Lorcaserin Receives Positive Vote From FDA Advisory Committee

http://finance.yahoo.com/news/lorcaserin-receives-positive-vote-fda-210200560.html

Lorcaserin Advisory Committee Chat Link

http://www.lorphen.us/

Click on the link above, get live updates, and post your comments.

Handicapping Lorcaserin's advisory committee review

This is my attempt to handicap the voting by members of Lorcaserin's advisory committee, given they are the same panel as Meridia's advisory committee.

ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE MEMBERS (Voting)

Eric I. Felner, M.D.
Associate Professor of Pediatrics
Director of Diabetes and Endocrinology
Hughes Spalding Children's Hospital
Emory University School of Medicine
Atlanta, Georgia
* Yes on Lorqess, due to lower HbA1c glucose levels

Lamont G. Weide M.D., Ph.D., F.A.C.E.
Chief, Diabetes & Endocrinology
Professor, Internal Medicine
University of Missouri - Kansas City
Truman Medical Centers
Diabetes Center
Kansas City, Missouri
* Voted No on Qnexa, wanted 2 year data
* Yes on Lorqess, due to 2 year echo data, and lower HbA1c glucose levels

Allison B. Goldfine, M.D. Associate Professor
Harvard Medical School Section Head of Clinical Research
Joslin Diabetes
Boston, Massachusetts
* Voted Yes on Qnexa
* Strong Yes on Lorqess, due to better safety profile, and lower HbA1c glucose levels

Abraham Thomas, M.D., M.P.H.
Acting Chair Division Head
Endocrinology, Diabetes, Bone, and Mineral Disorders
Henry Ford Hospital
Whitehouse Chair of Endocrinology
Detroit, Michigan
* Voted No on Qnexa
* No on Lorqess, didn't seem to believe in drug therapeutics for obesity

CARDIOVASCULAR AND RENAL DRUG ADVISORY COMMITTEE MEMBER (Voting)

Sanjay Kaul., M.D.
Director, Fellowship Training Program in Cardiovascular Diseases
Cedars-Sinai Heart Institute
Professor, David Geffen School of Medicine at UCLA
Division of Cardiology
Cedar Sinai Medical Center
Los Angeles, California
* Voted Yes on Qnexa
* Strong Yes on Lorqess, due to better safety profile and 2-year echo data

CENTER FOR DRUG EVALUATION AND RESEARCH TEMPORARY MEMBERS (Voting)

Melanie Coffin
Patient Representative Rockville, Maryland
* Voted Yes on Qnexa
* Strong Yes on Lorqess, due to better safety profile

Jessica W. Henderson, Ph.D.
Acting Consumer Representative
Professor of Community Health Education Division of Health and Physical Education
Western Oregon University
Monmouth, Oregon
* Voted Yes on Qnexa
* Strong Yes on Lorqess, due to better safety profile.

John M. Flack, M.D., M.P.H., F.A.H.A., F.A.C.P.
Professor of Medicine & Physiology
Chair, Department of Internal Medicine
Chief, Division of Translational Research & Clinical Epidemiology
Wayne State University School of Medicine
Detroit, Michigan
* Yes on Lorqess, due to 2-year echo data, and lower HbA1c glucose levels. Also, half-life for Lorqess is faster and metabolized in the kidneys, not the liver.

William R. Hiatt, M.D., F.A.C.P.
University of Colorado Denver, School of Medicine
Section of Vascular Medicine
Divisions of Geriatric Medicine and Cardiology
President, Colorado Prevention Center
Aurora, Colorado
* Yes on Lorqess, due to 2-year echo data.

Jacqueline S. Gardner, Ph.D., M.P.H.
Professor Emeritus
Department of Pharmacy
University of Washington
Seattle, Washington
* Strong Yes on Lorqess, due to no teratogenicity or unwanted pregnancy concerns (see Qnexa). Formulary journal endorses Lorqess as a safe, effective drug that can be taken for longer than 12 weeks, unlike phentermine.

Jodi B. Segal, M.D., M.P.H.
Associate Professor of Medicine
Health Policy and Management, and Epidemiology
Johns Hopkins University
Baltimore, Maryland
* Yes on Lorqess, due to better safety profile, and lower HbA1c glucose levels

Peter A. Gross, M.D.
Executive Vice President & Chief Medical Officer
Hackensack University Medical Center
Hackensack, New Jersey
* Don't Know

David D. Waters, M.D. Emeritus Professor
Division of Cardiology
San Francisco General Hospital University of California
San Francisco, California
* Yes on Lorcaserin, due to 2 years of echo data

REGULAR GOVERNMENT EMPLOYEES (Voting)

Dennis O. Dixon, Ph.D. Mathematical Statistician
Biostatistics Research Branch
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
Bethesda, Maryland
* Strong Yes on Lorcaserin, as clinical trials had the most patients and benefits are statistically significant.

Katherine M. Flegal, Ph.D.
Senior Research Scientist
Distinguished Consultant
National Center for Health Statistics
Centers for Disease Control and Prevention
Hyattsville, Maryland
* Voted No on Qnexa
* Yes on Lorqess, due to 2-year echo data and clinical trials had the most patients and benefits are statistically significant

Edward W. Gregg, Ph.D.
Chief, Epidemiology and Statistics Branch
Division of Diabetes Translation
Centers for Disease Control and Prevention
Atlanta, Georgia
* Don't Know
* Could be a yes for Lorqess as clinical trials had the most patients and benefits are statistically significant.

