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James W. Hill, MD, is a clinical assistant professor of radiology at the University of Southern California Medical School and a patent lawyer and partner at McDermott Will & Emery. Although he relies on publicly available information and makes reasonable efforts to confirm its accuracy, his... More
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  • FDA Panel Flubbed in Arena’s Lorcaserin Disapproval 58 comments
    Sep 21, 2010 3:26 AM | about stocks: ARNA, GSK, RHHBY, ABT

    Last week’s FDA panel that voted 9-to-5 against approving Arena Pharmaceuticals’ (ARNA) obesity drug Lorqess (lorcaserin) apparently blundered in its assessment that the company’s rat breast tumor findings merit concern, according to the FDA’s own published standards.

    Bloomberg reported that "a panel of outside advisers to the FDA voted against recommending the drug for approval, citing concerns about tumors seen in rats in early-stage testing of the drug. … Of particular concern was the increase of mammary tumors in rats treated with lorcaserin, the committee said."

     

    But here’s how the FDA panel was earlier briefed:

    Lorcaserin was investigated in a standard battery of genotoxicity, reproductive toxicity, general toxicity, and carcinogenicity studies. Lorcaserin showed no reproductive toxicity or genotoxicity. General toxicity studies were conducted in mice, rats, and monkeys at doses that produced very high exposure multiples relative to the human maximum recommended dose (MRD). In repeated dose Good Laboratory Practice (GLP) toxicity studies, lorcaserin was generally well tolerated at doses below the maximum tolerated dose (MTD) in all three species and there appeared to be no adverse findings of direct relevance to humans at therapeutic doses [emphasis added].

    Two-year carcinogenicity studies were conducted in mice and rats. There was no evidence of carcinogenicity in mice. In rats, and almost exclusively male rats, tumors were found in multiple organs primarily at the highest dose, which provided an exposure that was 56-fold greater than human and was clearly above the MTD [emphasis added].

     

    So lorcaserin was found not to be genotoxic, meaning it does not harm a cell’s genetic material, especially DNA.  Rather, lorcaserin’s mechanism for promoting breast tumors at only high, toxic doses may be hormonal, in a way that apparently does not exist in humans.  According to the FDA brief, “The mammary tumors are attributable to increased prolactin, a mechanism peculiar to the rat.”   

     

    Prolactin is the pituitary hormone that causes milk production in the breast.  Although a role for prolactin in the promotion of breast cancer has been proposed, recent research indicates that prolactin protects against aggressive human breast cancer, at least by blocking an oncogene called BCL6.

    Besides, lorcaserin does not raise prolactin levels in humans.

     

    The FDA brief:

    [T]he relevance of these tumors to humans is questionable because: 1) lorcaserin is not genotoxic; 2) substantial margins and/or rodent specific mechanisms were identified for each of the tumors; 3) the tumors were found primarily in one gender of one species at a toxic dose; and 4) no preneoplastic or neoplastic lesions were found in any other toxicity studies in the rat, mouse or monkey.

     

    Rat tumors, benign and malignant

    Male rats had a significant benign breast tumor (fibroadenoma) incidence only if they received 56 times the lorcaserin exposure humans would get at the proven-effective dose of 20 mg per day.

    Male rats had no significant increase in breast cancer (adenocarcinoma) at any dose of lorcaserin.

    Female
    control rats, who received no lorcaserin, showed high rates of spontaneous benign and malignant breast tumors at baseline. Forty-three percent of female rats that never touched lorcaserin developed cancer!  That's just how these animals' bodies operate.

    Female rats developed significantly more benign
    breast tumors (fibroadenomas) at all doses of lorcaserin, but this has no known implication for human cancers.

    Female rats showed a significant increase in
    breast cancer (adenocarcinoma) only if they received 84 times the lorcaserin exposure humans would get at the standard dose of 20 mg per day.



    Excerpts of the FDA briefing tables:

    Male Rats

    Mammary Gland Neoplasms in Male Rats and
    Lorcaserin Exposure Margins Above Human Exposure

    Dose (mg/kg)

    0

    10

    30

    100

    Lorcaserin margin over human

    --

    5

    17

    56

    Number of male rats

    65

    65

    65

    75

    Adenocarcinoma

    0

    0

    2

    2

    Benign fibroadenoma*

    0

    1

    4

    6*

     * Trend is significant (p = 0.0001). Significantly different from control at 100 mg/kg (p = 0.002).

    *******

     

    Female Rats 

    Mammary Gland Neoplasms in Female Rats and
    Lorcaserin Exposure Margins Above Human Exposure

    Dose (mg/kg)

    0

    10

    30

    100

    Lorcaserin margin over human

    --

    7

    24

    84

    Number of female rats

    65

    65

    65

    75

    Adenocarcinomaa

    28 (43%)

    34 (52%)

    35 (54%)

    60* (80%)

    Benign fibroadenomaa

    20 (31%)

    47* (72%)

    54* (83%)

    45* (60%)

     

    a Trend is significant (p < 0.0001).

    * Significantly different from control (p < 0.0001)

    *******


    Should the FDA worry if megadoses of lorcaserin cause tumors in rats?

