The conclusion about the FDA action: 'refused to approve lorcaserin ' was insufficiently reported as partly due to 'limited effectiveness that it works'.
The FDA asked for more evidence that the tumors in rats found in the preclinical tests was not a result of lorcaserin, but because of the increased amount of prolactin that specifically affects the rats, but does not exhibit the same effect in humans because the risk/benefit ratio was less convincing in a 9 to 5 ratio. The absolute efficacy was NOT a cause for the recommendation. It was a result of the FDA requirement that placebo efficacy be subtracted from active drug efficacy...not an item that a news team can easily reduce to a sound bite. This news item seems to be part of a concerted campaign (by unknown forces) to depress Arena in the minds of small investors while big investors accumulate shares expected to appreciate greatly once the actual approval is granted.
The voting at the review meeting in Sept 2010 was split: 5 yes and 9 no.
Ms. Coffin voted yes. 15
Dr. Connolly voted no. 16
Dr. Douglas voted no. 17
Dr. Felner voted no. 18
Dr. Flegal voted no. 19
Dr. Gardner voted no. 20
Dr. Goldfine voted yes. 21
Dr. Gregg voted no. 22
Dr. Henderson voted no. 1
Dr. Kaul voted no. 2
Dr. Proschan voted yes. 3
Dr. Segal voted yes. 4
Dr. Thomas voted yes. 5
And Dr. Weide voted no.
The comments by the yes voters did talk about modest weight loss, and Dr. Thomas summed up the difficulties of balancing the dosage used in the clinical testing with the risks and efficacy questions:
"And the reason for that is just that the actual efficacy is very small. And I think that?s not a problem with the sponsor, that?s actually what they were required to do.
To take a corollary, the space program built a program to send a man to the moon, and that?s what they got. If they wanted to send a man to Mars, they would have built it that way. If we want more effective drugs for weight loss we got to set higher limits. The concern is this efficacy was in a very selective population that was generally healthy for an obese population. And when this is translated to clinical practice, the weight loss is going to be much smaller. And then you wonder is it worth taking compared to placebo.
However, they did meet the criteria that the FDA has put forth. I think they did their best in trying to assess many of the other risks that was concerned with this type of agent, including valvular heart disease.
I am concerned about the tumor issues. And I think there actually has to be some type of registry or very significant followup, if approved, to look at this agents.
And if there are any animal studies that could be done, they probably should be started now, because they do take a long time to look at for tumorigenicity. And you?d want to have some idea before you actually have to start a study later on.
One reassuring thing is, unlike some other agents, is that the benefits of weight loss even though modest did seem to correlate with benefits in what we think are important factors, the glycemic control, inflammatory markers, and blood pressure, and heart rate. So I think the safety signal, even though this is a selective population, was better.
I do have to say one thing. I think you?re damned if you do, damned if you don?t. If you studied a riskier cardiovascular population, we probably would talk about why we don?t have enough data or what?s the benefit. And we may not see as much efficacy.
I think the point that Dr. Goldfine made earlier that there are patients that you want to treat before they get this diseases, and if this drug is effective in that population maybe it should be limited to people without some of these disease. And that could be a good use for this agent. '"
It appears to me that Arena did do their homework since the review meeting on the animal tumorigenicity, even though a complete review was made at the onset of this review meeting, they have now demonstrated conclusively that locaserin does not represent a cancer risk in humans.
The question of efficacy really needs to be answered in the marketplace by future patients taking the drug. The problem disclosed in the clinical testing was not that lorcaserin did not cause weight reduction, but for reasons not understand nor discussed, the pacebo patients also lost weight in higher than expected proportions. The placebo weight loss during the lorcaserin clinical trials was roughly twice as high as the placebo weight loss during the Qnexa clinical trials. This is truly a mystery.