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On December 3, 2010, an FDA advisory panel will review the NDA submitted by Orexigen Therapeutics for its new anti-obesity agent Contrave. This note previews and discusses possible issues that the panel will address.

Introduction

Their recommendation to the FDA as to whether Contrave should be approved obviously will have dramatic consequences for Orexigen’s stock. This note analyzes the issues that the panel will address in coming to its recommendation to the FDA. The panel recommendation is only that. The FDA will announce its decision on whether to approve Contrave on January 31, 2010.

 

Contrave

Contrave is a combination of two generic drugs, each of which has been on the market for over 20 years. Bupropion was approved in 1984 for depression and in 1997 received an additional indication for smoking cessation; it has been used by over 90 million patients. The other component, naltrexone is used to treat alcohol and opioid dependence and has been used by over 1 million patients. Contrave is dosed twice a day and delivers 360 mg. of bupropion in a sustained release dosage form and 32 mg. of naltrexone.

 

Bupropion has long been known to produce weight loss when it is initially prescribed, but over time it loses effectiveness. It blocks the receptor for serotonin in the brain preventing the re-uptake of that neurotransmitter, which results in a feeling of fullness or satiety and decreases the craving for food and consumption. It also increases energy consumption. Orexigen hypothesized that the loss of bupropion effectiveness over time was the result of a feedback loop in the body that bypasses the effect caused by bupropion and reduces its anti-obesity effects. The company believed that naltrexone could block this feedback loop and allow bupropion to retain its effectiveness. In more technical talk, Contrave is designed to activate the hypothalmic center in the brain associated with reduced appetite, while blocking beta-endorphin, which may be responsible for limiting this effect.

 

Will The Panel Recommend That FDA Approve Contrave?

 

The devil hates a coward, but frankly I think that in the case of trying to predict whether Contrave will receive a favorable recommendation from the panel that cowardice may be the right decision. If pressed to make a decision, I would say that the panel based on a close vote will recommend that the FDA approve the product. However, my confidence level is so low that I am not prepared to act on this judgment.

 

A favorable panel recommendation will not guarantee approval of Contrave at its January 14, 2011 PDUFA date It is becoming routine for the FDA to issue Complete Response Letters to almost all NDA’s, even those that are ultimately approved. I would expect the FDA would ask for more work on a REMS program or perhaps further analysis of existing data.

 

Discussion Points for the Panel

Trying to predict how the panel will come out on its vote on Contrave is difficult. Individual members will place more emphasis on one point than another. Perhaps one strident member can move the entire panel in one direction. It is like a jury. The facts of the case may be the same, but no two juries will view them in the same way. This makes handicapping the possible outcome of the panel vote an adventure. I have tried to highlight what I believe will be the key points of discussion and my take on how the panel consensus will come out.

 

Is Contrave Effective In Reducing Weight and Is This Effect Clinically Meaningful?

Contrave is more effective than reducing weight than Arena’s Lorques which the FDA described in its briefing letter to the Lorques panel as having a modest effect on weight loss, but good enough. There was a great deal of discussion in the panel meeting concerning whether Lorques produced a meaningful therapeutic benefit and this will probably come up again in the Contrave panel.

 

Orexigen may try to emphasize to the panel that the clinical endpoints set by the FDA for anti-obesity drugs are unusual and somewhat arbitrary. The FDA has set up specific guidelines to measure efficacy of obesity drugs. To be considered effective an obesity drug must meet one of two endpoints:

• At least 35% or more of patients on the drug lose at least 5% of their body weight and that this must be twice that for placebo and the results must be statistically significant, or
• Mean weight loss is ≥ 5% difference between active product and placebo group and the results must be statistically significant.

 

Orexigen conducted four phase III trials involving a total of 4,536 patients using the FDA guidelines as the primary endpoints of those trials. Contrave met the FDA defined endpoint in three of these four trials. The one trial that it failed compared Contrave to a control group that used intensive behavioral modification techniques and diet that were not used in the other Contrave trials.