    Is a significant increase in female rat breast cancer, seen at no less than 84 times the human exposure level of lorcaserin, even a problem for humans?


    Not according to the FDA’s prior reviews of scientific studies and its published guidance to drugmakers. 

    The FDA’s September 2008 Guidance for Industry: S1C(R2) Dose Selection for Carcinogenicity Studies says:


    It has been agreed that if a drug is only positive [for a cancer association] in rodents at doses above those producing a 25-­fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans.


    Arena
    found a significant benign tumor rate in male rats exposed to no less than 56-fold amounts of lorcaserin compared to what humans would receive, and a significantly increased cancer rate in female rats exposed to no less than 84-fold amounts.  These dosages are well above the FDA threshold of "25-­fold exposure over exposure in humans."  Therefore, "such a finding would not be considered likely to reflect a relevant risk to humans," according to the FDA’s prior, considered scientific findings and advice to pharmaceutical manufacturers.


    No wonder Arena CEO Jack Lief said in a conference call with analysts last Friday that it was a “shame” there were no experts in carcinogenesis or toxicology on the panel.
     

    "My view is they were having difficulty understanding the presentation," he said.

     


    How well did FDA no-vote panelists grasp Arena's rat tumor findings?

     

    BioWorld’s Donna Young reported:

    [FDA panelist] Edward Gregg, chief of epidemiology and statistics in the Centers for Disease Control and Prevention's Division of Diabetes Translation, said he was "spooked" by the rat study tumor results.

    Many on the panel of metabolic and endocrinology experts, however, acknowledged that their particular expertise was not in cancer, and therefore, had difficulty interpreting the rat study results. ...
     

    Given the potential for lorcaserin to be used by hundreds of thousands of women once it enters the U.S. market, "there is just too much uncertainty" without more studies to answer the tumor question, said [FDA] panelist Jacqueline Gardner, a professor of pharmacy at the University of Washington.

     

    What is the uncertainty to which pharmacist Gardner refers?  Could it be based on some panelists’ difficulty in interpreting Arena’s data, or in determining its applicability to humans in accordance with cancer biology principles? 

    Panelist Michael Proschan, a mathematical statistician at the National Institute of Allergy and Infectious Diseases, seemed honest about his perception of the rat tumor data. "I feel totally lost," he said. "I have no idea how to translate from animals to people."

    Lorcaserin may play an important role not just in weight loss, but also in treating complications of obesity.  According to the FDA brief, “Lorcaserin 10 mg BID caused significant improvements in blood pressure, lipid profiles, and insulin resistance in parallel with weight loss.”

    In a July 2010 New England Journal of Medicine editorial, obesity expert Arne Astrup, MD, wrote, “The justification for using lorcaserin to manage obesity is not greater efficacy than currently available drugs [orlistat (Xenical by Roche (OTCQX:RHHBY) and Alli by GlaxoSmithKline (GSK)), and sibutramine (Meridia by Abbott Laboratories (ABT))], but rather an apparently much better safety and adverse-event profile and very clear-cut beneficial effects on risk factors for type 2 diabetes and cardiovascular disease.”

    The FDA owes the public a commitment to competent scientific evaluation in its drug-approval decisions.  It should act consistently with its prior scientific findings and industry guidance, promptly overrule the lorcaserin panel's mistaken vote, and set the record straight on lorcaserin’s cancer safety findings.

     

     

     



    Disclosure: Long ARNA
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Comments (58)
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  • hey, appreciate the article as an Arena Long. I happen to agree with you. But what you're linking to is Arena pharmaceutical's Briefing Document, not the more negatively toned FDA Briefing Document on the subject of rat neoplasms. the FDA Briefing Document does not agree on a prolactin mediated mechanism, which would have saved Arena because like you said there is no prolactin increase in humans.

     

    Based on everything I've read on a short, inadequate crash course, I still don't agree rat data should be this relevant and I still think Arena will get this approved eventually. (Of course, I kinda WANT to believe that...)
    21 Sep 2010, 12:23 PM Reply Like
  • Every single person who is holding ARNA long absolutely needs to write thier congressperson a snail mail letter and send copies to the FDA department heads and also to the first lady. Mrs. Obama is a vocal advocate about the dangers that become multiplied in obese people. She knows viable treatments are needed and may even be following the Arena stink going on. If you are in need of some real payback on your investment like I am, you should write congressperson and senators minimum. There needs to be enough public outcry on this in order to get any real resolution in this disgrace of a highjacking by the FDA for some unknown reason. Most likely the shorts heavy hands are involved at a personal level. People about to lose billions on a bad short investment will do anything to change that including threats of violence on neutral or impartial parties connected to the final outcome in the decision making process. If you were in the position of controlling billions of investors dollars and therefore had the resources to have strong arms influence the positions of those in the decision making process, and those billions were at great risk of being lost also putting your livelihood and/or life at risk, wouldn't you also use whatever means you had available to you to tilt the outcome to your favor? I think the answer to that one is easy. Of course you would. Now that the shorts have had or will have time enough to cover their shorts up until Oct. 21st, hopefully if enough people write influential people who can lean on the FDA to make the correct decision, we will get that approval we need and Arena absolutely deserves. Arena spent hundreds of millions of dollars testing their drug and it passed everything and should have had no problem in that panel voting at all. It is obvious there is something wrong amiss here. I don't know what it is. I am only speculating. But what I am speculating sure seems like I have the right idea. Maybe not I don't know. Just write those people and cite the reasons the author of this article gives. Not mine. I have nothing to back my ideas up. This author does.
    24 Sep 2010, 12:51 AM Reply Like
  • Additional mention should be made that FDA deputy Coleman (a non-voting FDA presence) spooked the voting members with an inflammatory prejudicial warning about any approval voters having their names "forever linked to the recall" of Locaserin were it to receive
    approval.
    22 Sep 2010, 08:57 AM Reply Like
  • your quote from Arne Astrup is also misleading. The comment was made before the data on rat carcinogenicity was made public and therefore does not support your thesis.
    22 Sep 2010, 10:14 AM Reply Like
  • How do you know Dr. Astrup didn't know about the preclinical rat data? Patients in the trials were made aware of it. Or if he hadn't known, and later found out, would he have thought it relevant?
    22 Sep 2010, 10:43 AM Reply Like
  • Great article. Hope the FDA panel making the final decision on Oct 22 reads it!

