ARNA Investors

Obesity is a disease - AMA, Belviq launched, Ellie Wenker success story

2013-07-13T22:22:00.000-07:00

Arena Pharmaceuticals Reports on Launch of BELVIQ® (lorcaserin HCl) CIV for Chronic Weight Management in Adults who are

Overweight with a Comorbidity or Obese

 Arena Pharmaceuticals Reports on Launch of BELVIQ® (lorcaserin HCl) CIV for
 Chronic Weight Management in Adults who are Overweight with a Comorbidity or
                                    Obese

-- BELVIQ Available in US Pharmacies within One Week --

-- Arena Achieves $65 Million in Milestones and is Eligible for Additional
Payments Based on Product Sales --

Source:

http://invest.arenapharm.com/releasedetail.cfm?ReleaseID=769923

A.M.A. Recognizes Obesity as a Disease

The American Medical Association has officially recognized obesity as a disease, a move that could induce physicians to pay more attention to the condition and spur more insurers to pay for treatments.

In making the decision, delegates at the association’s annual meeting in Chicago overrode a recommendation against doing so by a committee that had studied the matter.

“Recognizing obesity as a disease will help change the way the medical community tackles this complex issue that affects approximately one in three Americans,” Dr. Patrice Harris, a member of the association’s board, said in a statement. She suggested the new definition would help in the fight against Type 2 diabetes and heart disease, which are linked to obesity.

Source:

http://www.nytimes.com/2013/06/19/business/ama-recognizes-obesity-as-a-disease.html

http://www.belviq.com/Consumer.aspx

Ellie Wenker Success Story

IMHO Ellie Wenker is a Belviq responder so please read her story in her blog and follow her progress along.

http://belviqdaily.blogspot.com/

Ellie's interview on Blogtalkradio.com

http://www.blogtalkradio.com/playgroundradio/2013/07/12/arena-pharmaceuticals-belviq-the-ellie-wenker-story

Formal way to request an investigation at the FDA

2013-07-13T21:03:00.000-07:00

This is a template to initiate a formal request for investigation regarding Lorqess's rat cancer issue mentioned on FDA Briefing document and during AdCom panel. Please Cut & Paste into Word document, sign, and send via certified mail to :

Office of Research Integrity

U.S. Department of Health and Human Services

1101 Wooton Parkway, Suite 750

Rockville , MD 20852

Please feel free to modify and/or enclose the online Petition as deemed necessary. Remember, there is a strength in number...

(Full Credit recognized and given to letthetruthring)

=====================================================

To: Office of Research Integrity

U.S. Department of Health and Human Services

1101 Wooton Parkway, Suite 750

Rockville , MD 20852

Request for Investigation of Research Misconduct

Allegation of Research Misconduct by Dr. Eric Colman (Respondent) in Review of NDA 22-529 (Lorcaserin hydrochloride)

The following is put forth:

Federal Regulation 42 CFR § 93 dealing with research misconduct applies to:

§ 93.102 (b)(1) allegations of research misconduct and research misconduct involving:

(ii) PHS supported biomedical or behavioral extramural or intramural research; and

(iv) PHS supported extramural or intramural activities that are related to biomedical or behavioral research or research training, such as the dissemination of research information;

Respondent is a PHS-supported researcher under 42 CFR § 93.102, 42 CFR § 93.221; 42 CFR § 93.222

Respondent is a Federal Drug Agency (FDA) employee and thus his work is directly supported by Public Health Service funds. He works for the Center for Drug Evaluation and Research. His activities in reviewing NDA 22529 qualify as “research” as they were a systematic evaluation designed to develop or contribute to specific knowledge relating broadly to public health by elucidating or confirming information about or the underlying mechanism relating to biological causes or diseases.

Federal Regulation 42 CFR § 93.103 defines research misconduct to include:

(b) Falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record.

Respondent’s written statements represent research misconduct as they do not accurately reflect the research

Complainant alleges in good faith that Respondent committed falsification by changing or omitting results such that the research was not accurately represented in the research record (FDA Briefing Document for NDA 22529). Such falsification occurred in the summary section discussing the safety of Lorcaserin, specifically the following paragraph:

“Malignancies in Rats: A number of malignant tumor types developed in rats treated with lorcaserin for up to two years. An excess number of malignant mammary tumors developed in female rats treated with lorcaserin at doses within 7-fold of the proposed clinical dose of 10 mg BID. Male rats developed malignant mammary tumors when treated with lorcaserin at doses 17-fold higher than the proposed clinical dose. Although the sponsor believes that lorcaserin-mediated increases in serum prolactin explain the excess risk for malignant breast tumors, FDA reviewers do not believe that the available data support this hypothesis. In addition to breast tumors, lorcaserin-treated rats had an excess number of malignant astrocytomas, squamous carcinomas of the subcutis, and malignant schwannomas. There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects in the phase 3 clinical studies.”

In the second sentence of the aforementioned paragraph, Respondent states “An excess number of malignant mammary tumors developed in female rats treated with lorcaserin at doses within 7-fold of the proposed clinical dose of 10 mg BID.” Malignant mammary tumors would only be any adenocarcinoma observed in the study. Respondent is a well-educated, medical professional, long familiar with the concept of statistical significance and long-familiar with the difference between benign tumors and malignant tumors. His statement about the excess number of malignant mammary tumors is patently false as there was no statistically significant excess of such tumors at the dose reported. Respondent has omitted significance levels provided to him by the study Sponsor for the incidence of malignant tumors at this level such that the research is not accurately represented in the research record (the FDA Briefing document)

In the third sentence of the aforementioned paragraph, Respondent states “Male rats developed malignant mammary tumors when treated with lorcaserin at doses 17-fold higher than the proposed clinical dose.” Again, Respondent is a well-educated, medical professional, long familiar with the concept of statistical significance. Only two tumors were seen at the reported dose level, a number that was far from statistically significant. Respondent has omitted significance levels provided to him by the study Sponsor such that the research is not accurately represented in the research record (FDA Briefing document).

In the 5^th sentence of the aforementioned paragraph, Respondent states “lorcaserin-treated rats had an excess number of malignant astrocytomas, squamous carcinomas of the subcutis, and malignant schwannomas.” Respondent recklessly or intentionally failed to mention that these results were only seen a dosage of 55 times the human dose. These three tumor types were only significant when the rats were given 55 times the human dose, and there were absolutely zero tumors for all three of these tumor types at 5 times the human dose. Respondent has omitted significance levels and dosage levels provided to him by the study Sponsor in reporting this finding such that the research is not accurately represented in the research record (FDA Briefing document). Further, Respondent has put forth a statement that is at odds with the FDA’s own May 2002 ‘Guidelines to Industry’ which indicates that “the highest dose to be included in a carcinogenicity study should be based on one of the ICH endpoints (referencing “Toxicity, Dose-Limiting PD Effects, Exposures 25 times Human AUC, Saturation of Absorption, Maximum Feasible Dose (MFD), or Limit Dose”). This Guidance is from Respondent’s own agency, and is guidance with which he undoubtedly is familiar. For Respondent to highlight a negative finding in a single sub-human species given 55 times the human level of a drug when the FDA acknowledges that the international standard is 25 times the human dosage underscores the extent of the alleged misconduct, i.e., the misrepresentation of the data submitted in NDA 22529.

In the 6^th sentence of the aforementioned paragraph, Respondent states “There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects in the phase 3 clinical studies.” This statement highlights Respondent’s inconsistency with regard to reporting results favorable to this drug application. Respondent has spent the whole tumor summary paragraph emphasizing non-significant data that casts the drug candidate in a negative light. In this instance the drug Lorcaserin evidenced fewer neoplasms (malignant or unspecified tumours) in a larger subject pool than did placebo (Table 97 of FDA Briefing document). Rather than state that Lorcaserin yielded a reduced number of tumors or that there was an “excess number” of tumors with the placebo, Respondent chooses the language “There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects”. Complainant agrees with this language and Respondent’s use of it here indicates he does understand the concept of statistical significance, and how the non-significant rat tumor findings should have been reported.

Federal Regulation 42 CFR § 93.104 requirements for findings of research misconduct:

A finding of research misconduct made under this part requires that— (a) There be a significant departure from accepted practices of the relevant research community; and (b) The misconduct be committed intentionally, knowingly, or recklessly; and (c) The allegation be proven by a preponderance of the evidence.

Respondent’s actions meet requirements for a showing of research misconduct

Respondent’s reporting of non-significant results, without qualification, as factual and relevant is a significant departure from accepted practices of the relevant research community. That non-significant findings are not to be reported as fact, especially without qualification, is so accepted throughout the medical research community that anyone who has taken a beginning statistics class accepts it as gospel. Indeed, a recent Journal of the Medical Association (JAMA) article questioned the motives of scientists that “spin” non-significant findings (JAMA. 2010;303(20):2058-2064.) Reporting of non-significant findings as fact, without any qualification, in a research record as important as an FDA brief for a new drug application, is a significant departure from accepted practices within the medical re4search community.

(b) Respondent’s misconduct was committed intentionally, knowingly, or recklessly. Respondent chose his own words in the Malignancies paragraph of the FDA brief. He understands the concept of statistical significance, as demonstrated by his failure to report the positive findings regarding neoplasms for human trials as anything other than “There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects”. Moreover, in reporting an excess number of three tumor types in male rats without indicating that this was only seen at 55 times the human dose, Respondent has put forth a statement that is at odds with the FDA’s own guidelines. May 2002 FDA Guidelines to Industry indicates that “the highest dose to be included in a carcinogenicity study should be based on one of the ICH endpoints and references. For Respondent to highlight in the FDA Brief a negative finding seen only in a single sub-human species at 55 times the human level when the FDA Guidance acknowledges that the international standard is 25 times the human dosage indicates that the misrepresentation of the data was done knowingly.

(c) A proper investigation will, by a preponderance of the evidence, indicate that Respondent did indeed commit such misconduct. The FDA brief was authored by him, and Respondent had full responsibility for its contents. These statements are not typos, they are summary declarations within an FDA briefing document intended to inform committee members and the public. Those statements were written knowingly and intentionally.

Addendum to Allegation

The recklessness of Respondent’s misreporting of the rat tumor findings is highlighted by the fact that within eight hours of the FDA Briefing document being released on September 14^th there were at least a ten media reports dealing with this brief such as the following from Reuters - FDA staff question Arena diet drug. All such media reviews highlighted the rat tumor data, and in a very negative fashion. All such media reports are a matter of public record and available to investigators.

The public record (Minutes of the meeting, interviews with hearing attendees) will further show that Respondent continued to show bias against this drug application at the Advisory Committee hearing itself in his statements there and in his failure to place an expert on the Committee that could speak to the significance of the rat data given that it was at odds with data from mice, monkeys, and humans and the testimony of the Sponsor’s nationally-recognized expert on the subject. The public record of the Committee proceedings will indicate that various panelists expressed a lack of understanding with regard to the rat tumor data.

Complainant requests a full and impartial investigation of this allegation of research misconduct by the Office of Research Integrity.

First Prescription Weight-Loss Treatment Approved by FDA in 13 Years

2012-06-27T23:03:00.000-07:00

NEW ERA BEGINS in the fight of obesity, long but worth fight.

Arena Pharmaceuticals and Eisai Announce FDA Approval of BELVIQ® (lorcaserin HCl) for Chronic Weight Management in Adults who are Overweight with a Comorbidity or Obese

-- First Prescription Weight-Loss Treatment Approved by FDA in 13 Years
-- Eisai to Launch BELVIQ in U.S. Following DEA's Completion of Scheduling Review

http://finance.yahoo.com/news/arena-pharmaceuticals-eisai-announce-fda-171300471.html

Media jumping on Lorcaserin/ARNA bandwagon

2012-05-12T21:44:00.000-07:00

Total 180 degrees shift

Video

http://video.cnbc.com/gallery/?video=3000089475

http://video.cnbc.com/gallery/?video=3000089703

http://abclocal.go.com/wabc/story?section=news/health&id=8657063

Artciles

http://www.cnbc.com/id/47385222

http://www.forbes.com/sites/matthewherper/2012/05/10/arena-pharmaceuticals-wins-big-whats-next/

http://www.bloomberg.com/news/2012-05-10/arena-wins-fda-advisory-panel-backing-for-obesity-pill.html

http://www.cbsnews.com/8301-505245_162-57432412/ahead-of-the-bell-arena-pharma-shares-soar/

http://www.cnbc.com/id/47378621/Arena_and_Eisai_Expand_Marketing_and_Supply_Agreement_for_Lorcaserin_New_territories_include_Canada_Mexico_and_Brazil

http://money.msn.com/business-news/article.aspx?feed=AP&date=20120510&id=15096319

http://online.wsj.com/article/SB10001424052702304070304577396501536786054.html

http://www.downeyobesityreport.com/2012/05/fda-panel-approves-arenas-lorcaserin/

This list is courtesy of "sktfilm" from YMB

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=298734&mid=298734&tof=4&frt=2

FDA BD Synopsis by Dr. Daniel Lopez

2012-05-09T18:57:00.000-07:00

FDA BD Synopsis by Dr. Daniel Lopez Link to this article on YMB

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=281086&mid=281086&tof=2&frt=2

Here is a summary of the FDA BD First I must disclose that I didn’t have the time to do an in depth analysis of the 248 pages but I did read it all. The following is a summary of key findings: Valvulpathy The receptor potency study provides supportive evidence that lorcaserin is not a valvulopathogen at the clinical dose of 10 mg twice daily. This in addition to the echocardiogram studies provides evidence that there is no valvulopathy risk. Carcinogenicity KEY point: FDA is satisfied that prolactin is the MOA for the higher incidence of fibroadenomas. As I have mentioned many times, prolactin, even in small doses, is responsible for increased incidence of fibroadenomas and the FDA examiner concurs. KEY point: PWG findings completely negated the rationale for combining benign and malignant tumors CRL #1: Diagnostic uncertainty PWG results definitive and therefore confirms that the only cancer risk is at the 100mg/kg dose of lorcaserin providing a safety margin of 24-fold and the FDA is satisfied this confers no human risk and therefore no MOA needed. CRL#2 Exposure-response relationship for lorcaserin-emergnet mammary adenocarcinoma Increased incidence of lung metastasis in the mid and high dose groups is equivocal, with no difference between control and low dose groups. What they didn’t say is important. Though there was an increase in lung mets in the mid and high dose the fact that was left out is that there were no statistically significant increases in other tumors found in rats. These tumors may have been responsible for the lung mets but because there was no statistically significant increase in other types of tumors they basically are stating this is not an issue With regard to increase in fibroadenomas they did make that statement that the clinical risk due to these tumors is less than adenocarcinoma. They almost made the statement that a tumorigenic MOA was not necessary. So people let’s put to rest the idea of a 12 month study – let it RIP. However, they did evaluate the MOA presented by Arena and though the results of the prolactin study were not impressive, they were sufficient to satisfy the proposal by Arena that prolactin was the MOA. However, as I mentioned, they intimated that the MOA was probably not necessary to determine human risk. And again, they agree that it only takes a minimal increase in prolactin to explain the increased incidence of fibroadenomas. Sound familiar to those who have read my posts? CONTINUE The Science Will Prevail Daniel UCLA MD Links to BD documents
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303198.pdf

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303199.pdf

Lawsuit filed by ARNA investors against Adam Feuerstein

2012-04-11T20:41:00.000-07:00

ARNA shareholders filed a lawsuit against Adam Feuerstein of thestreet.com

http://www.thestreet.com/story/11489090/1/vivus-obesity-drug-delay-is-good-and-still-means-arena-pharma-rejection.html

Link to defamatory lawsuit

http://www.jdlawfirm.org/uploads/3/0/6/0/3060978/letter_to_adam_feuerstein_to_cease_and_desist_from_making_false_fraudulent_and_defamatory_statements.pdf

Some informative and interesting comments in response to AF's blog post

andybaron - Adam, please take a few minutes to do some DD on Arena. A good place to start is their last 10-K; the discussion of the new data they've submitted to the FDA begins on page 5. You'll learn that a group of 5 pathologists, chosen by Arena and the FDA, found no increase in malignant mammary tumors over placebo except in the highest dosage group of rats that received 82 times recommended human dose.

Benign mammary tumors were increased in rats at all dosages. You can quibble over whether Arena was able to present convincing evidence that this was mediated by prolactin, which causes tumors in rats but not humans. I think the evidence was convincing, especially because blocking prolactin also eliminated tumor formation. But, in any case, the FDA did not express any concern over benign tumors, which do not progress to malignant tumors and present no serious health risk in humans.

It is true that mean placebo-adjusted weight loss was only about 3%, but that is partly because the placebo group did very well, and also because this includes those who dropped out of the study (as in all weight loss studies to date, about half the patients dropped out before completing the study). The weight loss for those who completed the studies averaged about 8% for those taking lorcaserin, and all the measured bio markers for CV and glycemic health improved significantly over placebo. The weight loss for Qnexa completers taking the recommended middle dose was only about 2% higher, and their bio marker improvements were no better, or worse -- although a head-to-head study would be needed for a meaningful comparison.

Lorcaserin has been proved to be highly selective for the 5-HT2C receptor, which affects satiety, over the 5-HT2B receptor, which affects heart valves. Echo-cardiograms performed on all 8000 of the patients in Arena's phase III studies showed no evidence of increased valvulopathy in those taking lorcaserin. On the other hand, fenfluramine had greater affinity for the B receptor. And, by the way, fenfluramine caused no more weight loss than lorcaserin when taken alone, even though fen-phen caused more weight loss than Qnexa.

These facts are readily available and have been presented to you many times. I'm frankly baffled about why you refuse to acknowledge them.

phillydan55 - Adam, Adam, again with the heart valve damage. There is none. You allude to data when you want to make your efficacy argument but when it comes to the valvulopathy issue, you ignore the data of the results from the study. Again, since you like to talk placebo, basically the placebo group had just as many instances of VHD as the drug group across all three studies. In addition, the percentage of patients showing a signal for VHD disease in both the placebo and drug groups was a bit over 2%, which is below the percentage for the general population.

The FDA never raised VHD as an issue in their CRL to Arena. Yes, fen is a distant cousin like maybe a 10th or 12th cousin. The truth is that Fen is known to affect several of the 2x receptors and particularly liked the 2B receptor which is the receptor identified by real scientists that caused the valvulopathy in people taking Fen-Phen. Lorcaserin has been shown in several studies that is has little to no affinity for the 2B receptor, in fact 104 fold.

