Obesity Is Hurting the U.S. Economy in Surprising Ways

http://www.bloomberg.com/news/articles/2015-03-05/american-economy-has-a-weight-problem-as-costs-of-obesity-mount

Arena Pharmaceuticals, Belviq (Lorcaserin), Obesity, and BORG

Arena Pharmaceuticals weight management pill Belviq (Lorcaserin) will have its commercial launch tomorrow.  It was a long, hard road to FDA approval and DEA scheduling.  I am one of the proud creators and members of the BORG activist investor group, now 47 strong.  There were many strong contributors, but Dr. Daniel Lopez deserves the most credit.  He challenged the manufactured safety risks--and proved they were false.

The naked short hedge funds, captured media, and factions of the FDA won the battle, but we won the war.  Millions of obese, overweight, and diabetics will live better lives due to Belviq.  I'm certain many lives will be saved.  Thank you Arena, BORG, the FDA for coming around, and the many clinicians who are treating their patients.

Obesity and its associated diseases cost this country hundreds of billion of dollars.  The availability of Belviq will be a major step toward alleviating pandemic obesity.

Here is an article in the Wall Street Journal on the beginnings of BORG:

http://online.wsj.com/article/SB10001424052702304023804575566731686435318.html

By ALICIA MUNDY And JENNIFER CORBETT DOOREN

WASHINGTON—Federal regulators are set to decide the fate of a new obesity drug as soon as Friday, and with it the future of a small biotechnology company whose investors are conducting an unusually aggressive lobbying campaign to get the pill approved.

The drug, lorcaserin, made by Arena Pharmaceuticals Inc. ARNA -0.23% of San Diego, was rejected in a 9-to-5 vote by a Food and Drug Administration advisory committee in mid-September.

That prompted outrage among Arena shareholders who have spent thousands of hours on their own scientific analyses, contacted Congress, set up an online petition and flooded the FDA with comments saying the agency didn't give the diet pill a fair hearing.

It is one of a few recent cases in which individual investors in a company—not just the company itself—made their presence felt in advance of a make-or-break decision.

Arena shareholders, about 40 of whom are in an investor group nicknamed Borg, say they're raising important questions about possible bias and ignorance among the FDA panel members.

"What has mobilized so many people, within our group and beyond, are the comments and behavior of some FDA officials and what we believe to be incorrect scientific conclusions," said Douglas Park, an Arena shareholder in San Diego who used to work for the company.

Some doctors and FDA officials fear the nascent trend poses dangers to the drug-approval system.
"It's a good thing everybody is allowed to have their say, but the FDA has to do its job," said heart-disease expert Sanjay Kaul, who served as an FDA adviser and voted against lorcaserin. "This is about patients, not about money."

The FDA is due to decide on lorcaserin by Friday, although it could seek a delay. The agency usually follows the advice of its outside panelists but isn't required to do so.

Investors are showing new assertiveness because of financial uncertainty in the biotechnology business and anger at a perceived lack of predictability in FDA decisions, said former FDA Deputy Commissioner Scott Gottlieb, now a partner in a health-care investment firm.

An Arena spokesman said the company isn't involved in investor lobbying and hasn't encouraged it.

Many investors saw Arena's pill, which affects a part of the brain involved in appetite control, as safer than rival drugs. They were surprised when the FDA staff and the agency's outside advisers gave it a thumbs-down in September. FDA reviewers said lorcaserin was only modestly effective in trimming pounds and had some safety issues.

The company's stock fell 73% in the week of the vote. Arena shares declined 6.4% to $1.46 in 4 p.m. trading Thursday on the Nasdaq Stock Market.

"I got punched in the belly real bad by the FDA," said Peter Becker, a retired Army colonel in Texas. The former administrative law judge said he had bought a "very, very large position in Arena" after he spent many hours studying the safety of lorcaserin versus other diet drugs.

The backlash began quickly. One investor accosted an FDA panel member with harsh words in a hallway minutes after the Sept. 16 vote, according to people who were there. It was first reported by The HealthCare Channel digital video site.

The Borg group says the FDA understated lorcaserin's efficacy in weight loss and exaggerated safety issues.

Another investor wrote to Dr. Kaul, the panelist, politely suggesting that, "to hear the scuttlebutt going around," the panelists incorrectly assumed a risk to humans after some rats on lorcaserin developed tumors.