     

    Long and strong on ARNA
    22 Sep 2010, 10:44 AM Reply Like
  • The FDA is not going around looking for articles like this in order to come to a decision. The only way they will get this articles information into their unfocused neural pathways is for all of us to copy it to a document template and then make some changes so they don't get a bunch of the exact same letter and just toss those out before reading them. Also the real movers in this equation are going to the people who can bring the most attention to this for us so the FDA will have no choice but to fairly give its ruling on October 22. Those people who can make the most noise are your congressman and senators and the first lady. These four people(your specific three in congress plus the first lady) should get bombarded with mail from the postman. Hand delivered with a return receipt request. This should be your top priority. If you lost more than five thousand then surely you can justify the small cost of making certain sure your letter is delivered to them and signed for. This will almost guarantee the intended recipient will open it and read it. This is really really important. We all know lorcaserine should have got the green light or the recommend vote to approve. The data is clear and easily speaks for itself. Try to save your investment a lot quicker and much easier than just waiting it out and hoping for the best. That won't work, the guy who is in charge is doing this misinformation campaign for a reason. WE have to put the pressure on that will force him to do the correct thing. To do his job the way it is intended to be done. Fairly and with an impartial non bias criteria. So write them and send them. Ten bucks is a lot less risk than you originally put up and the reward could be oh so sweet.
    24 Sep 2010, 02:27 PM Reply Like
  • The FDA appears to be arbitrarily "raising the bar" on obesity drugs when obesity is becoming a national epidemic. I think this is a big mistake by the FDA. Here's why:
    Please see this article about the Adverse Childhood Events (ACE) study : <www.psychotherapynetwo...;. It argues against there ever being a "homerun" drug for obesity and against too rapid weight loss without understanding and working with the powerful psychological factors underlying many obese patients. For me, it also argues for a safe and gradual approach to weight loss using many tools. I think Arena's drug Lorcaserin should and can be one of them.
    Also check out: www.newsweek.com/2010/.... which explains how rational arguments can fall on deaf ears since from an evolutionary standpoint it is better to be right than rational! I think many on the AC panel were too afraid of being wrong.
    22 Sep 2010, 12:53 PM Reply Like
  • The FDA appears to be arbitrarily "raising the bar" on obesity drugs when obesity is becoming a national epidemic. I think this is wrong, here's why: Please see this article about the Adverse Childhood Events (ACE) study : <www.psychotherapynetwo... >
    It argues against there ever being a "home run" drug for obesity and against too rapid weight loss without understanding and working with the powerful psychological factors underlying many obese patients. For me, it also argues for a safe and gradual approach to weigh loss using many tools. I think Arena's drug Lorcaserin should and can be one of them. Also see: Please see: www.newsweek.com/2010/.... which explains how rational arguments can fall on deaf ears since from an evolutionary standpoint it is better to be right than rational! I think the AC committee and Colman did not want to be "wrong" and made the safe but irrational choice.
    22 Sep 2010, 01:25 PM Reply Like
  • Can someone write about biological mechanism involved in hunger, over-eating? Or what it is in Lorqess that causes weight loss?
    22 Sep 2010, 02:27 PM Reply Like
  • Lorqess hits the satiety receptor in the brain and makes the patient feel full. The current most popular obesity drug, phentermine, stimulates metabolism to burn off calories, but can only be used for 12 weeks at a time. Patients lose weight on phentermine and then gain it back during the period they are off the drug. Lorqess would be very useful to help keep the weight off during this period - note that this is NOT combination therapy with phentermine.
    22 Sep 2010, 02:46 PM Reply Like
  • Oh my God! Mr. Murphy strikes back! where is the unanimous vote for approval??? and the stock skyrocketing to $20?
    24 Sep 2010, 06:27 PM Reply Like
  • Their seems to be some question on other boards if the "Briefing Document” you quoted is one submitted by ARNA and not the one written by the FDA. Could you please comment on the differences.

