Type II, or adult onset, diabetes, is the most widespread form of diabetes and the number of cases is rising. This is attributed to changes in lifestyle in both the industrialised nations and the developing world, such as increasingly unhealthy diets and lack of exercise. Many patients often progress to the stage where they require insulin to manage their disease, but in the interim a variety of oral medications are available. These include the gold-standard, metformin (a biguanide), sulphonylureas, thiazolidinediones (glitazones), meglitinides, and alpha-glucosidase inhibitors.
- Sulphonylureas: were for many years the cornerstone in managing Type II diabetes. Examples include Diabeta (glyburide), Glucotrol (glipizide) and Amaryl (glimepiride). They primarily work by increasing endogenous insulin secretion
- Biguanides: for example Glucophage (metformin), which acts by decreasing hepatic glucose production, decreasing glucose absorption, and increasing glucose uptake into skeletal muscle.
- Thiazolidinediones: Avandia (rosiglitazone) and Actos (pioglitazone). Thiazolidinediones act by stimulating the PPAR (peroxisome proliferative insulin-activated receptor) gamma receptor, which causes insulin sensitising effects on skeletal muscle and adipose tissue, and by inhibiting hepatic gluconeogenesis.
- Meglitinides: Prandin/NovoNorm (repaglinide) and Starlix (nateglinide). These act at the same receptor as sulphonylureas to stimulate pancreatic insulin secretion, but differ from sulphonylureas by possessing a rapid onset and short duration of action to lower post-prandial glucose.
Sales of Avandia, a major product for GlaxoSmithKline, have fallen since May 2007, when research published in the New England Journal of Medicine suggested that Avandia could raise the risk of myocardial infarction by 43%. The FDA said the research conflicted with that of other studies, but urged patients with heart problems to consult their doctor, while other experts said any risk to patients was small. Takeda's Actos has benefited from Avandia's problems and has increased its market share, making it the number one product in its therapeutic class in the 12 months to June 2007.
Januvia takes off…
These four are now being joined by a new class, the DPP-IV (dipeptidyl peptidase IV) inhibitors. The two main DPP-IV inhibitors developed so far are Merck & Co's Januvia (sitagliptin) and Novartis' Galvus (vildagliptin). Januvia was first launched in the USA and Mexico in 2006 and is now available in a large number of markets. Merck & Co has also developed Janumet, a combination of sitagliptin and metformin, which was approved by the FDA in March 2007. Januvia is reported to be one of Merck's major current growth drivers and Merck is now reported to be moving forward with regulatory filings for Janumet in countries outside the USA. The FDA also approved Januvia's use as a monotherapy, but it is often used in combination with other antidiabetics.
Top 10 oral antidiabetics (A10B class)
12 months to June 2007
|
Brand |
Company |
Percentage market share |
Fixed-rate $ growth |
|
Actos |
Takeda |
26.4$ |
16% |
|
Avandia |
GSK |
20.6 |
-1 |
|
Avandamet |
GSK |
4.8 |
63 |
|
Amaryl |
sanofi-aventis |
4.3 |
-27 |
|
Basen |
Takeda |
3.5 |
-9 |
|
Diamicron |
Servier |
3.2 |
8 |
|
Glucobay |
Bayer |
2.9 |
1 |
|
Novonorm |
Novo Nordisk |
2.8 |
7 |
|
Glucophage |
Merck KGaA |
2.6 |
-7 |
|
Januvia |
Merck & Co |
1.9 |
n/a |
Source: IMS MIDAS Quantum
Industry observers believe that DPP-IV inhibitors will be extensively used in the future, mainly because they do not appear to cause the weight gain and oedema associated with many other diabetes treatments. They work by targeting pancreatic islet cell dysfunction.
…while Galvus struggles to get off the ground
Galvus was launched in Brazil and Mexico in June 2007. It was approved in the EU in September 2007, for use in patients in combination with metformin, thiazolidinediones or sulphonylureas; a single-tablet combination of vildagliptin and metformin, to be called Eucreas, was also recommended for approval. In November 2007, however, Novartis submitted further safety information to the EMEA showing that taking 50mg Galvus once or twice a day was associated with less frequent liver enzyme elevations than the 100mg dose (0.21-0.34% versus 0.86%), even though the latter had been approved. In December 2007, the CHMP issued a positive opinion on the approval of the 50mg tablet, and the 100mg pill will no longer be launched. EU launches are forecast in the first half of 2008.
The FDA issued an 'approvable' letter for Galvus in February 2007, and at the end of the year Novartis was still in discussions with the agency regarding its final approval. Galvus was filed for US approval in early 2006, but the FDA has expressed some concerns about potential skin toxicity and peripheral oedema, and the approvable letter included a request for an additional clinical study in patients with renal impairment. Novartis is running extra safety trials and is now planning to resubmit Galvus for FDA clearance in 2009 – giving Januvia plenty of time to secure a strong lead.
Further away from the market, Bristol-Myers Squibb and AstraZeneca are collaborating on the Phase III programme for saxagliptin, while Takeda filed its DPP-IV inhibitor, alogliptin, for FDA approval in January 2008. A number of other companies are running Phase II studies with their candidates.
No product problem-free
Despite being recognised as effective and having advantages over older treatments, the DPP-IV inhibitors have not been entirely problem-free. GSK's Redona (denogliptin) was suspended from development in 2006 after the emergence of lung tumours in animals. Consequently GSK now lacks a DPP-IV in late-stage development.
In October 2007, US regulators approved Januvia's use in combination with both a sulphonylurea and metformin, when these two types of drugs provide inadequate control. They also approved first-line use in combination with metformin (Januvia had previously been approved in 2006 for use by itself or with metformin, or with thiazolidinediones). Januvia's label, however, was also updated to warn patients to stop taking Januvia if they develop an allergic reaction: some patients taking Januvia have developed a potentially fatal skin condition called Stevens-Johnson syndrome.
Nevertheless, analysts are positive that thanks to its relatively benign safety profile overall, and the growing incidence of diabetes, Januvia will almost certainly become a blockbuster. Indeed, IMS data suggest that it had climbed to sixth position in the oral antidiabetics class as of September 2007, up from tenth place in June.
This article was written by Sue Murray, Senior Editor of IMS Company Profiles. Covering more than 80 of the top pharmaceutical and biotechnology companies, the profiles offer authoritative insight into company strategy, portfolio management and R&D. Much of the information can also be sourced from IMS Knowledge Link, which integrates detailed data from a number of publications covering sales, R&D, news, patents and strategic issues on a single website. The extensive coverage includes more than 2,000 of the top biopharmaceutical companies as well as 300 therapeutic areas and 38 countries. For more information, contact Mike Raymond or call +44 203 075 5757.