Not So Benign: A Diet Pill Maker & Tumors In Rats
14 CommentsBy Ed Silverman // August 10th, 2011 // 8:47 am
Last week, Arena Pharmaceuticals did some advance work surrounding the impending release of crucial data about its Lorqess diet pill, which was denied approval last fall by the FDA due, in part, to concerns the drug may cause tumors in rats and that efficacy was marginal. To allay those fears, the drugmaker conducted one new study and retained a group of independent pathologists to review other data (see this and this).
The latest trial showed that concentrations of cerebrospinal fluid exposure were lower in human brains than in rat models given their pill (read here). The results prompted Needham analyst Alan Carr to write investors that the results “may alleviate certain FDA concerns with respect to the potential for brain tumors.”
And Arena ceo Jack Lief, who has been criticized previously for failing to disclose the tumor issue (look here), was quick to tout the outcome. “This means of course that we provide a higher safety margin” than was thought earlier, he told Bloomberg News.
Yesterday, however, the other proverbial shoe dropped. Arena released the results of its Pathology Working Group’s readjudication of female rat mammary diagnoses from a two-year carcinogenicity study. The incidence of malignant tumors was numerically lower than the control group in both the 10mg and 30mg doses of Lorqess, but was statistically higher than the control group in the 100mg dose. But the incidence of benign tumors was statistically higher than the control group for all dosages.
Wall Street analysts were not impressed. Carr wrote: “While the revised malignant tumor findings are encouraging, the still significant elevation in benign tumors may continue to pose an issue with the FDA. We believe a full understanding of the mechanism of action behind even benign tumor formation may be just as important to the FDA. In our view, this may be challenging…given modest weight loss in Phase III trials and the challenges of characterizing tumorigenicity risks to the satisfaction of the FDA, we continue to believe there are meaningful risks” before Lorqess wins approval.
Bill Tanner of Lazard Capital Markets was still more blunt: “We continue to believe prospects for approval of Lorqess (and other experimental obesity therapies) are dim as we see abundant reasoning in regulatory bodies sidestepping what would undoubtedly be a public perception nightmare if the Redux scenario were, well, redux-ed. A chief concern has to be intentional overdosing, and rodent studies…bear out a theoretical risk.” Why? Worries that consumers will simply take too many pills.
Then, he writes that the “data yield an unsettling observation.” Arena reported the percentage of rats with malignant tumors “was not statistically different between rats treated with placebo and those treated with (Lorqess) at 10mg/kg/day or 30mg/kg/day. The company’s notation that the percentage of rats treated with those doses of (Lorqess) was numerically lower than that for placebo appears nonsensical as we highly doubt (Lorqess) would have a preventative effect.”
The bottom line, according to Leerink Swann analyst Steve Yoo is that “we believe that the concerns raised by the FDA in the briefing document such as shortened survival for rats developing either malignant or benign tumors have not been adequately addressed with the readjudication.”
By the way, a planned FDA advisory committee scheduled for the first half of 2012 to review obesity drugs may have a wider mandate than previously thought. According to Leerink Swann analyst Josh Schimmer, execs at yet another would-be diet pill maker, Orexigen Therapeutics, disclosed earlier this week that, instead of focusing mostly on cardiovascular risks, FDA officials indicated in recent talks that a “broader panel touching on the risk/benefit of obesity drugs” will be held. Orexigen, Arena and Vivus are all struggling to win FDA approval for their diet pills (more here and here).
original industry insider
The following is the conclusion from the FDA briefing document for Flibanser, an analogue of lorcaserin, which was submiited for approval by Boehringer Ingelheim for Hypoactive Sexual Desire Disorder in women:
“Lifetime administration of flibanserin to female mice resulted in a significant increase in the incidence of malignant mammary tumors at drug exposure levels approximately three and ten times higher than those of women taking the recommended dose. Flibanserin is essentially non-genotoxic and does not increase serum prolactin levels in mice. However, flibanserin is a serotonin receptor agonist/antagonist with significant effects on brain neurotransmitter concentrations, which may have indirect effects on the growth of initiated cells of the mammary gland”.
Thus there is ample history here with the agency to reject this drug.
PS I hold no stock in any weight loss company.
original industry insider
My line got truncated. The correct spelling of the drug is Flibanserin.
Noel
I have seen comments stating that doses of flibanserin at 3 to 10 times HIGHER than recommended dosing resulted in a significant increase in the incident of malignant mammary tumors in women. This comment was further qualified by stating that it took LIFETIME ADMINISTRATION for the occurence, henceforth, lorcaserin should be rejected.
3-10 times the dose for a lifetime for the occurence.