Back to the efficacy. You always keep forgetting to mention the fact that lorcaserin did meet the FDA's defined guidelines for efficacy. Talk the placebo adjusted tango, all you want but lorcaserin is proved in it's studies on a categorical basis (that other criteria the FDA uses but you seem to think doesn't exist) to have shown weight loss of 5% or greater in 48% of people in the studies and is twice the placebo amount. In addition, lorcaserin has been shown to cause a weight loss of greater than 10% in 35% of completers and 25% of completers lost 16.7% of their weight.

In addition, when approved, like Qnexa, doctors will use phen in combination with lorcaserin to achieve safer and greater weight loss than Qnexa. So take that and put it in that little pipe you keep and smoke it, yes Adam, smoke it because you and your lying article have been smoked.

It is going to be fun when you and your buddy man Gekko creep are smoked on May 10th and lastly on June 27th. Victory for the world of the obese who will now have a safe weight loss drug that will help them lose weight and for type 2 diabetics reduce their A1C levels greatly. Defeat for the evil ones like Gekko and you.

BTW, I hear you both look good in orange and maybe they will let you share a cell....LOL!

Tran - Adam your poor logic astounds me. How well did the 3-month delay go for the investors of MNKD? Just because they issued a delay does not mean they agree to approve it. You who have a job to watch these things should know that! It just means a delay. It could be a delay to figure out how to handle REMS. Or it could be a delay because, after all, they pushed OREX back at least 4 years by asking they bring CV studies before approval, and now they have to figure out how to approve Qnexa without asking the same thing. Remember OREX got a favorable panel. OREX representatives were at the Qnexa panel to express their disgust at the FDAs double standards. Or they can't figure out to make a meaningful Qnexa REMS that can be easily circumvented by taking substantial equivalent generic doses of Topamax and Phentermine? I admit I am stumped by that one too. They agreed to restrict access to the drug so severely that they will encourage MDs to write the generic components. Maybe they have to decide whether to lift the stricture on Phentermine? Remember the FDA asks doctors to limit Phentermine administration to 12 weeks maximum. But with Qnexa people will take it for years. What should they do about Phentermine monotherapy? Expand access or be hypocrites and leave it as is? And if they expand access, what does that say about their so called "concern for the welfare of patients"? Isn't the reasons they put restrictions on Phentermine because of CV issues? So why suddenly should they fall in love with a drug that gets all of its kick from Phentermine? Seriously. The Qnexa trials were not well powered, nor did they even test for, CV issues. They split the drug into 3 doses and split the trials into 4 (high dose, mid dose, low dose, placebo) so there is no way they were powered well to determine serious AEs. If 1 in 1000 have heart attacks (as some did on the Qnexa trial) how will they know? One person on the panel questioned their methodology, eg the high rate of dropouts could be because of increased Heart Rate, thereby giving bias to the results. Combined with such small trials it is inconsciounable that they approve Qnexa without more aggressive CV testing.

TomJones45 - From Mo_Money_2make on IV board" Yes.

Adam is wrong as much as he is right.
This mornings piece is nothing more than a quick poke to ARNA longs
and fuel to light VVUS up. Hedge fund friends of Adam are making some
coin playing the volatility. He is so confident that a 3-mo delay =
approval but he has no clue. MNKD's 3-mo delay resulted in a CRL. It
just means the FDA hasn't figured out how to approve it with a complete
REMS. Will they approve it in 3-mo? Maybe or Maybe Not. Adam has no
clue and the FDA probably doesn't definitevely know yet. I think
Colman wants it approved but they still have to come up with a
reasonable REMS. Not an easy task.

Adam's
comments around ARNA speak for themselves. He believes ARNA causes
tumor in rats. He also just looks at the 3% placebo adjusted ITT-LOCF
mean weight loss but doesn't mention the positive improvements on
co-morbiity factors particularly the impact for diabetics.

But
the FDA may not either. They may still just focus on the 3% placebo
adjusted number and don't care about the rest. Even though it meets
their guidelines, they may not want another weight loss drug approved
even with pressure to approve one. None of us knows until it happens
and that is why the stock trades like it does and will go up 300% from
here with a positive AdCom or crash by 80% without one.

AF
doesn't deserve responding too. He doesn't give balanced reporting at
all and as such, has little credibility except with some real
investors. Bank of America, Goldman, Wells, Morgan Stanley, Jefferies,
etc. put ZERO weight into what AF has to say as do the hedge funds that
are trading ARNA. Retail shouldn't either."

catfishcoon - Just a simple question for you adam. If you are married, and your wife was childbearing age, and obese, and there was 2 different pills that could offer help , one of which worked slowly, and the desired weight loss could be lost in 12 months, and that pill was safe with no side effects, the other pill worked quicker, and the desired weight loss could be achieved in 6 months, however, with that pill, there was a potential of serious side effects that could harm the person taking it and also harm the fetus. Which of these would you advise your wife to take?

murry - Hey Adam,
Congrats on your call (or your "institutional traders" call) on a qnexa delay/ extension for fda rems review. It was spot on! I do find it a little strange that your trader seemed to have had that info (hunch) before the rest of the investment community. Maybe it was a good guess, maybe not. This is why the majority of people are scared to death of the stock market and feel that its totally rigged and the big houses are the only ones that make money at the expense of the individual investor. Big institutional traders seem to always have great info before the general public.

I do follow you (as many do based on the fact that arna tanked today on your article) and I gotta admit I am a little shocked by how absolutely positive you seem to be regarding ARNA being denied. I must admit I sold my Arna I had this morning immediately after reading this article and the previous article on top fda approval gurus opinions on vvus approval. Loved the bonus question at the end of that article asking if the guru's felt arna would be approved. Just not sure why it was included.
The timing is curious, only because you have never really said much about ARNA until the last couple articles.

I generally respect your writing and feel that your very informative. Im just uncomfortable with this articles timing and the lack of any real stats or info to back up such a superior judgement. Im not sure if you were off when you wrote it but after reading it I really thought your column may have been hacked by someone else. Just didnt seem like your writing.

I realize that The Street in an investment web site and your job is to inform those investors but im not sure we want to know how close you are to institutional investors and their information. Not saying you did anything wrong. Just saying it does not sound kosher. Maybe Im wrong. Im sure I will thank you later for helping to convince me (been on the fence) to sell my ARNA and save $$$.

Keep em coming. Just please give us some DD to back up what your saying if your gonna make such absolute predictions.

Thanks

Letter to Dr. Woodcock by Obesity Care Continuum(OCC)

2011-09-24T08:54:00.000-07:00

With a combined membership of over 100,000 healthcare professionals and patient advocates, the Obesity
Care Continuum is dedicated to promoting access to, and coverage of, the continuum of care surrounding the
treatment of overweight and obesity. The OCC also challenges weight bias and stigma oriented policies –
whenever and wherever they occur. The OCC is a coalition of the Obesity Action Coalition (OAC), the Obesity
Society (TOS), the American Dietetic Association (ADA), and the American Society for Metabolic and Bariatric Surgery (ASMBS).

Please read the letter in its entirety at

http://www.obesity.org/images/pdf/letter_to_fda.pdf

Another set back for Obesity fight - Amylin halts obesity drug study

2011-03-16T22:16:00.000-07:00

It is a sad day I must say, Amylin and Takeda halted their Obesity drug study. This might be good news for Arena but certainly bad news for Obese population that are running out of options.

Article from Minyanville

FDA are you listening? Diet and Exercise are not enough to fight obesity we need more options fight this battle.

Why the Astrocytoma Margin of Safety Requirements Will be Satisfied - By Dr. Daniel Lopez

2010-12-24T02:36:00.000-08:00

Response to the FDA’s CRL Request for Clarification of the

Astrocytoma Exposure Margins

1. INTRODUCTION

The following is a response to the FDA’s request in the CRL presented to Arena Pharmaceuticals to “provide additional data and information regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.” In the FDA briefing document section entitled: “Genotoxicity and Carcinogenicity Assessment for Lorcaserin” (6^th paragraph; Brain Astrocytoma), Dr. Alavi (FDA’s nonclinical pharmacology/toxicity presenter) concludes:

“Given the absence of brain-to-plasma partitioning data in human subjects, the most conservative approach is to disregard estimated brain levels and rather calculate safety margins based on plasma drug levels, which is known for rats and humans. The safety margin to the non-tumorigenic dose would then be 5x, with brain tumors occurring at doses of lorcaserin 17x higher than clinical exposure.”

Dr. Alavi reached an incorrect conclusion when determining the safety margins for lorcaserin. His rejection of the brain-to-plasma partitioning based on the absence of human data is not supported by the scientific literature. Furthermore, his proposal to use plasma drug levels from rats and humans as the basis for the calculation is flawed.

First, it is true that there is only a limited amount of “brain-to-plasma partitioning data” available for humans, but it is incorrect to disregard estimated brain levels to calculate the safety margins for lorcaserin. As we will show, there is sufficient information in the Brain Drug Discovery literature to contradict Dr. Alavi’s statement. Second, it is not scientifically appropriate to “calculate safety margins based on plasma levels.” To do so in the way Dr. Alavi proposes would assume that plasma pharmacokinetic profiles are similar between rats and humans, when various studies have shown that there are in fact marked differences between the two species that affect comparisons of plasma concentrations of unbound drugs. Dr. Alavi’s proposed method to use trans-species comparisons of plasma drug concentrations also completely ignores the blood-brain barrier, which exhibits very low paracellular permeability and contains multiple bi-directional and/or uni-directional drug transporters. Thus, there are serious flaws underlying Dr. Alavi’s proposed method to determine the extent of drug penetration to the brain, and hence to determine the safety margins for lorcaserin with regard to brain astrocytomas. Although there are acknowledged limitations to estimating brain concentrations using the blood-to-plasma ratio, this method is a scientifically sound way to determine the margin of safety, based on what is available in the literature.

The intent of this paper is therefore to present the relevant literature regarding the reliability of available in vivo and in vitro tools, and the appropriateness of using animal models for determining drug concentrations in the brain. Providing this additional data and information should allow a better estimation of astrocytoma exposure to lorcaserin as requested by the FDA. Evidence-based studies will be the basis for recommending what methodology is the most reliable and the most feasible for the required purpose.

2. THE ISSUE: ASTROCYTOMA EXPOSURE SAFETY MARGINS

Here, we will review the facts about the Lorcaserin 2-year rat carcinogenicity study, in respect of astrocytoma incidence. The relevant data from both male and female rats are presented in Table of the FDA Briefing Document in the section entitled: “Genotoxicity and Carcinogenicity Assessment for Lorcaserin” (Brain Astrocytoma):

Table 11: Incidence of brain astrocytoma in 2 yr rat study,

main study groups (Control n=65, 10mg n=65, 30mg n=65, 100mg n=75)

Lorcaserin dose, mg/kg/day

Control 10 (5-fold) 30 (17-fold) 100 (55-fold)

Males 1 (1.5%) 0 4 (6.1%)NS 8 (10.7%)SS

Lorcaserin dose, mg/kg/day

Control 10 (7-fold) 30 (24-fold) 100 (82-fold)

Females 0 2 (3.0%) 0 1 (1.3%)

It is important to note that there were no drug related tumors in mice. In female rats, there was no statistically significant increase in astrocytoma incidence even though the Lorcaserin dose used in the high dose (HD) group was 82-fold that intended for humans. Despite concluding that the rat astrocytoma lineage was unresolved^{^[1]} and although a plausible tumorigenic mechanism was not identified, Dr.Alavi decided that human risk assessment for Lorcaserin would then be based on the difference in exposure between the tumorigenic dose in rats and the clinical dose.

Although Dr. Alavi states that it is more appropriate to compare the distribution of Lorcaserin in the CNS of rats and humans than to compare plasma drug levels, he then summarily rejects his own assertion and recommends that the safety margins should be calculated based on the plasma drug levels. Dr. Alavi agrees that it is reasonable to believe that brain partitioning in humans is better mimicked in monkeys than rats, but he then argues against the reliability of this method, based on his assumption that there are no human data to substantiate the belief. This point is important for the following reason: If it can be shown that brain partitioning in monkeys can be extrapolated to humans, then a reasonable margin of safety can be calculated from Tables 13 and 14 of the FDA Briefing Document in the section entitled: “Genotoxicity and Carcinogenicity Assessment for Lorcaserin” (Brain Astrocytoma):

Table 13: Brain partitioning of lorcaserin in rats and monkeys
Species	Day of sampling	Brain to Plasma ratio (based on AUC)
		Range	Average
Rats¹	Day 1	13x - 35x	26x
	Day 14	24x - 35x	29x
Monkeys²	Day 1	10x - 23x	15x
	Day 14	8x - 12x	10x
Humans	--	Unknown

1Data source studies PDR-08218, 080097, & 08014. ²Data source study ARN-20080419.

Table 14: Estimated Safety Margins to Astrocytomas, based on estimated brain exposure to lorcaserin
Estimated Brain Exposure in Male Rats, ug*h/ml		Multiple to Estimated Brain Exposure in Humans at Clinical Dose (10mg bid)
10mg/kg (No brain tumors)	30mg/kg (brain tumors)	10mg/kg (No brain tumors)	30mg/kg (brain tumors)
115 - 168	405 - 591	11x - 17x	40x - 59x

Estimated brain exposure in rats assumes 24x - 35x brain: plasma partitioning

Estimated brain exposure in humans assumes 10x brain: plasma partitioning.

It can be estimated from the above data that the safety margin for the non-tumorigenic Lorcaserin dose (i.e., where there are no brain tumors are present) would then be 17 x the clinical dose (10mg bid or 140 mg per day) with brain tumors occurring at doses of lorcaserin 59x higher than clinical exposure (1180 mg per day). Dr. Alavi rejects this calculation and recommends disregarding the estimated brain levels; his preference is instead to use the rat and human plasma levels to calculate the safety margin dose.

The literature reveals that brain partitioning in monkeys can, in fact, be used reliably. First, the blood-brain barrier is well conserved across vertebrate species. As an example “functional characteristics of these membranes are basically similar in all vertebrate classes” (Cserr HF 1984)^{^[2]}. Second, there is an excellent correlation between unbound drug brain fractions across species which is indicative of a high degree of conservation of the CNS environment (Summerfield, et al. 2008).Furthermore, various case studies demonstrate that brain tissue binding in homogenates used to determine the extent of brain drug penetration is comparable across species (Summerfield, et al. 2008). Shen presented evidence that no significant species differences occur in CNS disposition (Shen, Artru and Adkison 2004). In a study of CSF and plasma free concentrations for the determination of brain free concentration, the author concluded, “CSF penetration studies in animals can serve as predictive models in human drug development” (Liu, Smith, et al. 2006). With regard to cynomolgus^{^[3]} monkeys there is an extensive library of data that “genes expressed in cynomolgus monkey are highly conserved throughout primate evolution, and that virtually all had human homologs” (Osada, et al. 2001). The cynomolgus monkey is widely accepted to be closely related to humans and that, compared to rodents, they “exhibit greater similiarity to human physiology, neurobiology, and susceptibility to infectious and metabolic diseases (Gibbs, et al. 2007). The cynomolgus monkey is used extensively “in drug metabolism studies, because of its evolutionary closeness to humans” (Uno, et al. 2010) as evidenced by the similiarity of the respective genomes “with an average human-macaque sequence identity of ~93% (Gibbs, et al. 2007). These findings would be consistent with the FDA preclinical recommendations regarding the relevance of of drug toxicities in animals to humans:

“Another integral part of preclinical safety evaluation investigates the relevance of drug toxicities to humans. Toxicological findings often occur in some animal species, but not others. An animal species exhibiting similar drug profile (pharmacology and pharmacokinetics) to that of humans will be considered more relevant to humans. Toxicologicial findings in these relevant species will be given more consideration. When there is a lack of evidence of human relevancy among animal species, toxicological findings in the most sensitive species will then be given the most consideraton.”^{^[4]}

We also note that the FDA was involved in every step of the product development program,

including the early ones that are most relevant here. The animal studies were presented to the FDA, which was therefore informed about the details of, and rational for, the planned study.

Positron emission tomography (PET) has enabled drug distribution to be studied in the living brain, including human brains. The cynomolgus monkey is the primary animal model used in PET studies to determine CNS drug and radioligand tracer distributions for use in humans.^{^[5]} However, a complication of PET studies is the need to develop radio-labeled versions of drugs, which is not always possible on technical grounds. The assessment of brain concentrations of drugs in animal models using this imaging technique is further complicated by the possiblility that “labeled metabolites may complicate the interpretation of brain concentrations” (Eyal, Hsiao and Unadkat 2009). Although this field is promising it is still in it’s infancy. In the following sections, we will address the following questions: 1) How should the brain-to-plasam ratio (K_p) be used to assess brain penetration? 2) What are the most reliable and practical in vivo and in vitro methods, using animal models, to determine the extent of CNS drug penetration? 3) Is it reliable to use plasma drug levels to assess brain penetration and drug margin of safeyt?

3. HOW TO USE THE BRAIN-TO-PLASMA RATIO (K_p) TO ASSESS BRAIN PENETRATION

3.1 The Blood-Brain-Barrier and Central Nervous System (CNS) Physiology

The brain is separated, and protected, from the systemic circulation by two barriers – the blood-brain barrier (BBB) and the blood-cerebrospinal-fluid barrier (BCSFB). The BBB is a neurovascular unit (Neuwelt, et al. 2008) comprised of three cell types – endothelial cells, astrocytes, and pericytes. The capillary endothelium of the BBB is not a passive membrane, but rather it is an active organ that limits brain exposure to systemic substances through a network of tight junctions that are fundamental to how the BBB maintains homeostasis. All substances regardless of their chemical nature (e.g., ions, solutes, hormones) have to traverse this membrane, whose function is to “keep this traffic under control” (Liu, Chen and Smith 2008). Most of these subtances enter the brain by simple transcellar diffusion via a concentration gradient between the blood and brain (Di, Kerns and Carter 2008). It has been estimated that “98% of all small molecule drugs cross the BBB only negligibly, and miniscule amounts of large molecule drugs cross the BBB” (Neuwelt, et al. 2008). The BBB therefore limits the access of drugs to the brain interstitial fluid (ISF)^{^[6]}. The endothelial cells of the BBB differ from those in the rest of the body by lacking fenestrations and by having only sparse pinocytotic vesicular transport properties that, together minimize paracellular transport (Shen, Artru and Adkison 2004).

