Takeda trial move could open up new diabetes treatment option

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News today that Takeda is moving its novel G-protein coupled receptor (GPCR) agonist for diabetes, TAK-875, into phase III trials could be a sign that the novel drug class is finally coming into its own.

Despite being one of the most prolific proteins for drug discovery, progress with the class has been slow as shown by the fact that TAK-875 is the first GPCR based agent that has made it into phase III trials (see table below). 

GPCR Agonists in Development for Diabetes
Status Product Pharmacological Class Company(s) Originator
Phase III TAK-875 GPR40 agonist Takeda Takeda
Phase II GSK1292263 GPR119/GDIR agonist GlaxoSmithKline GlaxoSmithKline
PSN821 GPR119/GDIR agonist Astellas Pharma Lundbeck
MBX-2982 GPR119/GDIR agonist Metabolex Metabolex
Phase I JTT-851 GPR40 agonist Japan Tobacco/Torii Pharmaceutical Japan Tobacco
Pre-clinical GPR 119 Project GPR119/GDIR agonist Swedish Orphan Biovitrum Swedish Orphan Biovitrum
GPR119 Agonists GPR119/GDIR agonist Bristol-Myers Squibb Bristol-Myers Squibb
AS1535907 GPR119/GDIR agonist Astellas Pharma Astellas Pharma
GPR119 Follow-on GPR119/GDIR agonist Metabolex Metabolex
ESN-280 GPR43 receptor modulator Euroscreen Euroscreen

Announcing the start of its pivotal trials in Japan, Takeda said the long-term aim was to roll development of the oral drug out world wide. Although Takeda gave no time frame for the trials, analysts have predicted the drug could reach the Japanese market by 2014.

TAK-875 is one of only two GPCR40 agonists in the clinic, the other is JTT-851, a phase I drug belonging to Japan Tobacco.

Both ’40 and ‘119 GPRC agonists work in similar ways, by stimulating pancreatic islet beta cells to increase insulin and also upping the release of incretin GLP-1 from the intestines, which lower blood sugar levels. Because of this mechanism of action many believe the drugs will offer better glucose control over existing therapies, with fewer incidents of hypoglycaemia and increasing the health of pancreatic islet beta cells.

Hard road to navigate

But despite their promise, the lack of certainty about GPCRs has been shown by the varying degrees of interest shown by large pharma groups.

In June 2010, Sanofi signed a deal worth up to $375m with Metabolex for its phase II GPR119, MBX-2982, to much fanfare (Sanofi snaffles novel diabetes drug, June 25, 2010). However, it was a much quieter story earlier this year when the French group announced in its first quarter results that it had decided not to exercise its right to develop the product, and handed it back to privately-held Metabolex.

GlaxoSmithKline has a home-grown GPCR of its own in phase II, GSK1292263, however, although several phase II studies have completed there appear to be no signs of the group initiating any fresh trials for the product. Analysts, notwithstanding, are forecasting a 2014 launch for the product and sales of $41m by 2016.

Some progress

One drug that has made some progress throught the clinic is Astellas Pharma’s PSN821, which has moved from phase I to phase II and is currently enrolling for a 12-week, 60 patient study evaluating pancreatic beta cell function.

Also encouragingly for the class, in May AstraZeneca struck a deal with Heptares, worth up to $188m, to develop a number of GPCRs (EP Vantage Interview- Heptares keeps up deal pace with Astra discovery pact, May 31, 2011). While the compounds were in CNS, pain and inflammatory disorders, the fact that Astra is developing GPCR drugs in a range of indications shows just how versatile GPCRs can be.

Hero or zero?

But the difficulty with the GPCRs, and perhaps the reason there are so few candidates in the clinic, is that it is very unstable when taken out of cell membranes. This makes the proteins hard to characterise and screen. 

Therefore, if Takeda does succeed in cracking this very tough nut, not only will it validate the GPCR pathway it will create a brand new way of treating diabetes, potentially revolutionising the space. It could also trigger a lot more interesting in this prolific but elusive class. Conversely if it fails, some may decide that this target is just too tough to conquer and withdraw.

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