Diabetes
Related Competitor Analysis:
- Index
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- 1-Diabetes: one of the most challenging health problems of the 21 st century
- 2-Progress in diabetes medication
- 3-Insulin Competitor Analysis
- 4-PAR Agonists
- 5-GLP-1 Analog
- 6-DPP-IV Inhibitors
- 7-SGLT Inhibitors
- 8-Emerging New Drugs
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Diabetes: one of the most challenging health problems of the 21 st century
The rapidly increasing prevalence of diabetes is a significant cause for concern. While the WHO report published in 1998 reported an estimation of 135 million people having diabetes, it is estimated today that around 194 million suffer from diabetes (from IDF source ). In 2003, it was estimated that 5.1 % of people have diabetes. Type 2 diabetes constitutes about 85 % to 95 % of all diabetes cases in developed countries and accounts for an even higher percentage in developing countries.
Also read Competitor Analysis:
Diabetes
Obesity & Diabetes
The European region and the Western Pacific Region have the highest number of people with diabetes, approximately 48 and 43 millions, resepectively. The highest rate of diabetes prevalence is to be found in the North American region, followed by the European Region.
There are 20.8 million people in the United States , or 7% of the population, who have diabetes. While an estimated 14.6 million have been diagnosed with diabetes, unfortunately, 6.2 million people (or nearly one-third) are unaware that they have the disease (from CDC source ).
It is forecasted that the prevalence of diabetes will rise to almost 333 million by the year 2025. The rise is caused by an ageing population, unhealthy diet, overweight and obesity; and a sedentary life style. An important contributing factor to the projected increase in diabetes is the situation in developing countries.Economic development in developing countries has been associated with the greatere adoption of western life styles, resulting in a substantial increase in diabetes prevalence (Diabetes Atlas ).
To read more about diabetes facts, please access the Diabetes Mellitus Fact Sheet kindly provided by Pfizer onits homepage
Progress in diabetes medication
The most recent approval of inhalable insulin in Europe and the United States ( Fact Sheet Exubera ) will make available by mid year the first inhaled form of insulin and the first insulin option that does not need to be administered by injection. The rapid-acting, dry powder insulin is inhaled through the mouth into the lungs prior to eating , using a hand-held inhaler. The product can be used by type 1 and by type 2 diabetes patients requiring insulin.
La Merie Businee Intelligence has evaluated in a series of research studies the competitve situation of novel and emerging diabetes drugs. Among them are
Insulin Competitor Analysis
Insulin market is characterized by an ongoing conversion from recombinant human (rhu) insulin to rhu insulin analogs. The three insulin giants Eli Lilly, Novo Nordisk and Sanofi-Aventis booked record sales of more than US$ 7.2 bln. in 2005 with double digit growth rates of their short- and long-acting insulin analogs. Only Lilly's insulin portfolio lacks a long-acting analog. The recent approval of inhaled insulin Exubera from Pfizer with technology from Nektar Therapeutics marks the beginning of the new era of needle-free insulin administration and the entry of a fourth Big Pharma player into the lucrative insulin market. Novo Nordisk and Eli Lilly have their own inhaled insulins in phase III, Sanofi-Aventis lost it by the merger due to a change-of-ownership clause. This opens the opportunity to reassess the needle-free insulin alternatives and to make the partnering choice among providers of inhaled, nasal, transdermal and oral insulins.
Among the needle-free insulin technologies, inhalation with deep lung delivery is the most Also read Competitor Analysis:
Insulinadvanced and validated technology. One approved, three phase III and three phase II and I products characterize the advanced stage. Intranasal delivery seems to become the lower cost alternative of the alliance between Bentley Pharmaceuticals and Biocon from India. Nasal delivery of insulin may have a several-fold higher bioabsorption than pulmonary inhalation of insulin. However, there is scepticism about nasal sprays due to the small area of absorption in the nose and the number of variables that could interfere with dosing such as mucous, colds and allergies.
