It's the end of the year 2009, and it may be the end of the road in the United States for two drugs that were developed for diabetes. After huge expenditures of time and money, both Galvus (vildagliptin, a DPP-4 inhibitor) and Victoza (liraglutide, a GLP-1 receptor agonist) are still awaiting FDA decisions about selling them in the US.

Both drugs completed the required large and costly phase III trials, and their manufacturers submitted the required New Drug Approval (NDA) paperwork; both expected approval from the FDA, but at the time of this writing, both still await approval or turndown. If they are turned down, they might either get an "approvable letter" telling the manufacturer to do more work and submit additional information, or might get a dreaded "not approvable" letter.

Galvus' NDA was originally submitted to the FDA by Novartis early in 2006. It was widely anticipated that it would be approved, and would beat the competition to become the first DPP-4 inhibitor on the market. But in November 2006, Galvus received an "approvable letter" from the FDA, in which Novartis was advised to do another study. The FDA was concerned about skin lesions Novartis that were seen in a monkey study (similar lesions apparently have not been observed in humans) and also wanted more information about the drug in patients with kidney impairment. Since then, two other DPP-4 inhibitors (Januvia/sitagliptin and Onglyza/saxagliptin) have been approved in the US, which would leave Galvus as a "me-three drug" with no discernable unique positive attributes and the very heavy baggage of safety scrutiny from the FDA. I suspect that it's the end of the road in the US for Galvus.

(In the meantime, European health authorities approved Galvus for sale in Europe in February 2008; it's also approved in other countries including for example Brazil. So Novartis is making back some of its investment in the development of the vildagliptin molecule, but nowheres near what they would have been making if it had been first to market in the USA.)

Victoza's NDA was submitted to the FDA by Novo-Nordisk in May 2008. Had it been approved, it would have been the second GLP-1 receptor agonist on the US market, after Byetta/exenatide, and would have a clear marketing advantage as it only requires once-daily injections (Byetta is given twice-daily). But the FDA's Advisory Committee reviewed the drug in April 2009, and was very concerned about thyroid cancers seen in animal studies. The committee voted 6 to 6 (with one member abstaining) that the cancer data in animals were sufficient not to recommend approval. Ordinarily, such cancer data could kill a drug completely; it was surprising that a drug with such a safety signal made it through phase III testing, but half of the the FDA Advisory Committee clearly was concerned.

Since then, there has been an expectation that the FDA would issue some sort of opinion sometime in 2009: for instance, in September, Novo-Nordisk announced that "formal feedback from the United States Food and Drug Administration... has been deferred until the fourth quarter of 2009."