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Diabetes Drug Pipeline

Competitor Analysis

Summary

Product description

The Competitive Intelligence Report Diabetes Drug Pipeline as of November 2008 provides a competitor analysis in the development pipeline of novel antidiabetic treatment modalities for type 1 and 2 diabetes. The report includes an overview of the major marketed diabetes drugs and the respective markets sizes and describes the corporate diabetes drug product portfolios and R&D pipelines of more than 160 companies worldwide.

The report contains seven chapters in its first part of Target Pipelines:

• 1. Insulin
• 2. PPAR Agonists
• 3. DPP-IV Inhibitors
• 4. GLP-1 Analogs
• 5. SGLT Inhibitors
• 6. CB1 Antagonists
• 7. Emerging Diabetes Drugs and Targets

The second part of contains the Corporate Diabetes Drug Product Portfolios and R&D Pipelines individually listed per company.

The report describes the competitor projects in a tabular format providing information on:

• Drug Codes,
• Target / Mechanism of Action,
• Class of Compound,
• Company,
• Product category,
• Indication,
• R&D Stage and
• Additional comments with a hyperlink leading to the source of information.

Overview

Diabetes is one of the most challenging health problems of the 21st century. It is estimated today that around 194 million people suffer from diabetes (more than 85 % are type 2 diabetes). Forecasts predict that the prevalence of diabetes will rise to almost 333 million by the year 2025. Sales of insulin based products in 2007 were more than US$ 10.2 bln and those of new PPAR gamma agonists from Takeda and GSK more than US$ 6.4 bln. The new class of incretin mimetics consisting of DPP-IV inhibitors and GLP-1 analogs has the first products on the market which generated 2007 sales of US$ 754 mln and US$ 650 mln, respectively. The next class of products in advanced clinical testing are SGLT inhibitors. Beyond these approaches are a plethora of more than 50 new treatment modalities under preclinical and clinical evaluation. More than 160 companies are involved in diabetes drug development activities.

The present report provides an extensive competitor evaluation of companies involved in the diabetes drug pipeline. It provides a detailed competitor analysis of the most advanced target approaches and describes emerging new targets for diabetes therapy.
Detailed description

Insulin therapy has evolved in the last century from purified bovine or porcine insulin to biosynthetic human insulin to recombinant human insulin and eventually to recombinant insulin analogs as the 3rd generation of human insulin. The worldwide market of the major human insulin products in 2007 was US$ 10.2 bln. Insulin analogs posted double digit sales growth due to successive replacement (67.5 % of total sales) of 2nd generation human insulin.

Three companies dominate the worldwide insulin market, but experience more and more competition in volume sales of insulin by local manufacturers in off-patent countries, especially in China, India and Russia. The first Indian company is conducting clinical trials in the US with its rhu insulin and even plans to develop and launch a biosimilar insulin analog in the Western countries upon patent expiry in 2014. Three companies in off-patent countries have locally produced insulin analogs either in the market or in pre-registration phases.

The next generations of insulin will be ""tailored"" insulin and oral insulin. Tailored insulin analogs and other long-acting insulins for injection with drug delivery solutions aim at optimized pharmacokinetic profiles in order to avoid hyperand hypo-glycemic episodes. After the failure of inhaled insulin (only one clinical stage project left), most of the R&D efforts are now made on oral insulin products.

The pipeline of oral insulin shows at least seven different oral insulin formulations in clinical development, and at least six in preclinical development. The first oral insulin product is already marketed and in advanced registration in many countries. Further six different projects with non-injectable drug delivery of insulin are in clinical development: intranasal, transdermal and rectal application.

Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear receptor superfamily which regulate gene expression and, thereby, controll energy metabolism. PPAR gamma has a key role in adipogenesis, insulin sensitivity, and glucose and lipid metabolism, and also plays a major role in vascular biology. Thiazolidinediones (TZDs) are the ligands of PPAR gamma. Rosiglitazone and pioglitazone are established and economically successful PPAR gamma agonists with combined 2007 sales of about US$ 6.6 bln explaining the high interest in next generation products.

The thiazolidinedione's (TZDs) recently found themselves in the spotlight when the safety of GlaxoSmithKline's rosiglitazone was brought into question by a meta-analysis that associated it with increased risk of myocardial ischemic events. As a consequence, sales of GSKs rosiglitzone declined by more than 20 %, but for the benefit of Takedas pioglitzone which raised by 23 %. A number of next generation PPAR gamma agonists are in clinical development, some of them including PPAR alpha agonistic action in a balanced manner.

A new area of interest are PPAR agonists targeting the delta receptor or including it in dual or triple PPAR agonist approaches. The PPAR alpha agonist fenofibrate from Solvay Pharmaceuticals and Abbott yielded 2007 sales of US$ 1.9 bln. Next generation products are in advanced development to stop generic erosion of branded product sales.