"Given the issues at stake here and the money invested by both ARNA [Arena] and its Stock Holders," the investor wrote, Dr. Kaul had a "responsibility to let the FDA know" that he would have voted "yes" if he fully understood the tumor issue. Dr. Kaul, based at Cedars-Sinai Medical Center in Los Angeles, says the rat issue didn't figure significantly in his vote.

The chairman of the advisory committee, Abraham Thomas of Henry Ford Hospital in Detroit, voted for the drug, but he said the shareholders are overstating what it can do.

"I could have gone either way. It's just not a very effective medication," said Dr. Thomas, who previously ran the obesity clinic at Brigham and Women's Hospital in Boston.

An FDA spokeswoman said the agency was careful in choosing panelists and reviewing drug safety and efficacy data. The FDA's meeting process was fair, she said.

One of the few precedents for the lorcaserin activism came in the fight over the prostate-cancer drug Provenge, which was rejected by the FDA in 2007. Following additional research and pressure from investors in Provenge maker Dendreon Corp., DNDN +0.64% the FDA approved Provenge in April of this year.

Several Arena shareholders said they had also invested in Dendreon, whose stock soared after the FDA approval.
 
Write to Alicia Mundy at alicia.mundy@wsj.com and Jennifer Corbett Dooren at jennifer.corbett-dooren@dowjones.com

Eisai's Coats on 2013 Sales of Arena's Obesity Drug

http://bloom.bg/15yNAkb

HBO Documentary Films: The Weight of the Nation - Part 2: Choices

http://youtu.be/hLv0Vsegmoo

ARNA investors fight back

http://www.signonsandiego.com/news/2010/oct/09/arena-investors-fight-back-against-fda/

Lorcaserin and diabetes mellitus

http://seekingalpha.com/instablog/523862-kllj-investments/86782-the-importance-of-arena-s-bloom-dm-study

Arena’s BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus) study for patients suffering from diabetes is now complete and the results are expected in late 2010. This study was a one-year, randomized, double-blind and placebo controlled Phase III trial on 604 patients with Diabetes Mellitus Type II who were overweight or obese and taking oral diabetes medications. These results will be filed as a Supplemental NDA (sNDA) after LORQESS (Lorcaserin) is approved. This study is of paramount importance for LORQESS to have an indication specific for the treatment or prevention of diabetes. Arena must clinically prove that taking LORQESS will improve HbA1c and Fasting Glucose to receive an indication for diabetes. If this proves to be the case, which was shown in BLOOM and BLOSSOM, then LORQESS could be covered by most Payers for the treatment of diabetes or the prevention of diabetes.

“Data from the 2007 National Diabetes Fact Sheet (the most recent year for which data is available)

Total: 23.6 million children and adults in the United States—7.8% of the population—have diabetes.

Diagnosed: 17.9 million people

Undiagnosed: 5.7 million people

Pre-diabetes: 57 million people

New Cases: 1.6 million new cases of diabetes are diagnosed in people aged 20 years and older each year.

Cost of Diabetes

$174 billion: Total costs of diagnosed diabetes in the United States in 2007

· $116 billion for direct medical costs

· $58 billion for indirect costs (disability, work loss, premature mortality)

See disclaimers in the side bar.

Disclosure: long ARNA shares.

Lorcaserin video

Lorcaserin's visibility is increasing with the peer-reviewed article in the New England Journal of Medicine, as indicated in this video.



http://www.youtube.com/watch?v=6d1y25lsa4I

New England Medical Journal peer review on Lorcaserin

Boldface is my emphasis.

ABSTRACT

Background: Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reducing body weight.

Methods: In this double-blind clinical trial, we randomly assigned 3182 obese or overweight adults (mean body-mass index [the weight in kilograms divided by the square of the height in meters] of 36.2) to receive lorcaserin at a dose of 10 mg, or placebo, twice daily for 52 weeks. All patients also underwent diet and exercise counseling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. Primary outcomes were weight loss at 1 year and maintenance of weight loss at 2 years. Serial echocardiography was used to identify patients in whom valvulopathy (as defined by the Food and Drug Administration) developed.

Results: At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 5.8±0.2 kg with lorcaserin and 2.2±0.1 kg with placebo during year 1 (P<0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evaluated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not increased with the use of lorcaserin. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea. The rates of serious adverse events in the two groups were similar.

Conclusions In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo.

