POST-ADCOMM By Reza Ganjavi To the FDA (includes appendices by Drs. Vig & Lopez

25 May 2012 

To:     - Honorable Dr. Margaret Hamburg, FDA Commissioner

- Honorable Dr. Janet Woodcock, Director, CDER

 Copy: - Dr. Fred Alavi, Dr. Todd Bourcier, Dr. Eric Colman, Dr. Julie Golden,

  Dr. Mary Parks, Dr. Curtis Rosebraugh, Mr. Paul Tran

 INTRODUCTION.. 1

WIDE INTEREST IN LORCASERIN.. 1

ATTEMPTS TO QUASH INNOVATION.. 2

REVIEW OF ADCOMM 2012. 2

FDA DID AN EXCELLENT JOB. 

UNPREPARED ADCOMM MEMBERS. 

DR. KAUL’S BIAS. 

THE VOTE. 

PUBLIC SPEAKERS. 

EFFICACY & DROP OUTS. 

NO NEED FOR REMS / ECHOCARDIOGRAMS. 

INTERNIST’S PLEA FOR SPEEDY APPROVAL. 

FUTURE POTENTIAL. 

CONCERNS ABOUT Qnexa (Qsymia)’S SAFETY. 

A FEW MORE DOCTOR COMMENTS. 

Appendix 1. REMS / ECHOCARDIOGRAMS NOT NECESSARY. 

Appendix 2. AN INTERNIST’S PLEA FOR SPEEDY APPROVAL. 

Appendix 3. LORCASERIN’S LOW POTENTIAL FOR ABUSE. 

Appendix 4. COMMENTS FROM THREE ADCOMM DOCTORS. 

CONCLUSION.. 

Dear Honorable Drs. Hamburg and Woodcock and your esteemed colleagues at CDER:

INTRODUCTION

I am not a doctor but have studied science and philosophy. All sciences including medicine are rooted in philosophy whose root meaning is love of wisdom and truth. Truth is a friend of a scientist. In writing this letter I have tried to stay objective and scientific. Please excuse my limited knowledge of medicine.  

WIDE INTEREST IN LORCASERIN

I am interested in seeing Lorcaserin (Belviq) approved because I see obesity around me every day. It is a very tangible problem and according to experts a dangerous epidemic. I know people who have died from obesity related conditions. All the research I have done indicates that Lorcaserin (Belviq) is a very good drug and should be approved. I have talked and questioned numerous physicians who treat obesity and they all want to see Lorcaserin (Belviq) approved. I am sure you are fully aware of the urgent problem of obesity so I won’t reiterate the shocking statistics. 

ATTEMPTS TO QUASH INNOVATION

At the same time, I read the press, and it was disheartening to see a fiction being built by people who have an interest to see Arena destroyed. As a student of philosophy, knowing that truth is the very foundation of a civil peaceful society, it is deeply disturbing to see some financial managers engage in promoting lies at the expense of the Nation, the wellbeing of citizens, the healthcare system, and the economy.  

Here’s a quote by Jim Cramer whose media outlet has disparaged Arena based on fiction not facts:

“What's important when you're in that hedge fund mode, is not to do anything remotely truthful, because the truth is so against your view that it's important to create a new truth, to develop a fiction.”

“Rather than love, than money, than fame, give me truth.”

After the AdComm they admitted to having been wrong but they had done damage already. These disparaging efforts hurt Arena’s ability to raise funds -- Arena is not subsidized by the Government. Instead of encouraging and promoting innovation our society tolerates entities who try to destroy innovation through means which under any justice system should be considered criminal (e.g. selling things which are not yours, you have not borrowed, and do not even exist) but that’s off-topic.

REVIEW OF ADCOMM 2012 

FDA DID AN EXCELLENT JOB

I was very impressed by your team both in terms of command of the subject matter and the logistics of the meeting which was impeccably executed. Thanks to the entire CDER team for a fantastic job at the AdComm, and their diligent work prior to the AdComm, and with the Briefing Documents.

I have read most of the public opinion about the AdComm on various forums and have talked to respectable people including several doctors who observed the proceedings. These two observations consistently stood out:

UNPREPARED ADCOMM MEMBERS

Some panel members were very unprepared. It is not fair for FDA nor the Sponsor that so much work goes into the Briefing Documents, public comments, citizens petition, etc., and some panel members apparently did not bother reading any of that prior to the AdComm.

Andy Baron, who viewed the AdComm proceedings, expressed the same concern:

"I have thought of writing to the FDA to express my disappointment at the low level of preparation and lack of familiarity demonstrated by the panelists. The sponsor spent thousands of man-hours leading up to that meeting and the FDA spent hundreds more, and the panel showed up insultingly unprepared and mostly gave what I thought was very superficial and uninformed advice. It really seemed that many hadn't even bothered to read the briefing documents."

DR. KAUL’S BIAS

 As we had suspected and warned the FDA, Dr. Kaul exhibited bias and perhaps an ulterior agenda. Attorney Joseph Dedvukaj expressed his disappointment at Dr. Kaul as follows:

"There is no doubt in my mind that Dr. Kaul had an agenda that was not for scientific purposes, which I believe the other panelists saw. He would always attack the method but offer no facts or logic to back his questions. He basically had questions suggestive of improper handling of the data, but nothing really helpful to anyone to offer. If I were the FDA I would replace him as a panelist in the future. He was flagrant in the lunch break patting FDA reviewers in the back, which I believe is an ethics violation in and of itself. The appearance of friendship or camaraderie with FDA reviewers in my opinion gives sense of impropriety. The panelists were instructed twice not to discuss the meeting during any break."

Andy Baron expressed his concern as follows:

"I'm not usually one to be paranoid about hidden conspiracies, but from what I've seen at the meetings I do believe that Kaul has some hidden reason to promote Qnexa (Qsymia) over lorcaserin (Belviq). His statements have shown extreme unscientific bias. What I found most outrageous at the lorc adcom was his statement that the 1.5 valulopathy relative risk figure should be stringently enforced because that was what Arena and the FDA agreed to, as if it was an SPA. This was a willfully incorrect and prejudicial statement in my opinion. I don't know what he's hiding, but I do think he is hiding something, because his behavior doesn't make any sense otherwise."

THE VOTE

In the post-voting comments the doctor who had “abstained” said the vote should have been Yes had it been known that abstaining was not acceptable. Therefore, the actual vote was 19 Yes to 4 No’s (82.6%). One of the no votes was by a very ill prepared panel member, and another was, obviously, from Dr. Kaul. If you removed Dr. Kaul and one poorly prepared member from the panel the Yes vote would have been (90.4%).

PUBLIC SPEAKERS

The public speakers’ hour consisted of medical doctors, patients, investors, non-profit organization representatives, and others. Everybody I have met who is for approval of Lorcaserin (Belviq) is primarily and genuinely interested in helping resolve this epidemic of obesity. They are either obese themselves, or have loved ones or patients who are obese. Having or not having a financial interest is secondary. Those I have met who have a financial interest do so because they first have an interest in obesity and view Lorcaserin (Belviq) as a novel, noble solution. George Merck phrases what I observe best:

“We try to never forget that medicine is for the people. It is not for profits.”

The public speakers were overwhelmingly supportive of the approval. Out of 16 or so speakers only two were against approval and they both used unsound and flawed arguments that contradicted with the FDA’s own BD’s. Some have questioned their affiliations. One was accused of having links to a hedge fund manager who could not come himself because of a schedule conflict but I have no way of verifying this.

I was one of the public speakers. I had to reduce 40 pages into 4 minutes and then change it within 3 minutes to address the frivolous arguments of the woman who went before me. Nevertheless, many thanks for the opportunity which was a demonstration of truly democratic process.

One of the public speakers pointed out that had Lorcaserin (Belviq) been approved in 2010 the obesity epidemic would not have gotten so bad.

EFFICACY & DROP OUTS

As Dr. Colman astutely stated in his opening remarks, Lorcaserin (Belviq) has met the FDA's categorical requirement for weight loss. The efficacy is far from marginal. In phase III studies, 47.5% of patients who took Lorcaserin (Belviq) lost at least 5% of their weight versus 20.3% for placebo patients. Of those completing the studies, 63.9% lost greater than 5% of their weight, 34.7% lost greater than 10% of their weight, and the top 25% lost over 16.7%. The average completer weight loss was 26 pounds or 8.2%.