Transdermal delivery technologies using gels, patches and additional aiding systems to allow penetration of the skin seem to be stuck in early development stages. Oral insulins include buccal sprays, enteric coated tablets and gel capsules and are in mid stage clinical development. Emisphere Technologies recently initiated a phase II study with 3-months treatment to evaluate if the technology is able to produce consistently and sufficiently high blood levels of insulin. Engineered insulins with the aim to prolong the half-life beyond that of insulin analogs have not yet reached clinical evaluation.
The demand for insulin is expected to substantially grow in the coming years due to the rising number of insulin-dependent diabetics and the exploding need for alternative insulin delivery technologies. Inhalation of insulins requires at least five-fold more insulin than injection due to the poor bioabsorption. Availability of high volume supply of insulin at a reasonable price will be a key issue to meet this expansion in demand. Production of insulin in transgenic plants may be an alternative. SemBioSys Genetics is aiming to initiate clinical testing of its safflower produced insulin in 2006. Alternative manufacturers of follow-on rhu insulins in Poland, Russia and especially India are scaling up their manufacturing capacities.
PPAR Agonists
The two peroxisome proliferator-activated receptor (PPAR) gamma agonists pioglitazone and Also read Competitor Analysis:
PPAR agonists rosiglitazone approved for treatment of type 2 diabetes achieved combined 2004 global sales of US$ 3.96 bln shared between Takeda & Eli Lilly (52 %) and GlaxoSmithKline (48 %). Companies with next generation dual PPAR gamma and alpha agonists lead by BMS with muraglitazar are prevented from entering this market by FDA's request for extensive preclinical and clinical characterization due to cardiovascular safety concerns on the PPAR agonist's fenofibrate-like alpha component. As a consequence, the four companies with improved PPAR gamma modulators will have a competitive advantage. The field of novel PPAR delta and of triple (or pan-) PPAR agonists is lead by GSK.
The use of insulin sensitizing, first generation PPAR gamma agonists is associated with an increased incidence of edema and weight gain. Clinical data with improved modulators of PPAR gamma from Metabolex indicate that this side effect can be avoided. While two other PPAR gamma agonist developers are active in diabetes, Daiichi Sankyo decided to begin clinical development of its PPAR gamma agonist CS-7017 in oncology although previous experience with a PPAR gamma ligand in metastatic breast cancer was negative.
At least 10 companies are engaged in R&D of dual PPAR alpha and gamma agonists for the treatment of type 2 diabetics with dyslipidemia. The companies most affected by FDA's requests are BMS & Merck, AstraZeneca and Eli Lilly. Impact of FDA's decision on the pipeline of PPAR alpha agonists with fenofibrate-like actions on triglycerides and HDL cholesterol is not yet evident as these project are in earlier clinical development.
GlaxoSmithKline leads the field of companies with interest in PPAR delta agonism which affects cholesterol transport. Apart from its PPAR delta agonist GW 501516, GSK has a triple PPAR alpha, gamma and delta agonst in phase II studies ahead of three other companies with pan PPAR agonists. The use of pharmacogenomics for patient stratification might be one strategy to select responders and avoid side effects as is intended by Perlegen in its MC-555 program. Other research strategies are to omit the PPAR alpha component and search for dual PPAR gamma and delta agonists or to work with completely new classes of chemical structures.
GLP-1 Analogs
Twice-daily injection is the benchmark set by exenatide, the first GLP-1 analog launched in the US by Lilly in June 2005 and half-year sales of US$ 74.6 mln, which now faces competition by GLP-1 analog treatment modalities with less frequent dosing. More convenience is brought to patients with once-daily dosing from the closest competitor (Novo Nordisk) which Lilly counters with a once-a-week injectable drug delivery. Other competitors follow with sustained release formulations of GLP-1 analogs or develop a nasal spray GLP-1 analog as a non-invasive alternative to injections. Another, yet IND or preclinical stage approach is the development of fusion proteins of GLP-1 with large carrier proteins such as albumin or transferrin leading to even longer half-lives, thus potentially allowing dosing every 2 or 3 weeks.