Michael A. Proschan, Ph.D.
Mathematical Statistician
Biostatistics Research Branch
NIAID, NIH
Bethesda, Maryland
* Voted No on Qnexa
* Strong Yes on Lorcaserin, as clinical trials had the most patients and benefits are statistically significant

ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE MEMBER
(Non-Voting)

Enrico P. Veltri, M.D.
Industry Representative
Pharmaceutical Industry Consultant
Princeton, New Jersey

FDA PARTICIPANTS (Non-Voting)

Curtis J. Rosebraugh, M.D., M.P.H.
Director
Office of Drug Evaluation (ODE) II
Office of New Drugs (OND)
Center for Drug Evaluation and Research (CDER)
Food and Drug Administration (FDA)

Mary H. Parks, M.D.
Director
Division of Metabolism and Endocrinology Products (DMEP),ODE II
OND, CDER, FDA

Eric Colman, M.D.
Deputy Director
DMEP, ODE II, OND
CDER, FDA

Monique Falconer, M.D., M.S.
Clinical Reviewer
DMEP, ODE II, OND
CDER, FDA

David Hoberman, Ph.D.
Mathematical Statistician
Division of Biometrics II
Office of Biometrics
Office of Translational Sciences
CDER, FDA

My best guess tally is 14 Yes, 1 No, and 2 Don't Know. Seven of the Yes votes are a Strong Yes. Even though cardiac valvulopathy has been ruled out based on 2 years of echo data, I did not include all of the cardiovascular voting members as a Strong Yes.

Worst-case scenario is 9 Yes, 8 No. ARNA shares probably drop to $3 - $4 in this scenario.

Best-case scenario is 16 Yes, 1 No. ARNA shares could soar to $15 - $20 in this scenario.

See disclaimers in the side bar. This is not financial advise, and any price or directional targets are my opinion only. Perform your own due diligence.

Disclosure: long ARNA shares, short January 2011 puts, long October calls and short October puts (bullish risk reversal spread, or synthetic long stock split strikes position).

September 15-16, 2010 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee

FDA and Sponsor briefing documents for Abbott's Meridia and Arena's Lorcaserin advisory committee reviews will be posted here.

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm191113.htm

JPMorgan adds to position despite downgrade

On August 2, 2010, JPMorgan Chase analyst Kory Casimov downgraded Arena Pharmaceuticals to "Neutral" from "Overweight", reaffirming a $6 price target. Shares declined as a result of the downgrade.

ttp://finance.yahoo.com/news/Arena-shares-fall-on-JPMorgan-apf-3217542724.html?x=0&.v=1

This downgrade occurred two weeks after JPMorgan had upgraded Arena on July 16, 2010, after competitor Vivus's anti-obesity drug Qnexa was rejected by an advisory committee.

Why the sudden flip flop from upgrade to downgrade, after positive news? Shares of ARNA had soared from below $3 to a peak of $8 a month later, after several positive developments. So perhaps ARNA was trading at frothy levels. But with pivotal events of Lorcaserin's own advisory committee review on September 16, 2010 and a PDUFA date of October 22, 2010, shares of ARNA could rise even more on positive outcomes.

But a closer look at ownership holdings triggers more questions than answers on JPMorgan's motivation for the upgrade and subsequent downgrade.

Records show that as of August 12, 2010, JPMorgan had a new long position for ARNA shares:

2010-08-12 2010-06-30 13F-HR J P Morgan Chase And Co -2.35% Institution 43,082 New Holding 43,082

Which brings up the question: Why would JPMorgan downgrade ARNA--only to build a new long position in ARNA shares? Could their downgrade allow their clients to cover their short positions at a lower price? Or perhaps could they enable long clients to buy in at a lower price--after missing the big run up? A cynic would deduce the downgrade simultaneously provided an escape hatch for trapped shorts, and a lower entry point for long clients who missed the boat.

Best-case, it's a conflict of interest to issue a downgrade and then build a long position. Worst-case, this could be blatant manipulation of a stock.

And Wall Street wonders why retail investors are retreating from markets. Perhaps they're tired of being fleeced by investment firms more interested in their own proprietary trading desk than their fiduciary duties to their retail clients.

ARNA Q2 earnings report

http://finance.yahoo.com/news/Arena-Pharmaceuticals-prnews-3737388002.html?x=0&.v=1

Arena Pharmaceuticals, Inc. (Nasdaq:ARNA - News) today reported financial results for the second quarter ended June 30, 2010, and recent developments, including the successful Pre-Approval Inspection, or PAI, of the company's Swiss drug product manufacturing facility by the US Food and Drug Administration, or FDA.

"We have recently achieved a number of important milestones, including the establishment of an agreement with Eisai for the commercialization of lorcaserin in the US, the successful completion of the FDA's pre-approval inspection of our Swiss manufacturing facility and the publication of our BLOOM trial results in the New England Journal of Medicine," stated Jack Lief, Arena's President and Chief Executive Officer. "We are continuing to execute on our plans for lorcaserin as we prepare for the September FDA advisory committee meeting and potential regulatory approval."

See disclaimers in the side bar.

Disclosure: long ARNA sharews.

