Another High-Profile Diabetes Candidate Goes Down

Bristol-Myers Squibb' decision to get out of the diabetes drug business is starting to make more and more sense. With Takeda Pharmaceuticals announcing on Friday that it was scrapping its phase 3 drug fasiglifam (or TAK-875, a GPR40 agonist) due to liver toxicity, another potential diabetes blockbuster has disappeared in a puff of smoke.

There are still multiple GLP-1 inhibitors under development and the SGLT1/2 class is about to get started, but Takeda's move leaves precious few innovative diabetes therapies in biotech and Big Pharma pipelines. Between the availability of oral DPP-IV and SGLT-2 inhibitors, (that offer effective glucose control for most people with diabetes), and FDA policies that demand increasingly large and expensive trials for new diabetes medication, more companies may choose to go the route of Bristol-Myers. That is, they may focus their attention on therapeutic areas like oncology.

Takeda goes down
Takeda was absolutely hoping that fasiglifam would help patch the multibillion dollar hole created by the loss of patent coverage on Actos, and there was reason to believe it could be a blockbuster. A prior phase 3 study showed a 0.75 and 1.01 reduction in HbA1c levels at the 25mg and 50mg dosages, results good enough to lead to blockbuster sales. Unfortunately, emerging data from ongoing studies indicated troubling liver toxicity issues and the company had little choice but to terminate the program.

Fasiglifam would have been the first in its class, and there are only a handful of companies I'm aware of that are working on GPR40 drugs -- Indian companies Piramal Healthcare, Advinus, and private company Connexios.

Big Pharma is managing risk/reward
When it comes to other well-known companies with long histories in the diabetes space, the goal today for diabetes drug development appears to be risk/portfolio management. Sanofi and Lilly are working on GLP-1 drugs to join Bristol-Myers/AstraZeneca and Novo Nordisk , and these companies are also working on both longer-acting injectable and oral formulations.

Several companies are also developing SGLT-2 inhibitors, looking to follow in the path laid out by Johnson & Johnson for what could become another blockbuster class of oral, relatively safe, and effective anti-diabetes agents. Even here, though, there have been challenges tied to the FDA's demand for more rigorous safety studies, and I believe the difficulties in getting Forixga through the FDA loomed large in Bristol-Myers' decision to leave the diabetes space.

Big Pharma is also actively working on various combinations, pairing together existing drugs like DPP-IV inhibitors, GLP-1 agonists, metformin, and others into new branded therapies. While these combinations can give diabetics better control over their disease and added convenience, I would argue the companies' motivations are just as much about maximizing revenue as moving the standard of care forward.

Where's the innovation?
Looking at the pipelines of companies like J&J, Novo Nordisk, and Sanofi, there isn't much in the way of new classes of diabetes therapy under development. I don't mean to denigrate Novo's efforts in an area like oral GLP-1, which would be a solid improvement for patients, but they are not exactly looking for new solutions to the problem.

There are still a handful of new approaches out there. Lilly is working on a glucagon receptor antagonist, and both Amgen and Isis are also exploring the glucagon receptor concept. Smaller companies are working on therapies like glimins, AMPK Activators, and 11-beta HSD1 inhibitors, but larger players have tried some of these before to little effect, and most of these compounds are still in the preclinical or research phase.

The bottom line
There's really no comparison between the pipelines for new oncology drugs and new diabetes drugs around the pharmaceutical and biotech industries. While I'm not arguing that there isn't a very real need for better cancer therapies, it does make me wonder if the state of care today, combined with a much stricter FDA, has effectively disincentivized large companies to invest significant resources in diabetes research. Perhaps all that is needed is for a small biotech to stir up innovation with a new blockbuster, but for now, it looks as though Bristol-Myers isn't the only company taking a break from the diabetes space.

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