Two drugs — Qsymia (phentermine/topiramate) and Belviq
(lorcaserin) — will soon be added to the armamentarium available for fighting
obesity, but how, when, and "if" these new agents will be used is far
from clear.
Qsymia may provide the
bigger bang in terms of total weight loss, but it also requires an FDA risk
evaluation and mitigation strategy (REMS), which means more paperwork for
physicians.
Belviq, which targets a
specific serotonin receptor, may be a safer option, but weight loss was less
dramatic in clinical trials, according to physicians interviewed by MedPage Today.
"I
don't see this as a horse race between the two drugs," Louis Aronne, MD,
of Columbia University, who has treated patients with both drugs in clinical
trials, toldMedPage
Today. "There will be specific situations where one or the
other may be indicated."
When prescribing for an
older diabetic patient, for instance, a clinician may want to use Belviq for
its safety, Aronne said.
"Initially,
physicians may not want to use phentermine" because of its association
with the failed diet drug Fen-Phen, which was pulled from the market for heart
valve risks, though the side effect was tied to its fenfluramine half.
"But I think as time goes on, that won't be an issue," Aronne said.
The FDA required more
postmarketing studies for Qsymia (a total of 10, compared with six for Belviq)
and those studies focus on cardiovascular outcomes including stroke and MI for
both.
The combination drug
also carries more contraindications, with glaucoma and hyperthyroidism on the
list of conditions that render patients ineligible. Those with recent or unstable
heart disease are also excluded because of the drug's potential to increase
heart rate.
Neither drug can be used
in pregnant women, but only the combination agent has a specific risk attached
to it. Topiramate, a treatment for seizures and migraine, has been shown to up
the risk of oral cleft in newborns. For this, FDA has recommended monthly
pregnancy tests for women on the drug, another potential barrier to use,
industry analysts say.
Aronne said topiramate
also carriers a higher risk of cognitive side effects such as memory or
attention disturbances, but the FDA only warned about these effects with
Belviq.
One advantage for
Qsymia, though, is its once-daily dosing; Belviq patients will have to pop two
pills a day. And Qsymia will make it to market first — possibly by the end of
this year — since Belviq has been flagged by the DEA as a potential drug of
abuse and will be subject to DEA scheduling, delaying its market entrance until
the beginning of next year, according to analysts.
Mitigating Heart Risks
Both drugs affect the
central nervous system, targeting behavioral pathways in order to make patients
stick to dietary and exercise changes that must be coprescribed with the
agents.
Belviq achieves that
primarily by acting on serotonin pathways. It's a newly developed compound that
activates the serotonin 2C receptor – unlike fenfluramine, which was foiled by
its activation of the serotonin 2B receptor.
Patients with heart
failure may have more of the 2B receptors in their heart tissue, according to
the FDA, and the overstimulation may have caused valve problems. That shouldn't
occur with compounds working on 2C, experts say.
For the combination
agent, phentermine is a known appetite suppressant and is currently prescribed
for weight loss, but only for a short period of time – about 3 to 6 weeks.
Aronne noted that it's
given in a much lower dose in the combination drug, which should also be
reassuring to clinicians.
"Some will say they
don't want to prescribe it until the studies show that there's no
cardiovascular risk," he said. "But the dose [of phentermine] is so
low" that heart effects are less likely. (The recommended dose of the drug
contains 7.5 mg phentermine and 46 mg topiramate.)
But Harlan Krumholz, MD,
a cardiologist at Yale University, said he does have concerns about the new
medications, given that efficacy studies are rarely large enough to turn up
suspicious events.
"We need to have
surveillance systems in place to get an early warning if these interventions
turn out to cause a net harm," Krumholz said in an email to MedPage Today. Since obese
patients likely have a higher prevalence of heart disease, he added,
surveillance studies need to demonstrate whether these patients are having more
events than would be expected.
A Long Dry Spell
Both mechanisms are
vastly different than the only other FDA-approved drug for long-term weight
loss, orlistat (Xenical), which prevents the absorption of fats from the diet.
The drug also has an over-the-counter formulation (Alli), and both were slapped
with an FDA warning about increased risk of liver injury in 2010.
Orlistat was the last
contestant standing in the obesity market after FDA pulled sibutramine
(Meridia) in 2010 over concerns about an increased risk of heart attack and
stoke.
In 2007, drugmaker
Sanofi withdrew its new drug application for rimonabant (Zimulti) after
associated reports of depression and suicide. Ten years earlier, FDA pulled
Fen-Phen as well as dexfenfluramine (Redux), which was also associated with
heart valve problems.
Given a 13-year drought
in new obesity drugs — a drought that tracked the nation's burgeoning obesity
problem — this is an attractive market for pharmaceutical companies.
And three companies have
been in the race for the brass ring: Arena Pharmaceuticals, Vivus, and
Orexigen. Arena, maker of Belviq, and Vivus, the company that markets Qsymia,
have completed the FDA approval hurdles, but Orexigen remains in the race.
Orexigen's entry is a
drug called Contrave, a combination of bupropion and naltrexone, which was
turned down by the FDA on its first pass at approval, as were Qsymia and
Belviq.
But unlike the case with
Belviq and Qsymia, when the FDA rejected Orexigen's initial application it told
the drugmaker to conduct its cardiovascular outcomes study before resubmitting
its new drug application.
McDavid Stilwell, a vice
president at Orexigen, told MedPage
Today that the
company expects to complete enrollment in the cardiovascular study during the
first quarter of 2013, with a target of 7,000 patients needed to hit a 1.5
percent event rate.
He said that Orexigen
expects interim data from the study by the second half of 2013 and may resubmit
its application next year. If all goes well, he said approval could come as
early as the first quarter of 2014.
Hunger for New Drugs?
Most analysts say that
the bigger question remains whether there will be much demand at all for the
new obesity drugs given the market's less-than-stellar record.
"A number of
treatments have made it to the market only to be withdrawn," James
Coutcher, of Global Data Healthcare, told MedPage
Today. "We expect physicians will be wary of prescribing
either one."
Sales of Xenical have
been sliding over the past 5 years, Coutcher noted, though this could have
something to do with patient preference for its over-the-counter formulation,
Alli.
Both phentermine and
topiramate are available generically, so clinicians could prescribe these
agents individually, Aronne said, though most will likely feel more comfortable
writing for an approved agent that's easier to take.
More likely is that some
clinicians may try combinations of the drugs, Aronne said: Belviq with
phentermine, for instance.
Other clinicians doubt
their colleagues will be that interested in working with the new agents. Lee
Green, MD, MPH, a family medicine professor at the University of Michigan in
Ann Arbor, wasn't enthusiastic about either option: "They really just don't
work that well."
Even if they did offer
10 percent weight loss – unlikely, given that trials often represent idealized
situations and real-world effects tend to be less amazing, Green said – many
patients would still have a long way to go.
"That takes an obese
250-pound man with a BMI of 38 down to 34 — still obese, still at risk for
diabetes, heart attacks, still having knee and back problems from the
weight," Green said in an email.
"I understand the
desire for a miracle pill, a silver bullet, to deal with the very difficult and
stubborn problem of obesity, but I don't think it's going to be that
easy," he added. "I will be surprised if either one is still on the
market in 5 years."