Both enzymatic cleavage and renal clearance contribute to a very short circulating half-life of Also read Competitor Analysis:
GLP-1 analogsseveral minutes for native GLP-1 which is a 30-amino acid gut peptide produced in enteroendocrine cells located in the distal ileum and colon. Thus, GLP-1 analogs have been constructed with resistance to enzymatic cleavage. These GLP-1 mimetics bind to GLP-1 receptors with similar affinity and produce biological actions identical to those of native GLP-1 which controls blood glucose via multiple actions including stimulation of insulin secretion and inhibition of both glucagon secretion and gastric emptying. Preclinical data suggest that GLP-1 analogs engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. However, it remains to be proven clinically whether GLP1 analogs may reverse the decline in beta-cell mass of the pancreas that is characteristic of the natural history of type 2 diabetes.
Exenatide from Lilly is approved for use in patients with type 2 diabetes who exhibit unaceptable glycemic control whil using meformin and/or sulfonylurea. GLP-1 analog therapy clinically has shown the advantage of reducing body weight, but is associated with nausea and vomiting as the most common adverse effects which might be reduced with optimized dosing regimens.
Apart from use of GLP-1 analogs in the treatment of diabetes, its usefulness currently is being investigated in clinical studies of irritable bowel syndrome and functional dyspepsia. Further studies explore the effects of natural GLP-1 and of AC2592 from Amylin Pharmaceuticals administered by continuous infusion in patients with congestive heart failure.
DPP-IV Inhibitors
The oral DPP-IV inhibitors vildagliptin (LAF237), sitaglitpin (MK-0431) and saxagliptin (BMS-477118) from Novartis, Merck & Co., and BMS are in advanced phase III development and compete to be “First in Class” of a new oral treatment modality for type 2 diabetes. One further phase III and at least five phase II and six phase I DPP-IV inhibitors are closely following and more than 10 further companies are in advanced preclinical R&D. Available data show differences in duration of action and anticipated dosing frequency, whereas data to compare clinical efficacy and safety presently is not available. The high interest of the pharmaceutical industry reflects the market attractivity. The WHO estimates that globally over 170 mln people have diabetes, with type 2 diabetes accounting for 90 % to 95 %. By 2030, the prevalence of diabetes is predicted to double, driven by adverse lifestyle changes.
Dipeptidyl peptidase IV is an enzyme that rapidly inactivates the insulinotropic hormone Also read Competitor Analysis:
DPP-IV inhibitorsglucagon-like peptide-1 (GLP-1). Inhibition of dipeptidyl peptidase IV by DPP-IV inhibitors enhances the hormone activity of GLP-1 and other bioactive peptides (GIP, PACAP38 and GRP), thereby stimulating the release of insulin and reducing the secretion of glucagon. Both effects contribute to regulation of the elevated blood glucose levels in type 2 diabetic patients as measured by hemoglobin A1c (HbA1c).
Available data from clinical phase II data suggest that long term treatment with DPP-IV inhibitors was well tolerated and was not associated with weight gain. The DPP-IV inhibitors are being evaluated as both monotherapy and in combination with other standard antidiabetic drugs, e.g. metformin. Regulatory filings of the first DPP-IV inhibitors are expected in 2006. The major advantages of DPP-IV inhibitors are the ability to achieve sustainable reductions in HbA1c with an orally administered, well tolerated agent. Other classes of new antidiabetic medications include GLP-1 agonists and dual PPAR agonists. However, GLP-1 agonists require administration by injection and dual PPAR agonists are associated with safety concerns.