Dipeptidyl peptidase IV (DPP-IV) inhibitors are a new approach to the treatment of type 2 diabetes. The efficacy of DPP-IV inhibitors is mediated primarily via stabilization of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretin action is very brief and is terminated by their breakdown by the enzyme dipeptidyl peptidase-IV (DPP-IV). Merck & Co has introduced the first DPP-IV inhibitor for treatment of type 2 diabetes. Sitagliptin already posted in its second year after the first launch 2007 global sales of US$ 754 mln demonstrating a quite enthusiastic acceptance by the market.

Although the FDA raised the bar for approval of new DPP-IV inhibitors by requesting more clinical data from Novartis before approving vildagliptin, this has not deterred competitors from pursuing development of novel DPP-IV inhibitors. At least 17 different molecules are currently in clinical development and further are to follow.

Binding of glucagon-like peptide-1 (GLP-1) analogs or agonists to the GLP receptor induces insulin secretion from pancreatic beta cells. Exendin (Byetta) is the first representative of this new class of incretin mimetics, first approved in 2005 for treatment of type 2 diabetes. Byetta sales in the first nine months of 2008 increased by 22 % to US$ 565 mln (vs 9-mth period of previous year). While Byetta requires twice-daily subcutaneous injections, closest competitor GLP-1 analogs already filed for registration or in phase III offer once-daily SC dosing and appear to be more effective in head-to-head comparison. Second generation GLP-1 analogs allow less frequent SC administration due to drug delivery, pegylation or genetic engineering technologies.

At least seven different long-acting GLP-1 analog molecules are currently in clinical development and at least further seven in advanced preclinical stages. A third generation of GLP-1 analogs and GLP-1 receptor agonists with oral administration is emerging. The first two orally delivered GLP-1 mimetics (one analog, one agonist) are already undergoing clinical development, further at least eight different compounds are in preclinical R&D. Traditional drug delivery solutions for non-injectable administration of GLP-1 mimetics, such as inhalation or nasal administration, are a minority approach.

Sodium-dependent glucose (co)transporters (SGLT) are specifically expressed in the intestines (SGLT-1) and kidneys (SGLT-1). Inhibitors of SGLT-1 suppress absorption of glucose from the gut, while SGLT-2 inhibitors block the reabsorptoin of glucose from the renal filtrate. Thus, SGLT inhibitors might be complementary approaches to traditional antidiabetics intervening with glucose metabolism. Most of the currently developed SGLT inhibitors are selective for SGLT-2, a minority is directed at SGLT-1 or SGLT-1/2. Although the most advanced SGLT-inhibitor now is in phase III clinical development, a high clinical stage drop-out rate characterizes the research and development efforts of novel SGLT inhibitors. At least ten SGLT inhibitors are in clinical development, predominantly by bigger pharmaceutical companies and many originating from Japan.

First generation cannabinoid type 1 (CB1) receptor antagonists are directed against CB1 receptors in the brain and in peripheral tissues such as adipocytes. Acomplia (rimonabant) from Sanofi-Aventis is the only representative of this class of CB1 antagonists so far approved. While the FDA rejected approval due to an unfavourable risk-benefit ratio, the EMEA at first approved it for treatment of obesity. Quite recently, the CHMP of the EMEA recommended to suspend marketing of Acomplia due to an increased risk of psychiatric disorders observed in post-marketing studies. Although Sanofi-aventis could continue its huge phase III program of rimonibant for treatment of type 2 diabetes, it decided to terminate all studies. Sales of Acomplia in 2007 for obesity just were EURO 79 mln.

Interestingly, Merck & Co. also recently discontinued development of taranabant due to a very small therapeutic window and Pfizer announced yesterday to stop its phase III CB1 antagonist. Nevertheless, there are still eight other different CB1 antagonists in clinical development. Ongoing preclinical research and development has identified non-brain penetrating, only peripherally acting CB1 antagonists which might be able to avoid the psychiatric side effects and better suited for treatment of diabetes and, thereby, solve the reimbursement problem.

A most recent analysis of emerging diabetes drugs and targets revealed that of the 59 different treatment modalities in clinical development, the majority (36) were metabolic approaches. Preservation of the pancreatic islet cell mass and function as well as intents to regenerate beta cells represent an area of increasing activity and relevance with eleven different programs in clinical stages. Althoug still in a pioneer phase, cell therapy is gaining momentum in corporate diabetes programs as islet transplant or stem cell approaches.

At least eight clinical stage programs aim at limiting inflammation leading to beta cell destruction and, thus, also preserve mass and function. Two classes of emerging metabolic approaches stand out from the remainder: the glucose-dependent stimulation of insulin release or secretion by glucokinase activators or direct activation of the GPR119 receptor and the suppression of glucocorticoid action by inhibition of the 11-beta hydroxysteroid dehyrogenase type 1 (HSD-1) or directly of the glucocorticoid receptor.

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