Orexigen Empatic That Results For Second Obesity Drug Will Help Lure Partner

Given the potential to cause birth defects, Orexigen's obesity drug Empatic is probably not suited for the masses. Still, executives say the promising combo pill could complement the company's better known obesity agent Contrave and help bring a partner on board.

Empatic combines two centrally-acting generic medications - the antidepressant buproprion and the anticonvulsant zonisamide. On Sept. 30, the company reported the first data for its second obesity therapy, from a Phase IIb trial in 730 patients.

Empatic met the trial's primary endpoint, showing statistically significant greater weight loss compared to its individual components and placebo. The company argues that the drug should meet FDA standards, even though the results actually miss desired efficacy results for combination drugs.

Orexigen is most often associated with its more advanced obesity agent Contrave, a combination of buproprion and the generic anti-addiction drug naltrexone. The company has been publicly on the prowl for a partner since releasing its first Phase III results for Contrave in January and an NDA is now expected to be filed in the first half of 2010 (¹ (Also see "Orexigen Starts Partnership Talks On Obesity Drug Contrave" - Pink Sheet, 13 Jan, 2009.)).

During a Sept. 30 call detailing the new trial results, Orexigen executives stressed that Empatic and Contrave are actually complementary, because they have different mechanisms of action and could potentially be targeted at different patient groups.

Will Birth Defect Risk Scare Off Some Women?

But while Empatic promises more weight loss than Contrave, the drug also raises more red flags. Among other risks - including depression and suicidal ideation - zonisamide carries a pregnancy class C warning reflecting teratogenicity risk. Obesity programs tend to include women in their 40s, which makes sense given that this population is an important target market for weight-loss drugs.

"The extent to which that [pregnancy] risk negates usage of the drug, particularly in women of child-bearing age, remains to be determined," noted Lazard analyst Bill Tanner.

Orexigen executives have a response to this potential problem: Contrave is more suitable as a first-line agent for obesity, while Empatic could be reserved as an alternative for a range of patients, such as men, those who are more overweight and/or who have failed another obesity drug, they suggest.

The company also stressed that zonisamide does not have a unique risk. Anticonvulsants across the board carry warnings for women who are pregnant or seeking to become pregnant. Another late-stage obesity candidate - Vivus' Qnexa - combines the anticonvulsant topiramate with the appetite suppressant phentermine (² (Also see "Vivus Obesity Pill Scores With Phase III Data, But Still Faces Major Market Hurdles" - Pink Sheet, 9 Sep, 2009.)). Qnexa was tested mainly in women in their 40s and the company has acknowledged that some study participants dropped out of research after becoming pregnant and went on to have normal babies.

In light of the pregnancy risk, Orexigen investors have been looking at Empatic as best-suited for men or post-menopausal women, while viewing Contrave as a drug fit for the masses, Tanner said in an interview. But combination pills that include anticonvulsants would not necessarily be contraindicated for women of child-bearing age; rather, the labels could advise use of contraception for these patients.

"Still, it seems like the side effect could make both drugs [Empatic and Qnexa] less desirable as alternatives. Orexigen may be looking at Empatic as an alternative to bariatric surgery where the risk profile is much higher," Tanner said.

Citing coverage of a broader range of the potential obesity market, as well as the potential for Contrave to be used in other indications, Orexigen argues that it is able to offer an "obesity franchise" and is uniquely positioned for partnership.

"Two shots on goal could allow Orexigen to rise above competition," Tanner wrote in a Sept. 30 note about the new Phase IIb results. "Viability of Empatic as a weight-loss drug could position Orexigen's product portfolio as more attractive to potential partners."

Orexigen will soon begin discussions with the FDA about design of a Phase III program, which is likely to include 4,500 to 5,000 patients at a cost of roughly $100 million.

Orexigen: Empatic Likely To Meet FDA Needs

The company said it has not decided yet which dose to test in Phase III. Two different doses of the combination pill were tested in the newly-unveiled 24-week Phase IIb trial: Empatic360 (bupropion SR 360 mg/zonisamide SR 360 mg) and Empatic120 (bupropion SR 360 mg/zonisamide SR 120 mg).

Study patients had a body mass index of 30 to 45, or as low as 27 in the presence of hypertension or dyslipidemia. The trial included six arms: placebo, one dose of bupropion monotherapy, two doses of zonisamide monotherapy and the two doses of Empatic.

Empatic patients experienced significant weight loss as early as their first post-baseline visit at week four and continued to lose weight through the end of the trial.

According to FDA's draft guidance on weight management drugs, fixed-dose combinations should be compared to the individual components and placebo in Phase II trials of sufficient duration to get maximal weight loss (³ (Also see "FDA Says No To Metabolic Syndrome; New Obesity Guidance Takes Hard Line" - Pink Sheet, 19 Feb, 2007.)).

The agency has not defined a minimum difference in weight loss between the combination and the components to show efficacy for the combo. However, a fixed-dose combination that is associated with at least twice the weight loss observed with that of each of the individual components will be viewed more favorably than combinations that do not achieve this degree of relative weight loss.

Based on an intent-to-treat analysis using last-observation-carried-forward for missing data, mean weight loss for Empatic360 was 7.5 percent versus 2.3 percent for bupropion 360 and 5.3 percent for zonisamide 360. Mean weight loss for Empatic120 was 6.1 percent versus 2.3 percent for bupropion 360 and 3.2 percent for zonisamide 120.

Therefore, Empatic at both doses does not meet the desired goal of having twice the effect of each individual ingredient.

Looking at the data in a different way, Empatic showed a synergistic effect at the low dose (6.1 percent versus 5.5 percent for sum of components) and almost an additive effect at the high dose (7.5 percent versus 7.6 percent).

Orexigen argues that in terms of placebo-subtracted weight loss, a more rigorous analysis, Empatic outperforms the monotherapy arms. The company also argues that the Empatic Phase IIb results demonstrate early and meaningful weight loss that exceeds both the mean and categorical efficacy benchmarks set by the FDA for one-year Phase 3 trials.

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 at least 5 percent of baseline body weight in the active product group is at least 35 percent and also double the proportion crossing that weight loss threshold in the placebo treated group (known as the "categorical" criteria).

Safety Profile Looks Good, So Far

Improvements were also observed in key markers of cardiometabolic risk such as waist circumference, triglycerides, fasting insulin and blood pressure, the company reported.

The most commonly reported adverse events in the Empatic arms were headache, insomnia and nausea.

After the problems experienced with Sanofi-Aventis' now-withdrawn obesity treatment Zimulti/Acomplia (rimonabant), depression and suicidality risk are of high concern with centrally-acting drugs and are likely to draw extra regulatory scrutiny (⁴ (Also see "Sanofi Withdraws Zimulti NDA For Weight Loss" - Pink Sheet, 29 Jun, 2007.)). And FDA has warned that anti-epileptic drugs are linked to suicidal ideation.

In the Phase IIb trial, there were no statistically or clinically meaningful differences between Empatic and placebo on measures of cognitive function, depression, suicidality or anxiety. However, during the investors' call, the company noted that risk for suicidal ideation and depression need to be assessed in a larger trial.

- Emily Hayes (⁵ [email protected])