Protein Binding

Metabolism

The BBB is not only metabolically competent, it also contains transporters that regulate the influx and efflux of endogeneous and exogenous compounds (Hammarlund-Udenases, et al. 2008). Drugs must not only first traverse the blood-brain barrier, they then have to remain within the brain for long enough to act at the target receptors. Efflux transporters are outwardly directed and act to remove compounds from the brain. There are at least six active efflux mechanisms in the BBB, the most prominent being Phosphorylated Glycoprotein (P-glycoprotein; P-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters (Alavijeh, et al. 2005). The main function of this efflux transporter is to remove free drug from ISF and return it to the systemic circulation (blood) or CSF (Jeffrey and Summerfield 2007). Conversely, some compounds pass through the BBB into the brain via facilated transport mediated by an inwardly directed, active influx mechanism. This is described anatomically by an expert reviewer in the Pharmaceutical Research journal: “To transverse the BBB, the compounds need to pass both the luminal (facing blood) and the abluminal (facing brain ISF) membranes of the endothelial cells (Hammarlund-Udenases, et al. 2008). Overall, metabolic processes and passive and actively facilitated transport properties at the BBB all affect the availability of drugs within the brain. Furthermore, the degree of tissue binding also differs between plasma/blood and the brain (Fig. 1).

Figure 1 Multiple mechanisms that affect brain penetration of molecules

Any description of the BBB would not be complete without describing the physiology and anatomy of the CSF^{^[7]}. The CSF is separated from the blood by the blood-cerebrospinal fluid barrier (BCSFB), which is formed by a continuous layer of polarized epithelial cells that line the choroid plexus. Of particular note is that the BCSFB is less quantitatively important than BBB transport in respect of most drugs that partition into the brain. Although there have been several reports on the use of CSF as a surrogate for the measurement of unbound drug concentrations in the brain (Liu, Smith, et al. 2006; Lin 2008; Liu, Chen and Smith 2008; Liu, Van Natta, et al. 2009;) it is not yet clear whether ISF and CSF concentrations can be accurately compared. Indeed, there are several reasons why ISF and CSF concentrations may differ (Shen, Artru, and Adkison 2004): 1) the ependymal lining the ventricles allows diffusional exchange from the CSF to the brain interstitium and the contribution of this exchange to the overall distribution of drugs is likely to be small; 2) the exchange between ISF and CSF is only diffusional (there are no facilitated transport mechanisms); 3) this exchange is counteracted by bulk flow of brain ISF to the CSF; 4) the diffusion distance from the CSF to most brain tissue is also considerably further than between the brain capillaries; 5) the concurrent transport of a drug across the BBB is likely to have a dominant effect on brain tissue concentrations after systemic administration because of the large area of the BBB and the short distance between brain capillaries. For these reasons, I will limit my discussion to the use of unbound and bound drug concentrations in brain homogenate as a surrogate for determining the same parameters in the living brain. It will be shown that this is the preferred and most reliable method to use for the present purpose. Of note is that the multiple mechanisms described above that affect the penetration of drugs into the brain are the main reasons why plasma-to-plasma comparisons should not be used to determine safety margins for CNS tumors, contrary to Dr. Alavi’s recommendations. In summary, P-gp substrates control the efflux and influx of compounds across the BBB; how a compound binds to proteins in the blood or plasma can significantly influence how much of it is present as a free entity in the blood; a compound that binds strongly to blood and plasma constituents could penetrate very poorly into the brain.

3.2 BBB Methodologies used in drug discovery

An excellent overview comparing the in vivo and in vitro models that have been developed to estimate brain penetration and exposure parameters can be found in Di, Li, Edward H Kerns, and Guy T Carter. "Strategies to assess blood-brain barrier penetration." Expert Opinion on Drug Discovery 3, no. 6 (2008): 677-87. Here I now summarize the methodologies used to determine the extent of brain drug penetration, highlighting their limitations and identifying the most current and reliable method.

3.2.1 Free Drug Hypothesis

This is the underlying principle that guides preclinical and clinical pharmacology. It is expressed in two parts. Part I states, “at steady state, the unbound drug concentration in plasma is the same as that in target tissues (e.g., brain, liver, muscle) when there are no transporters involved in the distribution process. Part II states, “the unbound drug at the site of action is the species that exerts pharmacological effects” (Di, Kerns and Carter 2008). As I shall show below, the unbound brain concentration is the most useful parameter for determining the extent of brain penetration. It is important to note that “the free drug hypothesis is supported by measurements, using the microdialysis technique, of the unbound drug concentration in the brain or other tissues and comparison with unbound concentration in plasma” (Lin 2008)^{^[8]}. Furthermore “it has been demonstrated that unbound brain drug concentrations most accurately predicted in vivo pharmacological activities for centrally active compounds” (Di, Kerns and Carter 2008). The most current thinking in the drug discovery field is to measure the concentration of unbound drug in the brain as the most reliable predictor of in vivo CNS drug penetration. As we shall see later, the total and unbound plasma and the total brain drug concentrations can be determined and be used as surrogates for estimating the brain penetration of a drug. The methodology to determine free drug concentrations involves the use of a brain homogenate in conjunction with equilibrium dialysis. The latter is an in vitro K_pdialysis method, which will be discussed in greater detail below.

3.2.2 In vivo methods for brain penetration

3.2.2.1 Brain perfusion assay. These assays are used to determine the rate of brain penetration and in situ brain perfusion. They are not commonly performed in drug discovery studies because they do not yield the concentration of unbound drug in the brain. Furthermore, the assay can be adversely influenced by the nonspecific binding of highly lipophilic drugs to brain tissue.

3.2.2.2 B/P ratio determination (K_p). This procedure will be discussed in more detail below.

3.2.2.3 Determination of CSF concentration. This method is not always useful as a surrogate way to determine the unbound drug concentration in the brain, because it is not always accurate. The limiting factor is the influence of efflux and influx transporters, which affect any estimate of brain drug concentration if equilibrium conditions are not established. In a recent study using CSF to assessing CNS exposure the author concluded, “CSF can only serve as a good surrogate for drugs that have good membrane permeability, but are not P-gp substrates…for drugs that are P-gp substrates or have poor membrane permeability, CSF cannot be used as a surrogate for assessing CNS exposure” (Lin 2008). In his study comparing unbound drug concentration in brain homogenate and CSF, Liu explains: “Because the drug transporters at the BBB and BCSFB are different, the C_CSF(CSF concentration of drug) is not necessarily identical to the interstitial fluid” (Liu, Smith, et al. 2006). The discussion on CSF above is also relevant.

3.2.2.4 In vivo microdialysis. Microdialysis is a useful way to measure unbound drug concentrations in the brain, but it is not commonly used because of the following reasons: 1) it has a low throughput;^{^[9]} 2) it is resource consuming; 3) it is labor intensive; 4) non-specific binding of highly lipophilic compounds to the dialysis membrane can cause a low recovery of the drug.

3.2.3 In vitro assays for brain penetration

3.2.3.1 PAMPA-BBB. This method is included in the BBB permeability assay category; it is limited by a lack of BBB transporters because an artificial membrane is used.

3.2.3.2 MDR1-MDCKII and cell-based monolayer transport assays. Monolayer transport assays are useful tools for assessing the rate of brain penetration but do not measure the extent of brain uptake. They are designed to measure BBB permeability (they account for P-gp efflux), and so would not be useful for determining the rat astrocytoma exposure margins.

3.2.3.3 In vitro B-P (K_p) dialysis. This method will be discussed in detail below.

3.3 Brain-to-plasma ratio (K_p)

The brain-to-plasma ratio was the method used to estimate the brain concentration of Lorcarserin in rats and monkeys in the carcinogenicity studies. The traditional K_pratio is based on a crude homogenization of brain tissue; it is expressed as the partition coefficient describing the total brain to total plasma concentration ratios.

The intent of the following discussion has its basis in Dr. Alavi’s statement to “disregard estimated brain levels and rather calculate safety margins based on plasma drug levels”^{^[10]} The literature suggests that although the K_pratio has its limitations, it remains the method of choice in CNS drug discovery programs, even to this day. It is unclear on what basis Dr. Alavi decided to disregard the brain-to-plasma levels, because the K_pratio “has been the in vivo gold standard in the industry and is routinely used to determine brain exposure for drug discovery programs” (Di, Kerns and Carter 2008). Humans have never been subjected to brain-to-plasma partitioning. All the results have been derived from animal experiments, and they are used in preclinical studies to evaluate potential CNS drugs. Using plasma levels exclusively to calculate safety margins is not supported in the literature. Not only did a Medline search fail to find any studies that used plasma-to-plasma concentration ratios to determine the extent of drug penetration into the CNS, not one study in this paper’s bibliography mentioned its use for this purpose.

In contrast, the following is a brief compiliation of quotes in the literature regarding the merits of the K_pmethod: 1) “K_p,brainis the most widely used in vivo parameter for assessing the extent of CNS distribution” (Kalvass, Maurer and Pollack 2007); 2) “K_phas been the most widely used parameter to evaluate and optimize brain penetration in drug delivery” (Liu, Chen and Smith 2008); 3) “Total brain concentrations (expressed as the K_pratio) have historically been the most common method of measuring CNS exposure” (Hammarlund-Udenases, et al. 2008); 4) “A wide variety of models have been developed over the years to predict blood-brain-barrier (BBB) penetration, most of them focused on predictiong total concentrations of drug and then expressing this as a brain-blood (or plasma) ratio” (Jeffrey and Summerfield 2007); 5)”The brain-to-plasma concentration ratio (K_p) is the most commonly used parameter for measuring brain penetration in a drug discovery setting” (Becker and Liu 2006). Finally Reichel adds, “our past understanding of brain penetration was based heavily on measuring total brain levels…and is the most common method to study brain penetration in rodents” ( (Reichel 2009). In summary, pharmacokinetic (PK) support of CNS drug discovery relies heavily on the brain/plasma ratio in vivo, although there are some acknowledged limitations.

3.3.1 K_plimitations. Although K_p is a simple measure of brain partitioning and is the most common method used in CNS discovery programs, it neither provides a complete PK profile [i.e., maximal concentration (C_max), half-life, and AUC] nor takes into account brain egress mechanisms (e.g., P-gp). In brain partitioning studies, it is commonly assumed that a drug with a large K_p ratio has extensive CNS penetration. Conversely, a K_p ratio less than 1 would mean that there is poor CNS penetration. However, K_p may be misleading because it does not take into account the “relative binding affinity of a substrate for proteins in plasma versus the proteins in the in the tissue in question” (Kalvass, Maurer and Pollack 2007). Alternatively, if the drug under evaluation has equal unbound plasma and brain concentration fractions then a K_p of 1 (known as unity) would be “consistent with the unrestricted distribution solely by passive processes” (Kalvass, Maurer and Pollack 2007). Therefore, the K_p ratio only provides a crude estimation of CNS drug levels because it does not take into account facilitated transport across the BBB or protein binding in plasma and brain. This has been confirmed in several case studies (Doran, et al. 2005; Liu, Chen and Smith 2008; Maurer, et al. 2005).

To summarize, factors that determine the extent of penetration of drugs into the brain are: 1) passive membrane permeability; 2) facilitated drug transport at the level of the BBB; 3) the degree of protein binding between plasma/blood and the brain; 4) metabolism; 5) the bulk flow of drug from the CSF (Figure 2).Thus, the K_p ratio is of limited value in the optimization of CNS drugs because it is a composite of all these factors. When using K_p in drug discovery to optimize brain penetration, the impact of plasma and brain protein binding must be understood. One must keep in mind that the goal in CNS drug discovery is to optimize the unbound drug concentration in the brain or the unbound brain-to-plasma ratio, and not the total (unbound/bound) brain-to-plasma ratio or the total brain concentration (Di, Kerns and Carter 2008). Despite this limitations, according to one expert, preliminary estimates of human K_p values derived from animal studies can be used as a suitable first approximation (Summerfield, et al. 2008).

In the Lorcaserin carcinogenicity study, Dr. Alavi dismissed brain-to-plasma partitioning and recommended using plasma concentrations from both rats and humans. However, this cannot be supported scientifically for two reasons: 1) there are no data to justify his assertion; 2) from the discussion regarding the BBB barrier it is clear that plasma drug levels cannot predict brain drug levels. In a study discussing methods to improve the prediction of human in vivo brain penetration the author compared the unbound fractions of a compound in plasma and brain across species and concluded, “For f_u(plasma)^{^[11]} there is a more marked difference on comparing human and rat values (R²= 0.49)”^{^[12]} On the other hand, “…a strong correlation ( R²> 0.9) is noted between the unbound brain fractions when comparing any two of these species^{^[13]}” (Summerfield, et al. 2008). Thus there was a good correlation in the unbound drug brain fractions across species, whereas the unbound drug plasma fractions provided a poor correlation. Since the issue at hand is brain astrocytomas it is clear that Dr. Alavi’s recommendation is unjustified. The use of unbound drug plasma fractions and unbound drug brain fractions to determine the extent of CNS drug penetration will be the topic of the next section.

Figure 2 Schematic of the major brain compartments and rate constants associated with brain penetration and efficacy. Unbound drug is assumed to be the fraction available to cross the BSCFB or BBB, the latter being associated with the influx clearance constant K1 (or Kin). The parameter k2 denotes back exchange to the peripheral arterial blood by means of passive diffusion or active transport. Association and dissociation constants between blood and receptor are denoted by kd, kon and koff. The values C (blood) and C (brain) represent total tissue concentrations while Cu (blood) and ECF (extracellular fluid) describe the free drug available in the peripheral and central compartments, respectively (Jeffrey and Summerfield, 2007).

4. WHAT IS THE MOST RELIABLE AND PRACTICAL METHOD, USING ANIMAL MODELS, TO DETERMINE THE EXTENT OF CNS DRUG PENETRATION?

4.1 Introduction

The discussion on the properties of the BBB shows that research in this area is greatly needed to develop methodologies that can help those involved in CNS drug discovery programs have a better likelihood of success. A researcher aptly described this need, “Methods for investigating drug candidates in this field, from in vitro to in situ and in vivo, are under evaluation. However, confusion remains, and an intense debate is currently raging regarding how to interpret the results obtained and which methods to use to select candidates for central nervous system (CNS) action” (Hammarlund-Udenases, et al. 2008). All current thinking regarding the extent of CNS drug penetration is based on the principle of the free drug hypothesis: it is the unbound drug at the site of action that determines its efficacy. In addition, the concept of brain penetration benefits from considering a few key PK compartments within the brain - Fig 3.

Microdialysis has been considered to be the standard method in the measurement of ISF concentration (the brain extracellular fluid), which represents the unbound drug concentration in the brain. The main limitations of this method are not the result of unreliability but rather its high resource requirements and low throughput, together with the special surgical skills needed to set up the experiment (Liu, Van Natta, et al. 2009). As a result, researchers have been persuaded to explore alternative methods to determine the concentration of unbound drug in the brain. There are at least three methods that have been evaluated recently: brain homogenate, brain slice, and CSF.^{^[14]} A similar degree of accuracy was observed between the brain slice and brain homogenate methods (Becker and Liu 2006). This conclusion was also supported by the data reported by Friden et al. (2007). Because the brain slice method is more labor intensive and CSF has its limitations we conclude that of the three, the brain homogenate method is the most reliable and practical way to estimate the brain unbound concentration (C_u,brain).^{^[15]}

4.1.1 Brain homogenate as a surrogate for C_u,brain. A brain homogenate was introduced as a surrogate to estimate C_u,brain in a study on the influence of nonspecific plasma and brain binding on CNS exposure (Kalvass and Maurer 2002). In this approach, the C_u,brain is estimated from the unbound fraction in brain homogenate, as determined by using equilibrium dialysis or ultracentrifugation.^{^[16]}

Equilibrium dialysis can be performed in parallel with the estimation of the free fraction in plasma. This method can rapidly produce data on f_u,brain (fraction unbound in brain) and f_{u, plasma} (fraction unbound in plasma) for a large number of compounds and has a high throughput. These data allow the assessment of the extent of brain distribution in vivo. As the brain ISF contains only a very small amount of proteins, f_u,brain can be used directly to estimate the unbound levels of a compound in brain ISF. Of note is that “there is very poor correlation between f_{u, plasma} and f_u,brain (Kalvass, Maurer and Pollack 2007). A possible reason for this discrepancy is the very different lipid and protein composition of plasma and brain, with plasma having twice as much protein, while the brain has 20-fold more lipids (Snyder, et al. 1975). The brain homogenate method, “which readily provides information on the free fraction of many compounds in brain tissue in vitro, has filled an important gap in our understanding of brain penetration and distribution” (Reichel 2009). This method allows routine access to drug concentrations in the brain.

Figure 3 Principal pharmacokinetic compartments of the CNS, and the relation between bound and unbound concentrations in the compartments. The dark boxes illustrate parameters that can be measured in vitro and in vivo, and their relation to the concentration in these PK compartments. The three boxes at the bottom summarize the methods by which the parameters shown can be obtained: 1) in vivo determination of the total brain to total plasma ratio Kp, the total amount of drug in brain A_total,brain, and total plasma concentrations C_total,plasma; 2) and 3) equilibrium dialysis of blood plasma and brain homogenate giving the fraction unbound in plasma and brain, from which the unbound concentrations in

plasma C_u,plasma and brain _C_u,brain from the in vivo study (1) can be derived (Reichel 2009)

4.1.2. In vitro assays: In relation to CNS penetration the in vitro methods are supplemented by two additional assays: 1) equilibrium dialysis of blood plasma; 2) equilibrium dialysis of brain homogenate (from the toxicological animal species) – Fig 4.

Figure 4 Schematic illustration – for our purposes only the equilibrium distribution on the right applies – the binding characteristics of the compound in blood plasma and brain tissue (homogenate) (Reichel 2009)

4.1.3 In vivo studies: The ‘classic’ total brain concentration vs. total concentration ratio (K_p) should be determined. This has already been done in the Lorcaserin carcinogenicity study in the Rat Astrocytoma section. The resulting data will now be expressed in several ways, acknowledging the lessons learned from the ‘free drug hypothesis’ concept of brain penetration. First, the classic K_pis calculated. Using f_{u, plasma} and f_u,brain data from the in vitro study above, K_pis then transformed into the unbound K_{p, uu} (unbound brain to unbound plasma concentration ratio). The unbound brain concentration can be calculated. For the purpose of this study the unbound volume of distribution will not be commented on – Fig 5.

Figure 5 Schematic illustration of in vivo studies – for our purposes only study on the right as it relates to exposure in the brain (Reichel 2009).

4.1.4 Interpretation, Use, and Implication of Results. While the classic K_pvalue seems to be driven predominantly by nonspecific binding to brain lipids, its unbound counterpart K_{p, uu} is much more useful. It is the extent of the distribution equilibrium of a compound between the unbound fractions in brain and plasma. The C_u,brain (unbound concentration in brain, a surrogate for brain ISF levels) can be calculated for every time point where brain levels have been determined by correcting the total concentration in brain with f_u,brain.(Reichel, 2009). In contrast to K_pvalues which are dose-static, C_u,brain values can be used to interpret dose-response results from efficacy studies and hence to establish dose/exposure/effect – Fig 6.

