Me-too and me-three drugs   (February 2, 2008)

Last month, there was a flurry of news stories that a new diabetes drug was being developed. Sounded wonderful, but it turned out to be just another me-too/me-three drug situation.

Turns out that a Japanese drugmaker, Takeda, has been developing a drug called alogliptin, and has recently applied to the FDA for approval to market it in the US for type 2 diabetes. Looking at the story, it turns out that alogliptin is another in a long line of "DPP-4 inhibitors" that are either on the market (Januvia, made by Merck) or in development (including Galvus from Novartis, saxagliptin AKA BMS-477118 from BMS, Redona/denagliptin from GSK, and others).

Januvia (sitagliptin) was the first DPP-4 inhibitor to become available on the US market. It was approved for the treatment of type 2 diabetes in the United States in October 2006, and has been a commercial success, as its once-daily dosing and lack of major side effects (such as lack of hypoglycemia and lack of weight gain) have been selling points -- even though it's been considered minimally efficacious (that is, the drop in A1C is not impressive), and it's expensive compared to older drugs such as metformin.

Approval of Novartis's DPP-4 inhibitor, Galvus (vildagliptin), had actually been expected before Januvia, but Galvus was delayed after the FDA requested more data showing that skin lesions that had been seen in monkey tests don't occur in people. Further studies are furiously underway by Novartis to try to answer the FDA's concern. In Europe, by the way, Galvus has been approved for sale.

Along with the other DPP-4 inhibitors being developed, it should be noted that Takeda has another DPP-4 inhibitor, which is called SYR-472. SYR-472 is being positioned as back-up and possibly a next-generation drug, according to news stories.

So, what's going on here? Clearly there's a market for what are sarcastically called me-too (second to market) drugs, and me-three (third to market) drugs. So there's a race to get these drugs through the laborious and expensive clinical trials that are required to get approval, and to share the market with the first drug out of the gate. And if the leader stumbles, as Galvus did with the monkey problem, then the putative second-place finisher might jump into the lead, as Januvia did in this class of drugs.

But is there a market for the fourth, or fifth, or sixth drug? Turns out that there is, even though many me-too and me-three drugs are really no better and no safer than the first one. Apidra (insulin glulisine, from sanofi-aventis), for instance, hasn't caught the eye of physicians, as Humalog (insulin lispro, from Lilly) and Novolog (insulin aspart, from Novo-Nordisk) had a huge head start getting to market, and to date, I'm unaware of any data showing Apidra is any better or safer than the other two rapid-acting insulin analogs. And sadly, it's not being promoted as being cheaper -- the second and third drugs rarely try to compete on price, even when there's generic competition. There even could be a me-four insulin in the USA: Wockhardt, a company based in India, has a similar product that they sell in other countries, and on their website, they say that the US "is one of the key focus areas for the company's growth strategies."

On the other hand, there are examples where a drug is developed as a me-too or me-three drug, and surprises everybody. An example in the diabetes field: Actos (pioglitazone) is the last man standing in the class of drugs called thiazolidinediones or glitazones, as the other two glitazones, Rezulin (troglitazone) and Avandia (rosiglitazone) have come under the regulatory microscope because of side effects: Rezulin was withdrawn because of liver problems, and Avandia has been under fire for cardiac problems; to date, Actos has had much less problems. Thus, relative safety may become a selling point for a me-too/me-three drug.

And in the hyperlipidemia treatment arena, there were quite a few statins on the market when Parke-Davis released Lipitor (atorvastatin) to a less-than-rousing reception -- as I vaguely recall, Lipitor was approximately a me-six statin; there are at least nine out there presently. But within a year of its release, Lipitor was noted to have spectacular efficacy compared to the other statins, and soon became described as a "superstatin." Sales took off, Pfizer bought Parke-Davis to get Lipitor, and Lipitor jumped to the head of the class -- indeed the most profitable drug overall: according to the Wall Street Journal, with 2006 sales of 12.9 billion dollars, it is the largest selling drug in the world. Hence, improved efficacy may also become a selling point for a me-too/me-three drug.

So don't be surprised that drug manufacturers keep coming up with me-too and me-three drugs. It's profitable to do so, and sometimes one of these drugs goes to the head of the class. And even if it doesn't, the second/third/etc. drug may add to the bottom line, and sometimes has better efficacy, and sometimes better safety. It's a gamble the drug industry will happily take.