Novartis, Takeda and B-MS challenging Merck’s market exclusivity in DPP-4 market

Merck’s position as the sole provider of an oral antidiabetic drug in the novel dipeptidyl peptidase 4 (DPP 4) inhibitor class is under challenge as at least three companies – Novartis, Takeda and Bristol-Myers Squibb - enter the final stretch of the development process. All four companies presented new data at this year’s American Diabetes Association meeting in Chicago.
At least eight other companies including Servier, Pfizer, Lilly and Boehringer Ingelheim are also developing DPP4 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. The potential market for antidiabetic drugs in the US is worth around $8 billion.
Of the DPP 4 inhibitors in late stage development Novartis’ vildagliptin (Galvus) is by far the most advanced having received an approvable letter in February this year and worked with the FDA 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 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.
The FDA has sought more data from Novartis on how vildagliptin affects renal impairment. Other data at ADA show Galvus may have an edge over Merck’s Januvia in an unexplained finding showing it reduces blood pressure – a cardiovascular risk factor to which Type 2 diabetes patients are prone. Galvus, also produced data to show it improves beta cell function in pre-diabetic conditions and that it achieves an additional substantial reduction in HbA1c (approx 0.6%) and reduced prandial glucose excursions (approx 1.3mM) when added to a sulphonylureas, glimepiride. Adding vildagliptin did not increase incidence of hypoglycaemia or weight gain.
Merck presented nine posters on sitagliptin (Januvia) and the fixed dose combination with metformin (Janumet) already available in the US. 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. Both Januvia and Galvus show additional reductions in HbA1c when metformin or sulphonylureas are added.
Takeda to file alogliptin with FDA mid 2008
Meanwhile Takeda’s DPP4 inhibitor alogliptin is in phase III. “The company is planning to file with the FDA mid 2008” said Takeda’s Clinical Science Vice President Dr Qais Mekki. Alogliptin is 10,000-fold more selective for DPP4 than Galvus and Januvia, he claimed. 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 1 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 4-hour post-prandial glucose levels and was well-tolerated. Pharmacokinetic data support a once-daily administration.
Six-month phase III data on B-MS saxagliptin added to metformin were presented by Dr Ralph DeFronzo of San Antonio, Texas, from a continuing study of 743 patients running for 18 months. 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 per cent was 17 per cent for placebo, compared to 37 to 44 per cent for patients on different doses.
Dr DeFronzo 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 and another oral antidiabetic product, he suggested. For BMS this could involve the DPP 4 product being combined in tandem with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor.
Olwen Glynn Owen
Field Reporter