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Orexigen Therapeutics, Inc. (NASDAQ: OREX) faces a January 2011 PDUFA date for its weight loss drug candidate Contrave, the combination of bupropion and naltrexone. Last month, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-7 in favor of approving Contrave for commercialization. We’ll briefly review eight factors that may impact Contrave approval and marketplace acceptance.

1. Seizures. Bupropion, approved for depression in 1985 (Wellbutrin®), smoking cessation in 1997 (Zyban®) and seasonal affective disorder in 2006 (Skittles® – just kidding), is “associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day.”[1] Some might consider it curious to accept bupropion for 20 million annual antidepressant prescriptions and not for chronic obesity.[2] Seizure risk attending bupropion appears reasonably certain and should, in our view, appear bolded in any Contrave label within the first few lines.

2. Blood Pressure. One death was reported in the Contrave trials. “Shortly after a study visit on Day 312 (Week 44), the subject’s wife informed the study site that the subject had experienced chest pain, and that he had made an appointment to see his primary care physician. On Day 324, the subject experienced a fatal myocardial infarction during a camping trip at a remote location.”[3] Mean blood pressure change in the Contrave trials appeared modest:

Contrave Phase 3 Trials Completer Population Group[4]

Mean Sistolic Blood Pressure Change (mm HG) (SD)

Contrave32 Not Losing 5% Weight (N=439)

+.80 (10.44)

Placebo Not Losing 5% Weight (N=551)

-1.34 (9.88)

Contrave 32 Losing 5% Weight (N=871)

-1.61 (9.74)

Placebo Losing 5% Weight (N=212)

-4.85 (11.24)

3. Hepatoxicity. Contrave ingredient Naltrexone carries a warning for hepatotoxicity. Yet “no changes in liver function tests were observed in the NB clinical studies, consistent with the naltrexone dose in NB being less than those associated with hepatotoxicity.”[5]

4. Kidney Function. Bupropion reportedly inhibits renal organic cation transporter 2, which impacts creatinine secretion. About 1.2% of 2,545 Contrave users vs. 0.5% of 1,515 placebo users showed a treatment-emergent adverse event related to kidney function, though no serious adverse event.[6]

5. Cognitive Effects. Among 2,545 subjects on Contrave32 and 1,515 subjects on placebo, 0.8% on Contrave showed memory impairment vs. 0.3% on placebo; 0.9% on Contrave discontinued for cognitive reasons vs. 0.3% on placebo; 1.5% on Contrave had attention disorders vs. 0.3% on placebo; 1.0% on Contrave had psychosis events vs. <0.1% on placebo; and 1.2% on Contrave had other cognitive disorders vs. 0.5% on placebo.[7]

The FDA summarized above risks:

"Potential Risks

  • Small mean increases in blood pressure and pulse relative to placebo

  • Attenuates or eliminates the BP and HR reductions that are normally seen with weight loss

  • Seizures (0.08%)

  • Increased psychiatric and neurocognitive adverse events

  • Small mean increases in serum creatinine”[8]

6. Absurdity of Getting It Assuredly Right. Certain FDA panelists insisted, “We need to make sure that we get it right the first time,” and “I think the public depends on us to get it right the first time.”[9]

This view appears erroneous and dangerous. We cannot know the long-term risks of any patented drug when patents last 20 years while patients’ lifetimes can last several decades after first drug use. Phase III drug trials may last a mere 1-5 years. Longer consequences can be extrapolated or guessed, not determined in advance. Initial drug approvals may be based on a view of measured risks and benefits along with an enforced commitment to collect and report patient data regularly over quarters, years and decades.

To know that drug approvals are durably right would require panelists to know full lifespan risks and benefits attributable to drug consumption before a benefits/risks judgment is deemed “right”. That may require 20-70 continuous years of data depending on the drug for all but near-term-mortal conditions.

This idea that the FDA can definitively weigh future risks and benefits at drug approval dates appears dangerous insofar as it engenders public perception that a commercialized drug is universally worthwhile for its targeted benefit, or that ongoing drug-use data are unimportant.

Every drug approval may reasonably be considered a conditional approval, conditional on the drug’s benefits continuously appearing to outweigh its risks in a targeted population based on updated data sets. When the FDA pulls approved drugs after longer-term data are evaluated, it means the FDA is doing its job.

7. Mortality and Cost of Obesity. “Overweight and obesity are associated with increased all-cause mortality” in “pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58).”[10]

“A number of medical conditions are exacerbated with increasing BMI [body mass index], including diabetes, dyslipidemia, hypertension, impaired quality of life, and coronary heart disease. For example, there is over a 3-fold higher likelihood of death due to diabetes and over a 2-fold higher likelihood of death due to hypertension in obese individuals compared with otherwise healthy individuals with the same conditions…. The average medical costs for an obese individual are estimated to be 42% higher compared to an individual with normal weight. In 2009 alone, obese individuals in the U.S. accounted for $147 billion worth of healthcare expenses; by 2018, when it is estimated that 103 million Americans will be obese, this cost is projected to be $344 billion.”[11]

Orexigen cites an estimated $73 billion productivity loss to obesity annually.[12] Quality of life measures that correlate inversely with obesity, including vigor and self-esteem, may be less agreeably measurable but highly valued. Extrapolating the $73b to 2018 and adding $344b, we appear headed toward an estimated annual $500 billion cost of obesity in the U.S. alone.