As a student of psychology and someone who’s worked extensively in anti-smoking campaigns, I found the discussion around statistical significance of drop outs very interesting. What I felt was missing from this discussion was the fact that obese people often have internal conflict. A psychiatrist friend I was speaking with who has obese patients told me that they often suffer from a variety of mental disorders. Based on my experience a compulsive person has a conflict between what they are and what they should be and in that friction they lose energy and motivation and this, in my mind, is the best explanation for why obesity trials in general have a high drop out rate, but I’m not an expert.

Anyway, it has been scientifically proven that even a 5% drop in weight can result in meaningful improvements in health and Lorcaserin (Belviq) patients often achieved much better than 5%.

We can not afford to get bogged down in theories while losing sight of the big picture which clearly shows   a) we have an epidemic on our hands   b) we have a good safe solution to address it.

NO NEED FOR REMS / ECHOCARDIOGRAMS

Dr. Daniel Lopez of Southern California Permanente Medical Group is eager to see Lorcaserin (Belviq) approved in order to treat his obese patients. Out of all the drug candidates Lorcaserin (Belviq) is his favorite due to its excellent safety profile and effectiveness. In an article he argues why REMS and Echocardiograms should not be required. Please see Exhibit

Dr. Murthy Andavolu, a specialist in hematology and oncology in California, was appalled by some of the Lorcaserin (Belviq) AdComm panel members' argument about need for EKG.

 "The most insane thing I heard in the Arena AdComm was about doing EKGs for

patients on Lorcaserin (Belviq). What is the screening value of EKGs for valvular heart disease? I find it appalling that some physicians talked about it in the AdCom. I am a physician - a non-cardiologist physician - but I can guarantee you that EKGs have no value in patients taking this drug (or any drug) to look for valvulopathy. If they recommend an echo I can understand though not agree with it, but an EKG, for Christ's sake!!"

Another cardiologist published a statement accusing Dr. Kaul of raising fear uncertainty and doubt and affecting some panel members who were not well versed in EKGs and valvolupathy. He states that valvulopathy is a "NON issue":

“Valvulopathy is a NON issue. The only person who made it an issue was Dr. Kaul, obviously a shill for VVUS and Qnexa (Qsymia).”

“I followed the ad comm via a couple of live blogs. It seemed that all of the cardiologists on the panel, except for that <snipped>, Kaul had zero concern for valvulopathy. Kaul, a <snipped>, swayed a couple of panelist to offer EKG as a way to handicap Lorq. These same panelist had difficulty distinguishing the clinical indication for EKG vs ECHO. They also had no idea how prevalent valvulopathy is in the general population at large. If they read any of ARNA's original publications in NEJM, Obesity Journal, they would have seen that.  

Not only will the FDA disregard these off the cuff suggestion with no scientific or empiric evidence, they will allow LORQ to be prescribed widely and freely by all physician as a bullet to combat the scourge of obesity sweeping across this nation and world. “

Dr. Golden stated that the 1.5 upper bound for the CI was arbitrarily selected and that the upper bound of 1.66 was not significant.

INTERNIST’S PLEA FOR SPEEDY APPROVAL

In a letter to the FDA on May 20 May, Dr. Steven Vig, a practicing internist in Tuscon who has many obese patients, encouraged the FDA to approve Lorcaserin (Belviq) as soon as possible (please see Appendix 2).

In a separate, recent article, Dr. Vig puts forth the argument that Lorcaserin (Belviq) has a very low potential for abuse and should not be classified as a controlled substance (please see Appendix 3).

FUTURE POTENTIAL

Every doctor I talked to who treats obese patients said lorcaserin (Belviq) is the answer. It is the best that medical science has today. It doesn’t mean it can’t improve but Rome wasn’t built in one day. This novel single agent provides tremendous growth potential for future combination therapies involving different receptor-selective weight-loss compounds. By approving lorcaserin (Belviq) FDA paves the way for further advancements.

Lorcaserin (Belviq)'s eventual application is not only obesity. According to an article published in the Journal of Pharmacology and Experimental Therapeutics on 6/2/2011 Lorcaserin (Belviq) showed efficacy in decreasing nicotine use.

Aside from potential efficacy in smoking cessation Lorcaserin (Belviq) effect on the dopamine reward pathway may address other compulsive behaviors such as drug use, gambling, and sexual addictions.

CONCERNS ABOUT Qnexa (Qsymia)’S SAFETY

 
I sense a concern among the physicians I talk to about Qnexa (Qsymia) being approved too quickly.

Dr. Syed Sayeed, medical director of Missouri Delta Medical Center is eagerly awaiting Lorcaserin (Belviq)’s approval because he faces the obesity epidemic every day.

“I have been dealing with a huge population of obese patients with comorbid diseases including diabetes and CAD, If someone is saying that physicians are waiting for Qnexa (Qsymia) it’s not true because Qnexa (Qsymia) is already in the market and any one could mix generic phen/topamax. Physicians here in Southeast Missouri are waiting for locaserin.

However, he has serious concerns about Qnexa (Qsymia)'s safety:

"Many obese patients have anxiety problems and when they're started on Phentermine it exacerbates the anxiety symptoms. Phentermine could cause severe aggression and agitation in patient with underlying bipolar disorder. Phentermine is used by physicians for short term because of addiction potential and if used for long periods it could cause dependency. If Qnexa (Qsymia) is used for longer periods and by millions of people it could be a disaster for our nation -- it will make millions of people addicted to Phentermine and government need to open rehab for Phentermine dependency. In Europe you will find Phentermine addiction clinics for those who were abusing Phentermine. There is a higher chance of Qnexa (Qsymia) being abused and no physician would write Qnexa (Qsymia) and prefer to write Phentermine alone for short periods if needed".

A leading Pediatric Endocrinologist who preferred to remain anonymous stated that he “would never prescribe Qnexa (Qsymia) under any circumstances”. He believes approval of lorcaserin (Belviq) is warranted.

The Citizens Petition and the numerous letters that FDA has received from numerous doctors testifies to the eagerness of the medical community for having lorcaserin (Belviq) approved sooner than later. One such letter reads:

“Lorqess, from my review of the information presented by Arena Pharmaceuticals, represents a safe and urgently needed medication to address the obesity crisis in the general population of the United States. The net weight loss results reported are effective across the age spectrum and compare most favorably with those of Qnexa (Qsymia) from Vivus with no negative comparable side effect profile.”

A FEW MORE DOCTOR COMMENTS

 A cardiologist who preferred not to be identified made the following testimonial:

“You have to have compassion for your fellow humans suffering from the worst pandemic of this century. It is not poverty, malaria, war, malnutrition, religious persecution, racism, sexism, cancer, alcoholism, cigarettes, methamphetamines, heroin, cocaine, communism, capitalism, Obama, Romney, etc. it is the increasing BMI that is plaguing this nation and spreading all over the world.

Almost every patient I see in the hospital started out with obesity as their first problem. Then diabetes follows, hypertension, atherosclerosis, renal failure, heart failure, amputations, dialysis, respiratory failure, myocardial infarction, sepsis, stroke, and death. You would think the hospital beds are filled with people dying from cancer or damaged lungs from smoking. Wrong, the hospitals are filled to capacity with obese people.

Everyday, young obese patients end up on life support machines, unable to breath on their own, let along move or walk, their hearts, kidneys, lungs collapsing under the extreme weight. Even some lucky one's who get bariatric surgery only live a little longer after losing 100 pounds, because it really is too late.

Wake up America. Arena is truly a force for good in this struggle against a scourge of mankind.”

Another testimony is as follows:

"I see overweight and diabetic patients every day. 2/3 of Americans are overweight, and 1/3 of Americans are obese. Physicians often refer to the BIG FOUR DIAGNOSES in a patient, which includes obesity, diabetes, hypertension, and hyperlipidemia. Patients who are obese have higher rates of cancer, back pain, knee pain, hip pain, fatty liver, venous insufficiency (swelling of the legs), cardiovascular disease, and sleep apnea compared to patients with normal weight. The cost to America in terms of morbidity, mortality, and work disability is enormous, and getting worse. Other than diet and exercise, current medications for weight loss are limited, and have side effects. Lorcaserin (Belviq) has a very benign safety profile, and I am convinced that lorcaserin (Belviq) will be the first medicine that most doctors will reach for when prescribing a treatment for weight loss in a patient."

Another testimonial:

“Let's just assume that both Qnexa (Qsymia) and LORQ are approved by the FDA and come on the market around the same time. If you are a physician, which would you prescribe 1st for your patient? Obviously, almost no physician would start both drugs for the patient at the same time.