Would the FDA approve an OTC (Over The Counter)medication that can cause 56,000 emergency room visits and about 200 fatal overdoses taken at excessive doses?
http://www.abc12.com/story/15165979/jj-cuts-maximum-tylenol-dose-to-prevent-overdoses?clienttype=printable
Oh wait, does acetaminophen fall into this category? Maybe excessive dosing is greater than 3-10 times the recommendation over a lifetime, therefore safer? If so, no wonder it is available to anyone off the street, without the opinion of trained medical personnel legally licensed to dispense more hazardous medicine.
original industry insider
Actually, 3-10X the recommended human dose as used in rats is an extremely small margin of safety by usual standards.
My teachers always taught that when developing a new drug for humans you would like the lowest human starting dose for humans to be at least 50-100X the LD50 in rats. Bease on my experience working with weight loss drugs, there will be patients who 1) treble their dose, and 2) will take it for a lifetime. Thus for these patients the margin of safety is zero.
Also, I view the lower CSF concentrations of drug in humans vs rats as a potential negative. It means you may not be able to get enough drug into the brain to do its job.
Jack Frost
OI,
You hold no stock in any weight loss company partially because diet “supplements” such as Sensa, Hydroxycut, Quick Trim, Zipfizz that imply weight loss / energy booster therapies are manufactured in the most scummy of scumbag ways, under the shield that the FDA has not sufficiently proven it’s competency in regulating such manufacturing facilities in an effective manner.
Let’s see how long that lasts.
Jack Frost
Point being, these manufacturing firms are double or triple blinded from the public, let alone being listed on the stock market.
original industry insider
Jack, I only put in that disclaimer because after I reamed the company the first time around people accused me of being a hedge fund manager selling short. Because I working in the pharmaceutical industry, I am generally held in extremely low regard by most posters on these borads; I don’t need to carry it a notch lower by being accused of working on Wall Street.
JimDan
Ed, you wrote the following at the end of your article:
“By the way, a planned FDA advisory committee scheduled for the first half of 2012 to review obesity drugs may have a wider mandate than previously thought. ”
Did you receive a formal notification of this meeting or reporting hearsay based on what OREX had allegedly heard from the FDA in their meeting with the FDA. The reason why I mention this is that I know from talking with key Arena people that they have not been formally notified of this advisory committee.
In addition, what Orex said is that the purpose of the meeting is to review the cardiovascular guidelines. If correct, then Lorcaserin will come out smelling like a rose. No VHD, no increase in HR or BP. A1c lowered by .9% in T2DM study patients.
Are you aware of the “Obesity” project that the FDA has commissioned GW University to conduct that will interview obesity patients, Doctors, Obesity Groups to among other things, determine what risks are patients willing to take with an obesity drug.
Janet Woodcock, Director of CDER will be in charge of overseeing that project.
In addition, the FDA also commissioned Dr. Songal Singh of John Hopkins University to work on a project to look at the whole risk/benefit assessment of obesity drugs that the findings will be used as a template for other drugs.
If you have a subscription to RPM, you can find a very informative article/interview with Janet Woodcock.
Back to the advisory committee meeting to review or make recommended changes for obesity drugs related to CV outcomes. The last time the FDA did this, it took two years for the new guidelines to be published.
Reference Bill Tanner’s comments. I know you copied them, but you could have added that Arena did not arrive at the results, it was the 5 Independent pathologists selected by both the FDA and Arena. Yes the lorcaserin low and mid dosage groups were lower than the control group. Mr. Tanner calling it nonsensical is idiotic.
As research shows and Arena pointed out yesterday, the benign tumors do not progress to malignant tumors. Read up on what rat experts like Dr. Gary Williams have to say about that. The FDA already knows this, maybe the analysts that you quoted should learn this as well.
In addition, in the NDA, Arena showed that there were slight increases in prolcatin in humans (female) but no signal for tumors. The FDA reviewer agreed with Arena’s analysis. In the FDA meeting in December with the FDA, the FDA conceded that prolactin increases in rats causes an increase in tumors. When not if, Arena proves that Lorcaserin has a causal effect on prolactin level in rats that will prove the MOA and put the double set of nails in the rat cancer issue.
The FDA also agrees that there is no relevant risk to humans with prolactin increases in humans as I stated above. Thus when the various studies that Arena has ongoing prove the MOA. Case closed.
JimDan
At OII: First of all, comparing Flibanserin to Lorcaserin is not appropriate.
Second the Low dose in the rat studies is 10x the equivalent human dose and the medium dose is 24x the equivalent human dose (EHD) and the high dose is 84x EHD.
Sprague-Dawley rats are known to get cancer at 40x of anything.
Lorcaserin is meant to be taken for a lifetime at the 10mg dose QID.
With your hypothesis of patients taking drugs regardless of their weight loss drugs or not, is that no drugs should be approved, because patients are bound to overdose. I take several medications (two kidney transplants in 11 years) and I have never taken more than the prescribed dosage. Your example is piss poor example for not approving a drug that can help millions of obese and T2DM patients lead a healthier life. 25% of the Completers lost greater than 35 pounds, a number lost more than 50 pounds. Do some sub-group analysis and learn something.