Editorial:

The justification for using lorcaserin to manage obesity is not greater efficacy than currently available drugs, but rather an apparently much better safety and adverse-event profile and very clear-cut beneficial effects on risk factors for type 2 diabetes and cardiovascular disease. Where lorcaserin will fit into the management of obesity remains to be seen. Future studies could investigate the potential for improved weight-loss efficacy by combining lorcaserin with other receptor-selective weight-loss compounds such as analogues of glucagon-like peptide 1. Given the history, we will need to be doubly sure about the safety of lorcaserin, used either alone or in combination with other weight-loss drugs.

Valvulopathy is why fen-phen was withdrawn in 1997, after 18 million subscriptions were written in 1996. Pfizer (formerly Wyeth, formerly American Home Products) set aside $21 billion for class action lawsuits.

The potential for a weight management treatment is staggering. Perform your own due diligence.

See disclaimers in the side bar.

Disclosure: no position in PFE. Long shares of ARNA. Short put options in ARNA.

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.

Qnexa briefing documents for advisory committee (update 3)

"Lastly, the safety profile associated with long term use of Qnexa is not known. It is notable that phentermine was approved only for short term use (“a few weeks”) for patients with obesity. Topiramate was approved for long term use, but in a population (epilepsy or migraine prophylaxis) that may have important clinical differences than patients who seek treatment for obesity."


Questions to the Advisory Committee
1) Taking into account the results of the assessments made with the PHQ-9 and the Columbia Suicidality Severity Rating Scale (C-SSRS), please comment on the significance of the increased adverse event reports of depression, anxiety, and sleep disorders in subjects treated with Phentermine/Topiramate (PHEN/TPM).
- If approved, please discuss need for monitoring, possible monitoring strategies, and contraindications for use.

2) Please comment on the potential significance of the increased adverse event reports of disorders of attention, memory, language, and other cognitive disorders in subjects treated with PHEN/TPM.
- If approved, please discuss need for monitoring and possible monitoring strategies.

3) Please comment on the potential clinical significance of the metabolic acidosis determined by decreases in serum bicarbonate levels with PHEN/TPM treatment.
- If approved, please discuss need for monitoring, possible monitoring strategies, and contraindications for use.

4) Please comment on the potential clinical significance of the increase in heart rate observed in PHEN/TPM treated individuals.
- If approved, please discuss need for monitoring, possible monitoring strategies, and contraindications for use.

5) Given the doses of topiramate in PHEN/TPM, please comment on whether you believe PHEN/TPM poses a teratogenic risk to the target population for weight loss.
- If you believe it does pose a risk, please comment on how this risk should be managed in women of child-bearing potential if PHEN/TPM is approved.

6) Based on the current available data, do you believe the overall benefit-risk assessment of PHEN/TPM (QNEXA) is favorable to support its approval for the treatment of obesity in individuals with a BMI ≥30 kg/m2 or ≥27 kg/m2 with weight-related co-morbidities?
- Vote: Yes/No/Abstain

"The incidence of TEAEs [treatment-emergent adverse events] in the cardiac arrhythmia subclass was higher in the QNEXA Top-dose group (4.7%) and Mid-dose group (4.2%) than in the placebo group (1.8%). Palpitations, increased heart rate, and tachycardia represented 36 of the 41 cardiac arrhythmia TEAEs in the Serious cardiac adverse events were examined in all subjects included in the Integrated Safety Analysis of the NDA. Overall, there were eight cardiac SAEs in the QNEXA groups (N=2559) and nine in the placebo group (N=1719). The relative risk was 0.60 (95% CI: 0.23-1.54), QNEXA vs. placebo. The incidence of TEAEs in the is 1-year cohort. Palpitations and increased heart rate are expected and dose-related side effects of phentermine and phentermine-containing products. The cardiac arrhythmia TEAEs were primarily mild or moderate in severity and were serious for 4 (0.3%) subjects in the placebo group, 2 (0.4%) subjects in the Mid-dose group, and 2 (0.1%) subjects in the Top-dose group ischemic heart disease subclass was low (0.4% overall) and similar for the treatment groups."

Safety
Although not a requirement for approval of a fixed-dose combination product, the Division looks more favorably on combination products that exhibit a potentially meaningful improvement in the safety profile compared to the individual components. In addition, the applicant has theorized that some of the expected side effects of the two drugs alone may be “mitigated by oppositional pharmacodynamic effects associated with the other component.” In particular, the cognitive slowing observed with topiramate treatment may be lessened with co-administration of phentermine.