     

    Go here to see the FDA’s briefing:
    www.fda.gov/downloads/...
    22 Sep 2010, 02:40 PM Reply Like
  • James - As you know, the FDA added the benign and malignant tumor counts together, and then focused on that number for statistical significance. Pure FUD, but they got away with it at the panel.

     

    But ARNA really should have given up on the "prolactin caused the tumors" argument and just said: "We don't know the mechanism of action that caused the tumors in these rats at these high doses, but it is not relevant to the panel's decision" and then cited the FDA guidelines you have quoted. Thanks!
    22 Sep 2010, 02:43 PM Reply Like
  • The rats did get fibroadenomas at lower level I think they need to explain the mechanism better, since adenoms can degenerate into carcinomaThis may why they grouped the tumors together.
    I'm on your side,but need better explanations
    22 Sep 2010, 04:28 PM Reply Like
  • Author’s reply » @Dr. Ritacca:

     

    Elucidation of a mechanism for development of rat mammary gland fibroadenomas would be helpful, but as to its applicability to human breast cancer, the article cited below suggests that as of 2006, no common molecular pathways between rat and human fibroadenomas, and no significant progression from fibroadenoma to adenocarcinoma in rats, had been identified.

     

    Quoting the article: “We conclude that in the [rat mammary gland] fibroadenoma tumours examined here, no progression to adenocarcinoma is likely.”

     

    www.sciencedirect.com/...

     

    Perhaps there are more recent data that contradict these findings, but I have not yet found any yet.
    22 Sep 2010, 05:24 PM Reply Like
  • Author’s reply » The link broke to the rat fibroadenoma article finding no progression to cancer. Here is an updated link:

     

    www.ncbi.nlm.nih.gov/p...

     

    Don't be surprised if lorcaserin is approved before further studies are required. The science and FDA policy should warrant such approval, even if only conditioned upon post-appoval studies.
    4 Oct 2010, 05:23 PM Reply Like
  • Author’s reply » Thanks to all who pointed out I cited the ARNA brief to the FDA, not the later FDA staff brief. I was unaware of the latter when I wrote the article, but I’ll review it and probably either write an updated article or further provide comments here.

     

    To my knowledge so far, the ARNA rat tumor data cited in the article is still correct, though the FDA properly notes there is not enough information to conclude that the rat’s tumorigenesis is prolactin-mediated.

     

    In any event, Michael Murphy appears correct that “ARNA really should have given up on the 'prolactin caused the tumors' argument and just said: ‘We don't know the mechanism of action that caused the tumors in these rats at these high doses, but it is not relevant to the panel's decision.’”

     

    In view of (a) the very high dose of lorcaserin needed to demonstrate a significant increase in rat breast cancer, and (b) FDA’s prior industry guidance on testing for drug-induced rodent cancer, ARNA’s prolactin argument seems a little like saying, “Santa Claus didn’t come this year because he was sick with the flu,” then wasting time trying to prove he really had the flu.
    22 Sep 2010, 04:22 PM Reply Like
  • The rats did get fibroadenomas at lower leves(10x).l I think they need to explain the mechanism better, since adenoms can degenerate into carcinoma.This may why they grouped the tumors together.
    I'm on your side,but need better explanations
    22 Sep 2010, 04:43 PM Reply Like
  • fibroadenomas do not degenerate into carcinoma. Are you telling all your patients to get their fibroadenomas excised because they can degenerate? If you believe in this malignant degeneration, you must be excising all of these.

     

    Where did you learn about this? If you've ever seen a case, you likely saw a misdiagnosed phyllodes.
    22 Sep 2010, 05:18 PM Reply Like
  • They rarely progress to adenocarcinoma.The histologic features of the fibroadenoma influence the risk of breast cancer. The risk of subsequent breast cancer is slightly elevated only if the fibroadenoma is complex, if there is adjacent proliferative disease or if there is a family history of breast cancer. For the majority of women with simple fibroadenomas, there is no increased risk of developing breast cancer. In fact, without these conditions f a biopsy proven fibroadenoma is asymptomatic, then it can be left in place.

     

    References
    A prospective study of benign breast disease and the risk of breast cancer.London SJ; Connolly JL; Schnitt SJ; Colditz GA JAMA 1992 Feb 19;267(7):941-4.

     

    Risk factors for breast cancer in women with proliferative breast disease.Dupont WD; Page DL N Engl J Med 1985 Jan 17;312(3):146-51.

     

    Benign breast disease and the risk of breast cancer.Hartmann LC; Sellers TA; Frost MH; Lingle WL; Degnim AC; Ghosh K; Vierkant RA; Maloney SD; Pankratz VS; Hillman DW; Suman VJ; Johnson J; Blake C; Tlsty T; Vachon CM; Melton LJ 3rd; Visscher DW N Engl J Med 2005 Jul 21;353(3):229-37.