I would chose Lorq 1st since it's mechanism of action is best understood and it has the least side effect profile. I think 99% of my colleagues will agree with me on this. When we prescribe a chronic medication, such as for diabetes, hypertension, cholesterol, we almost never prescribe the most powerful. Instead, we chose the safest and best tolerated.

What we are not comfortable accepting or facing are  consequences of birth defects and memory problems [associated with Qnexa (Qsymia)].

LORQ does not cause any birth defect. This will be a particular concern for the majority of our patients who are obese and of child bearing age. No physician wants to cause a bad outcome by having his/her patient give birth to a child with birth defects. This will be interpreted as malpractice by most docs. Likewise, physicians are very comfortable handling patients with valvulopathy. This is because almost all of our patients already have some. Just ask how many doctors see patients with mitral regurgitation, aortic regurgitation, aortic stenosis. Almost every other ECHO that is done shows some sort of valvulopathy in clinical practice.”

Appendix 1. REMS / ECHOCARDIOGRAMS NOT NECESSARY

 
May 2012 -- By Dr. Daniel Lopez 

The following discussion is the basis for my opinion as to why a REMS will not be required for valvulopathy.

First of all everyone talks about valvulopathy but does everyone understand the clinical significance of this entity? If you don’t I will first discuss it and then discuss the FDA findings regarding the risk.

The FDA case definition of valvulopathy: requires documented mild or greater aortic regurgitation OR moderate or greater mitral regurgitation.

REMS will not be needed. The FDA conditions for a REMS (from the guidance in the FDA website): REMS will be required if it is necessary to ensure that the benefits of the drug outweigh the risks of the drug – that is, the seriousness of any known or potential adverse effects that may be related to the drug. There are others but these are the relevant ones for our discussion. Remember, the word is SERIOUSNESS. Here are the reasons REMS will not be required:

 1. Clinical significance: Aortic regurgitation (AR): long term prognosis, especially those who are asymptomatic, has a favorable outlook and this has been well documented. It evolves in a very slow and insidious manner and has very low morbidity during a LONG asymptomatic course; this can remain for decades and usually does not progress to treatment. Only those that develop severe AR can result in left ventricular dysfunction, and eventually heart failure. This was rare with dexfenfluramine which by the way, AR was the primary lesion, not mitral regurgitation (MR). With lorcaserin (Belviq) it is the opposite – most common lesion was MR.

2. Mitral regurgitation (MR): isolated mild to moderate MR is without symptoms – very little overload of the heart – heart function remains normal. Even with severe MR, most remain without symptoms until there is left heart failure, pulmonary hypertension, or atrial fibrillation. There were no cases of this with lorcaserin (Belviq).

3. In fact, because of the benign nature of these lesions the guidelines for followup of patients who had been on dexfenfluramine are the following:

Physical exam with auscultation of the heart. In the absence of heart murmurs or other findings, exam is repeated in 6 months – the absence of heart findings by stethoscope predicted the absence of echocardiographic valvular regurgitation in 93% of patients, while the presence of murmur had only a positive predictive value of 19%;

Echocardiography is only indicated in the presence of murmurs, symptoms, or difficult exam by stethoscope due to body habitus;

If a lesion is found, depending on severity, followup is between 6-12 months because of the slow progression to more serious lesions. 

So those who are suggesting that echocardiograms will be required you can see this is nonsense. Any patient who presents to doctors office should have an exam, including the heart by stethoscope. You do not need to have a REMS requiring echos because all you need is what is normal practice in an office. Of course any patients on anorectic medications will especially need a heart exam in the office by the MD with a simple stethoscope 

CONCLUSION: ECHOCARDIOGRAPHY is not necessary to evaluate these patients who will be lorcaserin (Belviq).

2. THERE IS NO CLINICAL SIGNAL IN ANY OF THE CLINICAL TRIALS TO WARRANT A REMS – IT IS PURELY THEORETICAL BASED ON AN ARBITRARY CUTOFF.

Every author who wrote an article suggesting the need of a REMS based on valvulopathy [e.g. Adam Freuerstein who works for Jim Cramer] has no clue what they are talking about. If they had spent time understanding the clinical significance and the analysis of the data in the FDA BD they would not come to that conclusion.

The following is all based on the data in the FDA BD:

Plasma levels of lorcaserin (Belviq) at the clinical dose of 10 mg bid is substantially below the EC50 for activation of 5HT2A and 5HT2B based on functional receptor activation assays whereas the plasma levels of lorcaserin (Belviq) remain within the selective range for activation of 5HT2c. In plain English, plasma levels of lorcaserin (Belviq) are not high enough to activate 2a and 2b receptors but are high enough to active 2c receptors. That is, activation of 2a and 2b at therapeutic levels is unlikely.

Functional profiling studies showed that lorcaserin (Belviq) had the same potency for activating 2B receptors as did the compounds known NOT to cause valvulopathy – demonstrating a low risk of lorcaserin (Belviq) to behave as a valvulopathogen.

The FDA commented that the more appropriate data in determining risk for VHD was these functional profiling studies along with the receptor activation assays and the echocardiography data from the clinical trials.

ECHOCARDIOGRAPHY STUDIES:

FDA’s position was that ruling out a relative risk of 1.5 for FDA-defined VHD was an ARBITRARY but reasonable endpoint. They acknowledged the difficulty in obtaining a noninferiority margin smaller than 1.5 because it would require a very large study.

As noted above fenfluramine VHD was driven by increases in AR whereas lorcaserin (Belviq) was more MR than AR. I will spare you the statistical gymnastics and get to the conclusions:

Pooled phase 3 trials:

Only one patient in the phase 3 trials developed severe MR – and this was in the placebo group; no patients developed AR.

In the BLOSSOM and BLOOM DM trials patients were allowed to enroll with preexisting FDA-defined VHD. Lorcaserin (Belviq) did not develop worsening of their VHD over the 52 weeks as compared to placebo, which had an increase in worsening. 

Now when they looked at patients at week 52 (LOCF) you get the following: 

• 2.0% of patients on lorcaserin (Belviq) and 1.7% placebo developed moderate or severe regurgitation at week 52
• BLOOM – DM at week 52(LOCF) 1.9% of patients on lorcaserin (Belviq) and 1.0% placebo developed moderate regurgitation. NO PATIENTS IN BLOOM DM DEVELOPED SEVERE REGURGITATION AT ANY VALVE.
• NO patient in any phase 3 trial treated with lorcaserin (Belviq) required heart valve surgery or replacement. FURTHERMORE, NO patient treated with lorcaserin (Belviq) reported symptoms from valvular regurgitation.
• POOLED nondiabetic phase 3 trials: 0.3% on lorcaserin (Belviq) bid and 0.1% on lorcaserin (Belviq) qd and four on placebo had cardiac murmur
• BLOOM DM two (0.8%) on lorcaserin (Belviq) 10 bid had murmur – no increases in scores in regurgitation scores for any valve in those two patients.

CONCLUSION: The functional profiling, receptor activation assays, and the echocardiographic studies demonstrate the safety of lorcaserin (Belviq) and also demonstrate THE LACK OF ANY CLINICAL SIGNAL.

Any consideration for a REMS with regard to valvulopathy is purely theoretical based on a theoretical cutoff point period."

Appendix 2. AN INTERNIST’S PLEA FOR SPEEDY APPROVAL

May 2012 – By Dr. Steven Vig

As a practicing internist in Tucson, Ariz., I would encourage the FDA to grant approval for lorcaserin (Belviq) (Lorqess) on or before the PDUFA date of 6 27 2012. Lorcaserin (Belviq) will be indicated for weight loss in patients with BMI over 30, or for patients with BMI over 27 who have co-morbidities.  Arena Pharmaceuticals did a wonderful job of answering all questions in the Complete Response Letter, and the FDA Advisory Committee members voted 18 to 4 in favor of lorcaserin (Belviq) (with one member abstaining) on 5 10 2012.

Any concerns about breast cancer in rats were answered by the pathology review of the previous rat slides, and by additional studies on prolactin done in the last two years by Arena Pharmaceuticals. Obesity is associated with higher rates of cancer, and there is reason to believe that patients who lose weight due to lorcaserin (Belviq) may actually have lower rates of cancer. Average weight loss on patients who completed lorcaserin (Belviq) for a year was 18 pounds, and the top 25% of weight losers lost an average of 35 pounds.