Jim Cramer likes ARNA as a speculative play

http://www.cnbc.com/id/15840232?play=1&video=1547554002

Normally, Jim Cramer's endorsement is the kiss of death, since I tend to be a contrarian. He has shunned ARNA before, so I was comfortable being long ARNA. Now that shares of ARNA have almost doubled since the July 1 announcement of the marketing partnership agreement with Eisai, Cramer is jumping on the bandwagon. In all fairness, I don't always disagree with Cramer's assessments; his recommendations are just badly timed, and viewers (largely retail investors) end up buying and selling at the exact inopportune times. His viewing audience on CNBC will perhaps drive shares up some more for the time being, as he has a large following. But be careful, because Cramer's rosy predictions have been known to set up retail investors for a disappointment, as short hedge funds could manipulate shares down after the run up. The smart (and sometimes crooked) money ends up slaughtering the dumb money.

However, with this knowledge, longs might be able to wait and buy the dip. The danger is if the horse has left the barn, and shares run up further on anticipation of positive outcomes at the Advisory Committee review September 16, and of course PDUFA review on October 22. It also provides shorts an opportunity, but I don't recommend retail investors short any stock, because the potential losses are limitless, and unless you're in the know, you will lose money even if you are correct on the direction of the price, but wrong on the timing. Wall Street will whipsaw you out of your position, leaving you with losses, despite being "right."

Overall, shares are ARNA are heavily manipulated, with a huge short interest of up to 27% of the float recently. Expect high volatility. Due to recent bullish news, there is heavy buying pressure, but naked shorts will manipulate the stock in order to cover their shorts and escape intact. If the outcomes are positive, shorts without an escape hatch will get torched.

I've been long ARNA for over a year, with an average entry point above $3, way below the current price per share of $5.26. I can afford to spectate while the share price gyrates, confident in Lorcaserin's FDA approval and commercial launch--that's why I'm long. My initial buy of $5 last year was untimely, but due to my bullish conviction for ARNA, I accumulated more shares on the way down to its lows. In other words, I doubled down, a risky proposition, but potentially highly rewarding. I won't deny there were some nervous moments, but in hindsight, my conviction enabled me to accumulate more shares at lower prices. I was able to overcome fear and doubt, and the price suppression ended up being a gift--everybody loves a sale. Sometimes courage and conviction are rewarded.

I'm long, locked and loaded. I'm not interested in trading in and out of this stock. For those that are, good luck to you.

See disclaimers in the side bar.

Disclosure: long shares of ARNA, short January ARNA put options.

FDA panel rejects VVUS' Qnexa, citing safety worries

http://blogs.wsj.com/health/2010/07/15/fda-panel-rejects-vivuss-qnexa-citing-safety-worries/?mod=yahoo_hs

Vivus’s Qnexa, the first of three new anti-obesity drugs under FDA review this year, came before one of the agency’s advisory committees today — and it was a swing and a miss. The panel recommended against approval, with 10 panel members voting against it and 6 in favor, as the WSJ reports.

Trading in the company’s shares was halted at $12.38. But shares in Arena, which makes one of the other experimental drugs, lorcaserin, were up more than 9% in after hours trading, to $4.30. Shares in Orexigen, which makes the other drug, Contrave, fell 10% in after-hours trading, to $4.50. Contrave is similar to Qnexa in that it, too, is a combination of existing drugs.

The problem wasn’t Qnexa’s effectiveness. But panel members said that safety concerns, such as birth defects, depression, and a high heart rate experienced by some study participants, were worrisome in light of the fact that the drug might be taken by millions of otherwise healthy people over many years. They wanted longer-term data than the company had available in order to assuage safety concerns.

Advisory committee votes 10 - 6 No on Qnexa

As I expected, the independent advisory committee voted 10 - 6 (one panel member later changed his vote) against Qnexa being recommended for FDA approval. Shares in VVUS were halted this morning, but when trading resumes, the shares will plummet.

Shares of ARNA, a competitor to VVUS in the anti-obesity sector, gapped up 34% to a high of $5.72 in anticipation of the vote. After the Qnexa outcome, ARNA shares dropped in sympathy below $4, down approximately 10% for the day. However, upon further inspection, lack of sufficient safety data doomed Qnexa, but ARNA's Lorcaserin has a strong safety profile. Hence, I believe shares of ARNA will rebound leading up to its September 16 advisory committee review.

Edit: as I posted this, ARNA shares are recovering close to their previous close above $4 in after-hours trading. All that volatility, and ARNA ended up its round trip near yesterday's close. What a wild day of trading!

Wall Street was bullish on Qnexa's efficacy, but once again, safety ruled.

See disclaimers on the side bar.

Disclosure: no position in VVUS (and glad). Long ARNA shares.

Topiramate not recommended for treatment of obesity

http://www.apmhealtheurope.com/story.php?mots=TOPIRAMATE&searchScope=1&searchType=0&numero=L7098

Topiramate is one of two generic compounds in Qnexa, the other being phentermine. Qnexa is being reviewed by an independent advisory committee today, and will receive full review by the FDA on October 28. Draw your own conclusions.

Disclosure: no position in VVUS.