     

    Daniel
    UCLA MD
    22 Sep 2010, 05:45 PM Reply Like
  • they do NOT progress. there is absolutely no established malignant potential of a fibroadenoma. so-called complex fibroadenomas are thought to POSSIBLY represent a marker for carcinoma, but that is far from certain. Cases of malignancy are not thought to arise from the fibroadenoma itself.
    22 Sep 2010, 06:13 PM Reply Like
  • A better question would be:were these rat tumors of the 'complex variety'?if not- I 'm in agreement that they shouldn't be classified as premalignant.
    thank you.
    22 Sep 2010, 06:40 PM Reply Like
  • I stand corrected.Adenoma and adenocarcinome are not related in the breast
    22 Sep 2010, 10:39 PM Reply Like
  • In rats they progress to malignancies
    5 Oct 2010, 08:51 AM Reply Like
  • Oculoplastic surgeon with a weight loss clinic
    22 Sep 2010, 04:33 PM Reply Like
  • Dr. Ritacca,
    Given your explanation, does that mean that the FDA (possible) allowed the test to continue (on humans) while they had some doubt as to the fibroadenomas mechanism that could degenereate into carcinoma? Does that seem logical to you?
    22 Sep 2010, 04:51 PM Reply Like
  • They didn't see the overall picture of the rat cancers until phase 3
    was in progress from what I gleaned.
    22 Sep 2010, 06:18 PM Reply Like
  • i have been trained as an orbital cancer surgeon to remove all lacrimal gland adenomas-in tact- for the simple reason of degeneration into hihg grade malignancy. It may be different for the breast which I'LL BE HAPPY TO RESEARCH AND GET BACK TO YOU.
    22 Sep 2010, 06:24 PM Reply Like
  • What is confounding as regards this whole AdCom procedure is that Arena mngt. had access to the FDA briefing docs ahead of time...they should have been prepared to educate the panelists and refute any inappropriate or inaccurate inferences on the part of the FDA. Everything was riding on their preparation & presentation...they had sufficient warning, yet they failed to adequately assess the serious nature of their predicament and vigorously refute the FDA's pseudo-science. It is possible that Colman so poisoned the atmosphere with bias and intimidation that it wouldn't have made sufficient difference...but we will never know because they weren't prepared. Arena was ambushed, but they had time to recognize and prepare an aggressive defense...this is why strong, 'think on your feet' mngt. is so important.
    22 Sep 2010, 11:21 PM Reply Like
  • I think the statement that lorcaserin is only increasing cancer in these mice at the highest dose is based in an incorrect application of statistics.

     

    Statistical significance is the ability to exclude the "null hypothesis", e.g., that differences between two groups are simply due to random chance, with 95% certainty. It's a little bit like the "beyond reasonable doubt" standard in our criminal justice system. Not being convicted is not a certification of innocence. One can be 70%, 80%, or even 90% confident that a product is causing cancer at a specified dose level without meeting the "statistical significance" standard.

     

    Lorcaserin is clearly guilty beyond reasonable doubt at the highest dose. At lower doses, it is guilty at the lower "preponderance of evidence" level that pertains in civil trials. When we are talking about cancer, I believe the latter standard should be sufficient to keep most products for conditions that are not immediately life-threatening off the market.

     

    In male rats, the combined incidence of malignant tumors in the placebo, 10 mg/kg, 30 mg/kg, and 100 mg/kg doses groups was 3%, 5%, 22% and 37% respectively. Every dose group had a higher incidence of malignant tumors than placebo treated animals, and each lorcaserin-treated group had a higher incidence than groups treated with lower doses of lorcaserin.

     

    In female rats, the incidence of malignant mammary tumors was higher in all three lorcaserin dosage groups than in placebo, achieving the "beyond reasonable doubt" standard (80% incidence!) at the highest dose. This hardly seems to recommend the product for a patient population consisting largely of peri-menopausal women.
    23 Sep 2010, 01:34 AM Reply Like
  • John - Thank you for confirming that there was no statistically significant increase in malignant tumors except at the highest dosage levels.

     

    What is your evidence that cancer at very high doses in rats is significant to the decision to approve a far lower dose in humans?
    23 Sep 2010, 01:58 AM Reply Like
  • Mike, didn't you read my comment?
    23 Sep 2010, 02:05 AM Reply Like
  • Yes, I did. What is the percentage that equates to "preponderance of the evidence?" Is it 51%?

     

    And, to repeat, What is your evidence that cancer at very high doses in rats is significant to the decision to approve a far lower dose in humans?
    23 Sep 2010, 11:22 AM Reply Like
  • I'm confused.Are the tumors in the rats significantly/ statistically related to all doses.It appears Mr.Tucker thinks so but everyone else(except FDA) disagree.Is there a statistician in the house.
    My consensus from the Hill's article that they increased but not statistically at the 95% confidence level.Comments please.
    23 Sep 2010, 11:17 AM Reply Like
  • Go to the FDA briefing document at www.fda.gov/downloads/......

     

    In the left hand Table of Contents column, click Carcinogenic Assessment of Investigational Pharmaceutical Compounds.