 

Most clinical trial results are based on statistical significance which requires that there is a 95% confidence that the findings in the trial are true and did not occur by chance when compared to placebo or some other comparator. This is expressed as p≤0.05. In all of the primary and secondary end points for Contrave in its four clinical trials the p value was

 

The FDA is always trying to identify sub-groups who do unusually well on a drug as compared to the population as a whole. For obesity, the participants will self select. Those who find the treatment effective will continue on the drug and those who don’t will drop out. If the panel considers this point, it would benefit Contrave. Those who find the treatment effective will continue on the drug and those who don’t will drop out.

 

Orexigen will certainly point out to the panel that the statistical technique used in the trial was Last Observation Carried Forward (LOCF). This means that if someone entered the intended one year trial and for whatever reason dropped out after one month with no loss in weight, they would be counted the same as a patient who had lost no weight over the entirety of the trial. This patient would be given the same statistical weighting as someone who completed the one year trial and lost a very significant amount of weight. The overall dropout rate in the four phase III trials for Contrave ranged from 42% to 51% and for placebo ranged from 41% to 50%. This suggests that it is much more meaningful to look at how completers of the trial benefited. In the COR-1 phase III trial, Contrave completers lost 17.6 pounds while placebo completers lost 4.1 pounds. Based on the LOCF method, Contrave was calculated to have resulted in a 13.3 pound loss versus 3.0 pounds for placebo.

 

My Take: I have reasonable confidence that the panel will not have major issues with the effectiveness of Contrave. However, in the final decision of weighing risk against benefits, the efficacy is not so robust as to overwhelm concern with side effects. The FDA is always trying to identify sub-groups who do unusually well on a drug as compared to the population as a whole. For obesity, the participants will self select. Those who find the treatment effective will continue on the drug and those who don’t will drop out. If the panel considers this point, it would benefit Contrave.

 

Acute Side Effects

The most often reported acute side effects for Contrave are nausea, constipation and headache.

 

My Take: These probably won’t be given that much emphasis by the panel. They may have an impact on the willingness of patients to stay on the drug, but they are annoying, not dangerous aspects of the drug.

 

Cardiovascular Side Effects

The major side effect issues that panelists will be concerned with are those that may occur with long term usage. The bupropion component of Contrave can lead to an increase in blood pressure and heart rate. Contrave skeptics point to the similarity of its cardiovascular side effects to that of the anti-obesity drug Meridia which was just taken off the market because of a small but meaningful increase in cardiovascular events in the five year Scout trial that were presumably linked to these cardiovascular events.

 

Orexigen reported that in the clinical trials at week 56, mean blood pressure was unchanged from baseline for Contrave while placebo patients experienced a slight decrease of 2 mm Hg. Normally weight loss leads to lower blood pressure and indeed this was seen in the placebo group. It can be inferred that Contrave acted to increase blood pressure which was balanced out by the tendency of weight loss acts to reduce. Meridia increases blood pressure by 2-3 mmHg There was a slight increase in pulse of approximately 1 beat per minute in Contrave patients which compares to 3 to 5 beats per minute for Meridia.

 

My Take: I think that the potential for cardiovascular side effects will be a major discussion point. They have not been an issue for bupropion usage as an anti-depressant, and the panel could take the view that this historical experince vailidates Contrave’s safety. However, it is also possible that the experience with Meridia in the Scout trial will spook the p I anel and make this a formidable roadblock based on the judgment that the benefit to use ratio in obesity should have a higher benefit ration than that for depression. There also might be outliers who experience more severe side effects. For example, even though there is no increase in mean blood pressure for Contrave patients as a group, some might have a more significant increase.

 

Black Box Label for Suicidal Ideation a Virtual Certainty

Treatment with Contrave was not associated with increases in symptoms of depression or suicidal ideation. However, there is a black box warning for suicidal ideation for all anti-depressants including bupropion.

 

MyTake: It is a certainty that the bupropion component will require a black box for Contrave.