More excerpts from FDA briefing document on Qnexa

"When assessed as a group, the incidence of cognitive-related adverse events was 1.7%, 2.0%, 5.6%, and 7.8% in the placebo, low-dose, mid-dose, and high-dose PHEN/TPM groups, respectively. The most common adverse event related to cognitive dysfunction was disturbance in attention."

"Approximately 30% of individuals treated with high-dose PHEN/TPM experienced a
serum bicarbonate <21 mEq/L compared to 5.9% of individuals treated with placebo."

"A higher proportion of PHEN/TPM-treated individuals experienced a categorical
increase in heart rate compared to placebo treated individuals (>20 bpm: 19.6% high-dose PHEN/TPM versus 11.9% placebo)."

"Six individuals in the placebo group (atypical angina, coronary artery disease, left main coronary disease) and five individuals in the PHEN/TPM group experienced a non-fatal serious adverse event related to cardiac ischemia defined within this subclass. An additional placebo-treated individual died of cardiorespiratory arrest. Coronary artery disease was the most common adverse event within the placebo group and myocardial infarction was the most common adverse event within the PHEN/TPM-treated group."

"The incidence of depression-related adverse events in the PHEN/TPM clinical trials was 3.4% in the placebo group, 5.0% in the low-dose PHEN/TPM group, 3.8% in the mid-dose PHEN/TPM group, and 7.7% in the high-dose PHEN/TPM group."

These adverse side effects are problematic for Qnexa, in my opinion. We should find out more in today's independent advisory committee review, and the October 28 PDUFA event.

VVUS shares increase on Qnexa efficacy, despite safety concerns

Shares of Arena Pharmaceuticals and Orexigen also rise in sympathy with Vivus. Briefing documents for Qnexa's upcoming review by an independent advisory committee this Thursday (July 15) revealed Qnexa's efficacy for weight loss, but also expressed concerns regarding adverse side effects. The FDA has assigned a PDUFA date of October 28, 2010, for review of Qnexa's NDA.

http://finance.yahoo.com/news/Vivus-weight-loss-drug-faces-apf-1308428575.html?x=0&.v=2

See disclaimers on the side bar.

Disclosure: long ARNA shares.

More risk factors in VVUS' 10-Q on Qnexa

http://yahoo.brand.edgar-online.com/displayfilinginfo.aspx?FilingID=7238278-301188-514052&type=sect&dcn=0001104659-10-026546

In addition, the placebo rate in larger studies may be higher than
expected.

Although we believe Qnexa affects the two major causes of overeating, excessive hunger and the inability to feel satisfied, we may not be correct in our assessment of the
impact the combination of these two ingredients may have on weight loss or their mechanism of action.

In general, significant adverse events and side effects observed in pre-clinical, clinical and post-marketing studies are included in the full prescribing information or label for each drug. The label for TOPAMAX contains reports of side effects, warnings and precautions including metabolic acidosis, acute myopia and secondary angle closure glaucoma, decreased sweating and hyperthermia, cognitive-related dysfunction, psychiatric and behavioral disturbances including one completed suicide in a patient during a bipolar trial, somnolence and fatigue, sudden unexplained death in epileptics, kidney stones, paresthesia and various drug interactions. The label for ADIPEX, a popular branded form of phentermine, contains warnings and precautions including recommendation against coadministration of phentermine with other drugs for weight loss. Adverse side effects include, among other things, pulmonary hypertension, valvular heart disease, drug abuse and dependence, overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, dryness of the mouth, diarrhea, constipation, impotence and changes in libido.

In addition, if the FDA does not approve the full-dose of Qnexa, there is no assurance that they would approve the mid-dose or any other dose of Qnexa.

If we are required to complete a long-term cardiovascular safety outcomes study for Qnexa, the ultimate approval may be delayed for several years and the overall cost of the program will significantly increase.

In June 2007, an FDA advisory panel recommended against approval of rimonabant, an oral obesity treatment targeting the CB1 receptor system being developed by another company. Rimonabant was a centrally acting drug that reduces patients’ desire to eat. The advisory panel expressed concerns about the impact of the drug on depressed patients and also expressed concerns about patients having thoughts about suicide. In addition, concerns about rimonabant’s mechanism of action and interference with the CB1 receptor pathway were also voiced. The company withdrew its NDA for rimonabant shortly after the advisory panel meeting. Although the active ingredients in Qnexa have been previously
approved by FDA at higher doses for other indications, it is a centrally acting drug that may increase the risk of psychiatric side effects such as depression and/or suicidal ideation.

Does VVUS even understand Qnexa's mechanism of action?

Reading all the risk factors for Qnexa in their 10-Q is like watching a horror movie. VVUS has no marketing partner, and no manufacturing facilities. No way it gets approved in October, in my opinion.

See disclaimers in the side bar.

Disclosure: no position in VVUS.

VVUS's Qnexa advisory committee

Qnexa has an advisory committee review July 15, but the FDA's documents will be available July 13. I have many reservations on Qnexa's approvability, including censorship of titration drop out data, the high discontinuation rates, adverse side effect profile, among others. But this one could also be discomforting to VVUS investors:

VVUS's latest 10-Q :
"The number of patients on the low-dose in OB-302 or the mid-dose in the OB-303 study may not be sufficient for approval."

With drugs facing increasing scrutiny regarding safety from the FDA, Qnexa faces some head winds in the regulatory process, in my opinion. We'll find out soon enough later this week.

See disclaimers on the side bar.

