is safe. Let's just not mention that other thing.
In its weird and typically bureaucratic way Friday, the
Food and Drug Administration
restricted an advisory panel's discussion on Actos to safety issues involving the drug, developed by Japan's Takeda and to be co-marketed by
. The agency said it hadn't had time to review the entire new drug application package and therefore wasn't ready to allow a discussion of effectiveness.
Never mind that it doesn't make a whole lot of sense to discuss one without the other. No drug is without side effects, but drugs are typically approved when the benefits outweigh the risks. The decision was especially odd in light of last month's
, the first of the class of diabetes drugs colloquially known as glitazones that reached the market.
In rare cases, Rezulin can cause a potentially fatal liver failure. So a panel, the same one hearing the Actos arguments, took up Rezulin, even though it already was on the market. The idea was to look at Rezulin's risk/benefit ratio in light of the liver problems. The panel advised the agency to keep the pill on the market. But given the close scrutiny, the assumption was that the other drugs in the same class would be held up to the same standard.
But Lilly fans, don't worry. The FDA begged people at the meeting to not read anything into the limited discussion. That pleading made people think that Actos works. Investors and analysts figure the FDA doesn't need any advice from its panel on that matter and expect the FDA to approve the drug without a second panel meeting. (The FDA usually takes its panels' recommendations, though it doesn't have to do so.) Additionally, a Takeda researcher managed to slip it into the record that Actos had a statistically significant lowering of blood sugar at high doses and thus is effective.
The safety data on Actos looked comparable to
, which was
recommended Thursday by the same panel. That was especially true with regard to potential liver toxicity, the key issue given Rezulin's problems. The number of patients taking either Actos or Avandia who had elevated liver enzymes, a signal of liver damage, was comparable to those taking a placebo.
Actos does cause edema, or fluid retention, and may have some cardiac side effects. But the FDA suggested those issues were minor and related to the entire class of medications. There was little talk of potential carcinogenic effects. The Actos studies hinted that the drug didn't have the same problem with raising cholesterol that Avandia had indicated, and in fact, might actually lower triglycerides, a type of cholesterol. Differences in the way the trials were conducted make such comparisons difficult, but Lilly and Takeda sales reps are unlikely to be concerned with such scientific arcana.
Wall Street feels Actos' approval is a formality, but since it was filed after Avandia, Actos is likely to trail Avandia to market. Avandia should be approved by the end of May. Analysts say a several-month advantage could be meaningful in the marketplace.
The other question is how much liver-enzyme monitoring the agency will require. The majority of panel members suggested both Avandia and Actos have the same amount of monitoring that is recommended in conjunction with taking Rezulin. According to Rezulin's current package insert, patients who take the drug need liver-enzyme monitoring once a month for the first eight months, once every other month for the next four and periodically thereafter.
However, monitoring can be a barrier to adherence to a drug, since it is expensive. Doctors and patients find it inconvenient. There was much discussion Friday about whether the monitoring was necessary, with an outside panel of liver experts hired by Takeda determining it wasn't. It's extremely unlikely, given the publicity about Rezulin's toxicity problems, that the two will get labels that don't have any monitoring recommendations.
Analysts expect both drugs to have more than $1 billion in annual sales three to four years from now. However, since Takeda gets the majority of Actos' profits, it won't be a hugely profitable product for Lilly.
SmithKline announced a co-promotion agreement with
on Avandia Friday. That means SmithKline will be able to market Avandia with Bristol's
, or metformin, another diabetes medication. The two drugs showed good blood-sugar control when used together.
Financial terms weren't disclosed.
The deal will enable Bristol to buffer the anticipated market-share loss that Glucophage will likely endure at the hands of the glitazones. Why did SmithKline do the deal?
"As more and more information came out on Rezulin's
liver problems, the magnitude of the opportunity keeps increasing," David Stout, head of U.S. pharmaceutical for SmithKline, said in an interview. Bristol-Myers "has tremendous expertise in the area."
Lilly is a major vendor of insulin and has a huge presence in diabetes, and SmithKline needed help to compete, analysts said.
Stout gave a suggestion of the marketing strategy as he emphasized Avandia's potency. "I wouldn't take Actos' efficacy as a given. We know that Avandia is more potent. On top of metformin, it's has pretty impressive data," said Stout.
One advantage Actos may have is that it's a once-a-day drug, but Stout said that Avandia's "flexible dosing" as either a once-a-day or twice-a-day would be more attractive. But the data from Thursday suggested Avandia isn't as effective taken only once daily.
How damaged are the glitazones in the marketplace because of Rezulin? Stout says that it's been good that Rezulin hasn't been taken off the market. "With safer alternatives, the road is wide open," he said.
He expects patients to be switched off Rezulin. "There's going to be a high desire to do a lot of switching," he said. "How and when needs to be discussed. That's something the FDA's going to have to wrestle with."