Your CSF comment is not all that bright. Apparently enough lorcaserin got into the brains of the average person in the study to lose 26 pounds. For 35% of people to lose more than 10% of their weight and the top 25% to lose 16.5% of their weight.
Finally, the FDA is evaluating Lorcaserin not Flibanserin…
JimDan
“The bottom line, according to Leerink Swann analyst Steve Yoo is that “we believe that the concerns raised by the FDA in the briefing document such as shortened survival for rats developing either malignant or benign tumors have not been adequately addressed with the readjudication.””
I hope these analysts don’t get paid much!
Maybe Mr. Yoo can borrow my hearing aid. Arena stated they are currently doing studies to address this issue, it is right there in the CC, would have been nice of Mr. Yoo to mention that fact, but analysts only like to point to partial facts.
Here is a clue for you Mr. Yoo - rats get malignant or benign tumors, tumors grow therefore, the rat grows in size, particularly in the mammary area. Fat rats from the tumors have a hard time getting around and eating their food and drinking water. In addition, the extra weight puts stress on their hearts, if the rats were getting 24x or 84x the dosage, they are also suffering from toxic poisoning. Let’s see - my guess the rats were dead of heart attacks, kidney failure, etc.
An Animal pathologist that is an expert in pre-clinical rat studies for all types of drugs pointed this out on a conference call that we had with Keith Darce of the San Diego Union Tribune.
Ed Silverman
Hi JimDan,
Thanks for your interesting comments on this topic and as for your question, as I indicated, I conveyed what Leerink’s Schwimmer wrote in his investor note earlier this week.
And yes, I’m aware that Singh was commmissioned to work on that project and while I don’t subscribe to the RPM Report - can’t afford to pay for everything, unfortunately - I used to work with those guys and so I do sometimes get an opportunity to read an article, as I did in this case.
Again, thanks for the conversation. This is all very interesting and I appreciate the insights.
Regards
ed
Steve Knows
My two centavos worth; remember when Amgen paid a small fortune because the university owning the patent and their other contributors showed a pure miracle, one after another (the little guys, aka,’rats’) all lost weight? Certainly overweight and fatties, would be a thing of the past.
Well, Amgen then tried it on humans, after they paid a fortune for the license and voila, no weight loss. Outcome, money down the drain and Amgen stopped their work.
It is not a theory, but there is a weight loss proven effect, don’t eat!
By the way, the drug was called “LEPTIN”!
JimDan
Ed, thanks for your response. Actually I thought this article on what the analysts though is excellent. I might no necessarily agree with some of their comments but it is helpful to know what they are thinking.
Thomas Wei is one that I may not agree with at times, but I respect him because he in my opinion does his homework. Some of the others do and some don’t. I do understand, that they have other companies to follow and Arena at the current time is not high up on their list. That can change but will take time.
You have a great site by the way.
Yes, the RPM Report is a bit on the expensive side. I’m still debating on making the investment or not.
Regards
Jim Stevens
original industry insider
Jim, you are correct in that flibanserin and lorcaserin are different, but both are serotoniergic agents, have effects on prolactin, and therefore both may result in mammary tumors. You’re trying to tease out a dose differential effect here, but to the decision makers at FDA, they are much more obtuse about these things. Therefore, it if the drug were to ever to be approved, it would carry at least a bold faced or black box warning about mammary tumors, which would be a sales killer.
I agree that absolute concentrations of drug in CSF are not meaningful by themselves. What you need is some data on CSF/brain concentrations to see how much crosses the blood brain barrier. No problem doing this in rats, and I’m sure that anyone desperate enough to take a weight loss drugmay consent to a brain biopsy as well. I would be happy to put in a few Burr holes myself since I learned how to do this on one of my surgical rotations.
I personally worked on the development of Meridia, and contributed to the study protocol in which the hypertensive effect of Meridia was demonstrated in a 24 hour ambulatory blood pressure monitoring study. The FDA advisory committee voted 18-1 against approval back in 1996 and their doubts were confirmed by the long term safety study that resulted in withdrawal of Meridia worldwide over the past several years.
I have no problem with labeling that says lorcaserin should be taken for no more than one year max, both on the basis of safety and the well known fact that weight loss drugs lose their effectiveness within 6-12 months due to the body’s hypothalamic reset mechanism. We know from the Meridia data that eventually many patients regain weight and that only a very small fraction of patients were able to lose weight in a linear matter past two years.
Because of these considerations
Because of my serious doubts about the long term efficacy of diet drugs I have switched my interest to the modern day surgical approaches to weight loss. The lap band and other stomach reducing operations are a vast improvement over earlier procedures and a much higher percntage of patients maintain long term weight loss vs pills. IMO, the excellent safety record of the new procedures persuades may that they should be made available not just to patients with morbid obesity but to patients with lesser degrees of obesity.
Besides one of my good friends is a bariatric surgeon, and as he likes to say, “A chance to cut is a chance to cure”.