Receptor studies have shown a high degree of specificity of lorcaserin (Belviq) for the 5HT2C receptor (the weight loss receptor), and a very low activity at the 5HT2B receptor (the valvulopathy receptor). Heart rate and blood pressure levels are not increased by lorcaserin (Belviq).  Pooled analysis of the Bloom, Blossom, and Bloom DM studies have not indicated an issue with cardiac valve disease due to lorcaserin (Belviq).  In fact, the two year data in the Bloom study showed a 2.7% chance of valvulopathy on PLACEBO, and a 2.6% chance of valvulopathy on lorcaserin (Belviq).  Lorcaserin (Belviq) at exposures of up to 50 times the human dose for a year did not induce changes in cardiac valves or the pulmonary vasculature in monkeys. I do not believe that a requirement for echocardiogram monitoring is necessary in patients who take lorcaserin (Belviq).

The Bloom DM (diabetes mellitis) one year study produced a 27 point drop in the fasting glucose level on lorcaserin (Belviq), along with a 0.9 point drop in the hemoglobin A1C level (compared to a 0.4 point drop on placebo).  These improvements are comparable to many of the diabetes pills that we currently use!

I see overweight and diabetic patients every day.  2/3 of Americans are overweight, and 1/3 of Americans are obese. Physicians often refer to the BIG FOUR DIAGNOSES in a patient, which includes obesity, diabetes, hypertension, and hyperlipidemia.  Patients who are obese have higher rates of cancer, back pain, knee pain, hip pain, fatty liver, venous insufficiency (swelling of the legs), cardiovascular disease, and sleep apnea compared to patients with normal weight. The cost to America in terms of morbidity, mortality, and work disability is enormous, and getting worse.  Other than diet and exercise, current medications for weight loss are  limited, and have side effects.  Lorcaserin has a very benign safety profile, and I am convinced that lorcaserin (Belviq) will be the first medicine that most doctors will reach for when prescribing a treatment for weight loss in a patient.

Lorcaserin is a 5HT2c receptor agonist, and causes lower dopamine levels in the brain. Studies from Duke University Medical Center in 2011 showed that rats given lorcaserin (Belviq) used less nicotine.  Studies of 5HT2c agonists in rats also showed a decreased tendency to use cocaine. Decreases in dopamine lower the tendency for excessive gambling, and for sexual addictions.  25 years of research on the 5HT2c serotonin receptor has been documented in the 2010 medical textbook  “5HT2C RECEPTORS IN THE PATHOPHYSIOLOGY OF CNS DISEASE” by Giuseppe Di Giovanni.   

Physicians are in desperate need of weapons for the War on Obesity.  Please don’t send us back into battle unarmed. Please approve this novel agent lorcaserin (Belviq) (Lorqess) for weight loss as soon as possible!"

Appendix 3. LORCASERIN’S LOW POTENTIAL FOR ABUSE 

MAY 2012 – By Dr. Steven Vig

On May 10, 2012, the FDA advisory committee voted 18 to 4 (with one member voting to abstain) in favor of lorcaserin (Belviq) (Lorqess) to be used for weight loss in obese patients with BMI over 30, or overweight patients with comorbidities who have BMI over 27.    I look forward to final approval of lorcaserin (Belviq) by the FDA on or before 6 27 2012. The dose of lorcaserin (Belviq) will be one 10 mg tablet twice a day with or without food.  I anticipate European approval of Lorcaserin toward the end of 2012. 

I believe that concerns about breast cancer in the Sprague Dawley rats have been answered by the review of the original rat slides, and by numerous studies related to prolactin performed by Arena Pharmaceuticals in the last two years. Recall that obesity is associated with a higher rate of cancer, so there are reasons to believe that weight loss due to lorcaserin (Belviq) could actually cause a decreased rate of cancer in humans.

The combined echocardiogram studies from the Bloom, Blossom, and Bloom DM  studies, as well as receptor studies showing a high degree of  specificity for the 5HT2c receptor argues that periodic echocardiograms should not be required on  patients taking lorcaserin (Belviq).

However, the main reason I wanted to write this note is that I believe that lorcaserin (Belviq) has a low potential for abuse, and should not be considered a controlled substance.   Arena has performed studies for the FDA on doses of lorcaserin (Belviq)  up to  10 mg twice a day that showed no problems with withdrawal from the drug in terms of addiction (study APD356-003 and study APD356-004).    Doses of lorcaserin (Belviq) at  20, 40, and 60 mg per day showed a very low chance of abuse. (The withdrawal and abuse studies are discussed in the 2012 briefing documents in section 7.11)

To review, a Schedule 2 drug has a high potential for abuse, such as oxycodone  (for pain ) and Adderall (for attention deficit disorder).  Prescriptions must be written or printed and must be signed by the doctor and refills can not be given.  A schedule 3 drug has some potential for abuse, such as Vicodin (hydrocodone with acetaminophen). Prescriptions can be oral (called in) or faxed or written  and may be refilled up to 6 months.  A Schedule 4 drug has low potential for abuse, such as the sleeping pill temazepam.  Prescriptions can be oral (called in) or written, including faxed prescriptions, and  may be refilled up to 6 months.   Schedule 5 drugs also have low potential potential for abuse, and are subject to state and local regulation. Examples of Schedule 5 drugs includes Lyrica, the diarrhea pill Lomotil, and the cough medicine promethazine with codeine.  (Eventually, doctors will be able to send controlled substances through the electronic health records, when both the electronic health records vendors and the pharmacies are ready to do this from a secure standpoint.)

Lorcaserin is a 5HT2C  receptor agonist and causes decreased dopamine levels in the brain. Studies from Duke University Medical Center from June 2011 in the Journal of Pharmacology and Experimental Therapeutics demonstrated decreased nicotine use in rats who received lorcaserin (Belviq).  Other studies in rats show decreased tendency to use cocaine when 5HT2C agonists are given.  Decrease in dopamine levels can also be associated with decreased tendency for excessive gambling, or for sexual addictions. (See the books “5HT2C RECEPTORS IN THE PATHOPHYSIOLOGY OF CNS DISEASE”  by Di Giovanni  and “THE COMPASS OF PLEASURE” by David Linden.)

Lorcaserin causes decreased appetite, and also likely causes  decreased tendency to use nicotine,  to use cocaine, to be an excessive gambler, or to be a sexual addict.  I do believe that lorcaserin (Belviq) has a low potential for abuse, and in fact may in the future be used to treat multiple addictions.  I do not believe that lorcaserin (Belviq) should be a controlled substance.

I look forward to prescribing lorcaserin (Belviq) for my overweight patients after FDA approval later in 2012. 

Steven Vig md          internal  medicine      Tucson, Arizona       5 20 2012

Appendix 4. COMMENTS FROM THREE ADCOMM DOCTORS

Dr. Ed Hendricks of The Center for Weight Management spoke brilliantly about why Lorcaserin should be approved. Some highlights of his remarks:

"We spend a great deal of time here looking in minute detail at the risks. We don't look at the benefits in the same detail... The sponsors did a good job of investigating what happens with diabetics. They showed that the new onset of diabetes was lower in the treated population. I would submit to you that there are probably a number of cardiovascular factors [explains a number of conditions and benefits of Lorcaserin]... The benefits should be looked at with the same level of intensity that the risks are looked at. I don't think we've done that in the past 

I voted yes from a clinical perspective. I don't think placebo adjusted weight loss from a clinical perspective is a valid measure. I look at people who are true responders. There are plenty of people who are responders. There are 200 million people in this country could benefit from a drug like this... even 1/4 of them translates to 50 million people... Efficacy to me means more than just weight loss. Sometimes we use obesity drugs to prevent further weight gain [brings several examples and benefits]... Many clinicians are interested in this drug because they see it as a potential drug that could be added to some of the other drugs that we have. [brings examples]."

Dr. Peter Gross, chairman of the Hackensack Physician-Hospital Alliance stated:

"It's time to approve this drug and we do not put our head in the sand. I think the signals are not strong enough to require a risk management program [REMS]."

Dr. Robert Smith, Professor of Medicine (Endocrinology) at Brown University stated:

"I felt that there was a clear demonstration of what I consider to be a clinically significant benefit in a substantial number of individuals."

CONCLUSION

On behalf of many people who have a genuine concern about the obesity epidemic and want a good effective safe solution to be available to doctors and patients, I beg you to approve Lorcaserin as soon as possible, before, or prior to June 27 PDUFA date.

Thanks again for all your great service.

Best Wishes

Reza Ganjavi

<email, phone>

POST-ADCOMM BY DR. STEVEN VIG

Also see www.vigformulary.webs.com  for other wonderful articles by Dr. Vig.

PRE-ADCOMM BY ANDY BARON

PRE-ADCOMM BY REZA GANJAVI

Dear Madam Commissioner: 

 Sorry to take your precious time to share a couple of observations and concerns with you.

