Merck & Co’s position as the sole provider of an oral antidiabetic drug in the novel dipeptidyl peptidase-4 inhibitor class – Januvia – is under challenge from three companies – as data presented by Novartis, Takeda and Bristol-Myers Squibb at this year’s American Diabetes Association meeting in Chicago has shown.

At least eight other companies, including Servier, Pfizer, Eli Lilly and Boehringer Ingelheim, are also developing DPP-4 inhibitors or other drugs to target the incretin system. Better oral antidiabetic drugs that will do the job of reducing glucose more effectively without producing side effects are needed to fill an unmet need. DPP 4 inhibitors are the next big hope and the potential market for antidiabetic drugs in the USA is worth around $8 billion.

Of the DPP-4 inhibitors in late-stage development, Novartis’ Galvus (vildagliptin) is by far the most advanced, having received an approvable letter in February this year and worked with the US Food and Drug Administration to satisfy additional requirements for safety. The company expects to hear from European regulators by the end of this year.

Novartis’ drug, which has the most clinical experience, around 10,000 patients, followed for two to three years, featured in 14 posters and an oral paper at the ADA this year. Several of these confirmed the safety and efficacy of Galvus from pooled trial data, across the range of ethnic groups in the US population and in the over-65s. The latter are patients likely to suffer mild renal impairment and potentially higher drug exposures although only 20% of the drug is excreted renally. However, the FDA has sought more data from Novartis on how vildagliptin affects renal impairment.

Other data at the ADA showed that Galvus may have an edge over Merck’s Januvia (sitagliptin) in an unexplained finding which shows that it reduces blood pressure – a cardiovascular risk factor to which type 2 diabetes patients are prone. Novartis also produced data to show Galvus improves beta cell function in pre-diabetic conditions and that it achieves an additional substantial reduction in HbA1c (approximately 0.6%) and reduced prandial glucose excursions (some 1.3mM) when added to a sulphonylurea, glimepiride. Adding vildagliptins did not increase incidence of hypoglycaemia or weight gain.

Merck presented nine posters on Januvia and the fixed dose combination with metformin, called Janumet, which is already available in the USA. Januvia has also demonstrated safety and efficacy from pooled data and a durable effect on HbA1c out to one year. At 54 weeks, patients had a reduction in HbA1c of 0.7 per cent from baseline with the 100mg dose and 0.9 per cent with the 200mg dose. It also demonstrated an improvement in beta cell function in rodent studies and when co-administered with metformin. A synergistic effect has been found when Januvia is added to metformin and both the Merck drug and Galvus show additional reductions in HbA1c when metformin or sulphonylureas are added.

Takeda's alogliptin may file 2008

Meanwhile, Takeda’s DPP-4 inhibitor alogliptin is in Phase III and “the company is planning to file with the FDA mid-2008,” said Takeda’s clinical science vice president Qais Mekki. Alogliptin is 10,000-fold more selective for DPP-4 than Galvus and Januvia, he claimed, and the drug has been studied across a large dose range up to 800mg with no dose-limiting toxicity seen. The company has yet to decide on the recommended dose. Studies are in progress using monotherapy and combinations with sulphonylureas, metformin, insulin and thiazolidinediones.

Takeda has released only Phase I data so far and has not disclosed results of animal studies probing a risk of skin necrosis seen with some DPP-4 inhibitors (vildagliptin and saxagliptin) in primate models, although Dr Mekki said: “Takeda is comfortable these are not related to alogliptin.” Data at ADA showed it reduced mean four-hour post-prandial glucose levels and was well-tolerated and pharmacokinetic data support a once-daily administration.

Also chasing the DPP-4 market is B-MS and six-month Phase III data on the firm’s saxagliptin, which is partnered with AstraZeneca, added to metformin were presented from a continuing study of 743 patients running for 18 months. As reported earlier this week by PharmaTimes World News, a range of doses were studied against placebo in patients who were inadequately controlled on metformin alone and showed significant decreases in HbA1c compared to placebo without causing hypoglycemia. The percentage of patients achieving the ADA target of HbA1c 7% was 17% for placebo, compared to 37%- 44% for patients on different doses.

The data was presented by Dr Ralph DeFronzo of San Antonio, Texas who commented that until DPP-4 inhibitors are studied head to head, major differences are unlikely to be seen among them clinically. Companies already in the diabetes field would be likely to develop drug combinations with a DPP-4 inhibitor and another oral antidiabetic product, he suggested and for B-MS this could involve saxagliptin being combined in tandem with the firm’s experimental sodium-glucose transporter 2 inhibitor dapagliflozin. By Olwen Glynn Owen