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.
VivusVivus (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 TherapeuticsAnother 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 PharmaceuticalsThe 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.
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