 

 

Infrequent Serious Adverse Events of Bupropion

Across the four phase III programs involving 4500 pateints, there were seven serious adverse events that were attributed by investigators as possibly related to Contrave treatment. These were cholecystitis (gall bladder inflammation) (2 cases), seizure (3), palpitations (1), paresthesia (1) and vertigo (1).

 

Seizure is the most controversial side effect of bupropion, and was responsible for its withdrawal from the market at one time. The risk of seizure is highly dose-dependent. It is 0.10% at 100–300 mg of immediate release bupropion, 0.40% at 300–450 mg, and 2% at 600 mg. Contrave delievers 360 mg daily in a sustained release dosage form that is given twice a day This incidence of the first unprovoked seizure in the general population of 0.07–0.09%. Many anti-depressants are linked to seizures and the incidence with bupropion seems about average for an anti-depressant.

 

Cholecystitis is believed to be a complication stemming from rapid weight loss.

 

My Take: I don’t see these serious infrequent adverse events as being a show stopper in and of themselves. However, if there is a narrow balance between Contrave benefits vesus other risks, they might tilt the panel’s decision into the negative column.

 

Teratogenicity and Carcinogenicity Not Likely To Be A Concern

The company is filing Contrave under a 505 b2 which means that the FDA will reference carcinogenicity and toxicology studies done for Wellbutrin and naltrexone by the innovator companies. There have never been any indications that carcinogenicity and teratogenticity have been a concern with either drug. They were not required to do toxicology or carcinogenicity studies on the combination.

 

My Take: I don’t think this will be an issue.

 

Naltrexone Component Not Likely To Be A Concern

The label for naltrexone indicates that it shouldn’t be used in patients taking opioids or those having hepatitis C or other conditions of impaired liver function. At five times the therapeutic dose, it can cause liver toxicity. The recommended dose for new patients is 50 mg per day.

 

MyTake: I don’t think that naltrexone component side effect issues will gain get much attention at the panel.

 

Inadvertent Over-Dosing

There is one issue that Contrave faces that may be a focus for the panel. Bupropion is widely marketed as the anti-depressant and as Zyban as a smoking cessation. There is a risk that Contrave could be prescribed to patients already taking this drug and result in their receiving a very high dose of bupropion. This could lead to an increase in the incidence and severity of side effects and perhaps greatly increase the incidence of the previously rare side effects. For example, as the dosage of bupropion is increased from 450 mg per day to 600 mg per day, according to the Wellbutrin label, the risk of seizure increases ten fold.

 

My Take: This is not a trivial issue, but I would note that this is not a new risk for the public as it already exists with Wellbutrin and Wellburin XL (bupropion used to treat depression) and Zyban (bupropion used to treat smoking addiction). If this product is to be approved the FDA would require a rigorous REMS program to handle this risk.

 

Duration of Response

Contrave’s clinical trials were conducted over 52 weeks. The company will not have prospective trial data to show if there is any diminution in weight loss over loner periods of time and will rely on followup from patients who are followed from earlier trials.

 

My Take: This could be a significant issue for the panel. It will probably be bigger for the FDA when it makes its decision.

 

Other Issues

Contrave might run into problems for reasons other than the safety concerns discussed above. For example, there is the possibility for FDA to have issues with the statistical analysis of the data. I am not suggesting that this will be the case; I am just acknowledging the possibility. It is very difficult for an outsider to judge the potential for this.

 

Background on Anti-Obesity Drugs and The FDA Anti-Obesity Panel

Investors are skeptically eyeing the upcoming December 3^rd FDA anti-obesity panel meeting for Contrave and with good reason. This year started with great hope that three new anti-obesity drugs under development, Contrave, Arena’s Lorques and Vivus’s Qnexa would all gain recommendations for approval. However, Qnexa was turned down by the FDA panels by a vote of 5 for and 9 against. Then Lorques was turned down by a vote of 6 for and 10 agains. Both drugs were subsequently issued complete response letters from the FDA. Vivus and Arena are in the process of trying to determine a way forward to approval. Quite naturally, this has turned hope for approval of anti-obesity drugs into skepticism on Wall Street. In addition, a panel review of a major trial involving Meridia, one of the most widely used anti-obesity drugs, was instrumental in leading to that drug being voluntarily removed from the market.

