Is Partial Agonism the Key to PPAR Success?

In case you haven't had your fill of TZD news this week, we bring you word that Dr Reddy's Labs and Rheoscience have dosed their first patient in what will be the first of several large Phase III studies of their partial PPAR gamma agonist balaglitazone.

Say what?

The timing of the trial's launch missed the Avandia circus by only a day and suggests there are companies out there willing to put in the time and money and Herculean effort to make their case for potentially differentiated products in a problematic class. Some senior industry executives think the odds are stacked against success.

Among those skeptics is Wyeth R&D chief Bob Ruffolo, who when interviewed by the IN VIVO Blog only six weeks or so ago, asked (rhetorically): "Who is going to bring a new, improved version of Avandia to market" given the regulatory mountain the FDA will surely make such a company climb?

And it's a fair question, particularly in light of the past few months' events. Let's review.

• GSK's Avandia, subject of everyone's favorite meta-analysis, though allowed to remain on the market for now, will get slapped with some stern patient- and doctor-scaring warnings. Takeda's Actos has avoided the whirlpool so far.


• The PPAR class hasn't exactly had smooth safety sailing prior to Avandia's snafu. Warner-Lambert's Rezulin kicked off the parade back in 2000 and so-called next-generation dual gamma/alpha PPAR agonists like AZ's Galida and Merck's MK-767 and Merck/BMS' Pargluva eventually followed.
  
• Clinicians and patients may be moving beyond the PPARs in any case. The RPM Report has reviewed the winners/losers: Actos may have seen a bump in the wake of the initial Avandia news, but that hasn't lasted. Merck's first-in-class DPP4 inhibitor Januvia is enjoying wild success in its first year on the market and observers are salivating over potential newcomers like Amylin's once-weekly Byetta and Novo Nordisk's liraglutide.

Nevertheless, Rheoscience presses on. If Actos is now the TZD safety standard bearer, it makes sense that to get to market now companies will have to prove their drugs as safe or safer than Takeda's (in fact, European drug regulators require such an active comparator to prove non-inferiority). Rheoscience is aiming to do just that. The first balaglitazone Phase III will be a European "six-month, double-blinded, randomized, placebo-controlled multicenter trial in which type 2 diabetes patients will be given daily doses of either 10 or 20 mg of balaglitazone versus the active comparator Actos (45mg/day) as an add on to stable insulin treatment," according to Rheoscience.

Our interest piqued, we got in touch with Rheoscience CEO Philip Just Larsen, MD, PhD. (For background on Rheoscience, check out our 2004 profile of the company.) Rheoscience's September 2005 deal with Dr. Reddy's got the Danish biopharma company European and Chinese rights to balaglitazone in exchange for taking responsibility for execution and costs associated with the drug's US/EU Phase III program and US regulatory submission (Rheoscience will also receive an undisclosed milestone payment if an NDA is approved and undisclosed royalties on US sales). Novo Nordisk once held rights to the drug, but returned them to Dr Reddy's in 2004, back when dual PPARs were still expected to dominate the class, says Larsen.

Larsen stresses the benefits of balaglitazone's partial gamma agonist properties. "It doesn't take full agonism for full glycemic control," he argues, pointing out that Phase II studies of the drug as well as preclinical models suggest that 20mg of balaglitazone is comparable to 45mg of Actos in that regard.

What's more, he says, balaglitazone shouldn't raise the same safety concerns as other TZDs, since in vitro models and preclinical trials suggest it causes less fluid retention than Avandia and Actos and is less adipogenic than those drugs. The second Phase III trial for the drug is an international long-ranging study to generate a safety database; again that trial will use Actos as a comparator, but Larsen says he doesn't expect either drug to generate the same cardiac ischemia safety signals that have plagued Avandia.

"It's worth emphasizing that it's not the class as such that is under suspicion for inducing cardiac ischemia," he says. "Actos is not associated with cardiac ischemia," a notion backed by FDA's David Graham during Avandia's recent panel meeting, he says.

Nevertheless the series of trials required to get balaglitazone onto the European and US markets will be very costly (Larsen declines to say exactly how costly). Patients and clinicians may be wary of TZDs and hamper trial enrollment (a suggestion Larsen disputes, particularly in terms of European patient accrual). The future of diabetes treatment may indeed by combination therapy, but whether or not TZDs are a mainstay of those combos remains to be seen as newer drugs like the GLP-1s make progress. The regulatory environment--for all drugs, it sometimes seems--is increasingly tricky. Larsen remains optimistic.

"I'm not worried about the regulatory environment. The advisory panel was in favor of drugs in this class, they're a necessary tool in the toolbox," he says. "Treating diabetics is a challenge and by limiting the options you put yourself in a difficult position, and these [TZD] products are quite efficacious."

As for the class' past failures, he points out that "the entire concept of pursuing the dual agonists was a blind alley, and it took those Phase III trials to show that is the case. That is how the selective PPAR agonists like balaglitazone were revitalized," and now shown that pursuing partial agonism could control the side effects related to full agonists like Avandia.

Rheoscience and Dr. Reddy's have competition. A second partial-PPAR gamma agonist in late stage trials belongs to Metabolex and Johnson & Johnson (we wrote about their innovative deal last summer). But don't expect any winners for quite some time. Balaglitazone's NDA won't be filed before late 2009 at the earliest.