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The next big catalyst play on the horizon is Orexigen’s (NASDAQ:OREX) FDA advisory committee meeting for Contrave – its treatment for obesity. The FDA panel occurs next week – Tuesday, December 7 – with the briefing documents likely to be released this Friday.

Contrave is a sustained-release formulation of two currently FDA-approved drugs, naltrexone and bupropion. Naltrexone is an opioid receptor antagonist used currently for the treatment of alcohol and opioid dependence. Bupropion is a drug used primarily as an antidepressant and smoking cessation aid. Because Contrave consists of these two well known and commonly prescribed ingredients, we can make a reasonably educated guess about what the FDA will take issue with.

I’ll ignore efficacy for now – it meets the FDA’s efficacy guidelines relatively easily – and instead focus on potential safety issues. Keep in mind, however, that all safety issues will ultimately be balanced against efficacy, regardless of what the guidelines state.

Seizure

A significant side effect of bupropion, and the reason for its one-time temporary market withdrawal, is its ability to cause seizures. As the concern was significant enough for market withdrawal, it will most certainly be brought up at the advisory committee panel.

According to several studies, the risk of seizure in patients taking bupropion is highly dose-dependent. At doses of 300-450 mg/day – similar to the levels found in Contrave – the risk of seizure is approximately 0.4% when taken alone. This compares to a 0.04-0.09% risk of seizure in the general population. A suggestion has also been made that depression itself causes an increased risk of seizures and therefore antidepressant use is correlative with higher seizure risk, rather than causative.

In the phase III trials for Contrave, however, the incidence of seizures were very low. Of the approximately 4,000 patients that participated in COR-I, COR-II, and COR-BMOD trials, only one patient exhibited seizures. This is promising news, as there appears to be no significant trend of an increase of seizures in patients receiving Contrave. In fact, the number of seizures fell exactly in line with what was expected from populations not receiving the treatment.

However, showing no clinically significant increase and statistically ruling out an increase can be very different beasts. In addition, the FDA may want to consider the possibility of less well-controlled patient populations intentionally or unintentionally taking supratherapeutic levels of the drug, leading to seizure. Therefore, I would say there is a minimal, but not non-existent concern for incidence of seizures in Contrave patients.

Suicidality

Bupropion currently carries a black box warning because it may cause an increase in risk of suicide for person younger than 25. This designation is not unique to bupropion, but rather, is a relationship found with most antidepressants. Suicidality was brought up in the Qnexa Advisory Panel, so I would expect it to make an appearance in Contrave’s panel as the FDA performs its due diligence.

In order to show a statistical relationship between antidepressants and suicidal activity, the FDA pooled data from over 200 clinical trials with over 77,000 patients. There were no clinically significant increases in suicidal behavior in wider patient populations of antidepressant users. However, when subgroups were analyzed by age, there was a statistically significant increase in suicidal behavior and ideation in patients under 18 and a borderline increase in patients aged 18-24.

In the Contrave clinical trials, Orexigen reports no association between treatment and suicidal adverse events when compared to placebo. Given that Bupropion, along with other common antidepressants, has been so extensively studied, I don’t see how this will be a concern. It may, however, be grounds for a black box warning for Contrave to avoid treatment of those under 24. This may factor into market sizing analyses and REMS, but it is not likely to be a sizable issue for the advisory panel.

Cardiovascular Side Effects

Bupropion’s impact on heart rate and blood pressure, along with the broader impact of increased cardiac adverse events, has been mixed. In recent studies involving ADHD patients, an increase in heart rate by as much as seven beats per minute and a rise in systolic blood pressure by 6 mm Hg were observed. Other studies state that at doses of 300 mg/day (similar to those levels found in Contrave) there is no increase in blood pressure.

In the COR trials for Contrave, meanwhile, it was found that blood pressure was "generally unchanged" versus baseline in the treatment arm while patients in the placebo group experienced a slight decrease (about 2 mm Hg) in blood pressure. Heart rate increased by approximately one beat per minute in the treatment arm versus placebo.

I have to be honest here; this reason alone may be enough for the FDA to issue a complete response letter (CRL) to Orexigen. Recall that an increase of heart rate by a similar margin was listed as one of the reasons Vivus’ (NASDAQ:VVUS) Qnexa was given a CRL. I don’t believe the market as a whole is pricing in any chance of first-time approval, however, so price action will depend more on how long it will take to resubmit on a likely CRL. The obvious bull argument for this is that bupropion is already widely prescribed for other indications and there doesn’t appear to be anything particularly scary in the depression folks. While that’s true, I find it hard to believe the FDA will request more studies due to increased heart rate from one company and ignore it in another – especially with as conservative the FDA has been lately.

Hepatotoxicity

Naltrexone has been connected to liver toxicity in higher dose ranges (data here). I wanted to mention that here but as the dose level in Contrave is significantly lower (32 mg daily) than that found in the above study (300 mg daily) I don’t think it will be an issue in the least. Don’t be surprised, however, if it makes it onto the briefing documents; the FDA has been especially thorough lately.

Summary

Contrave will certainly have a long list of issues that will be dragged out during its advisory committee hearing. The potential issues - including seizure, suicidality, and cardiovascular side effects - seem scary given what we’ve heard from the previous obesity-related panels. However, I will say this: Contrave is in a unique position in that both naltrexone and bupropion have been approved for other long-term indications. In Qnexa’s case, phentermine was not approved for long-term use (and it’s still limited to only a few months for the indication of weight loss). Arena’s (NASDAQ:ARNA) lorcaserin obviously had to deal with the issue that it was a novel compound that had never been approved for any indication. Therefore, Contrave may stand a much better chance to squeak by with a positive panel than its obesity brethren.

I’ll save a formal prediction for after the panel briefing documents are released, but preliminarily I think the most likely outcome for Contrave’s panel is a split vote with equal but lesser probabilities of going one vote in either direction. I think it receives a better panel than either Vivus’ Qnexa or Arena’s locaserin due primarily to the "previous long-term indications" advantage. I am, however, skeptical that Contrave will ultimately be approved by the FDA on first pass regardless of panel outcome due to the cardiovascular risks. These are, after all, obese patients and would therefore differ somewhat from the depression bupropion populations (although I will concede there is significant overlap) and the FDA will likely want to see additional cardiovascular data for this group.

Do keep in mind, however, that I have decided against a play on this catalyst – reflecting my general uncertainty of the price action associated with any particular outcome. Good luck to those brave enough to make a play.

Disclosure: No positions.

Source: Orexigen's Contrave Obesity Drug Heads to FDA Panel: Analyzing the Safety Issues