Figure 6 Interpretation and use of the brain PK parameters derived from both the first and second tier of in vitro assays and in vivo studies - see also the excellent reviews of Hammarlund-Udenaes et al. (2008) (Reichel 2009).

4.1.5 Summary and outlook: The following is a quote from Reichel (2009):

“The complex structure of the CNS makes brain penetration a very complex feature which cannot be rationalized on the basis of any single parameter. Although total brain concentrations are still the most common measure of CNS exposure, it is now emerging that they are more an indication of high nonspecific binding to brain tissue rather than being pharmacologically relevant concentrations. Neither total brain levels nor BBB permeability can be taken without considering the binding capacity of the brain tissue, when a link between exposure and efficacy is needed. The current paradigm of brain penetration is, therefore, changing towards a more compartmentalized view which allows a better rationalization of the distribution of compounds within the brain and makes use of brain compartments which are more relevant pharmacological effects.

Central to the emerging new paradigm is a clear differentiation between rate and extent of brain penetration, and between total and unbound drug levels as parameters for drug distribution within the brain. In attempting of a more holistic view, the concept is able to resolve a number of apparently contradicting observations, e.g., why CNS effects can be seen in the clinic, even though a CNS drug poorly permeates the BBB, is substrate of efflux pumps, has low total brain levels, is poorly bound to brain tissue, or has a very high plasma protein binding. Currently, there are also attempts to merge the presented concept of CNS penetration with the field of preclinical drug development and clinical PET to make extrapolations from animal to human more realistic."

5. IS IT RELIABLE TO USE PLASMA DRUG LEVELS TO ASSESS BRAIN PENETRATION AND DRUG MARGIN OF SAFETY?

An elegant study by Summerfield et. al. ( 2008) compared the unbound fraction of a series of compounds, 11 marketed CNS drugs and 10 PET tracers in brain homogenates from rats, Landrace pigs, and humans. There was a strong correlation (R² > 0.9) ^{^[17]} between the unbound brain fractions when any two of these species were compared, indicating that the method works well across the species.^{^[18]} This conclusion has been corroborated in other studies (Fichtl, Van Niecieki and Walter 1982; Haug 1987). However, there was a more marked difference when human and rat values for unbound plasma fractions are compared (R²=0.49), indicating that using drug plasma levels to predict penetration of these drugs into the CNS is unreliable. The different outcomes of the two methods is likely because of the “relative tissue affinities between plasma (or blood) and the brain” (Summerfield et al. 2008). The very poor correlation between unbound plasma fractions and unbound brain fractions has been confirmed by other investigators (Kalvass, Maurer and Pollack 2007).

The degree of tissue binding between plasma/blood and the brain can determine the availability of a drug in the brain. For example, a drug that binds strongly to blood and plasma constituents could penetrate very poorly into the brain. Other factors that govern the extent of brain penetration of drugs into the brain must also be considered: passive membrane permeability; facilitated drug transport at the level of the BBB; metabolism. Each of these factors can cause significant differences between the concentrations of a drug in the plasma and the brain. Another factor to consider is the different lipid and protein composition of plasma and brain; plasma has twice as much protein, the brain has 20-fold more lipids. These various biomolecules bind different drugs to different extents.

In summary, CNS penetration of drugs involves several factors that include plasma/tissue binding and the passage of tissue across the BBB. It has been demonstrated that “brain tissue binding appears comparable across species” and that “plasma binding varies more markedly from one species to another and is likely the better to reflect adaptation to environmental factors” (Summerfield et al. 2008). It is clear that recommending the comparison of plasma levels between rats and humans to calculate the margin of safety for lorcaserin with respect to astrocyte tumors is scientifically flawed.

6. CONCLUSION

The FDA requested additional data and information regarding the lorcaserin concentration in the CNS to better estimate astrocytoma margins. The request was prompted by the uncertainties about what is the most accurate method for calculating the margin of safety levels for lorcaserin, and about the appropriateness of using monkeys as the animal model for determining drug concentrations in the human brain. The FDA’s nonclinical pharmacology presenter disregarded monkey brain-to-plasma partitioning data in favor of comparing plasma drug levels between rats and humans, based on his rationalization that human data was not available.

Predictions of human pharmacokinetics have been traditionally been based on in vivo brain-to-plasma partitioning ratios (K_p) derived using animal models. This has long been the method of choice in CNS discovery programs, and it is still in use today. It is important to note that human brains have not been used in these models except in rare studies that have utilized cadaver brains or commercially available human brain specimens. The vast majority of CNS drugs that are used clinically today were developed using the K_pmethod, the in vivo gold standard in the drug discovery industry. Furthermore, a review of the literature confirms the wisdom of using this methodology. However, there are acknowledged limitations to the method, the most prominent being that it only provides the extent of total (bound and unbound) concentrations of drug in the brain. This caveat does not limit the method’s usefulness as a suitable first approximation for estimating the extent of drug penetration into the CNS, for the specific purpose of calculating the margin of safety levels for lorcaserin. It must be kept in mind that the goal in CNS drug discovery is to know the level of unbound concentrations that are available at the specific target sites of action. On the other hand, the K_pmethod is appropriate for determining drug concentration levels in toxicology studies. PET imaging is still an investigational method for such purposes.

The rationale for comparing plasma drug levels between rats and humans to determine astrocytoma exposure risks is flawed scientifically. Several case studies have shown that plasma protein binding varies markedly from one species to another, which means that the method is unreliable for determining CNS penetration and margin of safety values. Furthermore, using plasma levels excusively for this purpose is not supported in the scientific literature. Not only did a Medline search fail to find any studies that used inter-species plasma level comparisons to determine the extent of drug penetration into the CNS, not one study in the bibliography of a seminal review mentioned its use for this purpose. Furthermore, using only plasma levels ignores completely the role of the BBB as the gatekeeper to the CNS and the effect it can have on levels of compounds in the brain. The scientific literature strongly indicates that this method is inappropriate for the purpose proposed by the FDA’s examiner.

The appropriateness of using animal models for predicting drug concentrations in the human brain is not only supported by common practice in the CNS drug discovery industry, but also by the proven inter-species conservation of the BBB. The similar morphology and composition of the BBB across species has been widely documented. Several studies have confirmed that brain tissue binding is comparable across species in homogenates. Brain-to-plasma partitioning is therefore a valuable tool in drug discovery for providing early estimates of human brain concentrations; K_pvalues are estimated by combining human plasma (or blood) drug levels with animal brain tissue binding values. Furthermore, non-human primates are particularly suitable for this purpose as their close genetic relationship to humans is universally accepted; compared to rodents, their neurobiology is much more similar to humans. Non-human primates are used extensively in drug metabolism studies, in HIV research, and in vaccination studies. To disregard their use for our purposes is unfounded.

Finally, if the FDA is resistant to using the brain-to-partitioning ratio already determined for lorcaserin, despite the strong scientific rationale in its favor, then Arena Pharmaceuticals has the option of using a method involving brain homogenates and equilibrium dialysis for determining the unbound drug concentrations in the brain. This method has recently been introduced and is now widely accepted as the most reliable and practical way to estimate the unbound drug concentration in the CNS. It is a relatively simple procedure that has a high throughput, as described in detail above. This approach may even provide better margin of safety data because it does not measure the total (bound and unbound) drug in the CNS, unlike the simple K_pratio. Thus, if the ratio between the brain unbound fraction and the plasma unbound fraction is lower (which is likely as it does not measure bound drug), then estimates of the drug levels in the brain would be reduced, increasing the corresponding estimates for lorcaserin’s margin of safety.

I would like to acknowledge Dr. John P. Moore for his assistance in editing this document.

Daniel P. Lopez, M.D., F.A.C.O.G.

Blue Ocean Research Group

References

Alavijeh, Mohammad S, Mansoor Chishty, M Zeeshan Qaiser, and Alan M Palmer. "Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery." NeuroRx 2, no. 4 (October 2005): 554-571.

Anan`eva, II, et al. "Glial tumors of the brain: current aspects of their classification and bases for genetic predisposition." Arkh Patol 69, no. 1 (Jan-Feb 2007): 54-60.

Becker, Stacey, and Xingrong Liu. "EVALUATION OF THE UTILITY OF BRAIN SLICE METHODS TO STUDY BRAIN PENETRATION." Drug Metabolism and Disposition 34 (February 2006): 855-861.

Cserr, HF, and M. Bundgaard. "Blood-brain interfaces in vertebrates: A comparative approach." American Journal of Physiology 246 (1984): R277-R288.

Di, Li, Edward H Kerns, and Guy T Carter. "Strategies to assess blood-brain barrier penetration." Expert Opinion on Drug Discovery 3, no. 6 (2008): 677-687.

Doran, A, et al. "The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model." Drug Metabolism and Dispostion 33 (2005): 165-174.

Eyal, Sara, Peng Hsiao, and Jashvant D. Unadkat. "Drug interactions at the blood-brain barrier: fact or fantasy?" Pharmacology & Therapeutics 123, no. 1 (2009): 80-104.

Fichtl, B, A Van Niecieki, and K Walter. "Tissue binding versus plasma protein binding of drugs: General principles and pharmacokinetic consequences." Advances in Drug Research 20 (1982): 117-161.

Friden, M, A Gupta, M Anonsson, U Bredberg, and M Hammarlund-Udenaes. "In vitro methods for estimating unbound drug concnetrations in the brain interstitial and intracellular fluids." Metabolism and Disposition 35 (2007): 1711-1719.

Gibbs, Richard A., and et al. "Evolutionary and Biomedical Insights from the Rhesus Macaque." Science 316, no. 5822 (April 2007): 222-234.

Hammarlund-Udenases, M, Markus Friden, Stina Syvanen, and Anubha Gupta. "On The Rate and Extent of Drug Delivery to the Brain." Pharmaceutical Research 25, no. 8 (August 2008): 1737-1750.

Hassan, Moustapha, et al. "In vivo distribution of [11C]-busulfan in cynomolgus monkey and in he brain of a human patient." Cancer Chemotherapeutics and Pharmacology 30 (1992): 81-85.

Haug, H. "Brain sizes, surfaces, and neuronal sizes of the cortex cerebri: A stereological investigation of man and his variability and a comparsion with some mammals (primates, whales, marsupials, insectivores, and one elephant)." American Journal of Anatomy 180, no. 2 (1987): 126-142.

Jeffrey, P, and G Summerfield. "Challenges for blood-brain barrier (BBB) screening." Xenobiotica 37, no. 10-11 (October-November 2007): 1135-1151.

Kalvass, Cory J, Tristan S Maurer, and Gary M Pollack. "Use of Plasma and Brain Unbound Fractions to Assess the Extent of Brain Distribution of 34 Drugs: Comparison of Unbound Concentration Ratios to In Vivo P-Glycoprotein Efflux Ratios." Drug Metabolism and Disposition 35 (2007): 660-666.

Kalvass, JC, and TS Maurer. "Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery." Biopharmaceutics & Drug Disposition 23 (2002): 327-338.

Lin, Jiunn H. "CSF as a Surrogate for Assessing CNS Exposure: An Industrial Perspective." Current Drug Metabolism, 2008 9 (2008): 46-59.

Liu, Xingrong, Cuiping Chen, and Bill J Smith. "Progress in Brain Penetration Evaluation in Drug Discovery and Development." The Journal of Pharmacology and Experimental Therapeutics 325 (2008): 349-356.

Liu, Xingrong, et al. "Evaluation of Cerebrospinal Fluid Concentration and Plasma Free Concentration As a Surrogate Measurement for Brain Free Concentration." Drug Metabolism and Disposition 34 (September 2006): 1443-1447.

Liu, Xingrong, et al. "Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid." Drug Metabolism and Dispostion 37 (April 2009): 787-793.

Liu, Xingrong, Olga Vilenski, Joyce Kwan, Subbu Apparsundaram, and Robert Weikert. "Unbound Brain Concentration Determines Receptor Occupancy: A Correlation of Drug Concentration and Brain Serotonin and Dopamine Reuptake Transporter Occupancy for Eighteen Compounds in Rats." Drug Metabolism and Dispostion 37 (April 20 2009): 1548-1556.

Maurer, TS, DB Debartolo, DA Tess, and DO Scott. "Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice." Drug Metabolism and Dispositon 33 (2005): 175-181.

Neuwelt, Edward, et al. "Strategies to advance translational research into brain barriers." Lancet Neurology 7 (2008): 84-96.

Osada, N, et al. "Assignment of 118 novel cDNAs of cynomolgus monkey brain to human chromosomes." Gene 275, no. 1 (September 2001): 31-37.

Reichel, Andreas. "Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept." Chemistry & Biodiversity 6 (2009): 2030-2049.

Shen, Danny D, Alan A Artru, and Kimberly K Adkison. "Principles and applicablility of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics." Advanced Drug Delivery Reviews 56 (2004): 1825-1857.

Snyder, WS, MJ Cook, ES Nasser, GP Karhausen, I Howellls, and H Tipton. Report of the Task Force on Reference Man. Oxford: Pergamon Press, 1975.

Summerfield, S.G, et al. "Toward an improved prediction of human in vivo brain penetration." Xenobiotica 38, no. 12 (2008): 1518-1535.

Uno, Yasuhiro, Shotaro Uehara, Sakae Kohara, Norie Murayama, and Hiroshi Yamazaki. "Cynomolgus Monkey CYP2D44 Newly Identified in Liver, Metabolizes Bufuralol, and Dextromethorphan." Drug Metabolism & Disposition 38 (September 2010): 1486-1492.

^{^[1]} It is interesting to note that although malignant astrocytic gliomas account for 50% of all primary brain tumors in humans the cells of origin are mostly unknown (Anan`eva, et al. 2007)

^{^[2]} This is a meticulously detailed article, a mine of information that is supported by a range of scholarly literature surveyed and assessed that is encyclopedic.

^{^[3]} This is the species of monkey used to determine brain-to-plasma brain partitioning ratios. It is an Old World macaque monkey.

^{^[4]} Downloaded from the FDA website at http://www.fda.gov/ohrms/dockets/ac/03/briefing/3976B1_02_F-FDA-Tab%205.pdf

^{^[5]} There are numerous reports of these PET studies, but for the present purpose a Medline search is appropriate.

^{^[6]} The interstitial fluid (ISF) is the brain extracellular fluid that is in direct continuity with brain tissue is separated from the cerebrospinal fluid via the brain-cerebrospinal-fluid barrier (BCFB).

^{^[7]} This discussion will be based on excellent review in Hammarlund-Udenases, M, Markus Friden, Stina Syvanen, and Anubha Gupta. "On The Rate and Extent of Drug Delivery to the Brain." Pharmaceutical Research 25, no. 8 (August 2008): 1737-50.

^{^[8]} Li Di mentions that this is a brilliant review on BBB concepts and applications of CSF as a surrogate for unbound brain drug concentration in drug discovery.

^{^[9]} Throughput refers to the number of tests that can be performed in a given time.

^{^[10]} From the FDA briefing document section entitled: “Genotoxicity and Carcinogenicity Assessment for Lorcaserin” (6^th paragraph; Brain Astrocytoma).

^{^[11]} f_u(plasma)describes the unbound fraction of a compound in plasma.

^{^[12]} A statistical measure of how well a regression line approximates real data points; an r-squared of 1.0 (100%) indicates a perfect fit. Here it is used to determine correlation of drug plasma and brain concentrations among various species of animal models.. An R²of one denotes a perfect correlation.

^{^[13]} The comparison was between rats, Landrace pigs, and human (human brain samples were obtained from Biomedical Solutions).

^{^[14]} The limitations of determining the unbound concentration in the CSF were discussed earlier.

^{^[15]} The discussion in this section will concentrate primarily on the brain homogenate method. It is just as reliable as the other two and it can be much more easily implemented in the drug discovery setting. I will also summarize the most current articles on this subject in the listed references (Becker and Liu 2006; Friden, et al. 2007; Liu, Van Natta, et al., 2008; Summerfield, et al. 2008; Hammarlund-Udenases, et al. 2008; Reichel 2009; Jeffrey and Summerfield, 2009; Liu, Vilenski, et al. 2009).

^{^[16]} The in vitro unbound fraction in brain homogenate and plasma for each compound was determined using a 48-well Rapid Equilibrium Dialysis device (Linden Bioscience, Woburn, MA). Brain tissue was homogenized in 2 volumes (w/v) of 0.9% saline. Brain homogenate or plasma was spiked with a compound for a concentration of 1000 ng/ml. Two-hundred

microliters of the matrix was added to the donor side of a dialysis chamber. The receiver side contained 350 µl of Sorenson’s buffer. The dialysis apparatus was maintained on a shaking device at 37°C for 4 h. The drug concentrations

were determined as described in (Liu, Van Natta, et al. 2009).

^{^[17]} A statistical measure of how well a regression line approximates real data points; an R² value of 1.0 (100%) indicates a perfect correlation. Here it is used to determine the correlation between drug plasma and brain concentrations among various species of animal models.

^{^[18]} Of note, is that this is further evidence supporting the use of cynomolgus monkeys as a predictive animal model for human brain drug concentrations.

Criminal investigations chief resigns, things are changing at FDA

2010-11-25T01:29:00.000-08:00

Story from CNBC, written by AP

Please read the full story on CNBC

Link: http://www.cnbc.com/id/40341826

EXCERPT

WASHINGTON - The head of the Food and Drug Administration's criminal investigation unit is stepping down, months after the latest round of criticism directed at his department by congressional investigators.

An agency spokeswoman confirmed Tuesday that Terry Vermillion told FDA staff this week that he would step down.

"We appreciate Terry's years of public service and wish him well in retirement," said FDA Associate Commissioner Beth Martino. Vermillion, who spent 20 years in the Secret Service before joining the FDA in 1992, is among the highest paid officials at the agency at roughly $200,000 per year. His department has been the subject of several investigations requested by federal lawmakers.

Earlier this year the Government Accountability Office said that the FDA must exercise more oversight over Vermillion's unit, which has operated largely independent of agency leadership, despite growing into a $41 million operation with 230 staffers over the last decade. In 2008, House and Senate Republicans questioned the priorities of the criminal investigations unit, specifically its focus on drug abuse cases instead of broader misconduct by large companies.

Improper influence of former Director taints FDA analysis of Lorqess

2010-11-24T16:36:00.000-08:00

Excellent post from Investor Village posted by "truth_sayer"

Link: http://www.investorvillage.com/smbd.asp?mb=633&mn=9444&pt=msg&mid=9801323

Improper influence of former Director taints FDA analysis of Lorqess

Dear Ms. Behr and Ms. Kremzer,

Re: FDA employee improperly influenced by a former FDA director with a financial interest

Please consider this letter the lodging of a formal complaint with your office and request for remedy.