     

    This will take you to page Alavi-3 , which is page 83 of the whole pdf. Read or scroll to page Alavi-6, which is page 86 of the pdf. You will find two tables, one for male rats and one for female rats.
    NS= not statistically significant SS=statistically significant
    Notice that the brain tumors were only SS at the highest level - that was 56x or 84x the human dose.
    The FDA had to combine the benign and malignant tumor data to get any SS on the mammary tumors in male rats. The other cancers were only SS at the highest level.
    For female rats, malignant mammary tumors were only SS at the highest level. FDA again had to combine the benign and mammary data to force SS at lower levels.
    Their argument for combining was that the female rats eventually died of the fibroadenomas due to organ pressure. Apparently, they think women might get a fibroadenoma and not bother to have it treated as it grows to 50 or 100 pounds.
    John Tucker's argument is that the higher the dose, the more tumors appeared, so let's lower the SS boundary to ??% and make them all SS.
    As you know, rats get cancer the way we get colds. If you inject water subcute in a rat, it will get tumors. The more water you inject, the more tumors it will get.
    I live on a farm. I know BS when I smell it.
    23 Sep 2010, 11:42 AM Reply Like
  • From my review of the literature and in conversations with oncologists,adenoms and adenocarcinoma are not related in the breast-maybe in other cancers such as gut or orbit.But in the breast one is benign and the other malignant, and the breast adenoma will not become a serious adenocarcinoma over time!
    From what my oncology friends tell me,they should not be grouped together when talking about breast cancer.
    23 Sep 2010, 11:58 AM Reply Like
  • Mike, in our past interactions you have always been a very gracious person, so I'm surprised that you would jump in and attempt to define my position without giving me the chance to do so myself.

     

    Basically my argument here is that when you define this entire issue in terms of statistical significance, you are implicitly assuming that the drug should be approved unless the FDA can PROVE that it is carcinogenic.

     

    That's not the way it does or should work. The burden of proof is on the sponsor to show that with a very high degree of confidence, the drug is safe.

     

    To respond to your question, I don't think the relevant standard is 51%, it's closer to 10%. It's certainly not 95%.

     

    Would you want a member of your family taking a drug if there was a 51% chance that it was carcinogenic? Of course not.
    23 Sep 2010, 12:15 PM Reply Like
  • I don't understand the 51%.If a result is SS,then one applies confidence intervals.My question is:are the cancers(carcinomas)
    SS at the 95% confidence level and for what dose.Does anyone know?
    Otherwise,I can't follow the discourse between Mr.Tucker and MM
    23 Sep 2010, 01:49 PM Reply Like
  • You're saying that the rat data is more important and relevant then the mice? And if so,why?
    23 Sep 2010, 01:51 PM Reply Like
  • John, the company had to show at the 95% confidence level that Lorqess does not cause a statistically significant increase in malignant tumors. They showed that at all but the highest levels of the drug. The FDA does not have to prove the drug is carcinogenic, they require the company to prove it is not carcinogenic. At the 95% confidence level, ARNA did that.

     

    Perhaps I am missing your point, but I thought you were saying in your opinion they needed to prove that at a much higher level of confidence. Or, alternatively, you were saying that it was proper to add together the benign and malignant tumors, and based on that there was a statistically significant increase in certain tumors.

     

    I apologize if I misunderstood the point of your post. I think one or the other of the above alternatives does describe your point. Am I wrong?
    23 Sep 2010, 03:07 PM Reply Like
  • This mechanism may not have an explanation or a correlation in humans if it hormonally regulated in the rats.i have a feeling that proving the pathway in the rats is going to be a lot more difficult than it looks.The positives are,it's not gentoxic or carcinogenic and doesn't effect hormones in humans.I would be hard pressed to believe this drug at These levels is stimulating brest tissue directly and causing carcinogenicity especially when they already proved the drug wasn't carcinogenic
    25 Sep 2010, 11:11 AM Reply Like
  • Hi Dr. Ritacca,

     

    The mice were not exposed at high levels because they died of cancer-unrelated causes at higher doses. As someone noted above, the usual cutoff for concern would be increased cancer incidence at an exposure 25x that of human exposure. The maximum mouse exposure was 4 - 8x. So there is not enough data to argue that the effect is specific to the rat.

     

    JT
    23 Sep 2010, 02:12 PM Reply Like
  • With regard to the statistical argument, perhaps it would be helpful if I expressed my idea another way:

     

    I think there is a very strong chance that if you repeated this study using a larger number of rats, the increased numbers of malignant tumors seen at lower doses of lorcaserin would become statistically significant.
    23 Sep 2010, 02:18 PM Reply Like
  • Maybe so. Who knows? Why did the FDA allow the human trials to continue if they agree with your position?

     

    And - most important - what is your evidence that cancer at very high doses in rats is significant to the decision to approve a far lower dose in humans?
    23 Sep 2010, 02:58 PM Reply Like
  • Dr. Ritacca is correct - they should never have combined benign tumors with malignant tumors to reach SS.

     

    Fibroadenomas rarely progress to adenocarcinoma.The histologic features of the fibroadenoma influence the risk of breast cancer. The risk of subsequent breast cancer is slightly elevated only if the fibroadenoma is complex, if there is adjacent proliferative disease or if there is a family history of breast cancer. For the majority of women with simple fibroadenomas, there is no increased risk of developing breast cancer. In fact, without these conditions f a biopsy proven fibroadenoma is asymptomatic, then it can be left in place.

     

    References
    A prospective study of benign breast disease and the risk of breast cancer.London SJ; Connolly JL; Schnitt SJ; Colditz GA JAMA 1992 Feb 19;267(7):941-4.