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.

High fructose corn syrup contributes to obesity

http://www.princeton.edu/main/news/archive/S26/91/22K07/index.xml?section=topstories

Time to end the corn subsidies, dontcha think?

ARNA 4th quarter earnings

http://www.reuters.com/article/idCNN1225473220100312?rpc=44

Arena Pharmaceuticals Inc (ARNA.O) expects to launch sales of its weight loss drug -- alone or with a partner -- within 12 weeks of U.S. regulatory approval, according to the company.

Shares are up 10% today.

Disclosure: long ARNA shares.

Smoking and obesity

The benefits of the anti-smoking campaign are paying off, as the life expectancy of the average American has increased. However, obesity has surged, and will likely undermine any life-extending benefits we have achieved from smoking cessation.

Studies show that at current rates, 45% of Americans will be obese by 2020. It is time to stop smoking AND stop over-eating.

http://www.dailyfinance.com/2009/12/06/weve-stopped-smoking-but-were-getting-fat-net-loss-eight-mon/

This will reduce healthcare costs by billions of dollars, extend life expectancy, and improve overall quality of life.

ARNA announces BLOSSOM results

In one of the wildest trading sessions in recent memory, shares of Arena Pharmaceuticals (symbol "ARNA") surged 40% in after-hours trading last night, after they issued a press release they would announce top-line results for Lorcaserin, their weight loss drug. Obviously, investors were anticipating that results would be positive. At midnight, when ARNA did publish BLOSSOM results, their second of two pivotal, Phase III clinical trials, the headline mentioned that positive results were achieved for efficacy and safety. The pre-close and after-hours buying of calls and shares appeared justified, as rumors of leaks were pervasive among trading desks.

However, once the data was released, the market's reaction in pre-market morning trading was negative, once again underwhelmed by Lorcaserin not meeting the 5% average placebo-adjusted weight loss. To make matters worse, unlike BLOOM, the categorical 5% weight loss did not exceed double the placebo categorical 5% weight loss either. Thus, shares dropped all the way to $3.80 from last night's $6.76 close.

Upon further analysis and cooler heads, shares have walked up back to the high $5's, meaning after all that whipsawing (which enabled shorts and market makers to profit immensely), shares of ARNA are above water from last night's by almost $1 per share.

Why have the shares rebounded, if the efficacy numbers are "bad"? First of all, BLOSSOM confirmed BLOOM's efficacy AND safety and tolerability. This is significant, as the weight loss sector is littered with marginally effective and intolerable drugs (phentermine has many adverse side effects) to the downright dangerous and lethal (Wyeth's fen-phen was withdrawn due to cardiac valvulopathy). Lorcaserin, on the other hand, has a clean safety profile very similar to a placebo.

BLOSSOM's 20 mg dose confirmed BLOSSOM's efficacy numbers, even if the placebo control group in BLOSSOM had better efficacy than the place group in BLOOM. But more importantly, the FDA guidance for weight loss efficacy needs further scrutiny. It is a minor but important point--one that even ARNA CEO Jack Lief missed in previous presentations, but one I captured several months ago.

ARNA's presentation and conference call today did catch incorporate it, because it is an essential point. According to the guidance established in 2007:

c. Efficacy benchmarks

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

Notice 35% of the Lorcaserin-active group has to lose at least 5% body weight. That group has to also be APPROXIMATELY double the placebo-treated group. It doesn't have to EXCEED the doubling of the placebo control group. It did EXCEED in BLOOM, but both BLOOM and BLOSSOM meet this "approximately double" co-primary end point. Additionally, when pooled together, BLOOM and BLOSSOM results exceed it.

I've covered other aspects on why Lorcaserin has a high probability of getting FDA approved, so I won't go into them here. But it is also worth noting that while the average placebo-adjusted weight loss end point of 5% was not met in BLOSSOM either, the either/or component of the co-primary end points (the other being categorical weight loss discussed above) is a good indicator that Lorcaserin is FDA approvable.

And with a clean safety and tolerability profile, it remains the best candidate to achieve FDA approval first, and perhaps reach the broadest target market of obese and overweight patients. The finish line is closer for ARNA, and the market is starting to warm up to it.

Disclosure: long ARNA shares.

