Atreyi Banerjee

Pipeline products in Phase III

IntroductionMajor mechanism of actionEnd points employed in clinical trialsDuration of trialsRoute of administration

Outline

Diabetes Diabetes is a chronic disease that occurs either when the pancreas does not

produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin is a hormone that regulates blood sugar. Hyperglycaemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially the nerves and blood vessels. Type 1 Diabetes (previously known as insulin-dependent, juvenile or

childhood-onset) is characterized by deficient insulin production and requires daily administration of insulin.

Type 2 Diabetes (formerly called non-insulin-dependent or adult-onset) results from the body’s ineffective use of insulin. Type 2 diabetes comprises 90% of people with diabetes around the world, and is largely the result of excess body weight and physical inactivity.

Gestational Diabetes is hyperglycaemia with onset or first recognition during pregnancy.

Epidemiology of Diabetes An estimated 285 million people, corresponding to 6.4% of the world's adult population,

will live with diabetes in 2010. The number is expected to grow to 438 million by 2030, corresponding to 7.8% of the adult population.

The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men.

While the global prevalence of diabetes is 6.4%, the prevalence varies from 10.2% in the Western Pacific to 3.8% in the African region. However, the African region is expected to experience the highest increase.

The number of deaths attributable to diabetes in 2010 shows a 5.5% increase over the estimates for the year 2007. This increase is largely due to a 29% increase in the number of deaths due to diabetes in the North America & Caribbean Region, a 12% increase in the South East Asia Region and an 11% increase in the Western Pacific Region.

Almost 80% of diabetes deaths occur in low- and middle-income countries.

WHO projects that diabetes deaths will double between 2005 and 2030.

50% of all diabetics are unaware of their condition.

The vast majority of people with type 2 diabetes suffer from a range of co-morbidities, such as obesity, hypertension and dyslipidaemia.

Major marketed products in the Type-2 diabetes market

Actos (pioglitazone) TakedaAvandia (rosiglitazone) GlaxoSmithKlineJanuvia (sitagliptin) Merck & Co., Inc.Starlix (nateglinide) NovartisByetta (exenatide) Amylin Pharmaceuticals, Inc. and

Lilly USA, LLC.Lantus (insulin glargine) Sanofi AventisLevemir (insulin detemir) Novo Nordisk

Primary drugs candidates undergoing phase III clinical trial for Type -2 diabetes

BMS-512148 (dapagliflozin) Victoza D-Tagatose JNJ-28431754 (canagliflozin) Albiglutide

According to New Pharmaceuticals research report from GlobalData 2010

Five major drugs under phase III clinical trial for Type-2 diabetes

Sodium Glucose Co-transporter (SGLT2 inhibitor)

Responsible for at least 90% of the glucose reabsorption in the kidney.

Subsides as blood glucose concentrations decrease and approach euglycemia

Oral dosageGlycemic control, trend to

weight loss

BMS- 512148 (dapagliflozin)

Analog of human GLP-1 and acts as a GLP-1 receptor agonist.

Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations.

Liraglutide also decreases glucagon secretion in a glucose-dependent manner.

The mechanism of blood glucose lowering also involves a delay in gastric emptying.

Glycemic control, trend to weight loss

Victoza

Significant decrease in blood glucose levels as compared to those receiving metformin and rosiglitazone

In the GI tract, tagatose blocks the digestion of sucrose,maltose, and other carbohydrates

Slows absorption of glucose, and results in little or no spike in glucose after meals.

In the liver, Tagatose competitively blocks the enzyme that metabolizes glucose to be referentially stored as glycogen.

Oral dosageGlycemic control determined by

a statistically significant decrease in hemoglobin

D-Tagatose

JNJ-28431754 (canagliflozin)Sodium Glucose Co-

transporter (SGLT2 inhibitor)Oral dosageglycemic control,stable blood

pressure, weight lossBut has some effect on renal

function

GLP-1 (Glucagon-like peptide 1) agonist

DPPIV resistance and fusion to human albumin

Once-weekly or less frequent; subcutaneous injection using pen with small gauge needle

Demonstrated effective glycemic control, trend to weight loss, low incidence of GI side effects and low immunogenicity

Albiglutide

Albiglutide is the only medication which fuses human GLP-1 to human albumin.  It is designed to have an extended duration of action and allow for weekly or less-frequent injections.

Major mechanism of action under development

SGLT-2 inhibitorsInterleukin-1¦Â antagonistsCCR2 antagonistsGLP-1 agonistsDPP-IV Inhibitors11¦Â HSD inhibitorsImmune modulatorsAntisense drugs targeting

glucagon receptor

End points employed in clinical trials

Survival Completes response Objective Response Rate Progression Free Survival Clinical benefit Endpoints for selected drugs were HbA1c change

from baseline and safety and tolerability with minimised or no adverse effects.

The secondary endpoints were change from baseline mean morning fasting body weight and renal glucose threshold maintenance.

(X) XX

X Censored

X X

The average duration of study is 2 years and 6 months as calculated from www.clinicaltrials.gov

Disease Progression

Duration of trials

Survival

Route of administrationOral

Digestive tract (enteral)Sublingual/ SublabialRespiratory tract

Parenteral Subcutaneous Injectione.g. Byetta (exenatide)

SurgicalIslet cell transplant predominantly Allogenic. The shortage of

human donor pancreases for islet cell transplantation has led to a search for alternative sources of islet cells. Autologous is used to treat Type-1 patients when diabetes is not already present.

WHO activities to prevent and control Diabetes WHO aims to stimulate and support the adoption of effective measures for the

surveillance, prevention and control of diabetes and its complications, particularly in low and middle-income countries. To this end, WHO: provides scientific guidelines for diabetes prevention; develops norms and standards for diabetes care; builds awareness on the global epidemic of diabetes; including

partnership with the International Diabetes Federation in the celebration of World Diabetes Day (14 November);

conducts surveillance of diabetes and its risk factors. The WHO Global Strategy on Diet, Physical Activity and Health complements

WHO's diabetes work by focusing on population-wide approaches to promote healthy diet and regular physical activity, thereby reducing the growing global problem of overweight and obesity.

Overall categorization of diabetes treatments

The key market players at present are Hoffmann-La Roche, Novo Nordisk, Merck & Co., Novartis Ag, Sanofi-aventis, Eli Lilly & Company and GlaxoSmithKline reinstated by the figure above.

Competitive dynamics of the leading players in the global diabetes market, 2005

Global* market share of leading insulins (%), 1999-2003,

The leading giant still is the US with more than 50% market share while the Pacific region is still growing owing to the large population of Diabetic patients in Japan and South Asia.

ConclusionThe U.S. diabetes market has grown to more than $5

billion as the disease becomes more prevalent. Thus a rise in competitors.

Seven out of ten marketed diabetic drugs are oral proving that patients prefer oral administration of medicines.

The presently developed drugs have good toxicity profile which is very essential in today's market.

Referenceswww.clinicaltrials.govwww.worlddiabetesfoundation.orgwww.who.int/en/www.gsk.comwww.globaldata.com/reportstore/www.uchospitals.eduwww.msnbc.msn.com