     

    Risk factors for breast cancer in women with proliferative breast disease.Dupont WD; Page DL N Engl J Med 1985 Jan 17;312(3):146-51.

     

    Benign breast disease and the risk of breast cancer.Hartmann LC; Sellers TA; Frost MH; Lingle WL; Degnim AC; Ghosh K; Vierkant RA; Maloney SD; Pankratz VS; Hillman DW; Suman VJ; Johnson J; Blake C; Tlsty T; Vachon CM; Melton LJ 3rd; Visscher DW N Engl J Med 2005 Jul 21;353(3):229-37.

     

    In a study exploring the proper managment of fibroadnenomas they discussed the issue of fibroadenomas and breast cancer and their conclusion from a review of the literature was this "...women with noncomplex fibroadenomas and no family history of breast cancer were not at a greater risk of breast cancer...Malignant transformations in the epithelial components of fibroadenomas are generally considered rare. The incidence of a carcinoma evolving within a fibroadenoma was reported to be 0.002% to 0.0125%."
    (Ron Greenberg, MD,1 Yehuda Skornick, MD,1 and Ofer Kaplan, MD: Management of Breast Fibroadenomas, J Gen Intern Med. 1998 September; 13(9): 640–645)

     

    The incidence of fibroadenomas ranges from 10-15% from a survey of the literature through Medline.

     

    So I think it is established that transformation of benign fibroadenomas to adenocarcinoma is rare.

     

    So what is the point. The two major problems with the rat study results. First, the rats were given excessive and toxic doses of the drug which went beyond FDA's own guidance on 2-year carcinogenicity studies - which state: "It has been agreed that if a drug is only positive in rodents at doses above those producing a 25-fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans."
    In the nonclinical 2-year carcinogenicity study, sexually-mature SD female rats were given an oral dose of Lorcaserin that was approximately 82-fold greater than the proposed therapeutic dose for human use, per mean blood plasma mean AUC levels. The female rats were therefore dosed with Lorcaserin at significantly above the 25-fold ICH limit dose referred to above, taking into account the mean plasma AUC concentrations.
    Second is the interpretation of the interpretation of the carcinogenic data in the FDA briefing. . In the section entitled "Safety of Lorcaserin" (6th paragraph; Malignancies in Rats), the FDA states: "An excess number of malignant tumors developed in female rats with Lorcaserin at doses within 7-fold of the proposed clinical dose of 10mg BID." This conclusion is incorrect. The statement implies that statistically, the 10mg/kg/day female SD rat dose (7x dose group) was significantly different from controls. However, the only malignant tumor detected in the females given Lorcaserin at 10mg/kg/day was mammary adenocarcinoma, but its incidence was not statistically different from that in theof control rats (Table 4, NS). Based on findings in Table 4, the breast tumor incidence is only statistically different from untreated control rats if the different tumors are combined, but this is not a valid procedure because one of the tumor types is malignant (adenocarcinoma), the other benign (fibroadenoma). While it is true that benign and malignant tumors are commonly combined, this should only be done if the following criterion is fulfilled: "Benign and malignant neoplasms of a particular histogenesis are often grouped because the one is seen as a progression from the other" (Preclinical Development Handbook Toxicology 2008 John Wiley & Sons New Jersey Carcinogenicity Studies 424- 455).

     

    The combination of the benign tumors and malignant tumors gave an incorrect impression of increased risk of "cancer" - which is far from the truth. Dr. Alavi made the the statement that the fatal tumors were the result of the "tumors." When one recognizes that the rats that died from the fibroadenomas died from the mass effect of the tumor then the only 'ridiculous' conclusion when being concerned about human females is that they would allow this tumors to get so large - relative to the size they get in rats to kill them - that they would eventually die from 100-150 lb tumors. Fibroadenomas are easily detected in the cm range and therefore no woman would ever die from a fibroadenoma.

     

    So with all due respect to John Tucker, I would not be concerned to recommend this drug to my relatives - based on this data. The only conclusion that can be drawn when it comes to mammary tumors is that statistical significance can only be applied to the rats that recieved 82x multiple the clinical dose and even this data has no merit because of the toxic doses given.

     

    Daniel
    UCLA MD
    23 Sep 2010, 03:08 PM Reply Like
  • Just a few more comments on this, I should really turn off my web browser and get some work done.

     

    I continue to believe that a lot of the statements being made on this page are based on a misunderstanding what the term "statistical significance" means. I apologize that I seem to be insufficiently articulate to make my point more clearly.

     

    Maybe if I have time later I'll throw up some of the graphs I have made of total malignant tumor incidence in the rats vs lorcaserin dose on the instablog so you can see what I mean. (The people from the Yahoo board will kill me!) I find these graphs troubling.

     

    Daniel, I think you are probably correct that combining malignant and benign tumors in a single analysis is questionable. Is it possible they were grouped because the reviewer hypothesized similar biochemical causation (turning on the same growth and proliferation pathways) rather than because of a mistaken belief that they have a similar prognosis?

