEART RATE

Lancet. 2009 Apr 18;373(9672):1341-51

Polycap reduces BP and Heart Rate similar to component drugs

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• Both groups showed reduction in LDL levels

• Similar reduction in 11-dehydrothromboxane B2

• Polycap conserved the LDL reduction and Antiplatelet activity

TIPS1: MEAN CHANGES IN LDL & PLATELET FUNCTION WITH POLYCAPTM

Polycap reduces Lipids and platelet activity similar to component drugs

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LDL

11-d

ehyd

roth

rom

boxa

ne B

2

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518 patients with previous vascular disease or DM

Assigned to a single (regular dose) or to 2 capsules of the Polycap (full dose)

Full dose showed superior reduction in BP LDL, compared to regular dose

Similar tolerability profile in both arms

THE INDIAN POLYCAP STUDY 2 (TIPS 2) POLYCAPTM: MEAN CHANGES IN BP

Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):463-71

Polycap can be titrated from regular to full dose for better control

Lipi

d lo

wer

ing

BP lo

wer

ing

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Potential reduction in CVD attacks

An apt therapeutic option for High risk CVD patients Secondary prevention

Easy Dosing Once daily dosing improves

patient compliance

Easy to titrate Start with 1 cap OD, move to

2 caps/day if needed

THE EVIDENCE OF POLYCAP’S EFFECTIVENESS

Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):463-71

TIPS 1 and TIPS 2: Result Summary

TIPS 1 (Regular Polycap)

TIPS 2 (Full dose Polycap)

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ARE THE EFFECTS INDEPENDENT IN REDUCING RISK? YES Evidence

the mechanisms are different cohort studies randomised trials

e.g. Heart Protection Study, 2002; EUROPA trial, 2002; TIPS (2009)

So, when used together in appropriate patients, up to 80% future CV events can be prevented

Potential benefits of quitting smoking, diabetes control and exercise can virtually eliminate the entire CVD risk in in high-risk individuals 17

THE PHARMACOKINETIC (PK) ISSUES WITH POLYCAP While the efficacy of giving multiple proven drugs in a

single pill or capsule has been proven, the questions are: Is such a combination of several active drugs safe and

tolerable? Is there any drug-drug and drug-metabolite interaction?

Such interactions can lead to toxic or suboptimal levels of one or more ingredients (and metabolites), which may lead to increased adverse effects or alternatively decreased efficacy

Is the bioavailability of some or all its components preserved or getting altered?

While TIPS1 and TIPS2 studied the efficacy of risk factor reductions and clinical safety, we also studied the PK and drug-drug interaction of Polycap 18

Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103

A five arm randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial in a total of 195 healthy humans 19

Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103

Ramipril Ramiprilat

Aspirin

Atenolol

Hydrochlorthiazide Simvastati

n20

Patel A., Shah T., ….Chakraborty B.S. (2010). Am

J Cardiovasc Drugs, 10:95-103

CONCLUSIONS OF THE POLYCAPTM PK STUDY Aspirin, ramipril, atenolol, and hydrochlorothiazide

from Polycap were absorbed with a comparable rate and extent with those of single ingredient formulations Preservation of bioavailabilty

There was no kinetic drug-drug interaction in vivo For simvastatin, there was a loss of bioavailability

(~20%) but >equal increase in bioavailability of simvastatin acid

The PK study of Polycap establishes the required bioavailability for all its component drugs, thus explaining its reported efficacy kinetically

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Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103

FINAL REMARKS

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Polycap provides potential primary reduction in CVD attacks

An apt therapeutic option for High risk CVD patients Secondary prevention

Once daily dosing improves patient compliance Easy to titrate

Start with 1 cap OD, move to 2 caps/day if needed No loss of bioavailability of individual

components when formulated as Polycap No drug-drug or drug-metabolite interaction Affordable in low income countries

THANK YOU VERY MUCH

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