Complaint

I allege that Fred K. Alavi an FDA employee has been improperly influenced by a former FDA director Dr. David Orloff. The result of the influence has to all appearances tainted Dr. Alavi’s work.

I cite as evidence Alavi’s unprofessional and unscientific contribution to the FDA Briefing document (UCM225631.pdf) for an FDA Advisory Committee meeting held Sept 16, 2010 on to consider the weight loss drug Lorqess.

To wit:

1. Arena Pharceuticals’s obesity candidate, Lorqess (lorcaserin) is widely acknowledged potential competitor of Vivus. Inc’s obesity drug candidate, Qnexa

2 Dr. David Orloff has a financial interest in Vivus. Inc’s obesity drug Qnexa because he oversaw the trials of this drug:

http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933

“MOUNTAIN VIEW, Calif., Sept 09, 2009 /PRNewswire-FirstCall via COMTEX News Network/ -- VIVUS, Inc. (Nasdaq: VVUS) today announced positive results from two final, phase 3 pivotal 56-week studies, EQUIP (OB-302) and CONQUER (OB-303), evaluating the safety and efficacy of Qnexa(TM), an investigational drug, in more than 3,750 patients across 93 sites……Wilson added, "We are proud of the results of our Qnexa phase 3 program, and I would like to thank Dr. Thomas Najarian, the inventor of Qnexa, the entire development team at VIVUS, Dr. David Orloff and his staff at Medpace, the clinical research organization that managed these studies, and the clinical investigators and patients who participated in the Qnexa clinical trials."…

3. Immediately proceeding Medpace, Orlof was a FDA director in the very same division that is currently overseeing the review of drugs to treat metabolic and endocrine disorders – including the obesity candidates Qnexa and Lorqess.

http://www.medicalnewstoday.com/articles/34644.php

“David Orloff, an FDA division director who oversees the review of drugs to treat metabolic and endocrine disorders, has announced plans to leave the agency and join Medpace, a contract research firm based in Cincinnati that runs clinical trials, the New York Times reports.

4. During the time of Orloff’s directorship in the very same metabolic and endocrine disorders division, one Fred Alavi was a subordinate reviewer under Orloff:

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B1_02_04-FDA-ClinPharm-Toxicology.pdf

“….Pharmacology/Toxicology Review And Evaluation…Nda Number: 21-868…
Pharm/Tox Reviewer: Fred Alavi, Ph.D.
Pharm/Tox Supervisor: Jeri Elhage, Ph.D.
Division Director: David Orloff, Md…”

5. The linchpin of the FDA’s rejection of Lorqess are analyses of trial results conducted by Fred Alavi, that I allege are faulty. See the following:

6. Dr. Alavi, authored the subsection, of the FDA Briefing document for the meeting to consider Lorqess (UCM225631.pdf) , entitled “Genoxicity and Carcinogenicity Assess ment for Lorcaserin”.

Page five of that subsection is entitled: “Rat Carcinogenicity Study.” In that subsection the word “carcinogenicity” appears at least four times. Yet the reader of this document discovers that benign, repeat benign, tumor data has been included. Namely, Table 4 of this subsection reports the occurrence of benign fibroademomas even though it is entitled, “Incidence of lorcaserin-induced tumors in the 2 year rat carcinogenicity study.”

Even worse, the occurrence of these benign tumors have been “combined” with the occurrence of malignant tumors to fabricate an ostensible statistically significance (“SS”) for carcinogenicity. It is only valid to group benign and malignant neoplasms of a particular histogenesis when malignancy is seen as a progression from the benign tumor. Cf. Preclinical Development Handbook Toxicology 2008 John Wiley & Sons New Jersey Carcinogenicity Studies 424- 455. And “ 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 incorporation of non-progressing benign tumor results in a conclusion about carcinogenicity is incorrect, unscientific and ridiculous.

6. Dr. Alavi furthermore “cooked the books” against Lorqess by disregarding monkey brain-to-plasma ratio partitioning data to ascertain brain concentrations of Lorqess. He instead compared plasma drug levels between rats and humans. The safety margin using the primate brain-to-plasma model is 17x the clinical dose, whereas the rat plasma-to-plasma model is 5x the clinical dose. This flies in the face of common sense – it is improper and deceptive to use a comparison between rodents and humans when a comparison between primates and human s is available.

Furthermore, species difference aside, the traditional in vivo brain-to-plasma partitioning ratio is the method of choice by CNS drug discovery programs. The vast majority of CNS drugs were developed using this method and it is still the gold standard in the drug discovery industry. The method proposed by Dr. Alavi was to use plasma-to-plasma levels to determine the margin of safety, which is widely reported as flawed in scientific literature. There is strong evidence that this is an unreliable method due to marked intraspecies variation in drug levels. Thus, the plasma-to-plasma level determination used by Dr. Alavi is an unaccepted method for margin of safety levels.

8. Dr. Alavi’s failure to use monkeys as the animal model is contrary to science, common sense and longtime industry practice. He founds his disregard on the queasy-sand circular logic that there was no human data. The vast majority of CNS drug discovery programs use animal models, precisely because there rarely are any human brain data -- and because of the proven inter-species conservation of the blood-brain barrier which is the primary obstacle for drug penetration into the CNS. Furthermore, several studies have confirmed that brain tissue binding is comparable across species. It is idiocy to assert genetic rodent neurobiology should be favored for comparative determination over that of non-human primates. Dr. Alavi ignores grade school science that monkeys are much more similar to humans than rats. Duh. Monkeys are the primary animal species used in drug metabolism studies, in HIV and vaccination studies. To disregard their use is unfounded scientifically.

Remedy requested

My request for remedy is that any and all requirements in the FDA’s Complete Response Letter issued to Arena Pharmaceuticals on Oct 23, 2010 that are founded on the mistaken and tainted Alavi analyses be waived and retracted.

Sincerely Yours.

Analysis of BLOOM-DM results and media bias

2010-11-12T09:40:00.000-08:00

Written by Erewenguy from YMB

Analysis of BLOOM-DM results

There are a couple of problems with the media’s stand-alone
interpretation of the valvulopathy data from the bloom-dm trial. The
first problem has been pointed out repeatedly, that although the
difference between the placebo and lorcaserin mean is large, it is the
placebo mean that is out of the ordinary. The lorcaserin mean is
consistent with other trials.

Some have suggested that the 0.5% placebo value should be discarded as
an outlier, but unfortunately, the data are the data. To pick and
choose what data to analyze leads one to pre-determined conclusions.
So the data WILL be included, which is causing so much
hyperventilating in the media.

The real problem then is a problem of perception which results from
bias inherent in comparing real numbers. This is one of the reasons
the field of statistics exists.

I don’t really want to turn this into a statistics lesson, but would
like to reduce some of the “6X INCREASE IN VALVULOPATHY!” panic and to
show that the actual situation is a bit more complicated than 7
patients vs 1 patient.

For rare-event data with non-normal distributions, such as VHD, the
data should be transformed prior to analysis. A typical transformation
is log(N+1), but I don’t know what specific transformation the FDA
requires. Transformation is performed to reduce type 1 errors, or
mistakenly rejecting a true null hypothesis. In our case, the null
hypothesis is that lorcaserin mean = placebo mean.

Actual raw data comparison is 2.9 vs 0.5 (a 5.8X difference)
Transformed comparison is 0.591 vs 0.176 (a 3.4X difference, using my
transformation value).

To further complicate the interpretation of the raw data, the FDA is
allowing a margin of error value to assess VHD, with the null
hypothesis that lorc mean is not greater than (1.5) x placebo mean.

So the actual comparison is not 2.9 vs 0.5, but 2.9 vs 0.75.
Transformed comparison now becomes 0.591 vs 0.243 (a 2.4X difference)

Even here, we cannot compare actual numbers, but we have to conduct
the statistical analysis to state with a relative degree of confidence
that these 2 values do not differ outside of what might be expected to
occur by chance.

If the FDA has an ounce of integrity, lorcaserin should be rejected if
it is proven to be unsafe. However, if a proper statistical analysis
does not reject the null hypothesis, I would expect that with that
same ounce of integrity the FDA should declare that VHD is not an
issue and we move forward.

I believe that in the cc it was stated that there was no difference
between treatments at P=0.10, and will assume arna’s statistician is
qualified and capable

SEC is MIA? - Letter by J. Bernard LoVerde, Jr.

2010-11-07T09:36:00.000-08:00

Copied and pasted in it's entirety from "Current.com", though this is old it is worth reading

Link:

http://www.sec.gov/rules/concept/s72499/loverde1.txt

or

http://current.com/1ko224c

Date:    01/31/2000  6:21 PM

Subject: Subject:  File No. S7-24-99 Comments

To Whom It May Concern:

I am a retired member of the Wall Street Community after spending years in the 
Operation & Compliance (as both a senior member and director of both 
departments) sides of NASD member firms.  This included the oversight of the 
trading activities of numerous branches, registered representatives, and the 
actual Trading Departments of the last two firms I worked for.  As part of these
activities I have spent numerous hours reviewing trading operations and 
compliance as well as immeasurable amounts of contact with both NASD and SEC 
regulatory officials.

I am writing this to you regarding the above referenced matter as I feel 
compelled to offer my comments on the subject at hand.

It is my persona belief that it is of the utmost importance to maintain, and 
strive for, the concept of "fair markets".  To that extent I believe that it is 
absolutely necessary that you level the playing field for the investing public 
with regard to the trading strategy of short selling. 

It is time to create, and enforce, a single set of short-selling rules which 
will apply to specialists, market makers, broker/dealers, and the investing 
public.  As such, I urge you to remove what I believe to be the inequitable and 
discriminatory regulations that restrict the public investor's ability to 
short-sell stocks, while providing preferential treatment only
for the market makers and broker/dealers.

While I understand that most novice investors do not understand, or appreciate, 
the critical check-and-balance afforded by the action of short selling in the 
exercise of free markets.  Since the industry itself makes no effort whatsoever 
to educate the public with regard to short selling (this is one of the more 
sophisticated investing strategies that they fail on, much less the proper use 
of margin and/or the trading of options), the public is left to draw the 
erroneous conclusion that it is short sellers who should be blamed when a stock 
goes down in price.  

Regrettably, this lack of understanding applies most directly to the new 
generation of "do-it-yourself" investors spawned by the proliferation of access 
to information and gossip enabled by the internet. Many treat the  internet as a
tool to generate "momentum" for stocks as though it is a  football game. Rapid 
runups are easily fabricated for reasons having nothing whatever to do with the 
value of the underlying security.  Furthermore, as I know the SEC actively is 
monitoring "chat rooms" on various internet investing websites this should be 
quite apparent to regulatory officials.  It is extremely disheartening when you 
see this in those rooms dedicated to the trading (loosely defined in some 
occasions) of stocks that trade on the NASDAQ Small Cap and/or OTCBB markets. 
In these cases the promoters, and/or the issuers paid posters who hype the 
stock, use the specter of short sellers to soothe the long stock holders who are
being materially damaged when the insiders in these stocks liquidate their 
shares into the buying of the unsuspecting public.  For example, most OTCBB 
investors on these sites are completely unaware that, in the US, you cannot 
short sell an OTCBB stock, yet this blaming of the short sellers routinely 
occurs.  A better educated public would not be so susceptible to this tactic.

However, on the flip side, market makers and broker/dealers have rigged the game
so they can play by a different set of rules than the general public and, to 
date, this ha been protected by the regulatory bodies.  These market makers and 
broker/dealers have done this for no other reason than to line their own 
pockets, under the sham of maintaining "fairness" in the market.  Every day, 
market pros short sell IPO's, short sell on downticks, and short sell without 
regard to the availability of certificates, all things done at the expense of 
individual investors, who do not have the right to do the same.  They do it 
quietly, without regulation, and without a requirement for disclosure; often in 
direct contradiction to the public "recommendations" of analysts
from the very same firms which I believe is another area that the regulatory 
bodies should be aware of (for example look at the recent action in AMZN where 
outlandish price targets were placed on the stock creating a price run right 
before the stock pre-announced a financial warning).  The public will be best 
served by administering the markets so that every investor wishing to place 
their own money in an "at-risk" trade be allowed to do so under the same rules.

Therefore, I urge you to eliminate current restrictions on short selling, and 
allow the public to sell short by the same rules as market makers.

I thank you for your time and consideration and would be more than happy to 
discuss this with anyone on your staff.

Sincerely,

J. Bernard LoVerde, Jr.

Facebook connections, bad journalism and naked short selling hedge funds

2010-11-07T09:14:00.000-08:00

Post is copied from Antisocialmedia.net, "Judd Bagley" is a good journalist

http://antisocialmedia.net/facebook-bad-journalism-and-short-selling-hedge-funds/

Recently, short-selling hedge fund Rocker Partners paid Overstock.com $5-million to settle the lawsuit filed against them in August of 2005. This is a major victory for all public companies targeted by bear raiding hedge funds. But thanks to the unusually skewed reporting surrounding it, chances are you either hadn’t heard about the suit, or were under the impression it was frivolous and certain to fail.
This presentation examines part of the story behind the coverage of the suit, using some innovative methods to explain why what you heard about the suit and its merits likely had little in common with the reality of it.

Another article on current.com titled

Destroying Companies For Profit

http://current.com/news/politics/89439340_destroying-companies-for-profit.htm

If you ever wondered how or why a stock price suddenly drops like a rock on incredible volume, or why executives battle damaging reports in the NY financial press and in analyst reports, see this video. But only if you want to know how Wall Street really works.

Wall Street has a profitable trading strategy that it has been carefully hiding, because it involves the destruction of companies.

Just recently Deutsche Bank was found by the NYSE to have been selling massive amounts of shares it did not have nor deliver over a period of 22 months. This floods the market with "shares" and sucks out investors money - unbeknown to investors - and damages the companies - the more the better. This trading scheme is called "Naked Short Selling". And it is very profitable for those who do it. The more a company goes down - the more they make.

NYSE spokesman Scott Peterson said that Deutsche Bank sold "A LOT.”

But this is just one example of many instances. Wall Street firms and hedge funds carefully hide this activity because it is amoral and illegal. But is is possible because the regulators, while they know about it, do nothing and journalists and analysts help put out the needed messages.

Companies that need access to the markets or bank on their good reputation are choked off this way. It's easy money. Collect investor money, then kill the company.

I added a link to RSS which you can find on top right. Please read facts about Lorqess on Meddy's blog uptheheat.blogspot.com

Thomas Wei of Jeffries, who at FDA did he talk to about ARNA and its data prior to Adcom?

2010-11-05T20:58:00.000-07:00

Who did "Thomas Wei" talk to at FDA about the data and statistical analysis? What info did he have before hand? Did Jeffries sell in the first minute after Adcom documents were released?

Very interesting posts

By Avo

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=105047&mid=105047&tof=1&frt=2

PART 1

From http://online.wsj.com/article/BT-CO-2010...

“Jefferies analyst Thomas Wei conducted an alternative analysis of available data and believes that Arena's data doesn't rule out heart-valve risk to a level wanted by the FDA. He said he believes his method will be preferred by the agency over the company's, citing two guidance documents from the agency and feedback from an FDA consultant statistician. Wei has a hold rating on Arena's stock and lowered his price target to $5 from $6.”

ARNA has already said, “The integrated BLOOM and BLOSSOM echocardiography data set rules out a risk of valvulopathy in lorcaserin patients according to criteria requested by the FDA. Echocardiographic evaluations showed no association between lorcaserin and the development of heart valve insufficiency. Rates of new FDA-defined valvulopathy in BLOSSOM at Week 52 were as follows: lorcaserin 10 mg twice daily (2.0%), 10 mg once daily (1.4%) and placebo (2.0%).

"The echocardiographic safety data show no risk of valvulopathy," commented Neil J. Weissman, M.D., Director, Cardiac Ultrasound and Ultrasound Core Labs, President, MedStar Research Institute, and Professor of Medicine, Georgetown University. "In the individual and combined BLOOM and BLOSSOM data sets there is no evidence of a difference in the development of valve disease in lorcaserin patients versus control for up to two years of continuous use. No prospective echocardiographic program has ever studied this many patients for this period of time."”

Why would ARNA’s method of analysis be in doubt? Since Wei hasn’t revealed what the difference is between the two methods, we’re left to speculate. Some of that speculation (certainly from my end) has been that Wei may be thinking the BLOOM and BLOSSOM data were not meant to be pooled, that the FDA wanted each trial to reach 80% power on its own. (The NEJM article stated that the BLOOM trial only reached 60%). However, ARNA has repeatedly stated that they will pool data from BLOOM and BLOSSOM in order to meet “the prespecified statistical criteria that allow [them] to declare lorcaserin to be non-inferior to placebo for development of cardiac valvulopathy.” What is that “prespecified criteria? “The FDA previously requested that Arena rule out a 1.5-fold or greater risk of valvulopathy with 80% power.”

So can they pool the data to meet this criteria or can’t they? Was that the original intent or wasn’t it? Did they not decide to pool the data until after seeing that the BLOOM trial only hit 60% power?

The data will be pooled and the FDA will have no problem with it. Below are some statements from past conference calls that appear to put this question to rest (caps emphasis is mine, obviously).

From the Q4 2008 Conference call:

Bret Holley, Oppenheimer: “Jack, I was just curious about your comment about looking at multiple data points from pivotal trials. Am I reading too much into that in regards to the partnership process? It sounds like if you are going to be looking at multiple data sets, it would certainly suggest that a partnership might be on a timeline behind the BLOSSOM results minimally.

Jack Lief (CEO): “Well, in partnering you never know for sure. If it was confusing, I apologize, but the multiple data that I was referring to was on the valvulopathy. There are two studies that are needed to fully address based on the way we power the studies addressing the FDA guidance to rule out valvulopathy and obviously there will be a lot more information. We haven’t unblinded the studies yet, so we don’t know the full results, but there will be a lot more information about that in a couple of weeks, SO WE’VE AGREED WITH THE AGENCY THAT BOTH THE BLOOM AND BLOSSOM STUDY WILL BE ABLE TO POOLED FOR THAT VALVULOPATHY ISSUE.” (emphasis added)

From the 3/30/09 BLOOM Trial Results Webcast:

55:40, Carol Werther, Summerstreet Research: “Do you definitely need the BLOSSOM results to meet the FDA . . . to rule out the 1.5?”

Christy Anderson, (VP of clinical development): "The agreement we have with the FDA is to have sufficient statistical power to rule out this 1.5 relative risk with a power of 80%. We’re not quite there with the number in the BLOOM trial. We will combine the BLOOM and BLOSSOM data and will have more than enough patients to satisfy those FDA criteria. Considering how large the BLOOM trial was, how many thousands of patients we have examined, we think it’s probably pretty accurately predictive of what we’ll see in BLOSSOM, so WE ANTICIPATE BEING ACTUALLY SUBSTANTIALLY OVERPOWERED TO ADDRESS THE AGREEMENT WITH THE FDA REGARDING THE VALVULOPATHY.”