     

    Mike, I agree that giving massive doses of compounds to rats for 2 years is a lousy way of predicting whether small doses taken by people for 5 to 10 years will cause cancer. But no one wants to pay or wait for the results of studies using thousands of chimpanzees given clinical doses for 10 years. These studies (when properly performed at doses below the MTD) have been shown to have reasonable predictive power, and nobody has come up with a better, affordable alternative. They admittedly err on the side of finding carcinogenicity where there is none, rather than erring on the side of missing it where it exists, but isn't this how it should be?
    23 Sep 2010, 04:30 PM Reply Like
  • Whether the grafts look good or bad is not a vaid arguument.The only
    point I would be concerned about is the SS with 95% confidence.The other point is if this is prolatiin effect or a mechanism associated in rat brains,how do we control for prolactin.I'm afraid Arena has to come up with a better explanation why this is not relevant in humans or do a larger rat study
    23 Sep 2010, 05:44 PM Reply Like
  • John,
    Prolactin levels were double the controls and in the past with rats this has been an explanation why they develop carcinomas.Does anyone know why FDA wouldn't accept this theory?
    I tried calling investors relations but have not received a reply.
    24 Sep 2010, 11:57 AM Reply Like
  • Dr. Ritacca, with respect to males the FDA's most important argument seems to be that the increase in prolactin is not sustained on chronic dosing. In females, Arena was apparently unable to show a statistically significant increase in prolactin due to large inter-rat and time-of-day variability in prolactin levels, and so went to studies involving castrated female rats treated with exogenous hormones. The FDA did not think this was a realistic model of the conditions in which the tumors were observed in the 2 year study, and was not impressed by the amount of increase. Perhaps more importantly, they noted that dexfenfluramine, which does substantially increase prolactin levels in intact and castrated female rats, does not induce mammary tumors. This is apparently historical tumor data from the dexfenfluramine NDA, I did not see it in the briefing document.

     

    I hope this helps, not sure I have told you anything you don't already know.

     

    JT
    24 Sep 2010, 07:42 PM Reply Like
  • How do you think they'll explain the mechanism for the rat problen.What did the FDA toxicologist mean when he said,"there still is a path to approval"?
    When I read the literature on prolactin causing mammary tumors,I get conflicting stories.The FDA doesn't think prolactin caused this problem because of(1) lack of a prolonged elevation of prolactin from lorqcaserin,(2)haloper... caused elevation of prolactin but not tumors and(3) the in some of the statements made by Arena prolactin, dopamine and serotonin in the rats have shown to cause cancer.What is it?You can't have it both ways.Either prolactin does or does not cause mammary cancer.Am I missing a piece of the puzzle?
    25 Sep 2010, 10:47 AM Reply Like
  • My understanding is that certain compounds acting on dopamine pathways (antipsychotics in particular) have been approved in spite of causing mammary tumors in rats, based on the belief that the carcinogenesis is due to stimulating prolactin levels, and that humans are much less sensitive to the carcinogenic effects of high prolactin levels. I haven't dug into it much deeper than that.

     

    The data in the haloperidol package insert does not appear all that exculpatory:

     

    www.accessdata.fda.gov...
    25 Sep 2010, 02:16 PM Reply Like
  • Excellent analysis and rebuttal, Dr. Daniel, kudos to you!

     

    The question I have is can you somehow use this analysis to influence the FDA or Congressional Oversight Committees of various flavors to overturn this travesty of justice?
    23 Sep 2010, 06:28 PM Reply Like
  • The appropriate people are being sent this information plus additional arguments that are sustainable.
    Daniel
    UCLA MD
    24 Sep 2010, 08:38 PM Reply Like
  • Thank you for your efforts, Doctor.

     

    Besides being on the losing side of trade in ARNA, I personally was looking forward to lorcaserin approval because of the lipid results - I've suffered from high triglycerides all of my life (congenital problem), nothing out there has been able to drop them below 300, and I've tried everything from Lipitor/Trichor to garlic/fish oil. Adding a new drug to the arsenal available to doctors (and not being a statin) was a big deal to me.
    25 Sep 2010, 12:52 PM Reply Like
  • This smells like trouble big trouble, dont entangle in it. For 10 cent its worth a gamble but not more.
    23 Sep 2010, 11:45 PM Reply Like
  • Another know-it-all academic who refuses to see the man (or should I say woman, hint-hint) behind the FDA curtain. I suspect October 23 will be even more of a let down to you then November 3, James. I just hope you longs can pump this loser stock back up to 3-4 so I can short it (again.) Keep up the good work. PS, go over the the Yahoo ARNA board if you want to jump on the "write your congressman" bandwagon.

     

    Riddle:What do you call someone with a scientific background who thinks they know biotech investing? ROADKILL!!!
    24 Sep 2010, 07:16 PM Reply Like
  • John Tucker ..from his profile " currently works as a consultant in biomedical technology assessment."... Translated that means that John works for hedge funds and is paid to offer an opinion... I will leave it at that... The dosage that we're talking about is not relevant per the FDA's own documents.... FDA just approved Victoza a drug that was shown to cause cancer in rats (both male and female) at clinicaly relevant dosage... John, I assume you have not comented on that anywhere... Furthermore, even the FDA subsequently admited that the panel wasn't constructed to deal with the rat issue... Let's face it, the only reason this came out is Colman, and we all know by now why that was ..
    20 Dec 2010, 04:50 PM Reply Like
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