Early Signs For Takeda’s TAK-875 Suggest The GPR40 Agonist Could Take On Other Oral Antidiabetics
By Emily Hayes

Full publication of Phase II results for Takeda Pharmaceutical Co. Ltd.’s diabetes drug TAK-875 – the most advanced GPR40 agonist – in the Lancet Feb. 27 suggests a profile potentially competitive with other new oral classes, such as DPP-4 and SGLT-2 inhibitors.

In the Phase II study of 426 patients, multiple doses of the drug were on par with the sulfonylurea glimeperide when it came to blood sugar lowering effects, according to a report by University of Michigan’s Charles Burant and colleagues. But Takeda’s candidate had a better side effect profile – most notably it is minus the hypoglycemia associated with sulfonylureas – and compared to baseline, did not cause significant weight gain. Earlier data from the trial were presented at the American Diabetes Association meeting in June 2011.

Based on these results, Takeda now is testing the drug in Phase III, with plans to enroll a total of 5,000 patients. The company expects to wrap up Phase III work in Japan in 2014 and in the West in 2015, said Thomas Strack, head of the metabolic development therapeutic area at Takeda.

Takeda’s drug is a member of an emerging class that activates free fatty acid receptor 1, or FFAR1, also called G-protein-coupled receptor 40, or GPR40, thereby stimulating insulin secretion in a glucose-dependent manner. In studies of mice, over-expression or activation of FFAR1 resulted in improved glucose tolerance, but development in humans is still in very early stages.

The drug is a potent glucose-lowering agent that works differently from other classes and so it could find a role prior to other classes or in combination with them, says Strack. “Novelty in itself is not necessarily better but it has implications for being durable in terms of efficacy over time,” the exec said in an interview.

The Phase III program should help answer questions about where it would fit in the armamentarium, he added. To make it a commercial success in the crowded therapeutic area, the drug would need to offer advantages over available therapies and demonstrate a solid safety profile. More than ten classes are available for treating diabetes; at the 2011 ADA meeting, some clinicians questioned whether more are needed, especially considering that safety problems that can emerge down the line after a product’s introduction ("Proliferation Of New Diabetes Drugs Prompts Call For Comparative Effectiveness Trials" — "The Pink Sheet" DAILY, Jun. 27, 2011).

Decision Resources analyst Christine Helliwell believes the just-published results for TAK-875 do suggest a good overall profile and may one day offer an attractive option for clinicians. The sulfonylulreas are among the most efficacious oral drugs for treatment of type 2 diabetes but they suffer from the major disadvantage of causing significant weight gain and hypoglycemia, the latter of which is worse than with any other non-insulin diabetes drug, she commented. TAK-875, in contrast, appears to offer similar glucose lowering efficacy, but without the weight gain and hypoglycemia. The positive Phase II findings fit with the enthusiasm of thought leaders who have frequently expressed optimism for the mechanism of action, Helliwell noted.

“TAK-875 could be viewed as an improved version of the widely prescribed, efficacious sulfonylureas,” said Decision Resources analyst Christine Helliwell.

“TAK-875 could be viewed as an improved version of the widely prescribed, efficacious sulfonylureas,” she said.

The results put TAK-875 in a good position compared to other classes, according to Helliwell. The popular DPP-4 inhibitors are associated with very low rates of hypoglycemia but they are somewhat less efficacious than sulfonylureas. And the Takeda candidate’s “apparent excellent glucose lowering capabilities” put it ahead of SGLT-2 inhibitors, which have a very low hypoglycemia risk and offer modest weight loss, but with glucose lowering capability similar to the DPP-4 inhibitors.

Should the profile of TAK-875 be confirmed in Phase III, the drug could potentially be used relatively early in the treatment algorithm for patients who need aggressive HbA1c lowering but are not suitable for therapy with a sulfonylurea, Helliwell said.

“This could correspond to relatively widespread usage and therefore robust sales,” the analyst said.

Dissecting The Results

The study randomized patients who were not responding to metformin or dietary changes to one of several doses of the test drug (6.25, 50, 100 or 200 mg), placebo or glimeperide. After 12 weeks of treatment, there were significant median reductions from baseline of hemoglobin A1c, in all TAK-875 groups, ranging from (0.65% at the 6.25 mg dose to 1.12% at the 50 mg dose). That compares to reductions of 1.05% for glimeperide and 0.13% for placebo. Aside from the 6.25 mg dose, the differences in efficacy between the test drug and glimeperide were not statistically different.

At doses of 25 mg or higher, from 33% and 48% of participants on the test drug achieved the ADA target for HbA1c of less than 7% after 12 weeks of treatment, which was on par with the outcome for glimeperide. Furthermore a significant change in HbA1c compared to placebo was seen at week 4 of treatment, suggesting a rapid onset of action, similar to glimepiride’s, investigators reported.

Takeda’s candidate offered a clear advantage when it came to hypoglycemia, which occurred in 2% of test drug patients vs. 3% for placebo and 19% for glimeperide.

In addition to hypoglycemia, weight gain is another troublesome side effect that affects sulfonylureas as a class. In the placebo group of Takeda’s study, surprisingly, a significant weight loss was reported (-.73 kg or about 1%) from baseline at week 12.

Relative to placebo, investigators reported statistically significant weight increases (0.86 kg to 1.27 kg) at week 12 for TAK-875 in the lower dose range of 6.25 mg to 50 mg. The weight gain compared to baseline was not significant for any dose groups, however. As for glimeperide, weight gain at week 12 was significant relative to placebo (1.59 kg) and also compared to baseline (0.86 kg).

Helliwell views the weight loss in the placebo group as a confounding factor as opposed to a sign that the investigational drug actually causes weight gain. Strack points out that the weight gain was not dose-dependent and questions whether it is a real effect. Weight gain has not been observed in preclinical studies and it’s possible that the changes reported for the middle doses will even out in longer term studies.

“We are fairly optimistic that down the road, this will be a weight-neutral drug,” Strack said.

Rates of treatment-emergent adverse events generally were lower for the test drug and placebo (49% vs. 48%) compared to 61% for glimeperide. Most events related to TAK-875 were mild or moderate. Changes in blood pressure and pulse were similar among the various groups with no significant change from baseline. Also, there were no reported changes in cholesterol levels or liver enzymes.

The outlook is promising though some questions remain. Sulfonylureas are incretin secretagogues that work by encouraging pancreatic beta cells to express insulin regardless of blood glucose levels, and are thought to play a role in diminishing beta cell function. GPR40 agonists are also insulin secretagogues, and consequently they may also hasten a decline in function and speed up disease progression, Helliwell said.

“As with any novel drug class, long term safety will be a concern that will constrain uptake, at least at first. And reimbursement continues to be an issue for emerging antidiabetic agents, particularly in the face of strong generic competition from metformin and sulfonylureas,” Helliwell concluded.
 
 

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