Disclosure: no position in VVUS.

Is a Magic Weight-Loss Pill Just Around the Corner?

According to the Centers for Disease Control and Prevention (CDC):

"American society has become 'obesogenic,' characterized by environments that promote increased food intake, nonhealthful foods, and physical inactivity. Policy and environmental change initiatives that make healthy choices in nutrition and physical activity available, affordable, and easy will likely prove most effective in combating obesity."

The obesity entry in Wikipedia states the following:

"Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy. Body mass index (BMI), which compares weight and height, is used to define a person as overweight (pre-obese) when their BMI is between 25 kg/m2 and 30 kg/m2 and obese when it is greater than 30 kg/m2.

Obesity is associated with many diseases, particularly heart disease, type 2 diabetes, breathing difficulties during sleep, certain types of cancer, and osteoarthritis. Obesity is most commonly caused by a combination of excessive dietary calories, lack of physical activity, and genetic susceptibility, though a limited number of cases are due solely to genetics, medical reasons or psychiatric illness.

Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, and authorities view it as one of the most serious public health problems of the 21st century."

With that backdrop, it is clear that treating obesity is a high priority among healthcare officials. Treating obesity will reduce the occurrence of many other diseases. One out of every third American is obese, while up to two out of three Americans are overweight. That's almost 100 million obese Americans, and almost 200 million overweight Americans. With healthcare reform and reducing healthcare costs national priorities, treatment and prevention of obesity has wide implications economically as well.

There are at least three investigational drug companies attempting to treat obesity therapeutically.

Vivus

Vivus (symbol "VVUS"), a Mountain View, CA-based biopharmaceutical company, released impressive top-line results for weight loss among clinically obese patients. According to their September 9, 2009 press release:

"Patients taking Qnexa, on average, reduced their weight by up to 14.7 percent in one trial, while the drug also prompted improvement in blood pressure and diabetes risk factors. A second study showed weight loss of about 13.2 percent. In both studies, patients taking placebo lost less than 3 percent of their weight."

Clearly, Qnexa exceeded its primary end points for weight loss, and have applied for Federal Drug Administration (FDA) approval. Shares of VVUS surged as a result. But questions of tolerability and safety remain. Qnexa is a combination of two generic compounds: phentermine and topiramate ("Topamax"). Both are FDA-approved compounds: phentermine is an appetite suppressant of the amphetamine class, while Topamax is used to prevent seizures and migraine headaches.

However, both compounds carry adverse side effects--some serious, and accompanying warning labels. Topamax side effects include: numbness and tingling, fatigue, taste change, nausea, diarrhea, and difficulties with cognitive function, including loss of memory and concentration.

Phentermine common side effects include: bad taste in mouth, changes in sex drive, constipation, diarrhea, insomnia, dizziness, dry mouth, exaggerated sense of well being, headache, impotence, nervousness, overstimulation, restlessness, sleeplessness, upset stomach. Serious adverse side effects include: severe allergic reactions (rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue), bizarre behavior, chest pain, fainting, fast heartbeat, pounding in the chest, shortness of breath, swelling of the legs and feet, tremor.

For these reasons, the exclusion criteria for patients was vast, and hence, limited the number of patients able to participate in Qnexa clinical trials. Patients with the following conditions could not participate in Qnexa clinical trials, according to clinicaltrials.gov:

"Exclusion Criteria:

Stroke/MI/unstable cardiovascular disease within 6 months
Clinically significant renal, hepatic or psychiatric disease
Unstable thyroid disease or replacement therapy
Nephrolithiasis
Obesity of known genetic or endocrine origin
Participation in a formal weight loss program or lifestyle intervention
History of glaucoma or intraocular pressure
Pregnancy or breastfeeding
Alcohol abuse
Smoking cessation within previous 3 months or plans to quit smoking during study
Eating disorders
Cholelithiasis within past 6 months
Excluded medications
Type 2 diabetes
Previous bariatric surgery
History of bipolar disorder or psychosis"

In other words, Qnexa was efficacious in inducing weight loss in patients, but due to the safety and tolerability profiles of phentermine and topiramate, the market potential may be limited should Qnexa achieve FDA approval.

VVUS submitted their New Drug Application (NDA) for Qnexa on December 28, 2009, and the FDA accepted the NDA on March 1, 2010. The Endocrinologic and Metabolic Drugs Advisory Committee (AC) will review the Qnexa NDA on July 15, 2010 to provide independent expert advice to the FDA on safety and efficacy. A full FDA review is targeted for October 28, 2010.


Orexigen Therapeutics

Another investigational drug company seeking FDA approval for a weight loss drug is Orexigen Therapeutics (symbol "OREX"), based in San Diego, CA. OREX also announced pivotal Phase III top-line results for Contrave, a combination of generic compounds bupropion and naltrexone. Bupropion is an anti-depressant and anti-smoking drug, while naltrexone is used to treat alcoholism and opiate addiction.

In their July 20, 2009 press release:

"In the two trials with non-diabetes patients, Orexigen said 48 percent and 56.3 percent of patients, respectively, reported weight loss of at least 5 percent. That compared to 16.4 percent and 17.1 percent for the placebo patients. That more than met FDA testing guidelines that require at least a third of patients must lose at least five percent of their body weight. At least twice as many patients must reach the 5 percent goal compared with those who take a placebo.