Your comments vs. Mr. von Eschenbach’s

I read your recent comments supporting new obesity drugs with great interest. However, it was a painful reminder of Commissioner von Eschenbach making similar remarks in February 2007; he even used the same term, a bridge. He spoke about FDA being a bridge not a barrier. Shortly after, the FDA did the exact opposite – it acted as a barrier against the strong positive vote of its own panel of experts and blocked tens of thousands of men from having access to Provenge which could have helped them spend more time with their loved ones.

A couple of doctors with conflict of interest tried to influence the FDA to go against the vote of the Panel and they succeeded. They were later linked to a network of hedge funds, journalists, analysts, and a convicted criminal. I can send you the link to the full story if you like.

As an ordinary human, what I witnessed back then, and reading this story, I get deeply disturbed. As the best country in the world we pride ourselves of a clean government. Following this saga, the FDA tightened its conflict of interest rules – which recently two Republican Congressmen are trying to overturn (Burr, Coburn)

Pleading for a fair hearing

May I kindly ask you, as a fellow concerned human, to please follow through with your recent statements, and see that Arena’s Lorcaserin gets a fair AdComm hearing on May 10^th, and upon a positive vote, a speedy approval on or before the June 27^th PDUFA.

As you know obesity is a serious epidemic and new studies show it may be more prevalent than CDC has thought. As far as I understand Arena’s scientific data is solid and clearly points to efficacy meeting and exceeding FDA’s requirement, and it has shown an excellent safety profile.

In phase III studies, 47.5% of patients on Lorcaserin lost at least 5% of their weight versus 20.3% for placebo patients. Of those completing the studies, 63.9% lost greater than 5% of their weight, 34.7% lost greater than 10% of their weight, and the top 25% lost over 16.7%. The average completer weight loss was 26 pounds or 8.2%. Arena will show the AdComm that there are no safety risks to humans whatsoever (unless Lorcaserin is taken at 82 times normal dosage).

Conflict of Interest Waiver

I am concerned about the COI waiver that was granted to Dr. Daniel  Bessesen since it is documented that he has a conflict of interest by consulting for a competitor drug, and he has referred to Lorcaserin in his lectures with what appears to be intellectual bias. I'd rather see fewer doctors on the panel than resorting to those with COI.

Heads Up About Manipulators

I am also concerned that there is negative propaganda being promoted by press which are sometimes linked to people who are on record for engaging in manipulative and deceptive practices. I am only bringing this to your attention because I believe you are a genuinely good person and you wouldn’t want these immoral forces to try to influence and derail your fine organization’s processes.

In an interview, Jim Cramer is on record for saying: “What's important when you're in that hedge fund mode, is not to do anything remotely truthful, because the truth is so against your view that it's important to create a new truth, to develop a fiction.”.  And his people, and others, have been trying to build a fiction against Lorcaserin. I trust FDA will stand tall, unaffected by their campaign and corrupt ways. 

Madam Commissioner, please help truth to prevail. Under your leadership, may the FDA be ruled by a truly scientific mindset, by love of truth (root meaning of “philosophy”) which is the essence of all sciences.

Very Best Regards & Respectfully

Reza Ganjavi
<phone>

PRE-ADCOMM by Jose Padilla (to First Lady)

April 30, 2012

[reprinted with permission]

Dear First Lady Michelle Obama:

My name is Jose Padila. I am a registered Democrat and a strong proponent of your anti-obesity campaign. I have seen more positive changes in grade schools’ lunch programs including kids’ healthy food awareness, as a result of your campaign.

I agree wholeheartedly with your belief on healthy diets and exercises which can make a difference for many Americans.   I also believe in the science of medicines that can provide some of us weight-challenged Americans with a safe head-start means to weight control and treatment as a part of our overall weight management program.

There are several pharmaceutical companies that have been working on weight treatment medicines. One of these, Arena Pharmaceuticals, has come up with an advanced stage working medicine called Lorcaserin.  Locarserin, in the form of pills, is a new generation of effective weight-loss medicine.

Lorcaserin has previously been reviewed by the FDA which has asked Arena Pharmaceuticals to provide additional tests.  The company has done more work and prepared more information and clarifications for the FDA during the next  review which will take place on May 10, 2012.

While many believers and I are hopeful for the FDA’s approval of Lorcaserin this time around, we are feared that the check and balance of the FDA review process of this drug is still in question.   There have been many allegations of bias in last FDA review process of Lorcaserin.

I am writing this letter to express my continued support of your anti-obesity campaign and also to share with you some information on the new weight treatment medicine, Lorcaresin, which, if approved by the FDA, can make a big difference in helping Americans’ weight management program.

Sincerely yours,

POST-ADCOMM by Dr. Ralph Ryback

[reprinted with permission]

PRE-ADCOMM by Reza Ganjavi (to First Lady)

(Fax number for the White House:  (202) 395-6179  Email: http://www.whitehouse.gov/contact/submit-questions-and-comments)

30 April 2012

TO: The First Lady, Mrs. Michelle Obama

SUBJECT: Please attend meeting in Silver Spring, MD, on May 10, 2012 to show your support for approval of a safe effective medication for obesity which hedge funds and Wall Street crooks are trying to derail – or at least, please do what you can to ensure a fair hearing is made.

Dear Mrs. Obama

Arena Pharma of San Diego has spent almost a Billion dollars and some 10 years developing Lorcaserin, a safe and efficacious medication to treat the disease of Obesity which kills 300,000 Americans every year. 1/3 of Americans are clinically obese and today there is no good treatment for it.

On May 10, from 8 am to 5 pm there is a hearing in FDA. It’s a public event. Would be great if you could attend even for just a few minutes to show your support. It’s held at the DoubleTree in Silver Springs. You can get more info from the FDA: 301-796-9001 Ms. Diem-Kieu Ngo

The science is solid but “naked short sellers” and hedge fund crooks have bet against this medication and have been publishing lie after lie about it in order to influence FDA’s decision against it.

A well known hedge fund manager has confessed to being a crook on a TV interview. He talks about not doing anything remotely truthful: “"truth is so against your view that it's important to create a new truth, to develop a fiction". These people are evil. The same folks have been writing negative articles about Arena and distorting the facts.

The FDA can be and has been manipulated by such forces before. We have evidence of it. Provenge 2007 is one example that even a strong AdComm vote didn’t convince the FDA to approve a drug because doctors with conflict of interest on that AdComm lobbied the FDA.

Ms. Obama, we need your help. Please do what you can to make sure we get a fair hearing. Obese people deserve to have this drug. I know so many doctors who want this drug. They’re willing to put their kids on it, it is so safe, and it works by controlling appetite through a very high tech brain receptor influence which has been proven to be safe.

Thanks & God Bless
Reza Ganjavi <email & phone>

POST-ADCOMM by Reza Ganjavi (to SEC)

(May 2012)

The Honorable Mary L. Shapiro, Chairman
U.S. Securities and Exchange Commission
100 F Street, N.E.
Washington, DC 20549

Dear Honorable Madam Chair,

Arena Pharmaceuticals has worked hard for 9 years and have spent almost a Billion dollars developing and testing a single molecule which in combination with diet and exercise helps obese people lose weight. As you might know obesity is an epidemic and currently the worst healthcare challenge of the US. Hundreds of thousands of people die every year from obesity-related conditions. And currently there are no effective medications for this disease.

Last week an FDA panel of nation's 28 top-notch doctors overwhelmingly gave their vote of confidence and recommendation to the FDA to approve Lorcaserin.

Prior to the AdComm short interest in Arena was an astronomical level of some 40,000,000 shares and all the typical weasels of Wall Street such as Adam Feuerstein of TheStreet.com, Matthew Herper of Forbes, Martin Shkreli of MSMB hedge fund, some analysts, and others were disparaging Arena. Disparagement naturally scares people into selling their shares, especially a company like Arena where the large majority of shareholders are retail -- and it is because of the investors which the company has been able to develop this life changing medication for 100's of millions of people globally.

Neither Main Street investors nor the company that's attacked know who the large shorts are but we witnessed "short and distort" at its worse. It's odd that certain entities can get away attacks on hard working companies that are trying to make the world a better place -- Freedom of Speech was never intended to protect people who misrepresent things, twist information, lie, etc., but that's beside the point.

The main point of this letter is this:

The FDA panel's approval occurred on May 10. On May 11 the stock nearly doubled. On May 15 after the market closed, the company announced an offering to be priced. That day. the stock tanked, BEFORE the news was released.

