End of the road?   (December 27, 2009)

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."

We're now down to one more week in 2009, and nothing recently to indicate that the FDA will suddenly surprise us with a long-awaited decision on the approvability of Victoza. Will it be a non-approvable letter? Approvable letter? It seems very unlikely considering the delays that the FDA will overrule its Advisory Committee and approve the product without further conditions be imposed on Novo-Nordisk, so if anything, the best that might be hoped for would be a demand from the FDA for more studies before approving the drug.

Is it the end of the road for Victoza in the US? Probably, as there is now a once-weekly formulation of exenatide undergoing FDA scrutiny, and other companies are also working on once-weekly versions of GLP-1 receptor agonists, thereby making Victoza not only a me-too drug with heavy safety baggage, but a drug that seems likely to be out-classed on its one potential claim to fame (that it needs be injected only once daily).

(In the meantime, European health authorities approved Victoza for sale in Europe in July 2009. Again, as is the situation with Galvus, Novo-Nordisk is making back some of its investment in the development of the liraglutide molecule, but nowheres near the level of profits that they would have been making if it had been rapidly approved in the USA.)

There's one final point to be made in this tale of two drugs. The end of the road in the US for these two drugs seems likely because of very appropriate caution by the often-maligned FDA. Regulators in other countries had access to the very same data that the FDA is concerned about, and those other regulators took a chance, and approved these drugs to be put on the market in their countries. But US citizens should take comfort that the FDA is closely scrutinizing the data, and doing its best to provide detailed look at the data and its potential implications for safety (versus the potential need for these two additional drugs). To which I say we owe a big thank you to the FDA.

[Editor's Note: Galvus has not been approved in the USA as of March 2012. Victoza was approved in January 2010.]