Vivus has submitted its anti-obesity drug Qnexa (phentermine plus topiramate) for review with the US FDA. The move comes only a week after Arena Pharmaceuticals filed its fat-fighting drug lorcaserin with the agency ( scripnews.com, December 23rd, 2009). A third candidate, Orexigen's Contrave (bupropion plus naltrexone), is due to be filed in the first half of next year.

Many analysts favour Qnexa as the best of the new wave of anti-obesity drugs, noting its "impressive" efficacy, and forecast blockbuster status if approved. Yet, while the drug induced weight loss of up to 14.7% (37 lbs) in some patient populations and has had a clean safety profile to date, some have raised questions about the side-effects associated with the components of the combination therapy – the appetite suppressant phentermine with the anti-epileptic and anti-migraine topiramate.

"The topiramate half of the combination is associated with cognitive impairment, peripheral sensory disorders, increased risk of depression/suicidality, vision impairment, metabolic acidosis, kidney stones and possible fetal damage during pregnancy," wrote Jefferies analyst Thomas Wei and his colleagues in a research note. "We believe there still remains a very high bar for safety given the indication, and we are nervous how an FDA panel may view the safety profile of Qnexa."

Both components have already been approved by the FDA, however, and are available individually as generics.

Arena's lorcaserin – a 5-hydroxytryptamine agonist that activates POMC neurons, which regulate energy expenditure and appetite – by contrast has a more modest efficacy, but may have a less controversial safety profile.

Orexigen's Contrave – which consists of the dopamine reuptake inhibitor bupropion and the opioid-antagonist naltrexone – activates, and simultaneously inhibits, the negative self-regulation of POMC neurons ( scripnews.com, November 20th, 2009). Its efficacy seems to fall between that of Qnexa and lorcaserin, but safety concerns could also pose a problem for approval.

EQUIP, CONQUER and EQUATE

The filing of Qnexa was backed by three positive pivotal trials including EQUIP, CONQUER and EQUATE.

In EQUIP, 1,267 morbidly obese patients spent four weeks in dose titration followed by 52 weeks of treatment with placebo, Qnexa low-dose (3.75mg phentermine plus 23mg topiramate) or Qnexa full-dose (15mg phentermine plus 92mg topiramate; scripnews.com, September 11th, 2009). In the intent-to-treat population, 45% of low-dose patients and 67% of high-dose patients lost at least 5% of their body weight, compared with 17% of placebo patients.

In CONQUER, 2,487 overweight and obese patients were similarly treated with placebo, mid-dose Qnexa (7.5mg phentermine and 46mg topiramate) or high-dose Qnexa. 62% of the mid-dose Qnexa patients and 70% of the high-dose Qnexa patients lost at least 5% of their body weight, compared with 21% of those on placebo.

Moreover, patients on full-dose Qnexa experienced on average 8.4% placebo-adjusted weight loss in EQUIP and 8.6% placebo-adjusted weight loss in CONQUER, noted the Jefferies analysts.

With these results, both trials have met both FDA guidelines for anti-obesity drugs: 35% of treated patients lost at least 5% of their body weight, and that group included at least twice as many patients as the number who achieved similar weight loss on placebo; and, therapy induced at least a 5% placebo-corrected weight loss.

Contrave met the first stipulation in two year-long trials, but the second only once ( scripnews.com, July 22nd, 2009). Lorcaserin, by contrast, clearly hit the first stipulation in one year-long trial, may have hit the first requirement in a second-year long second trial (depending on whether the FDA accepts the 47% of treated patients who lost 5% of their body weight to be double the 25% of placebo-treated patients who lost the same proportion of their weight), and failed to hit the second in both trials.

In the 28-week 756-patient EQUATE trial, 62% of patients on the mid-dose of Qnexa and 66% of those on the full-dose lost at least 5% of their body weight, compared with 15% of placebo patients. Those taking the full-dose and mid-dose Qnexa lost on average 9.2% and 8.5% of their body weight, respectively, compared with 1.7% of those taking placebo.

safety data

The anti-obesity field has faced several setbacks owing to safety issues, perhaps in part because these drugs are likely to be used chronically and in part because they may be misused widely for aesthetic purposes. Most recently, Sanofi-Aventis's Acomplia (rimonabant) was approved in the EU and then withdrawn after being linked to psychiatric side-effects; it was never approved in the US.

However, despite the concerns about Qnexa's safety, clinical trials have yet to yield any major safety signals. The most commonly reported side-effects were dry mouth, tingling, constipation, altered taste and insomnia. Vivus added that there were statistically significant improvements in cardiovascular, metabolic and inflammatory risk factors among treated patients. Encouragingly, noted Jefferies analysts, no serious adverse events of cognitive disorder, no suicide attempts and no signals for suicidality have been observed.

The analysts caution, however, that an absence of some safety data – particularly including cognitive impairment and serum bicarbonate abnormalities – makes it "difficult to develop a complete risk-benefit assessment".

The most common side-effects of lorcaserin included headache, nausea, dizziness, fatigue and dry mouth. It induced significant improvements in some, but not all, cardiovascular risk factors, and did not increase depression or suicidality. Jefferies analysts have noted that lorcaserin's strength may lie in its ability to be combined with other drugs for increased efficacy.

The most frequently observed adverse events for Contrave were nausea, constipation and headache. Orexigen has said that blood pressure is "generally unchanged" with Contrave, but pulse may increase slightly. As yet, Contrave is also not associated with depression or suicidality.