With its first Phase III results now in hand, Orexigen Therapeutics signaled at the J.P. Morgan Healthcare Conference Jan. 12 that it is ready to start partnership talks for its combination obesity drug Contrave ( naltrexone/bupropion).

Contrave is a fixed-dose, sustained release combination of bupropion, which acts on dopamine and is approved for depression, and naltrexone, the opioid antagonist used for alcoholism and drug addiction.

"It is not our intention to build a 3,000-person primary care sales force," Chief Financial Officer Graham Cooper said at the San Francisco analyst conference. "It is likely that this drug could get marketed by one of the large pharmas or by a large specialty pharma."

Potential partners want to see Phase III results, Cooper noted. As of Jan. 8, Orexigen now has something to show them. The company released the results of NB-302 - the first of four clinical trials in the Contrave Phase III program - immediately before the J.P. Morgan conference.

"We will initiate conversations based on these data [NB-302], but it will take a full data set to consummate a deal," Cooper predicted.

Results from the other three Contrave studies are due in mid-2009 and an NDA filing is expected by the end of this year.

La Jolla, Calif.-based Orexigen will be looking for a partner in the U.S. and ideally would like to retain some global rights, perhaps in some of the smaller subspecialties that it could manage on its own, the executive explained.

Meanwhile, Vivus and Arena also have late-stage obesity drugs in development, with Phase III results and NDA filings also expected this year.

"The time to partner is before Phase III or after, but not in between. Now three companies are pursuing Phase III individually and I think it's going to take opening those envelopes before large pharma gets serious about discussions," Cooper said.

Big Pharma still hungry for obesity drugs, says Orexigen

Some have implied the single status of all three companies suggests waning interest in obesity. But Cooper argues that interest in obesity candidates remains very high, despite high-profile failures with the cannabinoid-1 antagonists, such as Sanofi-Aventis's Acomplia (rimonabant) and Merck's taranabant, due to psychiatric safety concerns (¹ Also see "CB-1 Targeters For Obesity Dropping Fast" - Pink Sheet, 2 October, 2008.). And despite the setbacks, obesity remains an unmet need with a significant market potential - and a fertile ground for partnering (² Also see "Metabolic, Diabetes Landscape “Fertile Ground” For Partnerships" - Pink Sheet, 3 December, 2008.).

Cooper put an optimistic spin on the failure of the CB1 antagonists, suggesting that it leaves more room for new therapies. "If anything, a company like Merck has less internal conflict in trying to bring in something from the outside in at this point," he said. "I wouldn't read too much into the CB1 episode, other than to say they have their own class effects that were problematic."

Certainly in a disease area marked by safety problems and development failures, it makes sense for a potential licensor to take a cautious approach and wait for mature data.

Mountain View, Calif.-based Vivus won't start partnership talks for Qnexa (phentermine/topiramate) until this summer, when Phase III data are available, executives confirmed during a briefing at the J.P. Morgan meeting Jan. 12.

When asked about Orexigen's news, Vivus CEO Leland Wilson declined to comment, aside from to say: "We're rooting for them."

Arena is expecting to release data from the pivotal Phase III BLOOM trial of its serotonin activator lorcaserin in March, followed by a second pivotal trial called BLOSSOM in September.

"We've met with potential partners and will continue to do so, even before the Phase III data this March. However, it's more likely that any partnership would happen sometime after that," said CEO Jack Lief.

Efficacy results for Contrave stir mixed feelings

Even though Contrave met all of its endpoints in the NB-302 trial, some viewed the results as a mixed bag.

In the 56-week study, the company tested a formulation of Contrave (32 mg naltrexone SR/360 mg bupropion SR) with an intense behavior modification program (including diet and heavy exercise) against placebo with the same lifestyle modification program, in almost 800 patients.

Intent-to-treat and completer analyses showed that obese patients treated with Contrave lost an average of 20.3 pounds to 25.0 pounds, or 9.3 percent to 11.5 percent of their baseline body weight, versus 11.0 pounds to 16.0 pounds, or 5.1 percent to 7.3 percent of baseline body weight, in the placebo group.

Furthermore, 41.5 percent of patients on Contrave lost 10 percent or more of their body weight, versus 20 percent of those on placebo. All the results were statistically significant.

The relative difference in absolute weight loss between the Contrave and placebo groups of 4.2 percent did not meet investors' expectations. The company, however, attributes the result to the intense nature of the behavior modification program, which led to very good results in the control group.

The firm pointed to the safety results as particularly reassuring, noting that there were no increases in symptoms of depression, suicidality or worsening of mean blood pressure.

Despite the concerns about the efficacy results, Orexigen is confident the data meets FDA's current requirements, as expressed in the most recent draft guidance on products for weight management (³ Also see "Obesity Guidance Should Be More Lenient On Indications, Firms Tell FDA" - Pink Sheet, 18 June, 2007., p. 5).

FDA guidance sets high bar for obesity drugs

According to FDA guidance, obesity products are deemed effective if they meet one of two standards: 1) 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; or 2) 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 and is approximately double the proportion of that in the placebo treated group, and the difference between groups is statistically significant.

The results on the proportion of patients who lost 10 percent or more of their baseline body weight (41.5 percent for Contrave vs. 20 percent for placebo) appear to clearly satisfy the second standard.

During a Jan. 8 call on the NB-302 results, Cooper specifically addressed concerns that the Contrave efficacy results did not meet the first standard in FDA's policy. "There is some confusion out there as to whether you need to hit either or both methodologies. The draft guidance is clear that you need to hit one of them and we have checked that box," he stated.

The pending Contrave trials feature much more modest lifestyle modification components - which should leave room for more robust results versus the control arms. Neither Vivus or Arena are testing their obesity drugs with lifestyle modification programs that match the intensity of the one used in the NB-302 study.

Execs downplay generic risk

Though naltrexone and bupropion are available in generic form, doctors are unlikely to prescribe them together on an off-label basis for a number of reasons, Orexigen executives argued during the J.P. Morgan presentation.

First, there is no economic incentive to do so because the generics are particularly costly at a total of $8 a day. Contrave will be priced significantly lower, they said.

Titration would also be very complex with separate pills and Contrave features a unique pharmacological profile due to its sustained-release formulation, said Chief Medical Officer Eduardo Dunayevich.

Also, "physicians in this space are not terribly inclined to prescribe off-label" due to safety issues experienced with other obesity drugs, he noted.

[Editor's note: Profiles of companies presenting at the JP Morgan conference are available courtesy of Strategic Transactions, a database of deal-related information published by Elsevier Business Intelligence. For information, contact James DeFalco at 203-838-4401 ext. 104.]

- Emily Hayes (e.hayes@elsevier.com)

Orexigen Starts Partnership Talks On Obesity Drug Contrave

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