In those trials, the Contrave patients had mean weight loss of 8.1 percent and 8.2 percent, or 17.6 pounds and 17.5 pounds. In the diabetes trial, 44.5 percent of patients lost at least 5 percent of their weight after 56 weeks, compared to 18.9 percent of patients who took a placebo. Contrave patients reduced their blood sugar by 0.6 percent, compared to 0.1 percent for the placebo group."

Once again, efficacy for weight loss among Contrave-active patients was enough to be FDA-approvable, but questions of adverse side effects arise as well. Common bupropion side effects include: agitation, constipation, headaches, nausea, vomiting, dizziness, increased sweating, tremors, blurred vision, rapid heart beat, confusion, hostility, arrhythmias, hearing changes, menstrual problems, hypertension, palpitations, indigestion, arthritis, anxiety, decreased libido, impotence, taste changes, and fainting.

Naltrexone common side effects include: anxiety, chills, constipation, delayed ejaculation, diarrhea, dizziness, drowsiness, headache, increased thirst, irritability, joint and muscle pain, low energy, nausea, nervousness, sleeplessness, stomach pain/cramps, and vomiting. Serious adverse side effects include: severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abdominal or stomach pain; cramping; dark urine; depression; suicidal thoughts or behaviors; unusual tiredness or weakness; vomiting; white bowel movements; yellowing of the skin or eyes.

According to clinicaltrials.gov, exclusion criteria for Contrave include:

"Exclusion Criteria:

Obesity of known endocrine origin (e.g., untreated hypothyroidism, Cushing's syndrome)
Serious medical condition or medical condition that limits participation in the prescribed exercise program:
(e.g. unstable cardiovascular disease including congestive heart failure, angina pectoris, and myocardial infarction; stroke; claudication; acute limb ischemia; acute renal or hepatic disorder; renal, hepatic or respiratory insufficiency)

Active malignancy or history of malignancy (other than non-melanoma skin cancer or surgically cured cervical cancer) within 5 years of enrollment
Serious psychiatric condition (e.g., any history of bipolar disorder, psychosis, suicidal attempt or post-partum depression; a history of major depression, suicidal ideation or antidepressant use within 1 year)
Type I or Type II diabetes mellitus requiring pharmacotherapy
Excluded concomitant medications: anorectic agents; weight loss agents; dietary supplements to promote muscle building, enhance mood, or reduce appetite; adrenergic blockers; beta blockers; anti-psychotic agents; clonidine; theophylline; cimetidine; oral corticosteroids; anti-depressant; topiramate; Depo-Provera®, smoking cessation agents; frequent, known use of opioid or opioid-like analgesics
History of surgical intervention for obesity
History of seizure disorder or predisposition to seizures (e.g., history of cerebrovascular accident, significant head trauma, brain surgery, skull fracture, subdural hematoma, or febrile seizures)
History of bulimia or anorexia nervosa
History of drug or alcohol abuse within 5 years
History of treatment with bupropion, or naltrexone within 12 months
History of hypersensitivity to bupropion, or naltrexone
Use of drugs, herbs, or dietary supplements known to significantly affect body weight within one month of baseline
Use of investigational drug, device or procedure within 90 days
Participation in any previous clinical trial conducted by Orexigen Therapeutics
Any condition which in the opinion of the investigator makes the subject unsuitable for inclusion in this study"

Due to the high number of exclusion criteria, my assessment is that Contrave will address the extremely obese with few other indications, which will also limit the available market for the drug. This assumes Contrave will attain FDA approval.

OREX announced their submission of their NDA for Contrave on April 1, 2010. A Prescription Drug User Fee Act (PDUFA) date is expected in the first quarter of 2011.

Arena Pharmaceuticals

The third candidate for weight management is Lorcaserin hydrochloride, a novel single agent developed by Arena Pharmaceuticals (symbol "ARNA"), based in San Diego, CA. Lorcaserin is the only agent developed specifically for weight loss, among Contrave and Qnexa. In other words, it is not a combination of generic compounds which were developed for other indications. Hence, advantages include strong patent protection until at least 2023, reduced risk of contraindications from not combining compounds, and reduced adverse side effect profile.

A brief glimpse into the checkered history of the weight loss sector is instructive. Fen-phen, a compound of fenfluramine and phentermine, was a blockbuster anti-obesity drug in 1997. However, due to fatal pulmonary hypertension and cardiac valvulopathy problems, fen-phen was quickly withdrawn. Over $21 billion of class action lawsuit payments have been paid by Wyeth as a result. Since that time, the FDA has been deservedly very conservative in approving weight management drugs. Many anti-obesity drug candidates have failed, including compounds by big pharmaceutical giants by Merck, Sanofi-Aventis, and Pfizer. The two existing approved drugs, Orlistat and Sibutramine, are marginally effective, and carry significant adverse side effects--including liver damage, which limits their market penetration and duration of usage. Thus, an estimated $10 billion market for weight management is largely unmet.

In addition to efficacy (i.e. statistically significant weight loss), safety is even more important to the FDA, given the fen-phen disaster. First-year medical students understand "Primum non nocere," Latin for "First, do no harm." VVUS, OREX, and ARNA hope to capitalize on past failures from other pharmaceutical companies. The worldwide market (Europe is second in size behind the US) can support more than one treatment, but safety and efficacy will determine FDA approval and commercialization success.