Here’s another encouraging comment from Jack:

103:55 Matt Osborne with Lazard: “Can you remind us, Jack, what you expect in terms of labeling for lorcaserin. Do you expect a requirement for screening for valvulopathy or no requirement at all upon getting a final label?”

Jack Lief: “Obviously labeling is important. We expect that the data will show that there’s no reason to require screening. THE FDA ALLOWED US TO NOT REQUIRE SCREENING IN THE BLOSSOM AND BLOOM-DM STUDIES AFTER THEY SAW THE SIX MONTH DATA REPORT FROM OUR ESMB IN THE BLOOM STUDY. The BLOOM study also shows that even over a long period of time there’s no signal whatsoever in valvulopathy so there’d be no reason to screen patients, so I’m excited about that.”

What, then, is the difference between ARNA's method and Wei's method? The fact that he hasn't revealed what his method is renders his motives suspect. I think we can just about put this baby to bed.

By Johngray on YMB - He posted his letter to Thomas Wei,

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=105146&mid=105146&tof=2&frt=2

Sunday, August 15, 2010 6:41 PM
From:
"John Gray" <johngray101@yahoo.com>
View contact details
To:
twei@jefferies.com
Thomas Wei,

You make a very strong claim, please back-up your data by posting it or please e-mail the information.

If your data is true then you have nothing to fear, but if your data is false when it comes to light on 9/14/10 when Arena pharma provides documents and stats otherwise. Especially at the AC 9/16/10. You'll have a ton of people reporting you to the SEC for false and misleading information.

see link:
http://online.wsj.com/article/BT-CO-2010...
http://www.benzinga.com/analyst-ratings/...

You make a very strong claim, please back-up your data by posting it or please e-mail the information.

Thank you, JG

Is 3% weight loss SIGNIFICANT? Qnexa vs Phentermine math

2010-11-03T07:52:00.000-07:00

Why is FDA biased?

Is 3% weight loss SIGNIFICANT? Qnexa vs Phentermine math

"PHEN/TPM achieved significantly greater weight loss compared to its components"

Now check slide 6 from FDAs presentation

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM227050.pdf

Mid dose(7.5/46 mg)
      LS Mean % loss for Qnexa        - 8.5
      LS Mean % loss for Phentermine - 5.5
-----------------------------------------------------
      LS Mean % loss difference       - 3.0
-----------------------------------------------------

High dose (15/92 mg)
      LS Mean % loss for Qnexa        - 9.2
      LS Mean % loss for Phentermine - 6.1
-----------------------------------------------------
      LS Mean % loss difference       - 3.1
-----------------------------------------------------

Do your math for Topiramate and now answer, do you get the picture?

Lorqess a novel compound has 3.8% mean adjusted weight loss compared to placebo arm with clean safety profile.

How can FDA not see this? If they do see, why are they biased? Is 3% considered SIGNIFICANT or "SLIM MARGIN"?

Why do we need approval for Qnexa? Why can't other doctors try what Dr Thomas Najarian had been for years?

2010-11-02T17:39:00.000-07:00

Dr Thomas Najarian seems to be doing that successfully for years

If that is legal why do we need to get FDA approval for Qnexa?

What is stopping other doctors from trying similar treatment especially with phentermine and topiramate?

Why would VVUS think it can sell the combo successfully if other can use it without FDA approval?

Any board certified doctor can try the combo, what is stopping them from doing that?

http://www.najariancenter.com/patient.information.html

What weight loss should you expect?

As long as you follow the program, you can expect to continue gradual weight loss for up to 24 months on medication. The weight loss should exceed 15% of your starting weight. Thus, if you weigh 200 pounds, you might expect to lose at least 30 pounds in a period of 12-18 months. In addition, a weight loss maintenance phase is instituted once the desired weight loss has been achieved.

==================================================
Excellent comments by "wichhazl"on YMB

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=181010&mid=181195&tof=7&rt=1&frt=2&off=1

Their "invention" of Qnexa is just a poor pretext, trying to cover how easy it is to induce the same effects with the generics. The pre-Phase III trials just gave phen in the morning -- to rev metabolism & inhibit appetite during the day, but so it would wear off by night-time to prevent insomnia. Then they took top in the afternoon, to keep a lid on appetite in the evening.

Actually, besides being much cheaper to do it that way, it also offers more flexibility in prescription. A doctor could give more or less of either drug to try to optimize benefit & minimize side effects, based on a particular patient's medical history.

It is true, of course, that a lot of doctors won't monkey around with this, & would rather just prescribe Q -- it would limit their liability, for one thing. The birth defect lawsuits will go straight to Vivus.

But, when patients are dismayed because they can't pay the high price of the prescription, many doctors will let them take the generics.

The patent lawsuits haven't even started yet. Qnexa is such a joke & a fraud. The market will realize this eventually.

=================================================

Investigate the Colman/Orloff Connection

2010-10-30T10:35:00.000-07:00

I urge caution with accusations

Below is a post from YMB which is interesting yet questionable, some of the accusations are strong and not sure if proofs exist. This might be good story for some investigative journalist to pursue.

Check this link to Adcom meeting from 2004 where Colman and Orloff presented and worked very closely

http://www.fda.gov/OHRMS/DOCKETS/AC/04/transcripts/2004-4068T1.htm

====================================================

Post by "knospeaba_robert"

http://messages.finance.yahoo.com/Business_%26_Finance/Investments/Stocks_%28A_to_Z%29/Stocks_A/threadview?bn=1339&tid=177714&mid=177967

If this is looked into, i am sure it would lead back to the fact that the Qnexa study writer Dr. Orloff and Dr. Colman have connections that would lead one to see foul play as possible specifically based on Colman's actions surrounding the Qnexa and Lorq panels. This was posted on the MB and I hope someone here puts some time into following up and if correct, posting it on the Deepcapture blog. To me this is the smoking gun issue at hand and serves to motivation, the only thing (other than the idea of money) that we have to show why there would be a bias.

Evidence suggests that Orloff and Colman worked closely together while at the FDA (not only on obesity related matters):

David Orloff and Eric Colman worked together on the 2004 Report of the Working Group on Obesity -
FDA Obesity Working Group Subgroup Members
THERAPEUTICS - Lead: David Orloff. Members: Eric Colman, Patricia Beaston

http://www.fda.gov/OHRMS/DOCKETS/AC/04/transcripts/2004-4068T1.htm

Eric Colman had authority to sign some documents for David Orloff. For examples:
see page 9
http://www.accessdata.fda.gov/drugsatfda...
see page 3
http://www.accessdata.fda.gov/drugsatfda...

When Orloff caused an FDA scandal he immediately found a new position at Medspace. Was this payback to Orloff for his controversial decisions and a deflection from a proper investigation?

New York Times article - December 7, 2005
A Food and Drug Administration official whose office was involved in a recent controversial application for drug approval said yesterday that he was resigning to join private industry. Dr. David Orloff, a division director who oversees the review of drugs to treat metabolic and endocrine disorders, is set to join Medpace, a contract research organization based in Cincinnati that runs clinical drug trials.
http://query.nytimes.com/gst/fullpage.ht...

Orloff was involved with qnexa at Medspace, but the level of involvement is not entirely clear:
Dr. David Orloff and his staff at Medpace, the clinical research organization that managed the qnexa clinical trials…
http://www.health2sport.com/patients-on-...

VVUS’s obesity clinical trials are being led by Dr. David Orloff, former director of the FDA’s Division of Metabolic and Endocrine Drug Products
http://obesityinvestor.typepad.com/obesi...

Dr. David Orloff, former head of the FDA’s Endocrine and Metabolism Division helped Vivus craft a data package that has a high likelihood of passing the scrutiny of the FDA.
http://www.investorvillage.com/smbd.asp?...

While at Medspace, Orloff believed that the FDA guidelines for combination drugs was irrelevant:
Dr. David Orloff served as the Director of the Division of Metabolism and Endocrinology Products at FDA from 2000-2006. Dr. Orloff felt that investors were over-interpreting FDA obesity guidelines. He believes that data to date shows qnexa to be very well tolerated and very effective, asserting that nothing so far should "sound any alarms." Dr. Orloff feels the issue of combination synergy (demonstrating 2x the weight loss of individual components) that has plagued VVUS is “ridiculous” and should “in no way be considered a requirement for approval."
http://www.investorvillage.com/mbthread....

Did he believe the FDA guidelines were irrelevant for assessing qnexa because Colman (his former close associate) was now responsible for reviewing NDAs? Orloff may have groomed Colman in how to game the approval process? The appearance of a conflict of interest gets worse...

===========================================================

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=180062&mid=180062&tof=2&rt=1&frt=2&off=1

Copied from YMB which was posted by "erewenguy"

There has been ongoing conversation in the comments section of one of Herper's latest articles.

http://blogs.forbes.com/matthewherper/2010/10/28/vivus-diet-drug-denied/#comment-1353

The accusations were called a "conspiracy theory", so I tried to outline the situation as I see it.

...

The “conspiracy theory” arises when looking at the total picture. If this were a court of law, enough circumstantial evidence exists for a grand jury to issue an indictment. Events are presented chronologically with the best information I have:

I believe Gebbe or his associates published the first information on the topo/phen combination in 2003 (?).

The FDA obesity workshop was conducted in 2004, where Orloff was chair of the theraputics subcommittee, which included Colman. It was time to advance the concept of combination therapies. Orloff and close associate Colman are on the regulatory “cutting edge” of understanding obesity theraputics.

Orloff’s office approves qnexa trials. Orloff’s office apparently recommends monotherapy trials of lorcaserin – a modification of a discredited drug.

Orloff becomes involved in controversy over approving a drug found to be dangerous (a questionable approval).

Orloff resigns from FDA and accepts a position at Medpace, where he oversees qnexa clinical trials his office approved.

Orloff publicly states that although qnexa DOES NOT meet combination therapy efficacy guidelines, there is no reason to believe it will not be approved.

Orloff writes qnexa NDA for Vivus, who submits it to FDA-CDER (Colman's office)

Colman is a guest on a television show which features Qnexa.

Qnexa panel review is conducted with proper diligence. “Abstain” IS allowed to panel members as a valid vote. Panel recommends rejection (no abstains) and Colman is on public record that he is surprised by the recommendation.

Lorcaserin panel meets, with well documented omissions or errors in regards to science and FDA guidelines for toxicity and efficacy, and conducted with biased innuendos and comments by FDA personnel Colman and Rosebraugh throughout the meeting. Critical cancer and toxicology experts are not on the panel. During voting instructions “abstain” is explicitly NOT allowed as an option. Panel members express ignorance of cancer/risk issues and vote to reject in the absence of abstain option.

Lorcaserin CRL is issued by Colman's office. ARNA to request type A meeting to clarify FDA requirements for path to approval.

Qnexa CRL issued by Colman's office. VVUS will respond in 6 weeks. No clarifications are needed concerning path to approval.

...

There are other side-bar facts to fill out the drama, such as potential document leaks and options activity, but the information presents the highlights.

I’m really not a conspiracy theory kind of guy, so I would welcome an alternative viewpoint compatible with Occam’s razor.

======================== End ============================

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=180062&mid=180091&tof=2&rt=1&frt=2&off=1

Response by "diogenes_32bc"

Here's what JL said at the BMO conference (this was after the July EMDAC) in response to a question on LorPhen:

~~~~~~~~~~~~~~~~~~~~~~~~~~
RE: Lorcaserin-phentermine study:

JL: You know, in the past, when I asked the FDA that question, they were not in favor of such a study... they discouraged that study... and we've recently seen what another company with phentermine as part of their product... some of the liabilities that phentermine brings to that product in terms of heart rate and pressure effects... and that sort of thing... so we're flexible, we're open, we'll have a dialog with the FDA later on... I should mention that phentermine is not available in Europe at all, it's not available in Canada, I don't think it's available in Japan... so it's certainly not.. something that's cookie-cutter way of losing weight throughout the world... so we'll just have to see.. how that works out... and I should also mention that since we'll be doing these agreements with countries throughout the world, we'll look at the local regs and that sort of thing.
~~~~~~~~~~~~~~~~~~~~~~~~~~

This is not verbatim, and is most likely not the final word on this so keep it in context.

==========================gopher_post============================

All fair questions raised by "gopher_tunnel"

“The FDA obesity workshop was conducted in 2004, where Orloff was chair of the theraputics subcommittee, which included Colman.”

Who else was in on that workshop? Do any of those names appear other places of interest?

“Orloff’s office approves qnexa trials. Orloff’s office apparently recommends monotherapy trials of lorcaserin – a modification of a discredited drug.”

What was Orloff’s role in this? Further documentation needed.

“Orloff resigns from FDA and accepts a position at Medpace, where he oversees qnexa clinical trials his office approved.”

Did he actually oversee Qnexa trials? Such a charge would need to be substantiated.

“Orloff publicly states that although qnexa DOES NOT meet combination therapy efficacy guidelines, there is no reason to believe it will not be approved.”

Link?

“Orloff writes qnexa NDA for Vivus, who submits it to FDA-CDER (Colman's office)”

Did Orloff write the NDA? Proof?

“Qnexa panel review is conducted with proper diligence. “Abstain” IS allowed to panel members as a valid vote. Panel recommends rejection (no abstains) and Colman is on public record that he is surprised by the recommendation.”

Link to Colman’s comments?

“Lorcaserin panel meets, with well documented omissions or errors in regards to science and FDA guidelines for toxicity and efficacy, and conducted with biased innuendos and comments by FDA personnel Colman and Rosebraugh throughout the meeting. Critical cancer and toxicology experts are not on the panel. During voting instructions “abstain” is explicitly NOT allowed as an option. Panel members express ignorance of cancer/risk issues and vote to reject in the absence of abstain option.”

Untrue. “Abstain” WAS an option but the panelists were pressured repeatedly to vote “yes” or “no”.

The theory may be correct, but the case requires more detail.

http://messages.finance.yahoo.com/Stocks_%28A_to_Z%29/Stocks_A/threadview?m=tm&bn=1339&tid=180062&mid=180158&tof=2&rt=1&frt=2&off=1

========================gopher post============================

Unbiassed Reporting...Not!

2010-10-29T10:17:00.000-07:00

Obviously Thomas Gryta of DOW JONES NEWSWIRES has a bias towards VVUS.

"Vivus Sees Pathway To 2011 Approval For Rejected Diet Drug

11:29 AM ET 10/29/10
By Thomas Gryta

NEW YORK (Dow Jones)--Despite the regulatory rejection of its weight-loss drug, Vivus Inc. (VVUS) is confident that it can meet requests from the Food and Drug Administration and get approval for its drug next year.

Late Thursday, the Mountain View, Calif., company said it received a so-called complete response letter for its drug Qnexa that requests additional information but states no need for more clinical trials at this time. The company believes that it has sufficient data to meet the agency's needs and will file a formal response in about six weeks.

The FDA request is "just a step in the process towards approval," Vivus Chief Executive Leland Wilson said on a conference call Friday. He said the FDA requests were "clear and specific" and the company will not meet with the agency before filing a response.

Vivus shares rallied on the news, trading up 26% to $7.72."

VS

"Arena Shares Drop As Diet Pill May Face Long Delay
By Thomas Gryta
NEW YORK (Dow Jones)--Arena Pharmaceuticals Inc. (ARNA) are down 2.5% as the company likely faces a long and challenging road for its weight-loss pill lorcaserin after a Food and Drug Administration rejection.

The San Diego drug maker said the FDA wants more information about cancer incidence in rat studies and requested more data on lorcaserin's effectiveness. The company may need to conduct more clinical trails to answer those requests, possibly delaying any approval for years, and raising questions about the ultimate future of the drug.

"We view the task of disproving potential negatives (cancer risk) while arguing for approval on the basis of 'marginal' efficacy to be a difficult challenge," Canaccord Adams analyst Adam Cutler said.

Arena's stock, recently at $1.59, lost almost half of its value after an FDA panel recommended against approve in September. With a significant delay for lorcaserin, trading in Arena shares may be volatile because more than 30% of its shares were sold short as of late September."

AND

OCTOBER 25, 2010, 2:26 P.M. ET

Arena Diet Drug Rejection Reflects High Bar To Treat Obesity
By Thomas Gryta

NEW YORK (Dow Jones)--The rejection of Arena Pharmaceuticals Inc. (ARNA) and Eisai Co.'s (ESALY, 4523.TO) weight-loss drug, lorcaserin, confirms the high regulatory bar for such therapies, something that may not bode well for others making the same effort.
...
The rejection is the first official feedback from the FDA on the latest crop of diet drugs. A panel of outside experts recommended against approval last month. ...........

Although the lorcaserin decision shows the FDA's seriousness, it doesn't have any direct correlation to the other two drugs because they work in a completely different manner. ..

Vivus's drug is widely expected to get a similar FDA response .., but many expect less onerous requirements for approval.

Lazard Capital Markets analyst William Tanner said he doesn't expect more pre-clinical or clinical data will be required for Qnexa, but he believes there will be questions about birth-defect risks for one of the drug's components. ..

It seems that Gryta is getting directives from above to give a better light on VVUS than on ARNA.

How nonprofit organizations can be bought - Article by Alicia Mundy in 2003

2010-10-27T22:07:00.000-07:00

I read this post on YMB and that brought back some memories about a passionate obese woman talking about breast cancer at the panel meeting. I am suspicious of her testimony after reading Alicia Mundy's article yet respect her opinion if independent(not bough out)

http://www.washingtonmonthly.com/features/2001/0301.mundy.html

In this article, the head of the National Women's Health Network says their organization doesn't take money from pharmaceutical companies -- but says nothing about whether they take money from hedge funds or their employees that may be investing in the biotech sector.

For any nonprofit, you can request a copy of their Form 990s to review the donations they received for the last 3 tax filings that are available. If this information is requested in person at a nonprofit's principal office, generally the organization must provide the information that day. If the information is requested in writing, the organization usually has 30 days to comply.

The 990 will itemize the org's donations, but the names and addresses of donors will be blacked out. These might at least tell us if the groups received any unusual large donations immediately before or after the AC. Unfortunately, any donations for 2010 won't be available until after they file 2010 taxes next April.

In the meantime, a donor-disclosure law would help and there just happens to be one stalled in the Senate right now.
http://philanthropy.com/blogs/government-and-politics/donor-disclosure-bill-again-stalls-in-senate/27177

The following organizations spoke against approval. This is highly unusual.

