Vivus’ Qnexa Combo For Obesity Needs FDA ‘Persuasion’ To Take First-Line In Diabetes

CEO hails positive Phase III data, but not all analysts are convinced.

Vivus' Phase III data from the EQUATE study testing Qnexa in obesity show a noteworthy 9.2 percent weight loss at the full dose, but that number falls short of FDA's recommended synergy - a doubling of the benefit gained by using either of the drugs combined in the pill.

There could be other trouble ahead, too, at least in the view of some analysts. Qnexa adds the norepinephrine releaser phentermine, an appetite suppressant, to topiramate, an anti-convulsant that is the active ingredient in Ortho-McNeil's epilepsy and migraine therapy Topamax . Regulators have questioned the safety of Topamax because of suicidality concerns (¹ (Also see "FDA Convenes Panel To Review Drug-Associated Suicidality Study" - Pink Sheet, 6 Jun, 2008.)), nor are they necessarily fond of combination products.

During an investor day Dec. 12, Vivus CEO Leland Wilson called the data "wonderful" and said Qnexa, because it leads to weight loss, will be positioned as a first-line therapy for Type II diabetes. He conceded that "a lot of persuasion and a lot of changes at the FDA" would be necessary for Qnexa to take the place envisioned by Vivus, "and that's some time away."

In part, that's because Vivus wants to be the first company to pursue a diabetes label claim for a weight loss product. While adding that claim - if successful - should help in terms of reimbursement and physician acceptance, it also increases the regulatory risk at a time when approval of any obesity drug is fraught with hazard.

Along with knocking down HbA1c, Qnexa seems to improve blood glucose and blood pressure, and "may be the first obesity product to make such a claim," wrote Jon Alsenas, an analyst with Leerink Swann, in his Dec. 15 research note.

The problem is that, individually, phentermine and topiramate each lead to about a 6 percent weight loss, so the 9.2 percent in EQUATE total seems short of FDA's preferred 12 percent. Alsenas wrote that Leerink's regulatory consultant advised taking FDA recommendation seriously, since "recommendations often become requirements if the FDA has concerns regarding any other aspect" of an NDA.

EQUATing the results

That's where the worries over topiramate come in. EQUATE, which included 756 obese subjects (599 females and 157 males) showed no suicidality signals during the 24 weeks of once-daily treatment, but 6.6 percent of mid-dose and 3.7 percent of high-dose patients had attention deficits, compared to 0.9 percent of those on placebo. A separate diabetes extension study, DM-230, listed six "cognitive adverse events" from Qnexa vs. one for placebo.

The DM-230 study was a continuation of a previous double-blind, placebo-controlled trial of 206 obese type 2 diabetes. Investors questioned the drug's efficacy, in particular because weight loss in patients taking DM-230 leveled out after six months--a finding that could limit Qnexa's use if it also proves true in the EQUATE trial.

Wilson downplayed that concern, noting that "All God's medicines plateau." He asserted that Qnexa's results are "unseen in weight-loss drugs, period."

In EQUATE, patients with higher BMI continued to lose weight longer on Qnexa and at a higher percentage rate than lower-BMI patients. "If you have a lower-weight individual, they will plateau sooner," he said. "Where it goes from here, we'll see as we have further studies in this area." Qnexa "causes a patient to eat less, and reduces excess calories by about 50 percent of what a person needs to maintain optimum weight." Exercise is also necessary, but "what we think we're seeing is that as patients lose weight, they're able to exercise more," he said.

As more data with Vivus' drug emerge from longer and larger studies, investors will be able to better compare Qnexa with the likes of Byetta (exanatide), which showed a sustained average weight loss of 9.5 pounds when given weekly over a 52-week period. Meanwhile, Amylin/Lilly said earlier this month that FDA is unlikely to complete its review of the sNDA for the use of Byetta as monotherapy by the end of the year as previously forecast. The two companies could not say whether the delay is related to an increased risk of pancreatitis associated with the compound (Also see "FDA Review Of Byetta Monotherapy Heads Into 2009" - Pink Sheet, 8 Dec, 2008.).

Along with EQUATE, the Phase III Qnexa program includes two pivotal, double-blind, placebo-controlled, multi-center studies comparing Qnexa to placebo during a 56-week treatment period. The first year-long study, EQUIP (OB-302), has enrolled about 1,250 morbidly obese adult subjects with a Body Mass Index of 35 or greater with or without controlled co-morbidities. The second trial, CONQUER (OB-303), has enrolled overweight and obese adult subjects with BMIs from 27 to 45 and at least two co-morbid conditions, such as hypertension, dyslipidemia and type 2 diabetes.

The co-primary endpoints for EQUIP and CONQUER are the mean percent weight loss and the percentage of subjects achieving a weight loss of 5 percent or more, with results expected in mid-2009. In all, the Phase III program has enrolled about 4,500 patients.

Vivus currently has no plans to partner Qnexa before Phase III data are published. "We look forward to the end of the diabetes Phase III program for a partnering effort," said Wilson during the earnings call.

In reality, it may take even longer to sign a partnership-at least one with good terms for Vivus. Given the regulatory risks associated with obesity and diabetes drugs, many among big pharma firms may be unwilling to in-license the product based on the pivotal data, preferring to wait until FDA has approved it.

And Qnexa is not immune to the off-target effects that have scuttled the approval chances of other obesity meds. According to Leerink's Alsenas, parasthesia (tingling in the extremities) is likely to give FDA and doctors pause. The side effect surfaced in 20 percent and 15 percent of mid-dose and high-dose EQUATE patients, respectively, vs. 3 percent on placebo.

Meanwhile, Vivus is not the only biotech wading into the obesity fray with a combination product. Orexigen has developed two different combination products: Contrave, an extended-release formulation of naltrexone and bupropion in Phase III development; and the Phase II Empatic, which ties zonisamide and bupropion. But Orexigen's shares plummeted earlier this month when the company said three managers including CEO Gary Tollefson were leaving, and Phase II studies with another obesity product, OREX-003, would stop in order to conserve cash.

- Randall Osborne ([email protected])