Lorcaserin is unique because of its specificity to the G-protein coupled receptor (GPCR) 5-HT2C, located in the hypothalamus. Fenfluramine caused valvular lesions because it also was an agonist for the 5-HT2B subtype, which impacts cardiac valves. Hence, fen-phen caused irreversible valvular regurgitation.

Lorcaserin, on the other hand, only activates the seratonin 5-HT2C receptor, which controls satiety. Cardiac valves are unaffected. Echocardiograms during clinical trials showed no valvular irregularities in the Lorcaserin-active group above the placebo-control group. Weight loss from Lorcaserin was quick and more likely to encourage patients to continue compliance. Adverse side effects like headaches, dizziness, and nausea were transient and mild. In fact, more patients on placebo dropped out than patients from the Lorcaserin group.

Here is the list of exclusion criteria for BLOOM, one of the pivotal Phase III trials, according to clinicaltrials.gov:

"Exclusion Criteria:

Diabetes
Pregnancy
History of heart valve disease
Serious or unstable current or past medical conditions"

Two other Phase III clinical trials included diabetics and patients with heart valve diseases (see BLOOM-DM and BLOSSOM below), so Lorcaserin appears to be safe for many obese patients.

On March 30, 2009, ARNA announced top-line results for BLOOM, the first of two pivotal Phase III trials, for categorical and average mean weight loss above placebo:

"Primary Endpoint Analysis

The hierarchically ordered endpoints were the proportion of patients achieving 5% or greater weight loss after 12 months, the difference in mean weight loss compared to placebo after 12 months, and the proportion of patients achieving 10% or greater weight loss after 12 months. Compared to placebo, using an intent-to-treat last observation carried forward (ITT-LOCF) analysis, treatment with lorcaserin was associated with highly statistically significant (p<0.0001) categorical and average weight loss from baseline after 12 months:

-- 47.5% of lorcaserin patients lost greater than or equal to 5% of their
body weight from baseline compared to 20.3% in the placebo group. This
result satisfies the efficacy benchmark in the most recent FDA draft
guidance.

-- Average weight loss of 5.8% of body weight, or 12.7 pounds, was achieved
in the lorcaserin group, compared to 2.2% of body weight, or 4.7 pounds,
in the placebo group. Statistical separation from placebo was observed

by Week 2, the first post-baseline measurement.

-- 22.6% of lorcaserin patients lost greater than or equal to 10% of their
body weight from baseline, compared to 7.7% in the placebo group."

Many Wall Street analysts misinterpreted the data, believing the weight loss was insufficient for FDA approval. They did not understand that FDA guidances for weight loss required only one of the first two primary end points to be met.

The FDA website lists the following efficacy benchmarks for weight loss, published in 2007:

"In general, a product can be considered effective for weight management if after 1 year of treatment either of the following occurs:

• The difference in mean weight loss between the active-product and placebo-treated groups is at least 5 percent and the difference is statistically significant
• The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35 percent, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant"

Clearly, Lorcaserin met the 2nd primary efficacy end point, based on ITT-LOCF analysis, which the FDA uses in order to reduce clinical trial bias. By exceeding FDA weight loss guidances and satisfying general safety assessments, Lorcaserin appears to be FDA-approvable.

In the clinical practictioner world, prescribing doctors also evaluate per protocol efficacy, which only includes compliant patients--those who complete the clinical trials. On June 6, 2009, ARNA announced per protocol efficacy for Lorcaserin in BLOOM trials:

"In addition to supporting the previously announced results on all three co-primary endpoints on an intent-to-treat, last observation carried forward (ITT-LOCF) basis, the data presented today demonstrated strong efficacy in patients who completed one year of treatment according to the trial's protocol. In the per protocol population, nearly two-thirds (66.4%) of lorcaserin patients lost at least 5% of their weight compared to 32.1% of patients on placebo (p < 0.0001), and over one-third (36.2%) of lorcaserin patients lost at least 10% of their weight compared to 13.6% for placebo (p less than 0.0001). The average weight loss in this population was 17.9 pounds in the lorcaserin group, compared to 7.4 pounds in the placebo group. Patients randomized to remain on lorcaserin for Year 2 maintained a significantly greater amount of weight loss compared to the lorcaserin patients who switched to placebo at Week 52 in both the ITT-LOCF and per protocol populations."

This data was even more encouraging, as it suggests that patients who stay on Lorcaserin not only lose weight, they keep it off. Even though the FDA only looks at ITT-LOCF in the approval process, per protocol efficacy is what prescribing doctors will also assess, which ultimately determines commercialization success.

In addition, secondary benefits were also realized by Lorcaserin-active patients:

"Secondary Endpoint Analysis

New data demonstrate that treatment with lorcaserin over one year was associated with highly significant improvements compared to placebo in multiple secondary endpoints associated with cardiovascular risk, including:

-- Blood Pressure: systolic blood pressure, diastolic blood pressure and
heart rate

-- Lipids: total cholesterol, LDL cholesterol and triglycerides

-- Glycemic Parameters: fasting glucose, fasting insulin and insulin
resistance

-- Inflammatory Markers of Cardiovascular Risk: high-sensitivity CRP and
fibrinogen

Quality of Life, as assessed by the Impact of Weight Questionnaire - Lite, also improved to a significantly greater extent in the lorcaserin group than the placebo group at Week 52."