ACTION REQUESTED: We beg the SEC to investigate trading of ARNA on May 15, 2012 especially of clients of the the brokers involved, to find out if there was leakage of insider information. This leakage has caused the company to lose millions in potential proceeds and for investors to lose over a 100 Million Dollars.

ARNA has been on the RegSho list. Madam Chairman, selling what you do not have is criminal under any criminal justice system. The stock has been pounded down by naked shorts -- this is outrageous. How can investors have confidence that the shares they buy exist or not?

ACTION REQUESTED: What can you do to ensure ARNA is removed from the RegSho list IMMEDIATELY? I hope the answer is not "nothing".

ACTION REQUESTED: Please implement the pre-borrow pilot program contemplated by Section 417 of the Dodd-Frank Act immediately. This is the most important step you can take towards cleaning up the current criminal environment which short sellers and their lobbyists are enjoying. Create an aggressive plan for the pilot and plan to implement it soon (we can not afford another 10 years of this corruption).

Have you seen the leaked papers of Goldman and Merrill Lynch that show naked short selling? http://www.bloomberg.com/news/2012-05-15/goldman-merrill-e-mails-show-naked-shorting-filing-
says.html?cmpid=yhoo

I believe abusive and naked short selling should be a crime -- and it is happening in our own back yard. What can the SEC do about this? Are the Republican Commissioners still as sympathetic with short sellers as they were during your Roundtable on short selling a couple of years ago?

I trust you've also seen this statement that Jim Cramer, the founder of TheStreet.com boasted about manipulation by hedge funds:  "What's important when you are in that hedge-fund mode is to not do anything remotely truthful because the truth is so against your view, that it's important to create a new truth, to develop a fiction."

The foundation of a civil society is based on truth. These out of control hedge funds, naked short sellers, and brokers who break the law are raping every citizen of the society by raping the companies that seek to improve the lives of the citizens and contribute to economic development, and killing innovation, and the government allows them to do it.  In some other countries the government nurtures innovation. In the US the government allows people to legally kill innovation. That is what this sympathy with shorts and naked shorts is all about.

The whole justification of preventing front running as a way to rationalize holding large shorts' identities confidential completely lacks logic except in the minds of lobbyists and regulators who sympathize with them. If you just made the identity of large shorts public, like you require with large shareholders, the transparency would help companies a great deal.

ACTION REQUESTED:  Disclose identity of holders of large short positions publicly.

Allowing market makers to naked short is another green light for killing innovation. We all know how ethical market makers are! The article above demonstrates it perfectly well.

Many Thanks and Best Regards
Reza Ganjavi
<email & phone>

POST-ADCOMM by Reza Ganjavi (to SEC about leakage of secondary)

(May 2012)

Complaint About Possible Leakage of Arena’s Secondary Offering


Dear SEC

Arena’s stock (ARNA) took a nose dive on 15 May 2012 without any negative news or market weakness. After market close the company announced a secondary offering.

We have seen this far too often and we respectfully request that SEC does something about it. Somebody must have known about this upcoming offering news and traded on it illegally. Who it is, we have no idea but SEC has tools at its disposal that could investigate the trading of ARNA on May 15, including any short selling that occurred.

We have seen in the past that Jefferies & Co has acted inappropriately and immorally – in the case of Avanir (AVNR) they put a high price target on the stock, did a secondary, then changed analysts and lowered the target to a ridiculous level, and we saw short interest rise significantly, and we saw Jefferies bash the day light out of the stock through their analyst Thomas Wei. We don’t have the data to allege the short sellers were their clients but two and two is usually four.

Trading on insider information and leakage is illegal. Please investigate Arena’s trading on 15 May 2012. I am more worried about the brokerages involved than the company itself because I know the company and I know at least the CFO is very tight lipped.

Thanks & Regards
Reza Ganjavi and other concerned investors.
<phone>

POST-ADCOMM by Reza Ganjavi and Others (to SEC about bear-raid)

(24 June 2012)

Charles Fischer to FDA (Pre-PDUFA - 26-Jun-2012) in reaction to Dr. Sidney Wolfe's Stupid Letter

[This was sent to Dr. Hamburg on the 26th and Dr. Woodcock on the 27th]

[reprinted with permission]

It was just an edited version of Dr. Wolfe's hit letter, with corrections and data from the briefing document. I wish I had had more time to do a better job.

Here it is:

Margaret A. Hamburg, M.D.
Commissioner
Food and Drug Administration
Department of Health and Human Services
WO 2200
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002

Dear Dr. Hamburg:

Tomorrow is the user fee (Prescription Drug User Fee Act) deadline for the Food and Drug Administration’s (FDA’s) decision on whether to approve the new diet drug lorcaserin (Belviq) (Lorqess), manufactured by Arena Pharmaceuticals. I strongly urge you to take personal responsibility and make a preventive public health decision to approve the drug.

From a review of the FDA Briefing Documents (BD) and the transcript of the May 10, 2012, FDA advisory committee meeting at which lorcaserin (Belviq) was discussed, it is now clear that the committee overwhelmingly voted 18-4 for approval. It did so with some reservations, particularly because of widely shared concerns about evidence of heart valve damage in people using the drug in clinical trials. This fear should be mitigated by the fact (from the BD) that lorcaserin (Belviq) is a very weak 5HT2B agonist unlike the FDA banned fenfluramine and dexfenfluramine, the “fen” components of Fen-Phen, in 1997. Also unlike fenfluramine, lorcaserin (Belviq) did not have an association with mitral valve regurgitation (from the BD).

A key discussion point at the meeting was “whether the phase 3 echocardiography [a test for abnormal heart valves] data are sufficient to rule out a clinically meaningful increase in the risk for valvular heart disease in patients treated with lorcaserin (Belviq).” The committee chair summed up the comments of the other advisory committee members on this question by stating, “There’s probably not sufficient data at this time to rule out a clinically meaningful increase in the risk for valvular heart disease.” The FDA, in its briefing package for the committee, had stated that “in the pooled analysis of the Phase 3 echocardiographic data, the relative risk for FDA-defined valvular heart disease (VHD) … was 1.16, with a 95% confidence interval (CI) of 0.81 to 1.67. This upper bound exceeds the arbitrary (from BD) 1.5 upper bound requested by FDA to rule out an excess risk of VHD.” This means that the upper bound of 1.67 — a possible increase in valvular heart disease of 67 percent above that seen in people getting a placebo or up to a 19 percent decrease.

Regarding the drug’s benefits, after a year of exposure, 47% of patients lost 5% of their body weight. Patients not losing weight in the first three months of treatment will discontinue and therefor not be exposed to long term risks. The important take away for the BD is that lorcaserin (Belviq) works very well for a lot of patients and not at all for others. Because of the short time to find the responders, the average patient is a bad indication of the potential benefits of lorcaserin (Belviq).

Dr. Kaul was a very strong voice for voting against approval, but even with his strong opinion, 18 members of the committee voted to approve lorcaserin (Belviq).

Faced with serious concern for the obesity epidemic in the US and the world, it would be dangerous and unconscionable for the FDA to not allow patients access to lorcaserin (Belviq). Just say yes.

After seeing Dr. Wolfe's letter, I could not let it go unanswered. Thank you for your time and service. Please forgive the typos, this was done on very short notice.

Sincerely,

P. L. Charles Fischer
Just one of many overweight concerned citizens

Reza Ganjavi to FDA (Pre-PDUFA - 27-Jun-2012)

Reza Ganjavi to FDA (Pre-PDUFA - 26-Jun-2012)

Reza Ganjavi to FDA (Pre-PDUFA - 25-Jun-2012)

SUBJECT: Sharing a new quote on Obesity; Feedback on Minutes; Looking forward to this week's approval of lorcaserin (Belviq)

Dear Honorable Drs. Hamburg and Woodcock:

So many people, doctors, patients, those who have an interest in Arena and many who don't, are looking forward to FDA's approval of Lorqess (lorcaserin (Belviq) hydrochloride) by the PDUFA date, this Wednesday, June 27, 2012.

We regularly hear read and see what an enormous problem obesity is. Just today I read the following in a published article:

Thank you for approving Lorqess without a delay. Many believe the minutes of the AdComm were not a good representation of what was discussed. Hardly any of the positive remarks of many of the panel members were reflected. But I trust the FDA will do the right thing and despite any pressure from those who are against progress, FDA will approve Lorqess without any delays.