Someone needs to dig deeper into who invited these groups and what motivated them to speak against ARNA

National Women's Health Network http://nwhn.org/
National Research Center for Women and Families http://www.center4research.org/
Washington Center for Weight Management and Research http://www.wtmgmt.com/
Council on Size and Weight Discrimination http://www.cswd.org/

Obesity Action which has more than 18K members called for approval of new treatments

http://www.obesityaction.org/home/index.php

CRL Requirements and their interpretation

2010-10-27T01:06:00.000-07:00

What do the CRL requirements for Lorcaserin mean in practice?

1. Non-clinical issues

Issue 1.1 “Detailed accounting of all microscopic pathology slides prepared from FEMALE rats that contributed to the mammary tumor incidence data in each update to the FDA and the final study report”

a. Requirement: account for all slides done on those tissues – exactly what it says – an accounting issue.

b. In total, 65+65+75 = 205 FEMALE rats were given lorcaserin along with 65 untreated control FEMALE rats - see Table 6 in the section: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin” (Mammary Tumors).

c. This task should not take more than 4 months, leading to a revised report (if needed).

Issue 1.2 “Independent pathologists/group of pathologists to re-adjudicate all mammary and lung tissues from all FEMALE rats (205)”

a. Requirement: It is unclear why lung tissue is included here and this is a specific question for the FDA. For the mammary tissue, it appears this refers to a discrepancy between the week-96 tumor incidences at all doses and this should also be confirmed with the FDA. If this is indeed the reason for the accounting check – these independent pathologists would re-read the histological slides and give a final decision on what the true incidences are, so as to settle any misinterpretation or discrepancies.

This re-adjudication procedure should not take more than 4 months. The response does not require a new study based on advice from a non-clinical safety assessment toxicologist.

b. During the Arena conference call on October 25, 2010, the reason for the discrepancy was provided: The preliminary slides were reviewed on a set frequency by one pathologist and initial findings were sent to the FDA prior to the final submission – this was not required but was a courtesy preview for the FDA to observe the interim results. However, at the end of the study, three independent pathologists’ performed a peer review of the data and submitted their results and these were included in the final NDA.

c. The perceived discrepancy between assessments made by the different pathologists was mentioned in the section: “Genotoxicity and Carcinogenicity Assessment for Lorcaserin” (5^th paragraph; Mammary Tumors), where Dr. Alavi (FDA nonclinical pharmacology / toxicity presenter) makes the following statement:

“In subsequent updates and in the final study report, the incidence of adenocarcinoma in the MD and HD females was lower than that reported at week 96 (Table 7a). The incidence of adenocarcinoma increased in the controls and stayed consistent in the low dose group over the same period. The incidence of fibroadenoma increased in all dose groups from week 96 to the final study report, though the numbers notably varied in the mid- and high dose groups (Table 7b). It appears that some of the decrease in the number of adenocarcinoma after week 96 was accompanied by an increase in fibroadenoma, potentially a consequence of the sponsor/CRO reclassifying the observed tumor types.”

This raises an important question. Why did Dr. Alavi not know that the slides had been reviewed by a single pathologist during the study and then by three independent pathologists at the end of the study? It is well known that inter-observer variation can occur in assessments of this nature. This should have been taken into account, rather than implying that the sponsor/CRO had acted improperly in respect of the discrepancy in the final numbers.

Issue 1.3 “Demonstrate that the apparent increase in aggressiveness of adenocarcinoma in rats administered lorcaserin is REASONABLY irrelevant to human risk assessment.”

a. Requirement: With regard to the re-adjudicated results, a statistical analysis must be conducted to assess the significance of rat incidence of fibroadenomas and adenocarcinomas with respect to human risk. This is not a new study, but a re-assessment of the previous analysis. Unless the re-adjudication accounting yields different results, then a new study will not be necessary; however, this approach should be confirmed with the FDA.

b. The results are expected to be the same. If they are the same, then Arena needs to demonstrate that the adenocarcinomas seen at the very high and toxic Lorcaserin doses, and the statistically significant increases in fibroadenomas, do not portend a risk to humans.

c. The following information is relevant to this analysis:

The incidence of malignant adenocarcinoma tumors identified in the 10 mg/kg/day female group was no different to the normally-occurring incidence of these tumors identified in the untreated control group. Furthermore, in the 30 mg/kg/day female group, a dose 24-fold greater than the anticipated human therapeutic dose, the incidence of malignant mammary tumors was no greater than the normally-occurring malignant mammary tumor incidence reported in the untreated control female rats. Only at 100 mg/kg/day was there a statistically significant increase in adenocarcinoma incidence, but this lorcaserin dose is 82-fold that intended for human use. (Note that if Arena decides to fall into the FDA ‘mechanism of action (MOA) involves prolactin’ “trap”, they will fail and spend an eternity attempting to find the answer. They should not attempt to open Pandora’s box. There are numerous drugs on the market today for which the MOA for pathology is not understood).

Although the fibroadenoma incidence in the rats was found to be statistically significant at all doses, and the practice of combining benign tumors with malignant tumors is commonly done when the cell types are the same, this does not pose a human risk for the following reasons:

· Fibroadenoma and adenocarcinoma arise from cell types with different histogenesis. Adenocarcinomas are classified under the epithelial histotype, fibroadenomas under the epithelial-stromal histotype (Russo, Gusterson, et al. 1990 and Russo, Russo, et al. 1989).

· Benign mammary fibroadenomas can only be transformed to malignant mammary carcinosarcoma and never to mammary adenocarcinoma (Russo, Gusterson, et al. 1990 and Russo, Russo, et al. 1989). These are distinctly different tumors.

· The rat model of tumorigensis closely mimics human breast tumor development.

· Fibroadenomas rarely progress to adenocarcinoma in the rat.

· Fatalities from benign fibroadenomas do not translate as a risk to humans.

· Fibroadenomas rarely progress to adenocarcinoma in the human female and are relatively common (London, et al. 1992).

Issue 1.4 “Provide ADDITIONAL DATA/INFORMATION regarding the distribution of lorcaserin to the CNS in animals and human subjects that would clarify or provide a better estimate of astrocytoma exposure margins.”

a. Requirement: Since brain partitioning—brain to plasma (BPD) ratio—was not determined in humans, the FDA is concerned that estimates of safety margins based on extrapolation from monkey brain-to-plasma ratios are not reliable. Additional documented information and data are required to address this issue. Proven case studies may also help to demonstrate validity, although this approach should be confirmed with the FDA.

b. An assumption made by Dr. Alavi regarding the reliability of extrapolating monkey BPD ratios to human subjects is paraphrased as follows:

Brain partitioning in human subjects was not determined. Thus, estimating safety margins based on assumptions of partitioning in human subjects is not entirely reliable. Assuming that the monkey best models human partitioning, the estimated safety margin to a non-tumorigenic dose in rats may range from 11x to 17x, with tumors associated with brain exposures that are 40x to 59x higher than clinical exposure. More conservatively, safety margins based on plasma drug levels, which is known for rats and humans, yields a safety margin to the non-tumorigenic dose in rats of 5x, with brain tumors occurring at doses of lorcaserin 17-fold higher than the clinical dose” from the section in the FDA briefing document: from the section “Genotoxicity and Carcinogenicity Assessment For Lorcaserin. (Note this abstract is paraphrased, not a verbatim quote).

c. The actual measured BPD ratio for lorcaserin is not known in humans since it is a novel new drug that has not yet been studied in this way. However, we do know:

· The BPD ratio for lorcaserin for mice is 25 times higher in the brain vs. plasma (of note, there were no brain tumors in mice including the high dose group).

· The BPD ratio for lorcaserin for rats is 29 times higher in the brain vs. plasma.

· The BPD ratio for lorcaserin for monkeys is 10 times higher in the brain vs. plasma.

d. The solution: An extensive review on this very issue (Shen, Artru and Adkison, 2004) clearly indicates that extrapolated partitioning in human subjects can be a reliable means of estimating risk safety margins. Referring to the monkey model, the authors state:

“In the second part of our analysis, we examined the issue of whether CSF penetration studies in animals are predictive of human data. We obtained animal and human CSF data on 27 drugs, including 13 antiepileptics, 1 psychotropic drug, 5 anesthetics or analgesics, 5 antibiotics, 1 antiretroviral, and 2 anticancer drugs, and across six animal species, including rats, dogs, rabbits, cats, guinea pigs and monkeys. As can be seen in Fig. 9, there is a reasonably good correlation for the majority of drugs in this survey."

In the same article the authors conclude that:

"Despite the complexity of CSF physiology and pharmacokinetics, CSF penetration studies in animals remain a practical option for the assessment of CNS drug delivery in early preclinical drug development"

e. The interpretation: Monkey brain partition studies can, therefore, be used with reasonable assurance for estimating a drug's margin of safety in the human brain. The brain-to-plasma ratio for lorcaserin for rats is 29 times higher in the brain vs. plasma and the for monkeys it is 10 times higher in the brain vs. plasma

f. Lorcaserin application: There is 29x more lorcaserin in the rat brain, so the dose given to rats at the LD, MD, and HD will be much higher in the CSF and therefore more toxic. In practice, this means that at any given dose, the higher the brain exposure in rats, the higher will be the estimated brain exposure in humans. Tables 13 and 14 in the FDA document in the section: “Genotoxicity and Carcinogenicity Assessment For Lorcaserin (Brain Astrocytoma)”:

· Brain exposure in the rat at 30mg/kg (brain tumors present in the rat) = 405-591 mcgm/ml.

· Using the brain-to-plasma ration of 10x in the monkeys (multiple the brain exposure in rats by 10).

· Brain exposure in humans at the 30 mg/kg (brain tumors present in the rat) = 40x-59x multiple of the clinical dose (10mg bid (twice a day).

· Therefore, from the Table, we can see that the margin of safety is at 11x-17x multiple of the clinical dose, which would satisfy the concern brought up in the CRL.

· The 17x dose is when the tumors first appeared (the 30 mg/kg dose). Hence the tumorigenic dose for humans, when discussing brain/plasma ratios, would then be 40-59x multiple of the clinic dose - far above the 25-fold limit dose in the FDA guidelines.

· So from the data on the male rats the risk of developing statistically nonsignificant astrocytomas in the human, assuming that this can be transferred to human risk, would only arise at 40-59 x multiple of the clinical dose. The margin of safety dose would be 17x multiple and perhaps anywhere up to 39x multiple, although the precise value would have to be determined at incremental increases in the dose of lorcaserin (which is not necessary).

· However because Dr. Alavi used plasma levels, he concluded that the nontumorigenic dose (level where there are no tumors) gave a margin of safety at only a 5x multiple of the clinical dose. Our analysis suggests that he erred in doing this.

g. Astrocytoma was only statistically significant in male rats in the high dose group, but none of these tumors was found in the female rats.

h. The solution: To address the Astrocytoma issue Arena must supply all MBTD and brain-to-plasma ratio data to FDA in a simple, easy-to-read format. Given adequate resources, this administrative task should not take long.

2. Clinical issues

Issue 2.1 Provide BLOOM-DM trial results and analysis with respect to efficacy and diabetic health factors.

a. Results on the BLOOM-DM trial results. There is nothing more to say on this point.

3. Labeling requirements

Issue 3.1 Labeling requirements will include the following.

a. Schedule IV: This is not a significant issue. Schedule IV does not necessarily preclude long-term use, although FDA may add restrictions to that effect. They did leave the door open for removal of this label later after certain post approval studies are completed.

b. Arena must discuss with FDA any nonclinical studies conducted to address abuse concerns regarding the long-term use of lorcaserin.

4. Conclusions

In conclusion, no new studies need to be done except perhaps brain partitioning studies on humans. However, this may not be necessary if the information provided above is correct. If such studies were performed, they would not be long-term experiments and could be completed in a relatively short period, and they may not even need to be carried out under GLP conditions. However, I sense Arena already has all the data required to address this particular concern. Every other aspect of the CRL involves a REVIEW of existing information, nothing else. If everything is submitted in a timely manner, the estimated timeframe for the completion of these reviews should be less than 6 months.

REFERENCES CITED

London, S.J., Connolly J.L., S.J. Schnitt, and G.A. Colditz. "A Prospective Study of Benign Breast Disease and the Risk of Breast Cancer." JAMA 267 (1992): 941-4.

Russo, Jose, Barry A. Gusterson, Adrianne E. Rogers, Irma H. Russo, Seft R. Wellings, and Matthew J. Van Zwietien. "Biology of Disease: Comparative Study of Human and Rat Mammary Tumorigenesis." Laboratory Investigation, 1990: 267.

Russo, Jose, Irma H. Russo, Matthew J. van Zwieten, Adrianne E. Rogers, and Barry A. Gusterson. "Integument and Mammary Glands of Laboratory Animals." In Classification of Neoplastic and Non-neoplastic Lesions of the Rat Mammary Gland, edited by T.C. Uones, U. Mohr and R.D. Hunt, 275-304. Berlin:Springer-Verlag, 1989.

Shen, Danny D., Alan A. Artru, and Kimberly A. Adkison. "Principles and Applicability of CSF Sampling for the Assessment of CNS Drug Delivery and Pharmacodynamics." Advanced Drug Delivery Reviews, 2004: 1825-1857.

Daniel P. Lopez, M.D., F.A.C.O.G.

Diplomate American Board of Obstetrics and Gynecology

BORG Member

Many people are wondering how the Drug Ombudsman Mary Kremzner responded

2010-10-26T09:40:00.000-07:00

Many people are wondering how the Drug Ombudsman Mary Kremzner responded to comments to her. The BioWorld reported:

"FDA spokeswoman Ayse Yeaton told BioWorld Today that the agency sent nine hard copy letters and 89 e-mails to members of the public last week in response to inquiries and accusations about the lorcaserin panel."

I was one who received an e-mail response and I am recording it here for others to read.

On September 27, I emailed Capt. Mary Kremzner the following message:
Dear Capt Kremzner,

I thought you may be interested in seeing this online petition being promulgated regarding the lorcaserin panel review and effect on approval:

http://www.petitiononline.com/passlorc/petition.html

--

R (Bud) T

On October 21, I received from MK, the following response:

Dear R(Bud) T-----,

Thank you for communicating your concerns to the U.S. Food and Drug Administration (FDA or the Agency) about the lorcaserin advisory committee meeting. As you know, on September 16, 2010, FDA held a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (Advisory Committee) to discuss the safety and efficacy of lorcaserin, a drug developed by Arena Pharmaceuticals, Inc. (Arena) to treat obesity. The Advisory Committee—made up of physicians, scientists, statisticians, and patient and consumer representatives— reviewed extensive background information prior to the meeting. The sponsor, FDA staff, and members of the public gave presentations during the Advisory Committee meeting. After thoroughly considering all the available information, the Advisory Committee voted 9-5 to recommend that FDA not approve lorcaserin for marketing.

After the Advisory Committee meeting, FDA began receiving correspondence from numerous parties questioning the views of FDA staff and comments made by FDA staff during the meeting, as well as accusations that scientists with appropriate expertise had not evaluated lorcaserin’s safety and efficacy data. FDA takes all comments and concerns about advisory committee proceedings seriously and wants to take this opportunity to address some of the concerns about our policies and procedures.

FDA achieves its mission to protect and promote the public health through rigorous evaluation of all data submitted in support of a new drug application (NDA). Often, the data submitted raise challenging or novel scientific issues relating to the drug’s safety and/or efficacy. FDA advisory committees serve an important function by providing the Agency with an independent, expert evaluation of the data during the drug review process. FDA ensures that during the meeting, the full spectrum of views of the data are presented to the committee and that all committee members have the opportunity to ask questions and present their own views on the data. FDA staff also routinely present their own reviews, conclusions, and individual perspectives of the data. This practice ensures that differing opinions are transparently presented and debated and allows the committee to make recommendations after taking into account all perspectives. This public process helps FDA obtain expert advice during the review process and increases the transparency to those with an interest in a particular matter. Although FDA highly values the opinions of the independent experts on the committee and often incorporates those opinions into its decision-making process, FDA makes the final decision about whether a drug should be approved. Advisory committee votes and recommendations are not binding on the Agency.

FDA has strict rules governing conflicts of interest for both employees and advisory committee members. With certain limited exceptions, FDA employees and their families cannot hold a financial interest in any company that is significantly regulated by FDA. FDA employees must report their financial interests on a yearly basis and their reports are reviewed by Agency ethics staff. FDA has not been made aware of any evidence to suggest that these rules were not followed by the FDA staff at the lorcaserin Advisory Committee meeting.

Similarly, advisory committee members must report to FDA any financial interests they hold related to the subject matter of the advisory committee meeting. FDA screens advisory committee members broadly for financial or other relationships that could present even the appearance that they have conflicts of interest that could affect their impartiality. For the lorcaserin meeting, as with all advisory committee meetings, all Advisory Committee members were appropriately screened for conflicts of interest.

Although FDA strives to have broad representation of appropriate medical and scientific specialties on its advisory committees, optimal representation is often difficult to achieve given the strict conflict-of-interest regulations that apply, as well as calendar conflicts, which may limit the availability of experts for the selected meeting dates. The lorcaserin Advisory Committee included representation from the fields of Endocrinology, Cardiology, Pharmacology, Health Policy, Epidemiology, Biostatistics, Internal Medicine, and Clinical Research. In hindsight, FDA regrets that no toxicologist participated in the meeting. However, a team of FDA toxicology experts reviewed the lorcaserin NDA and interpreted the data related to the lorcaserin carcinogenicity studies. Moreover, the lorcaserin carcinogenicity studies were also thoroughly reviewed and discussed by the Center for Drug Evaluation and Research (CDER) Executive Carcinogenicity Assessment Committee, and the results of this scientific assessment were included in the background documents provided to the committee and discussed in Agency presentations at the Advisory Committee meeting.

Consistent with the FDA’s policy on transparency, FDA announces the dates for advisory committee meetings in advance through publication of a notice in the Federal Register, and the Agency posts all advisory committee briefing materials on its public website 48 hours prior to the meeting. Prior to the public posting of the documents, they are kept in strict confidentiality with only the advisory committee members and the sponsor having the opportunity to review them. As soon as possible after an advisory committee meeting has concluded, a transcript of the meeting is made available on FDA’s public website. In this way, the diverse views of all participants, both FDA employees and advisory committee members, are made available to the public.

After obtaining advisory committee input on an NDA, FDA completes its review of the application and communicates its findings to the sponsor. FDA considers all of the data contained in the application and conducts its own independent analysis of the data before making a decision as to whether the benefits of the drug outweigh its risks for the proposed use. FDA believes that this rigorous review process leads to the most appropriate decisions about the safety and efficacy of proposed new drugs.

FDA remains committed to ensuring that its advisory committee process is conducted according to applicable statutes and regulations and will continue to make these proceedings transparent to the American public. With regard to the specific allegations made against FDA staff, FDA will continue to review these allegations and if misconduct is identified, will take appropriate action.