SGLT Inhibitors
A plethora of SGLT inhibitors in the patent literature and seven compounds in early clinical Also read Competitor Analysis:
SGLT inhiborsdevelopment indicate an abundance of interest in the therapeutic use of SGLT inhibitors for the treatment of type 2 diabetes. SGLT inhibitors do not intervene with glucose metabolism, thus being complementary to mainstream approaches to glucose regulation, i.e. PPAR agonists, DPP-IV antagonists and GLP-1 analogues. While SGLT-2 inhibitors block the reabsorption of glucose from the renal filtrate, SGLT1 inhibitors suppress absorption of glucose from the gut. Most of the known SGLT inhibitors are selective for SGLT2, but there are also mixed type inhibitors and SGLT1 inhibitors. Among the leading companies with clinical stage SGLT inhibitors are Sanofi-Aventis (AVE2268), GlaxoSmithKline (869682) and Bristol-Myers Squibb.
SGLT2 is a molecular target to directly induce glucose excretion and to safely normalise plasma glucose in the treatment of type 2 diabetes. Chemically, most of the SGLT2 inhibitors are derived from the prototype phlorizin and structurally are glycosides. Exceptions are the second generation antisense approach from ISIS Pharmaceuticals and SGLT peptide antagonists from Theratech, both in preclinical stages. Japanese companies have pioneered the SGLT inhibitor arena (Tanabe Seiyaku with T-1095) and are still dominating the patent application field. SGLT2 inhibitors are also promising for other therapeutic uses such as obesity as they cause the net loss of calories from the body in form of glucose. In fact, GSK's lead compound 869682 is under clinical investigation in obesity.
So far, little is known about the therapeutic efficacy of SGLT inhibitors due to the early development stage in the clinic. Theoretical safety concerns about increased glucosuria by SGLT2 inhibtion do not appear to be relevant as patients with familial renal glucosuria by an inherited defective form of SGLT2 have normal kidney function, are not hypoglycemic and have no pathology caused by the transporter defect.
Emerging New Drugs
The complexity of glucose metabolism and the number of cellular processes affected by diabetes provides ample space for new drug targets and for first-in-class molecules. Some of them have reached or are close to early clinical development in type 2 diabetes. Roche pioneered and leads the field of glucokinase activators with a phase I compound. Karo Bio has a first-in-class hepatic glucocorticoid receptor antagonist which is in preclinical development. Bayer is about to enter phase I in the first half of this year with Bay 76-7171 which has an undisclosed novel mechanism of action. Sankyo and Metabasis reached clinical proof of concept with its first-in-class fructose 1,6-bisphosphatase inhibitor. Leaders in the arena of glycogen phsophorylase inhibitors are Pfizer and Sanofi-Aventis with clinical stage projects. Isis is ahead in the field of protein tyrosine phosphatase 1B inhibitors with its 2 nd generation antisense project.
Glucokinase activators (GKA) enhance glucose-stimulated insulin release from pancreatic islet cells and glucose disposition by the liver, thus reducing blood glucose and reducing weight as shown by Innodia's ID1101 in phase I. The compound had an excellent safety profile and now serves as an anti-obesity drug candidate. The stimulation of insulin secretion by GKAs is Also read Competitor Analysis:
Emerging diabetes drugs glucose-dependent which should make it less likely that GKAs cause hypoglycemia. Inhibition of glycogenolysis by glycogen phosphorylase inhibitors (GPI) is another strategy to reduce blood glucose and has attracted the interest of many companies with drug discovery activities. The opposite approach is to inhibit gluconeogenesis by antagonizing the activity of fructose 1,6-bisphosphatase. Sankyo's and Metabasis' CS-917 was shown to cause a clinically significant reduction in blood glucose.
Protein tyrosine phosphatase 1B (PTP-1B) downregulates the insulin receptor. Inhibition of PTP-1B should prevent downregulation of the insulin receptor, thus improving insulin action. Isis showed clinically that its antisense compound could induce insulin sensitizing activity in healthy volunteers. Results of 12-weeks treatment of diabetes patients with ISIS 113715 are expected this year. Small molecule PTP-1B inhibitors are in the pipeline, but do not lead the field after failure of Wyeth's phase II compound. Further novel approaches include a beta3 adrenergic agonist in phase II, a phosphodiesterease 11A inhibitor and a dually acting small molecule in preparation for phase I which increases insulin secretion and peripheral insulin sensitivity.