Lorcaserin clinical trial

Ed Susman, a medical doctor who participated as a patient in an obesity clinical trial, blogs about it on MedPage. He still doesn't know if he was part of the Lorcaserin group or the placebo control group--as it is a double-blinded study, but the extreme weight loss for the diabetic points toward the Lorcaserin active group.

Here's the video:

http://neurologicalcorrelates.com/wordpress/2009/02/20/weight-loss-trial-final-report-52-pounds-of-fat-melted-away/

Here's his personal account of it:

http://www.medpagetoday.com/PrimaryCare/Obesity/13506

The results of Bloom, the first of two pivotal Phase III clinical trials, were announced in March. Researchers were upbeat about Lorcaserin's FDA approvability, due to its safety and tolerability profile, as well as meeting one of the FDA weight loss efficacy guidances. Wall Street analysts were underwhelmed, causing the share price of Arena Pharmaceuticals to decline by 25% overnight. I later picked up some more shares when the price per share (pps) bottomed out around $2.50.

Results for Blossom, the second of two pivotal trials will be announced next month, and due to the statistical significance of Bloom's 3000+ patients, Blossom results for 4000+ patients should be similar to Bloom's.

Dr. Susman participated in the non-pivotal Bloom-DM Phase III clinical trial for diabetics. Anecdotally, diabetics find it more difficult to lose weight, so his weight loss of 52 points is especially significant.

Disclosure: Long ARNA shares.

Is ARNA finally getting its day in the sun?

http://news.yahoo.com/s/nm/20090606/hl_nm/us_arena_obesity;_ylt=Agl0ZWk9m9Vdus.M9J3KpqXVJRIF;_ylu=X3oDMTJsNWlvcTc3BGFzc2V0A25tLzIwMDkwNjA2L3VzX2FyZW5hX29iZXNpdHkEcG9zAzEEc2VjA3luX2FydGljbGVfc3VtbWFyeV9saXN0BHNsawNhcmVuYWNvbXBsaWE-

I believe I got it right on ARNA, even if Wall Street analysts misinterpreted the Bloom trials top-line data on March 30, condemning the efficacy of Lorcaserin as "disappointing". There was agreement on the safety profile and tolerability of Lorcaserin, but the media focused on the 5% mean weight loss above placebo criterion. What they missed were the FDA guidelines on categorical weight loss of 5% and 10%, which Lorcaserin exceeded. The minimum 5% categorical weight loss also had to be above 35%, which was it was at 47.5%, which meant almost half the subjects experienced at least 5% weight loss on Lorcaserin, whether they dropped out of the trial or not. Upon further data analysis, almost 67% of subjects on Lorcaerin who didn't drop out of the trials lost 5% or more body weight.

The primary end points of weight loss were met, as were secondary end points like improvements in blood pressure, cholesterol, triglycerides, lipids, glucose levels and quality of life.

The number of overweight Americans is approaching 200 million, with 100 million of those obese, so the market potential for weight management drugs is huge. Phen-fen was a blockbuster, but due to heart valve problems and countless lawsuits later, it was recalled. Lorcaserin's tolerability and safety profile was favorable, with comparable rates of depression and cardiac valvulopathy in the placebo group. The probability of FDA approval in 2010 has increased with the latest news.

Blossom results will be announced in September, and the Bloom-DM trial for diabetics will also wind up soon. Expect a partnership agreement with a big pharma later this year, which should ease cash flow concerns and clear the path to an NDA submission in Q4 2009, and PDUFA in Q4 2010.

Disclaimer: Do your due diligence. Investing is risky and you can lose most or all of your investment.

Disclosure: I am long ARNA shares and also write covered calls.

ARNA Press Release tomorrow at 5:30 am Pacific time

Now that the press release is issued, I can mention the name of the company I've been raving about. I didn't want to invite scrutiny from regulators about pumping and dumping. Some of my friends and family have known about this speculative play for several weeks and months. I'm glad to say a few acted upon it. It was entirely their decision and they performed their own due diligence.

The timing of the conference call, 5:30 am Pacific time, is significant. It is pre-market opening, which suggests good results from their Phase III clinical trials. A positive announcement post-market close, leaves market manipulators plenty of time that evening and the next morning to manipulate the stock price, punishing shareholders in after hours training. Regarding the timing of announcements of pivotal trials: negative announcements are usually scheduled after market close, while positive announcements usually occur before market opening.