 

Many well informed investors were expecting a thumbs up from the Qnexa and Lorques panels based on the clinical data for both drugs. They were blindsided by unanticipated or under appreciated issues.

 

Vivus, Qnexa Panel Meeting

The FDA panel focused on teratogenicity for the topiramate component of Qnexa. This issue was known but little emphasized by investors as the FDA had allowed topiramate to be broadly marketed (primarily for seizures) for over 20 years. The Qnexa panel also focused on and expressed concern about cardiovascular issues associated with phentermine, the other component of Qnexa, and topiramate associated central nervous system side effects. The concern with phenterine wa also a little surprising as it is currently the most widely prescribed drug for treating obesity. However, it is a stimulant and related to amphetamines. However, it is my opinion that the teratogeicity issue lost the day for Qnexa and absent this concern the drug would have been recommended for approval.

 

Arena’s Lorques Panel Meeting

In the Lorques panel meeting, investors were truly blind-sided by a link to carcinogenicity in rats. Arena had thought that the rat carcinogenicity would not be a major issue and had not felt it necessary to disclose it to investors prior to the meeting. However, the FDA spotlighted the issue for the panel and once again we believe that this issue was central to the negative vote by the panel. There was some talk about the marginal efficacy of Lorques, but the FDA termed it good enough. Surprisingly, there was not much focus on the potential for valvulopathy, a concern which arises from lorcaserin having some of the same biological targets as the notorious fenfluramine component of fen-phen. The panel seemed to feel that Arena had done as much as it could possibly do and its work gave some comfort that the potential for valvulopathy is not an unacceptable risk. My judgment that the carcinogencity concern tipped the balance against Lorques and based on what I have read from other investors, this is widely accepted.

 

Panel Meeting on Meridia’s Scout Trial

The third setback for anti-obesity drugs was a negative panel assessment of a trial conducted by Abbott for its anti-obesity agent Meridia, which was approved in the US in 1997. The Scout Trial was a five year trial in approximately 10,000 patients who were randomized to Meridia or placebo. The trial was intended to assess cardiac risk associated with Meridia. The entry criteria included being 55 or older and being at high cardiovascular risk as determined by having had a prior cardiovascular event or type II diabetic pateints with a cardiovascular risk factor. Pateints had to have a BMI > 30 kg/ mm². This patient population may be representative of only a small sub-population of those that undergo treatment with anti-obesity agents in the real world. Most patients who take anti-obesity drugs are in their 30’s and 40’s and in relatively good health.

 

The study found that there was a 16% increase in cardiac events associated with Meridia in the study. These events were driven by non-fatal heart attacks and non-fatal strokes. The incidence in Meidia patients was 11.4% and in placebo patients was 10.0% Assuming 5000 patients treated with Meridia and 5000 with placebo, the number of events with Meridia would have been 570 and in those treated with placebo would have been 500. The implication is that there would be 70 more events (1.4%) in 5000 Meridia patients than would be expected placebo.

 

The FDA briefing documents pointed out that it is well known that Meridia caused a 2 to 3 mm Hg increase in both diastolic and systolic blood pressure and increases the heart rate by 3 to 5 beats per minute. This was a direct inference that these were contributors to the increased cardiovascular risk. The effect on weight loss at five years was described as a very modest 2.8% decrease. The bupropion component of Contrave is assocated with a 2 to 3 mm Hg increase in blood pressue when used alone. Contrave in its clinical trials showed no increase in blood pressure. Bupropion is associated with an increase of one beat per minute when used alone and Contrave also has a one beat per minuts increase.

 

The panel vote on Meridia was as follows:

• 8 voted to withdraw the product from the market,
• 6 voted to allow continued marketing with restrictive distribution and revised labeling, and
• 2 voted to continue marketing and adding a black box warning to the package insert.

 

Abbott tried to define a population at risk and come up with a REMS program to mitigate risk. However, it could not convince the FDA and Abbott voluntarily withdrew Meridia in September of 2010.

 

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