Again, we appreciate you taking the time to express your concerns.

Sincerely,

Division of Drug Information LC
Center for Drug Evaluation and Research
Food and Drug Administration
-----------------------------------------

A lot of boilerplate here, but I think we got our message through and it had on effect on the CRL sent to Arena. It also reached the media that an unprecedented amount of investor watchfulness has been established in ARNA. This can largely be attributed to the Yaho0 Message Board and this Blog Site.

Why did Carcenogenic expert change his mind to attend Adcom in last minute?

2010-10-26T07:24:00.000-07:00

This is an article from BIOWORLD

http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=56203

FDA spokeswoman Ayse Yeaton told BioWorld Today that the agency sent nine hard copy letters and 89 e-mails to members of the public last week in response to inquiries and accusations about the lorcaserin panel.

Some of the FDA's outside advisers admitted during the September meeting that they were perplexed by the carcinogenicity data and lacked the expertise to weigh the decision before them.

Indeed, the 15-member panel consisted mostly of diabetes experts, with a few cardiologists and statisticians thrown in, along with a patient representative and a nonvoting pharmaceutical industry consultant.

FDA spokeswoman Karen Riley told BioWorld Today in September that "We did have an expert on rodent carcinogenicity slated to attend the meeting, but he changed his mind late in the process." Nonetheless, the FDA argued that a team of "FDA toxicology experts reviewed the lorcaserin NDA and interpreted the data related to the lorcaserin carcinogenicity studies."

[Verso] Read the last paragraph, they had an expert slated and he changed his mind in the last minute, why? doesn't that smell?

Eisai Vote of Confidence

2010-10-24T23:48:00.000-07:00

"Lonnel Coats, President and Chief Executive Officer of Eisai Inc., stated, "Eisai is committed to collaborating with Arena to address the FDA's requests. Obesity is an epidemic in America, and our goal is to bring lorcaserin to physicians and patients who need additional weight loss options."

With Eisai's backing, ARNA will have a deep pocket to draw from !
In the meantime, in Asia this morning 10/25/2010, Eisai share price jumps after clarification of FDA CRL is understood: http://www.google.com/finance?q=TYO:4523

Bashers Handbook - Everything you need to know about them

2010-10-24T15:12:00.000-07:00

I am adding this only because I fear the publisher can choose to shut the website down any day and we will be at loss. This is a very helpful HANDBOOK on BASHERS.

Disclaimer: This content is COPIED and PASTED from "Message Board Fools - http://messageboardfools.com/bashers.htm",

None of this content was written by me but I fully endorse it.

Link: http://messageboardfools.com/bashers.htm

Full credit goes to "Message Board Fools" and KUDOS!!

The Basher's Handbook

Reprinted here as a service to those who doubt this actually exists, or is simply an unfounded urban legend.

Is the "Bashing" of a stock an essential part of the online investment landscape?

Our Constitution guarantees us free speech and we have always valued the lessons gleaned from dissent. When does dissent cross over that imaginary line and become "Bashing"? To often we find well grounded dissent capriciously labeled as "Bashing" by over zealous investors bent on protecting a stocks reputation at any cost. The "Bashing" that is addressed on this site is quite different from dissent. The Anatomy of a Basher strives to look at the calculated erosion of confidence in a given stock. Erosion by means that are, in every sense, void of truth, hinged on deception and innuendo, and motivated by greed at the expense of others. This compendium is offered to aid in identifying the telltale signs of "Bashing", and hopefully provide a counter balance to this heretofore unchecked manipulation of investors fears for personal gain.

IS IT EASIER TO SCARE PEOPLE INTO SELLING THAN IT IS TO SCARE PEOPLE INTO BUYING A STOCK? I have asked some knowledgeable investors this question and the answer is always: "YES, OF COURSE YES!"

WHO BASHERS PREY UPON

Consider the elderly that are investing for retirement, they find their way to the message boards for validation only to see false posts about "SEC Violations" and "Class action suits"... or the head of a "typical growing family", with children to put through college, who is monitoring a message board only to read posts by a "pack of 15 to 20 Bashers" (probably 5 or 6 under various alias's) posting continuous disinformation... what do you think these new investors will do? It's safer to not buy or even sell the stock, put the money back in the bank than to deal with all this whirl wind of "unsupported" negative chaff.

The Internet has lured a whole new class of investor into the market. A new investor is just that - New! This new investor, while learning the basics, is particularly vulnerable to the tactics of professional Bashers. New investors tend to lurk in the background of message boards, content to form independent opinions based on what they read with their own eyes. Very often, honest, intelligent and cautious people can easily be overcome by a well orchestrated propaganda effort.

You must always remember that their is a lot of money to be made in just the motion of a stock UP or DOWN it doesn't matter! And Bashers have money at risk just as you do. But they have the edge of fear, lies, and falsehoods to post while preying on the un-initiated. The average investor dose not have the edge of organized deception.

Recent revelations have indicated that even Market Makers (those charged with keeping the playing field level) have been involved in stock manipulation by Bashing on a stock message board. HAVE NO DOUBT THAT THIS IS A REAL THREAT!

Lesson 1: Remember, BASHERS NEVER Bash A BAD STOCK. Check the boards for stocks with no potential. They never have any Bashers. Bashers only go after stocks that are moving up or have excellent potential to do so. Bashers work to bring the price down to either increase their position at the expense of others or help a Short make their bones.

Lesson 2: BASHERS ALWAYS BRING UP OLD NEWS THAT YOU HAVE HEARD MANY TIMES. New startup companies always have a few bits of bad news. The Basher will post this over and over again. Unsophisticated Bashers will try to freshen up old news with a new date or by-line in an attempt to fool you.

Lesson 3: BASHERS POST MANY TIMES A DAY. They try to wear you out. They comment on everything, every other post, and can answer every question. THEY KNOW IT ALL! There is no positive comment they won't Bash. They try to control the board. True longs may have to confront the Bashers or they will appear to the newbies as being the people with all the information. This is best accomplished by posting positive, well researched data on the company, repetitively, while trying hard not to engage the Bashers in direct repartee. REMEMBER - LONGS... RESIST USING THE BASHERS ALIAS!

Lesson 4: BASHERS WILL LIE TO YOUR FACE. Never trust a Basher. The truth on startup companies is that they make mistakes. What new company hasn't? The Basher will compare your issue to a another companies, financials - deals - management, etc., trying to lure you into making an Apples to Oranges comparison. Remember each company is unique and while it is prudent to seek out established indicators, do so with care and don't take someone else's word for it. Strive to come up with at least a "six-pack" of indicators so your vision of the state of a company is not tied to a single barometer. Not doing so is tantamount to going to a Race Track and betting on the "Pretty Brown Horsey". BASHERS WANT TO WHISPER IN YOUR EAR - PLANT A SEED OF DOUBT, AND HOPE THAT YOU ARE NOT SAVVY ENOUGH TO RESEARCH THE TRUTH ON YOUR OWN. This is how they achieve their greatest success.

DOUBT + FEAR + LAZINESS = BAIL OUT!

This is your investment... work for it, protect it and don't panic on the words of very shadowy figure that "has your best interest in their heart". Consider that one factor: Someone you have never met, is not a member of your family, is now, out of the goodness of their hearts - GIVING YOU FREE ADVICE (that you didn't ask for). It's a no brainer. They have motives $$$$$$$$$$$$.

Lesson 5: Bashers know YOU CAN'T VERIFY THEIR STATEMENTS. That's why they make the vague statements they do. They rely on you being to lazy to research their droppings other than to scan the board for others opinions. This is particularly dangerous when you consider that Bashers work in packs and often validate and back up each others nonsense with what appears to be "innocuous and unsolicited" verification by comrade Bashers. Let's face it, we are all conditioned to "believe" everything we see in writing. If others by virtue of their "posts" also confirm this belief, then we are subconsciously doomed to swallow the hook, line and sinker... Basher - 1 Honest Investor - 0

Lesson 6: The Bashers PLAY ON YOUR LACK OF KNOWLEDGE. They can lie about information and you won't know the difference (unless you have done your own DD on the company and know the truth and facts).

Lesson 7: Bashers play on your lack of patience. You have held a stock for a while. You knew it will be a big stock someday, but the BASHER CAN GET TO YOU BECAUSE YOU ARE TIRED OF WAITING FOR YOUR GAIN. That's when the Basher is best. You are tired. You have forgotten the goal for the stock was to hold it for one year. The Basher is bothersome, so you dump it on a bad day. Some others also dump. Then you get mad for your loss and return to let everyone know how mad you are. Then you turn into a semi-Basher as well. THE BASHER HAS WON, AND GAINED A NEW ALLY - YOU!

Lesson 8: BRING THE PRICE DOWN. That is the Basher's job. The truth is not important. Lies are the norm. Post continuously on the board every day. They are trying to scare the newbies that are just investigating a stock. They are trying to wear down the faithful longs on the board and gain free reign and control.

A BASHER HANDBOOK:
Do not underestimate a Bashers influence on a stock. The Pro's are good at what they do and what they do is profit from your losses. Below is their "hand-book". Learn from it or you will be donating your hard earned money to them!

Rules for Successful Bashing:

1. Be anonymous

2. Use 10% fact. 90% suggestion. The facts will lend credibility to your suggestions.

3. Let others help you learn about the stock. Build rapport and a
support base before initiating your Bashing routine.

4. Enter w/ humor and reply to all who reply to you.

5. Use multiple ISP's, handles and aliases.

6. Use two (2) or more aliases to simulate a discussion.

7. Do not start with an all out slam of the stock. Build softly.

8. Identify your foes (Longs) and the boards "guru" Use them to
your advantage. Lead them do not follow their lead.

9. Only Bash until the tide/momentum turns. Let doubt carry it the
rest of the way.

10. Give the appearance of being open minded.

11. Be bold in your statements. People follow strength.

12. Write headlines in caps with catchy statements.

13. Pour it on as your position gains momentum. Not your personality.

14. Don't worry about being labeled a "Basher". Newbies won't
know your history.

15. When identified put up a brief fight, then back off. Return in an hour unless your foe is a weak in reasoning powers.

16. Your goal is to limit the momentum of the run. Not to tank the
company or create a plunge in the stock; be subtle and consistent.

17. Kill the dreams of profits, not the company or the stock.

18. Use questions to create critical thinking. Statements to
reinforce facts.

19. DO NOT LIE, NAME CALL or USE PROFANITY.

20. Encourage people to call the company. 99% won't. They'll take your word for claims made. If they do call you can always find something that is inaccurate in how they report their findings.

21. Discourage people from believing Press Releases.
Encourage them to call the company. They won't out of laziness.

22. If the companies history/PR's are negative constantly point to that. Compile a list of this data prior to beginning your efforts.

23. If the price rises blame it on the hype or the PR, temporary
mass reaction, the market, etc. Anything but the stock itself.

24. If other posters share your concerns, play on that and share theirs too.

25. Always cite low volume, even when it's not.

26. Three or four aliases can dominate a board and wear down the longs.

27. Bait the Longs into personal debates putting their
focus/efforts on you and not the stock or facts. Divert their attention from facts.

28. Promote other stocks that would-be investors can turn to
instead of the one your Bashing.

30. Do not fall for challenges on the "values" of what you are doing, it's a game and you are playing it with your own rules.

Grade 'A' Basher:
If you post lots of old news, respond to all positive posts with a negative side. Never respond to being called a Basher, never post on another board with same alias. Can spend up to 80 hours a week Bashing a stock.
Grade 'B' Basher:
Very good way with words, always claims to be your "friend" taking the positive poster into confidence, never posts on another board, spends about 60 hours a week.

Grade 'C' Basher:
Spends less time than the others but is somewhat effective and gets a C grade due to getting excited when Bashers rules say not to get excited, spends about 40 hours a week.

Grade 'D' Basher:
Needs to learn the basics about being convincing when making a negative statement. Spends a good amount of time working the stock, maybe 20 hours a week.

Grade 'F' Basher:
A complete idiot, most readers are not convinced he knows anything about stocks in general. The type that says a stock "sucks", but gives no rationale, shows up every so often but no regular schedule.

LEARN ABOUT HOW BASHERS WORK: For instance: did you know that some Bashers are paid?

Golden Rule:

IGNORE THEM ...learn how professional Bashers are paid: When you REPLY to Bashers you give them an opportunity to earn appox. 5-7 dollars. The service agreement they enter into with their employer states their messages will be monitored for content, profanity, lies, etc. but Overseers and the like don't have the time to check all their Bashers messages. Only occasional spot checks are done. Those who manage the Basher will generally read the headlines to see if a Basher is replying to other posters by name. That tells them the Basher isn't just "posting blindly" or repeating the same message over and over since they won't pay for those.(True to form a Basher will put the bite on anyone, even their unscrupulous employer). A Basher will attempt to milk three to five replies per post at one to two dollars each. This way the Basher spreads negative influence to as many stockholders as possible. A Basher will create this discussion thread because it takes less time reading more messages than is necessary. This ultimately allows the Basher more time to post and make money. In general, NEVER ENGAGE A BASHER. Make them read all the posts and think up ways to enter the discussion. NEVER ENGAGE A BASHER; if you do so then YOU BECOME THE BASHER,S AID! If you feel compelled to challenge a Basher do so without mentioning his/her true alias in your response. This will make it hard for the Basher to use your post as a revenue stream. Read the news, do your own homework and make your own decisions. Get real time quotes and follow the stock for a couple of weeks. Due Diligence is key here. Know that there will be a time when the stock runs up which will be followed followed by the Bashers and those that missed the boat. The Bashers will trash the stock by saying such things as "it's a Pump and Dump" and "the company is lying" and deceiving. There goal is to scare off newbies and potential new investors by "shaking" you out of your shares. Take the time to confirm your DD ,trust your own judgement and believe in yourself, pick your point of return or loss and live with it. Don't listen to hype or Bashers trust your own judgement. Live by the rules you have created .

HOW TO IDENTIFY A BASHER

1. Check the "Born on Date" Bashers create identities on a regular basis. Rarely do you find a Basher with older "Created On" date. So click on the Identity icon for more details.

2. Take the time to look at the Basher's history of Posts. Go to other boards and see if their is a pattern to the theme of the posts. Bashers rarely waste time trying to blend in with "positive" posts, unless they are cultivating a new uninformed assistant.

3. When did the Basher show up. Bashers rarely show up when activity is in at a Lull. They show up when activity up/down..

4. Bashers never answer direct questions except with another question.

5. Bashers do work in teams (sometimes themselves as a team). So be suspicious of someone showing up and automatically having a Shadow to converse with who supports their argument.

6. Bashers always select "an argument" that can never be resolved by research.

The Basher 'Pack' Mentality

Bashers love to work in packs. It provides the quintessential cover to achieve supposedly "independent" validation of an argument. It is neither independent nor validating.

Pack Structure: Basher Packs can be comprised of any number of Bashers. They can be purposely formed within an organization or they can be "ad hoc" formed during a conclave on a particular board. In fact a pack mentality can be achieved by an ambitious "party of one" with a few select aliases.

Once a pack is formed, a leader emerges. This leader is usually acknowledged by other Bashers because of 1. Knowledge of the stock. or 2. Recognition by current board Longs (high visibility). Once established the Leader will usually work the Pack members up in to a posting frenzy. Constantly changing themes and even occasionally biting the ear of another pack member (this earns instant credibility), and it doesn't offend the bitten Basher because he/she knows it is all part of the effect. Quite sophisticated.

Packs will disband and slink away without notice. Usually this is the call of the Pack Leader who is adept at recognizing overplay. More often than not, Pack members must move on because they have other Bashing commitments to fulfill. They will return to the site of a good hunt over and over again, until hamstringing is achieved.

What calls a pack together. The Cry of the Leader. Certain Bashers love to work together. They know each others bite, how to feign in and out, it is a well choreographed Bash when pack members have worked together before. They constantly check their "Sites Du Jour" for signs of Pack activity. Occasionally they will throw out a "Nibbler" Bash to see if the pack responds or if not they can work the site themselves. It's all about effectiveness, time and earning money.

< BEWARE OF THE PACK >

ARNA Investors

Obesity is a disease - AMA, Belviq launched, Ellie Wenker success story

Arena Pharmaceuticals Reports on Launch of BELVIQ® (lorcaserin HCl) CIV for Chronic Weight Management in Adults who are

A.M.A. Recognizes Obesity as a Disease

Formal way to request an investigation at the FDA

First Prescription Weight-Loss Treatment Approved by FDA in 13 Years

Arena Pharmaceuticals and Eisai Announce FDA Approval of BELVIQ® (lorcaserin HCl) for Chronic Weight Management in Adults who are Overweight with a Comorbidity or Obese

-- First Prescription Weight-Loss Treatment Approved by FDA in 13 Years-- Eisai to Launch BELVIQ in U.S. Following DEA's Completion of Scheduling Review

Media jumping on Lorcaserin/ARNA bandwagon

FDA BD Synopsis by Dr. Daniel Lopez

Lawsuit filed by ARNA investors against Adam Feuerstein

ARNA shareholders filed a lawsuit against Adam Feuerstein of thestreet.com

Letter to Dr. Woodcock by Obesity Care Continuum(OCC)

Another set back for Obesity fight - Amylin halts obesity drug study

Why the Astrocytoma Margin of Safety Requirements Will be Satisfied - By Dr. Daniel Lopez

Criminal investigations chief resigns, things are changing at FDA

Improper influence of former Director taints FDA analysis of Lorqess

Improper influence of former Director taints FDA analysis of Lorqess

Analysis of BLOOM-DM results and media bias

SEC is MIA? - Letter by J. Bernard LoVerde, Jr.

Facebook connections, bad journalism and naked short selling hedge funds

Destroying Companies For Profit

http://current.com/news/politics/89439340_destroying-companies-for-profit.htm

Thomas Wei of Jeffries, who at FDA did he talk to about ARNA and its data prior to Adcom?

Is 3% weight loss SIGNIFICANT? Qnexa vs Phentermine math

Why do we need approval for Qnexa? Why can't other doctors try what Dr Thomas Najarian had been for years?

Investigate the Colman/Orloff Connection

Unbiassed Reporting...Not!

How nonprofit organizations can be bought - Article by Alicia Mundy in 2003

CRL Requirements and their interpretation

Many people are wondering how the Drug Ombudsman Mary Kremzner responded

Why did Carcenogenic expert change his mind to attend Adcom in last minute?

Eisai Vote of Confidence

Bashers Handbook - Everything you need to know about them

-- First Prescription Weight-Loss Treatment Approved by FDA in 13 Years
-- Eisai to Launch BELVIQ in U.S. Following DEA's Completion of Scheduling Review