In drug development, it can be difficult to follow the crowd. And that goes double for a market like obesity that's struggled to gain traction.

A couple of obesity drug companies have taken alternative paths – not necessarily by choice – but it appears to be working out well for them.

A few years ago, Zafgen Inc. chose to focus on orphan diseases that lead to obesity rather than enter the larger obesity market.

"As a small company that was venture backed, the economic environment didn't support IPOs at the time," Thomas Hughes, CEO of Zafgen, told BioWorld Insight. "We picked the financially efficient course where we didn't have to raise hundreds upon hundreds upon hundreds of millions of dollars."

The Boston-based biotech is now public but hasn't abandoned its roots. The company is testing its lead molecule, beloranib, in two orphan indications, Prader-Willi syndrome (PWS) and hypothalamic injury-associated obesity (HIAO).

PWS is a genetic disorder that results from a deletion or loss of function of a cluster of genes on the 15th chromosome. Patients with the condition have unrelenting hunger that drives them to eat, causing life-threatening obesity.

In a phase IIa trial, beloranib reduced body fat content of PWS patients by 8.1 percent vs. placebo after four weeks of treatment at the highest study dose of 1.8 mg, an impressive feat considering patients were allowed to increase their daily caloric intake by 50 percent.

Zafgen is currently running a phase III trial testing beloranib in PWS, which should read out by the end of the year. Given the unmet need, Hughes said he thinks if the data are "sufficiently compelling" the FDA may allow Zafgen to file a new drug application (NDA) with data from a single phase III trial.

HIAO is caused by damage or removal of the hypothalamus, most commonly due to the removal of a craniopharyngioma tumor. Since one of the functions of the hypothalamus is to promote satiety, HIAO patients can overeat and become obese.

At the Endocrine Society meeting this month, Zafgen presented phase II data in patients with HIAO. After four weeks of treatment, there was a statistically significant difference (p = 0.01) between patients that received beloranib, who lost an average 3.4 kg, compared to a loss of just 0.25 kg for those that were given placebo.

After a four-week open-label extension where all patients received beloranib, the patients that had been on beloranib the entire time ended the study with a loss of 6.15 kg and the patients that switched from placebo to beloranib lost 3 kg.

"This rapid weight loss, which showed no signs of slowing down at the eight-week timepoint, was achieved without the aid of increased exercise or dietary changes, underscoring the impressive efficacy of beloranib," RBC Capital Markets analyst Simos Simeonidis wrote in a note to clients.

Zafgen plans to start a phase III trial testing beloranib in HIAO patients early next year.

The biotech hasn't given up on the idea of developing drugs for larger indications. It's developing follow-on molecules targeting metAP2, the same target as beloranib inhibits, in patients with nonalcoholic steatohepatitis (NASH) and obesity. Zafgen expects to file an investigatonal new drug application for ZGN-839 to treat NASH and start clinical trials this year.

HELPING THE HEART

Orexigen Therapeutics Inc.'s Contrave (naltrexone and bupropion) was approved by the FDA more than two years after Belviq (lorcaserin, Arena Pharmaceuticals Inc./Eisai Inc.) and Qsymia (phentermine/topiramate, Vivus Inc.) despite the three drugs being issued complete response letters around the same time because the FDA required Orexigen to run a cardiovascular outcomes trial (CVOT).

The first interim look at the CVOT – dubbed the Light Study – ruled out an excessive cardiovascular risk for Contrave. Specifically the data excluded a hazard ratio of 2, using the upper limit of the 95 percent confidence interval, for excess risk of major adverse cardiovascular events (MACE) in patients given Contrave as compared to placebo. (See BioWorld Today, Nov. 26, 2013.)

San Diego-based Orexigen didn't release data at the time because the trial was ongoing, but apparently shared the information with enough people at the company that the FDA considers the blind broken; Orexigen will have to run a new CVOT trial as part of its postmarketing requirements.

It turns out that the first interim analysis after 25 percent of MACE not only ruled out an excessive cardiovascular risk for Contrave but actually showed a decrease in MACE. There were 35 MACE in patients taking Contrave compared to 59 in patients taking placebo (p=<0.0001). Subgroup analysis of the components of MACE showed fewer myocardial infarctions, strokes and cardiovascular death in patients taking Contrave compared to those taking placebo.

Data from the ongoing Light study, which the FDA has publicly said it didn't want released, was disclosed this month in an SEC filing by Orexigen announcing the issuance of a U.S. patent claiming the positive effect of Contrave on cardiovascular outcomes.

"The obvious caveat is that this was an early, interim look, based on 25 percent of the events. The second interim look, based on 50 percent of the events is expected in a few weeks," RBC's Simeonidis wrote.

POTENTIAL GENERIC COMPETITION

Last week, Vivus disclosed that Teva Pharmaceuticals USA Inc. had filed an abbreviated new drug application (ANDA) with the FDA for generic versions of Qsymia.

Under the Hatch-Waxman Act, Vivus has 45 days from receipt of the notice to determine if it will file a patent infringement suit although it sounds like the decision has already been made. "The company intends to vigorously enforce its intellectual property rights," Vivus said in the SEC filing announcing that it had received notice from Teva.

Vivus is already in patent litigation with Actavis plc, which filed an ANDA with the FDA for generic versions of Qsymia last year. (See BioWorld Today, May 12, 2014.)

That lawsuit triggered a 30-month stay on the approval of an ANDA that expires on Nov. 7, 2016, if the patent litigation isn't worked out before then. Filing a lawsuit against Teva would result in a similar 30-month stay on Teva's application.

Cheap generic competition would obviously hurt sales of Qsymia, but Simeonidis pointed out that it could also affect sales of other branded obesity drugs. "We believe that these filings will continue to have an impact on both Vivus and the overall obesity space," he wrote.