8. Benefit. Contrave appeared beneficial for some patients in pooled statistics and memorable testimony.

Click to enlarge

Study 302 included “intensive lifestyle modification counseling” for all subjects. Study 301 evaluated a lesser dose of Contrave also with lesser efficacy. Other Contrave trials had re-randomization complications or diabetes patients but appeared broadly similar to 301. Panelist and patient representative Melanie Coffin suggested Orexigen market the more successful behavior modification (“BMOD”) itinerary of Study 302.[14] Physicians might consider Contrave only for patients who undergo such a behavioral program without satisfactory results.

One patient’s testimony conveyed memorable benefit:

"My name is Sharon Oxx…. Orexigen is compensating me for my travel expenses so I could testify here today, but these words are my own.

I participated in a trial of the medication Contrave from March 2008 through April 2009. I’ve been putting on weight steadily over the past 10 years. It can be insidious, creeping up on you and masking its impact on your daily life and well-being….

As a nurse, I knew I was testing fate. Living on borrowed time relative to my health, I had tried all kinds of diets and exercise programs, with minor success here and there….

I thought long and hard about it [participating in the Contrave trial], as I had never taken any medication for weight loss before. As a nurse, I knew there could be side effects. But the advantage I had in this trial was that it involved two medications that had been on the market for quite some time. I had studied the possible side effects and my risk factors for those medications and decided I would give it a try. I knew I could drop out at any time.

I lost weight steadily on the medication. I had no real side effects. As I completed the questionnaires at my monthly visits, I began to think about what had changed for me that was allowing this steady weight loss. I came to realize that while I always knew what to eat, I always had trouble with quantity and frequency, never content to feel even a little bit hungry. But as I took this medication, those cravings were under control. I was no longer planning my next meal as soon as I finished eating my current meal. I wasn’t thinking about food all the time. I abdicated my position as president of the Clean Plate Club, and, lo and behold, I actually could live on half a sandwich and half a serving at a restaurant.

Don’t get me wrong, I had an appetite. But what was different was that I was able to feel hunger again and actually delay satisfying it. I realized I was eating in proper proportions and only eating if I was hungry. I was able to participate in more activities. The achy knees, snoring and GERD went away, and my stamina improved.

At the end of the study, I had lost almost 70 pounds, just over 25 percent of my body weight. I know my results are not the norm, but they are my results, and I am all for another weapon in the fight against obesity, especially for people like myself, people who have not yet developed co-morbid conditions, but surely will if they continue down the path set before them.

I was feeling pretty lucky, when something unexpected happened. My 52-year-old brother had to go on dialysis for kidney failure in May of 2009. He needed a transplant. I was a match. What I came to learn in the intensive process of preparing to become a donor was that there were very strict BMI [body mass index] requirements in the donor program. I would not have met them prior to participating in this trial. Now I did.

So on August 31st, 2009, Pearl, my right kidney, went to live with my brother, and she seems quite happy there. Funny how you do something to change your life and it impacts someone else’s.”[15]

In Part 2 we consider Orexigen’s valuation.

Notes

[1] Wellbutrin label accessed via http://tinyurl.com/3ygawbp, line 355.

[2] Orexigen Therapeutics, Inc. 10-K filed March 11, 2010 and accessed via www.10kwizard.com, p. 5.

[3] FDA Briefing Information for the December 7, 2010 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee accessed via http://tinyurl.com/4995khx, p. 71.

[4] FDA Core Presentations for the December 7, 2010 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee accessed via http://tinyurl.com/5umqxlo, p. 60.

[5] Orexigen Briefing Information for the December 7, 2010 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee accessed via http://tinyurl.com/4995khx, p. 11.

[6] FDA Core Presentations [4], pp. 105-6.

[7] Orexigen Core Presentations for the December 7, 2010 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee accessed via http://tinyurl.com/5umqxlo, pp. C68, C72.

[8] FDA Core Presentations [4], p. 115.

[9] Transcript for the December 7, 2010 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee accessed via http://www.fda.gov/AdvisoryCommittees/Calendar/ucm230339.htm, pp. 404-5, 410.

[10] Amy Berrington de Gonzalez et al., “Body-Mass Index and Mortality among 1.46 Million White Adults” in NEJM 363.23 (2010), p. 2211.

[11] Orexigen Briefing Information [5], p. 29.

[12] Ibid., p. 30.

[13] Orexigen Core Presentations [7], pp. C41-2.

[14] Transcript [9], p. 311.

[15] Ibid., pp. 248-252.

Disclosure: I am long OREX. The author manages a limited partnership and separate accounts, including personal accounts, that own stock or call options on stock of Orexigen Therapeutics, Inc. The author increased these positions after the December 7, 2010 FDA Endocrinological and Metabolic Drugs Advisory Committee meeting. The author may buy or sell any position at any time. The author may change positions in light of emergent facts or considerations, including price-to-value-estimates of the author’s current and alternative investments.

Source: Eight Factors That May Impact Approval of Orexigen's Weight Loss Drug