ARNA also announced top-line results for BLOSSOM, the second of two pivotal phase III clinical trials on September 18, 2009 with the following results.

"Our BLOSSOM trial confirmed the BLOOM results and completed the lorcaserin pivotal Phase 3 clinical trial program of 7,190 patients evaluated for up to two years.

In BLOSSOM, lorcaserin met all primary efficacy and safety endpoints, and lorcaserin patients achieved highly statistically significant categorical and absolute weight loss. Treatment with lorcaserin also resulted in statistically significant improvements as compared to placebo in multiple secondary endpoints associated with cardiovascular risk. Lorcaserin was very well tolerated, did not result in increased risk of depression or suicidal ideation and was not associated with the development of cardiac valvular insufficiency.

Efficacy

Patients treated with 10 mg of lorcaserin dosed twice daily who completed the one-year trial according to the trial’s protocol demonstrated the benefits of long-term treatment with lorcaserin:

* 63.2% of lorcaserin patients lost at least 5% of their body weight, compared to 34.9% for placebo.
* 35.1% of lorcaserin patients lost at least 10% of their body weight, compared to 16.1% for placebo.
* Lorcaserin patients achieved an average weight loss of 7.9%, or 17.0 pounds, compared to 3.9%, or 8.7 pounds, for placebo.
* The quartile of lorcaserin patients with the greatest weight loss lost an average of 35.1 pounds, or 16.3% of their body weight.

Measurements of efficacy using an intent-to-treat last observation carried forward, or ITT-LOCF, analysis showed that lorcaserin met all primary endpoints. Patients treated with 10 mg of lorcaserin dosed twice daily achieved highly statistically significant categorical and average weight loss after one year:

* 47.2% of lorcaserin patients lost at least 5% of their body weight, compared to 25.0% for placebo. As with BLOOM, this result satisfies one of two alternate efficacy benchmarks in the most recent FDA draft guidance, which provides that a weight-management product can be considered effective if after one year of treatment the proportion of subjects who lose greater than or equal to 5% of baseline body weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant.
* Lorcaserin patients achieved an average weight loss of 5.9%, or 12.7 pounds, compared to 2.8%, or 6.3 pounds, for placebo.

Safety and Tolerability Profile

Treatment with lorcaserin was very well tolerated, resulting in few adverse events with greater frequency than the placebo group. The most frequent adverse events and their rates for lorcaserin twice daily and placebo patients, respectively, were as follows: headache (15.6% vs. 9.2%), upper respiratory tract infection (12.7% vs. 12.6%), nasopharyngitis (12.5% vs. 12.0%), nausea (9.1% vs. 5.3%) and dizziness (8.7% vs. 3.9%). Adverse events of depression, anxiety and suicidal ideation were infrequent and were reported at a similar rate in each treatment group.

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%).

Secondary Endpoints

Treatment with lorcaserin over one year was associated with statistically significant improvements or favorable trends compared to placebo in multiple secondary endpoints, including blood pressure and lipids."

Clearly, BLOSSOM results confirmed BLOOM trials. One difference is that BLOSSOM included patients with pre-existing valvulopathy, while the BLOOM clinical trial did not.

BLOOM-DM, another Phase III clinical trial, includes diabetics. Blinded data suggests weight loss among diabetics reduces or eliminates medications for other indications. This will be attractive to healthcare providers and insurers seeking reduced healthcare costs. BLOOM-DM (Diabetes Mellitus) is not a pivotal trial, but data will be submitted as a supplement to Lorcaserin's NDA.

ARNA is well-financed after a series of equity offerings and warrant issuances. They have enough cash to last until the expected Prescription Drug User Fee Act (PDUFA) event late next year. They also own their own manufacturing facilities in Switzerland. Hence, while they seek a marketing partner, they have contingency plans in place to market Lorcaserin independently. Senior management and the Board of Directors have vast experience in the FDA approval process, and the ability to attract financing in difficult credit markets. Recent insider buying by six of eight Directors indicate bullishness. There is heavy institutional ownership, indicating long-term shareholder value. There is high insider ownership, and high short interest, approximately 20% of the float at last count. Shares have been manipulated down, a common occurrence for microcap biotech companies. The smart money has accumulated shares at lower prices. Should shares continue to rise above the moving averages, shorts will cover, potentially causing a short squeeze.

ARNA submitted an NDA for Lorcaserin on December 22, 2009, and was accepted by the FDA on February 24, 2010. An Advisory Committee review is expected in September, with the PDUFA date assigned for October 22, 2010.

Conclusion: Due to ARNA's Lorcaserin positive safety and tolerability profile, the novel single agent has a high probability of FDA approval for weight management. Lorcaserin's efficacy meets FDA draft guidances for statistically significant weight loss. By meeting primary end points for weight loss efficacy and safety, and also demonstrating improvements in multiple secondary end points associated with cardiovascular and diabetes risks, Lorcaserin is a potential game-changing, block-buster drug which addresses a $10 billion weight management market.

Disclaimer: These are my opinions and not recommendations. This article contains forward-looking statements that involve risk and market uncertainties. Actual results and events may materially differ from the article's expectations. Please do your own due diligence.

Disclosure: I am long ARNA shares.