In fact, market manipulation is why this stock stayed at $4 for many days in March. The shorts drove the share prices down, making a profit on the share price decline. Shorting also benefited institutions betting on the share price rising, as they get to buy shares at a lower price. That's why it's common to see analysts downgrade stocks before an important announcement, which is exactly what happened with Arena. Market manipulation is nefarious and illegal, and these individuals and institutions should be bird-dogged and reported to the SEC. However, as an individual investor, and as one who acknowledge sometimes the system is rigged, one should adjust one's investment strategies accordingly. In my case, it allowed me multiple entry points to accumulate shares, because investor sentiment was negative, and I had conviction that Arena was on to something big--I had confidence that Lorcaserin is a game-changer.

Friday's close was $4.50. After positive results, I expect the market to gap up before tomorrow's market opening in the teens, with high volatility throughout the week, amid price spikes for the next few days. I will avoid trading as orders will be difficult to fill--I will just monitor it and watch the shorts scramble, while the share price soars.

Investing is risky and investing in biotech stocks even riskier. Do your own due diligence and consult your financial advisor, altho 99% of them are behind the learning curve. Proceed with caution, and good luck to all.

Disclosure: I own shares in ARNA underlying shares and ARNA call options.


http://finance.yahoo.com/news/Arena-Pharmaceuticals-to-Host-prnews-14777035.html

SAN DIEGO, March 29 /PRNewswire-FirstCall/ -- Arena Pharmaceuticals, Inc. (Nasdaq: ARNA - News) today announced it will hold a conference call and webcast on Monday, March 30, 2009 at 8:30 a.m. Eastern Time (5:30 a.m. Pacific Time) to discuss top-line results from BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), the first of two pivotal trials evaluating the safety and efficacy of lorcaserin for weight management. Jack Lief, President and Chief Executive Officer, Dominic P. Behan, Ph.D., Senior Vice President and Chief Scientific Officer, William R. Shanahan, M.D., Vice President and Chief Medical Officer, and Christen M. Anderson, M.D., Ph.D., Vice President, Clinical Development, will host the conference call.

The conference call may be accessed by dialing 877.874.1565 for domestic callers and 719.325.4758 for international callers. Please specify to the operator that you would like to join the "Lorcaserin BLOOM Trial Results" conference call. The conference call will be webcast live under the investor relations section of Arena's website at www.arenapharm.com, and will be archived there for 30 days following the call. Please connect to Arena's website several minutes prior to the start of the broadcast to ensure adequate time for any software download that may be necessary.

About Arena Pharmaceuticals

Arena is a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing oral drugs in four major therapeutic areas: cardiovascular, central nervous system, inflammatory and metabolic diseases. Arena's most advanced drug candidate, lorcaserin, is being investigated in a Phase 3 clinical trial program for weight management. Arena's broad pipeline of novel compounds target G protein-coupled receptors, an important class of validated drug targets, and includes compounds being evaluated independently and with partners, including Merck & Co., Inc., and Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Snow in California and slippery slopes

I drove down I-5 thru the Grapevine, where we got tons of snow yesterday. I actually pulled over at a rest area to throw a bunch of snowballs (at trees, not people). It was the most fun I've had in a while, but my hands got really cold, and all I had on was a t-shirt.

Then as I descended upon the Valley, the full moon was shining brightly against a backdrop of some clouds. It was as clear an evening as I ever remember in LA. The rain must have cleaned out the smog temporarily. Traffic was light, probably due to the tattered economy.

The City of Angels really is beautiful when you can see all the lights against the hills. It made the long drive more bearable.

It was a good day, as the biopharma company was up big again, with CNBC now reporting it in New York at the biotech conference. I got in at $4 last week, and it closed above $6 today. If Phase III trials are positive, it'll double from here. If they're negative, it'll collapse back to $4. We'll know next month. Biotech investing is a slippery slope--it can be dangerous as most drugs in clinical trials fail, but when they hit, it's a beautiful thing. Kinda like LA.

Next up is a melanoma drug company, with results due in the 2nd quarter. People afflicted with this aggressive cancer can't wait--there hasn't been an FDA-approved drug in 30 years. It's do or die. Which makes this play dicey for investors, but more importantly, patients really need some positive news.

The government's stimulus plan should include investments in biotech and stem cell research--that's where the new frontier is. We need to find cures for these terrible diseases. A lot more than we need more frisbee golf courses.