Inside the Phase III Pipeline
The three Phase III candidates in the pipeline offer fairly modest weight loss; some miss the top 5 percent mark, but all
promise to meet at least the secondary criterion. This overall middling efficacy, combined with the massive size of the market
demand, makes winning a "race to market" less important than in any other therapeutic areas.
"The different drugs are close enough in time, and there is such a large, undeveloped market that no drug will have a huge
first-to-market advantage," says Chang. "Being first won't put much of a restriction on subsequent drugs. Although if the
first one is tolerable, the patients who go on it may not want to switch."
Qnexa, by Vivus, is a combination of two widely prescribed drugs available as generics: phentermine, an amphetamine derivative
that was the safer half of Fen-phen; and topiramate, an anti-convulsive medication approved for epilepsy and used off-label
for binge eating. Taken together for 28 weeks in a Phase III study, the two drugs (15 mg phentermine and 92 mg topiramate)
dropped patients' weight 7.5 percent compared to placebo. Cutting the dose in half resulted in a 6.8 percent weight loss,
according to a Vivus press release from May 2009.
The drug is likely to face some skepticism among primary-care physicians, according to Wong, as few may be comfortable with
prescribing an epilepsy treatment for weight loss. Vivus expects to file an NDA for Qnexa by the end of 2009. Approval could
come as soon as July 2010, according to Sagient's data. InThought, a unit of Wolters Kluwer, forecasts revenues of $522 million
for Qnexa in 2016, while Sagient sees worldwide sales of $750 million the same year.
Contrave, by Orexigen, is another novel combination of two widely prescribed generics: the antidepressant bupropion is a dopamine
and norepinephrine re-uptake inhibitor; Naltrexone is an opioid receptor antagonist used to treat alcohol dependence. Each
has demonstrated modest weight-loss effects. "They show some synergies," Wong says. "Weight loss is about five to ten percent—nothing
Contrave reported Phase III data in July. While the drug failed to achieve the primary end point of 5 percent weight loss
compared to placebo, it did meet the FDA's categorical efficacy requirement. The percentage of patients in the drug group
who lost at least 5 percent of their body weight was three times that in the placebo group—55.6 percent to 17.5 percent at
28 weeks; longer trial arms showed similar results. More important for reimbursement, the drug documented statistically significant
improvements in cardiovascular risk factors. Orexigen expects to file an NDA in the first half of 2010, according to a company
"Contrave has the best chance of approval." Cuttler says, noting that regulators are already familiar with the safety profile
of both drugs in the new therapy. In 2016, Sagient predicts revenues of $406 million, compared to InThought's rosier $673
The most ambitiously conceived drug in Phase III is Lorcaserin, by Arena Pharmaceuticals. The San Diego–based biotech designed
a drug that closely resembles fenfluramine—the half of Fen-phen that damaged heart valves and was banned by FDA—but it appears
to boast greater selectivity and therefore a much cleaner toxicity profile. "Arena is trying to make a drug that is specific
for the [serotonin 2C] receptors in the brain without damaging those [serotonin 2B receptors] in the heart," Wong says.
So far, Lorcaserin's clinical efficacy has not been inspiring, Wong says. It hovers around 5 percent average weight loss.
But when the drug works for a patient, it works well. About 48 percent of patients on the drug lost more than 5 percent of
their body weight compared to about 20 percent for placebo. This satisfies FDA's categorical efficacy criterion. Additional
Phase III data is due this month. Arena's latest press releases do not give a date for the NDA filing, but some analysts see
it coming as early as December. InThought sees $849 million in revenues for the drug in 2016, while Sagient forecasts just
$346 million the same year.
One of the main selling points for these drugs is the pent-up demand in a market that has not seen a new weight-loss drug
since Glaxo's splashy OTC launch of Alli two years ago. "Doctors will prescribe them because their patients want a drug therapy,
and there are not a lot of other options," Cuttler says. He also expects doctors to try newly approved obesity drugs in combination
with diabetes drugs in the hope that it causes enough weight loss to improve cardiovascular health.
Some analysts, notably Datamonitor's Angell, are less optimistic: "The obesity market peaked in 2007 at about $600 million
instead of $8 billion," he says. "Do we really think that by offering an incremental change in what we already have, we will
get any closer to an $8 billion market?"