One of the panel members, Dr. Hendricks, an obesity specialist who wrestles with this epidemic every day -- unlike some of the doctors on the panel who were neither familiar with obesity issues nor with lorcaserin (Belviq) -- made the following remarks at the AdComm. (Text below and video: http://www.youtube.com/watch?v=QNy_1vhG304  The video also contains his post-voting comments which are very important):

Another panel member, Dr. Gross made these remarks, again, no sign of these sentiments in the minutes:

Of course the enemies of progress somehow timed an attack to coincide with the release of these minutes, but we know FDA's true sentiments from the Briefing Documents, your good people who spoke during the panel, and we know the strong 19-4 positive vote (video: http://www.youtube.com/watch?v=Q7o7f2MXkjo).

Here's another touching video of a doctor and a patient speaking at the AdComm: http://www.youtube.com/watch?v=vih0pxY23lY

Looking forward to hearing the approval news, all the positive media coverage about FDA's historic approval of lorcaserin (Belviq) later this week, and FDA truly acting as a bridge to bring a state-of-art,  safe, effective medication to a population which is desperately in need of help.

Thank You & Best Wishes

Respectfully
Reza Ganjavi
<phone>

Article by Mark Benjamin

Today I want to talk about a novel drug called Lorcaserin which recently received a favorable nod from the medical community recommending it for passage in the next couple weeks.

What makes this drug novel. Well unlike it's competition it is a new therapy. The competition (Qnexa (Qsymia)) fuses together two existing drugs which have been on the market for quite awhile. The two components of the drug can be prescribed today. So one has to ask why even bother provide this drug in a single pill? The FDA also asked that a 3 month extension be added before possible approval to clearly evaluate the consequences of taking their drug. One major risk with Qnexa (Qsymia) is the possible development of cleft pallets in new borns. For that reason pregnant women will be advised against it's use.

On the other hand Lorcaserin, developed by Arena Phamaceuticals, is a novel drug with minimal side effects one of which is a headache that may or may not occur and goes away with a short amount of time.
Recent studies have shown that completers in studies could lose up tp 35% of their body weight.

Some have pointed out that drugs like Lorcaserin cover up a problem with obesity in this country. Well the fact is that people have done literally nothing to stop the epidemic and something has to be done now. Locaserin is not a hollywood designer drug to help one keep 5 pounds off. It is a drug that can help ward off a problem that has been with us for years. The benefits of Lorcaserin do not stop with weight loss. Benefits also include a reduction in the A1-C count of diabetics that is a measure of sugar in the bloodstream. Furthermore, Lorcaserin has shown a benefit to people with high blood pressure and an ability to help smokers quit this habit as well.

I have listed facts about Lorcaserin to help readers understand the benefits of Lorcaserin and it's approach to curbing the obesity epidemic that faces our country today. Getting this drug to individuals who are in need of losing weight in a safe effective manner should be at the top of this countrys' priority list. 

[reprinted with permission]

The Case Against Qnexa (Qsymia): Why a CRL is The Best Play for the FDA

By Anita Gurak

[reprinted with permission]

The FDA has a difficult choice to make in the coming weeks:  approve Qnexa (Qsymia) with incomplete information or delay the approval to reassess the optimal position to take going forward.  Either decision will bring its share of critics with Wall Street pumpers leading the charge if a delay occurs.  The extent “big money” can influence the outcome remains to be seen.

The February 22, 2012, Qnexa (Qsymia) Advisory Committee documents reveal clues to the dilemma facing the FDA.  A 20-2 Ad Com vote in favor of approval would seem to indicate that the outcome is a fait accompli, with Wall Street jumping on the Vivus bandwagon like school girls at a Justin Beiber concert.  Upon more detailed reflection, however, this celebration may be premature.

Adcom Discussion Topic #1 was posed as follows:

1.      Discuss your interpretation of the available data regarding teratogenicity of topiramate, including whether you believe the data indicate an increase in the risk for oral clefs.

Excerpts from the FDA Briefing Document:

The Food and Drug Administration (FDA) previously issued a Complete Response letter on October 28, 2010 citing adverse cardiovascular effects and an insufficient assessment of Qnexa (Qsymia)’s teratogenic potential as safety reasons for not approving the application.

The risks of OCs (oral clef) and MCMs (major congenital malformations) associated with TPM use in the first trimester of pregnancy have not been fully answered in this interim report of the FORTRESS study due to the limited sample size in the TPM monotherapy subcohort, the pending study results using the entire SMP cohort, and the poor data quality issues with the analyses for MCMs. 

Excerpts from the Vivus briefing doc:

Analyses of data on all major congenital malformations is in process, and will be made available once final validated results have been obtained. The study will be completed in the second half of 2012. Final results from the FORTRESS study are expected to provide a more statistically precise estimate of effect than previous studies.

If the FORTRESS study were specifically required to address a CRL topic, why would the FDA accept interim and insufficient results as final proof of Qnexa (Qsymia) safety?  Would another delay be more appropriate to allow Vivus to complete the study and provide “label worthy” conclusions?

Adcom Discussion Topic #2:

2.  Discuss the potential strengths and weaknesses of the proposed teratogenicity risk

management strategy for PHEN/TPM.

Excerpts from the FDA briefing doc:

 The applicant proposed to mitigate the risk of teratogenicity by contraindicating use for women of childbearing potential (WOCBP), and implement a Risk Evaluation and Mitigation Strategy (REMS) using restricted distribution to enforce this contraindication.

The Agency believes the contraindication is too broad, and does not agree that, should Qnexa (Qsymia) be approved, the risk of teratogenicity would outweigh Qnexa (Qsymia)’s benefits for every woman capable of becoming pregnant. Secondly, although it might be feasible to restrict use of Qnexa (Qsymia), such a restriction would not preclude use of the individual components of Qnexa (Qsymia) by WOCBP for weight loss. Since the resubmission of the application, Vivus, Inc and the Agency have discussed possible approaches to mitigating the risk of teratogenicity. Given the availability of the separate ingredients of Qnexa (Qsymia), an ideal risk mitigation strategy is not apparent…

Hats off to Qnexa (Qsymia) as the FDA clearly indicated a deference to the drug’s efficacy, but the briefing document excerpt also displays the dilemma facing the FDA regarding approval of Qnexa (Qsymia).   Approve Qnexa (Qsymia) and they directly endorse the topiramate and phentermine combination pill, but they would also be indirectly endorsing the separate ingredients as weight loss agents.  Where is the study that shows that the Qnexa (Qsymia) whole is better than the sum of its parts?   Without proof that the combination as constructed is better, a logical approach that MDs may take to save patients money is to prescribe each ingredient separately.   The FDA recognizes this potential MD behavior with the following excerpt from their briefing document: 

It is likely that some prescribers would prescribe the individual ingredients in an amount that would approximate Qnexa (Qsymia) capsules to circumvent the requirements of the REMS.

 The FDA approval of Qnexa (Qsymia) would provide MDs with the required legal “cover” to justify their decision in prescribing the individual ingredients to approximate Qnexa (Qsymia).  Will the FDA want to tacitly endorse this behavior by approving Qnexa (Qsymia)?  For an agency that has been burned many times in the past, risk aversion must exert a certain gravitational pull that could cause them to pause in their final decision.

The Adcom also addressed the findings of Qnexa (Qsymia)’s impact on heart rate. An increase in heart rate that was consistent across subgroups was observed over 2 years with Qnexa (Qsymia).  That coupled with insufficient data in high risk populations would not appear to be a ringing endorsement for Qnexa (Qsymia)’s response to the 2010 CRL.  The FDA does not appear to be leaning towards a pre-approval study similar to the one required of Orexigen, and the Adcom participants were comfortable with either a pre- or post- approval timeframe, but the uncertainty as part of an overall package of issues would be further justification for a delay in approval or even an outright rejection.

What is the most likely outcome of this debate?  Probabilities would suggest a delay in approval of Qnexa (Qsymia) to take additional time to determine how best to update topiramate labeling without impacting patient treatment for indications outside of obesity.  Or, the FDA can reject Qnexa (Qsymia) and the problem simply goes away.  Odds favor a delay in the hopes that an answer can be found in the interim.  With the recent approval of Belviq, the FDA has afforded the indicated population a safe and effective obesity treatment. 

As we have learned in the past, sometimes the magic bullet of higher efficacy just ends up shooting you in the gut.  The FDA should exercise caution while handling Qnexa (Qsymia)’s loaded gun.

LETTER TO SOME FRIENDS ABOUT BELVIQ  --  By Reza Ganjavi

August 16, 2012

Subject: ARNA as an investment to address the giant obesity pandemic market

My dad used to say never recommend doctors, lawyers, and marriage partners. I add to it, stocks. I have resisted telling friends about this so far but it's time to share this area of interest. I hope you do your own research.

About 6 months ago a very intelligent friend told me about Arena. It seemed like a long shot then. The stock was under two dollars. Based on his recommendation I did my own research and was astound at the number of doctors who were swearing by Arena's upcoming product, which is today known as Belviq. At the time it was referred by its scientific names, Lorcaserin (Belviq).

I finally found the conviction to buy and hold the shares. By then it was in the 2's. Being a writer I wrote some articles about the company. The first one quoting some of the doctors I had talked to triggered a rally in the stock. My article was quoted by other news sources that it's predicting Lorcaserin (Belviq) will get FDA approval in June.

At that time all the weasels and what a friend calls sewer-rats of Wall Street, like Jim Cramer and his side-kick Adam "Frogstein" Feuerstein, Forbes Magazine's Matthew Herper, message board bashers, analysts, crooks, etc., were saying Lorcaserin (Belviq) won't get approved. THEY WERE ALL PROVEN WRONG.

FDA HEARING

On May 10 2012, FDA held a panel of advisers including top doctors from around the country, to review Lorcaserin (Belviq). I flew to Washington DC to speak at the public comments hour because I wanted to help this cause because I could see there are crooks who are fighting against the approval and I wanted to contribute my voice because I viewed this as a war between reason, science, truth on one hand, and fiction, fallacies and criminal intent on the other hand. I am convinced the speaker hour made a positive difference especially as one of the panel members was spreading FUD and some others were not well prepared and were buying into his FUD. What we, the public provided was an important voice that the panel heard.

The panel voted 19-4 for the approval. You can see some videos of it on www.rezatv.com including my speech.  The credit for this major achievement solely belongs to Arena's team who worked very hard for a whole decade and spent a Billion dollars to bring Belviq to market.

OBESITY IS A DISEASE

Just look around you and you'll see overweight people and likely obese people. 2/3 of Americans are overweight - 1/3 are clinically obese. That's some 70 Million people. They should eat right and exercise but they can't or don't do it and end up getting all kinds of diseases as result of being overweight like diabetes, kidney failure, heart failure, etc. etc. -- not only this causes early death and suffering to people, it burdens the entire nation, from healthcare system to transportation system with hundreds of Billions of dollars of costs.

Obesity in the US is an epidemic and globally it's a pandemic. In Switzerland where people are supposed to be fit, 1/3 of the nation is overweight and there are lots of obese people. Don't even mention Germany! China, Saudi Arabia, India, it's everywhere -- we are living in a fat world!

FIRST FDA APPROVED DRUG FOR OBESITY IN 13 YEARS

Arena's Belviq (Lorcaserin (Belviq)) is a single molecule which triggers a brain receptor which makes a person feel not hungry. It is prescribed by doctors together with diet and exercise. In clinical trials of over 8000 patients it proved to be efficacious and met and in some cases exceeded FDA's efficacy requirement. 47.5% of patients who took Lorcaserin (Belviq) lost at least 5% of their weight versus 20.3% for placebo patients. Of those completing the studies, 63.9% lost greater than 5% of their weight, 34.7% lost greater than 10% of their weight, and the top 25% lost over 16.7%. The average completer weight loss was 26 pounds or 8.2%.

These numbers are often misquoted by Wall Street crooks to be 3% weight loss without providing the context --  the meaningful numbers in my opinion and those of many doctors I have talked to is the 8.2% weight loss for average completers. 8.2% may not seem to be much but for a 200 pound person that translates to 16.4 pounds and it's been proven that even a 5% weight loss can significantly improve overall health. Belviq has shown to be effective for prevention and treatment of diabetes as well as obesity which makes it even more exciting from both medical and financial standpoints.

On June 27, the FDA approved Belviq -- a major breakthrough for medical science, obese and overweight patients, doctors, healthcare system, Arena and its investors.

SAFETY

In the past FDA has been concerned about the safety of weight-loss medications but Belviq's excellent safety profile alleviated those concerns.

Recently, FDA also approved a second drug, Qsymia which is a combination of two generically available drugs (phentermine and topiramate) by an over-hyped company, Vivus. Of all the doctors I've talked to not a single one said they'd prescribe Qsymia -- because of safety concerns such as birth defects and other serious side-effects. Belviq's most common side effect on the other hand is mainly a mild headache for a couple of days. Safety is very important to doctors and that's why most would prefer Belviq.

THE STOCK / COMPANY

Arena (www.arenapharm.com)  is based in San Diego, and trades on Nasdaq as "ARNA". Its latest price is $7.82 - it's tripled since the first article I wrote about it. It was higher after approval but I believe it pulled back as shareholders who are mostly retail investors like me sold some shares to take profit. But I believe it still has a long way to go (up).

What I love about the stock is:

1) Low institutional interest (25% end of June - already up to 31% and will at least double in my opinion to keep up with its peers).
2) High short interest (shorts were very wrong - they made the wrong call - they're in deep with 40million shares and we will see a short squeeze, in my opinion.
3) I've met the management - they're solid. They have manufacturing in Switzerland ready to produce 1/2 a billion pills.
4) Eisai, the giant Japanese pharma has partnered and will sell Belviq in North and South America once DEA scheduling is done. Belviq should be available in pharmacies before end of the year. The partnership involves nice milestone payments.
5) EU and Swiss approval is progressing and company is applying in many other countries for approval.
6) EU partner, ROW partner, and/or an outright buyout is very much in the picture. Even the weasel, Cramer predicted Big Pharma will buy Arena. All the valuation models I've seen point to an at least a purchase price of $25 if not $40+.
7) The target market is HUGE. I believe Belviq will become a block buster. Even a fraction of it means billions in sales. I personally think the stock will be at least $20 by next Spring and that's without the prospects for a bidding war + short squeeze which can make the stock go a lot higher. But please don't rely on my estimates - these are just guesses.
8) Wall Street and its analysts are still living in their pre-approval fiction they made. They're slowly waking up and we should see some upgrades.

You can see a collection of letters etc. that I and others wrote on  http://tinyurl.com/7rh9w2w
I also published several articles that won praise, e.g., Editor's Choice, about Arena.

If you like more information from me I'll be happy to share with you what I know but for any medical advice see your doctor and for investment advice a licensed adviser - I provide neither medical nor investment advice.

IF YOU'RE OBESE, OVERWEIGHT OR KNOW SOMEONE WHO IS

Ask your doctor about Belviq as soon as it's available (my guess is mid-November). I know some patients who took if in the trials and they swear by it - they lost a lot of weight which changed their life for the better.

Best Regards
Reza

A Physical Education Teacher's Note on Efficacy

By David Pena
[reprinted with permission]

Just a little info about me. I've been a physical education teacher for 14 years. I have seen many things that frighten me about where we are going (or where we are) as a country in terms of overweight & obesity. That's what pushed me to start researching pharmaceutical companies aimed at containing obesity. I know that the market for this is huge. There are so many overweight people even at the high school level 14-18 years old. These young adults are already in a decline in their ability to exercise at high intensity levels even in intervals. A small handful of kids ask me what they can do with diet & exercise to maintain or lose weight. The attitude and indifference for their health astonishes me. Most of them will not become concerned with their weight & health until after their first heart attack. So what's my point?

I've studied the results of Lorcaserin & I'm impressed. Even with this study adults were given directions to follow and the most compliant patients lost an average of 35.1 pounds in a year from their baseline weight. These were patients that were taking two 10mg doses a day. I'm certain that these patients were not involved in a high intensity program which makes this weight loss unbelievably efficient. These are best case results from the most compliant patients.

The patients who were either non compliant (lazy) or the 10mg a day patients still showed a weight loss of 5% from their baselines. With a new baseline established every 52 weeks the results of this medication combined with an improvement in attitude that naturally comes with successful results has a much higher implication of weight loss from even the most non-compliant patients.

People saying that ONLY 5% weight loss isn't good enough do not know what they are talking about. This drug has been proven safe and effective. This is safer than surgery. This COMBINED with exercise and compliance will be a turning point for the overweight and obese. Even those who don't want to change their lifestyle can lose 5% instead of maintaining their current weight or worse yet, gaining weight. Anytime you get an obese person to lose weight despite their slow metabolism you have to acknowledge the impact.

In the long run this will have implications on diabetes, cardiovascular disease, cancer, and the big big problem in the US, medical/insurance costs. Insurance companies should be all over this drug pushing for approval. The savings that it will generate for medical expenditures will be dramatic within the first five years of approval.