West Coast Editor

Riding on third-quarter profits that surprised some analysts thanks to the sale of its spray drug for menopause symptoms earlier this year, Vivus Inc. began the first of two pivotal Phase III trials with Qnexa, the combination phentermine/topiramate drug dosed once daily for obesity.

Just last week, Mountain View, Calif.-based Vivus nailed down a special protocol assessment with the FDA for the Phase III program, the first study of which will test Qnexa in morbidly obese patients, with the second targeting obese patients with serious co-morbidities.

Vivus' stock (NASDAQ:VVUS) closed Friday at $4.56, down 7 cents.

Qnexa, consisting of immediate-release phentermine and controlled-release topiramate, will be tried in three forms during the Phase III push: full-strength (15 mg phentermine, 92 mg topiramate); mid-dose (7.5 mg phentermine, 46 mg topiramate); and low-dose (3.75 mg phentermine, 23 mg topiramate). Studies have confirmed the highest dose is comparable to the twice-daily formulation used in the Phase II study, which reported favorable results over the summer. (See BioWorld Today, July 25, 2007.)

The EQUIP study will enroll about 1,250 subjects in up to 120 centers, and is randomized, double-blinded, and placebo-controlled, with participants getting treatment with the low-dose Qnexa (250 subjects), full-strength Qnexa (500 subjects), or placebo (500 subjects) for 56 weeks. Randomization will be stratified by gender, and at least 20 percent of subjects will be male.

"This represents the first time Vivus has disclosed the doses of phentermine and topiramate used in Qnexa," noted Ian Sanderson, analyst with Cowen & Co. in New York, noting that 96 mg per day is the lowest dose of topiramate previously tested as monotherapy for obesity.

Those taking part in the EQUIP study will be instructed to follow a mild hypocaloric diet representing a 500-calorie/day deficit and to modify their lifestyles in the study period. During the first four weeks of treatment, study medication will be titrated to the assigned dose level, with the dosage increased each week as determined by randomization group. During treatment weeks 5 through 56, the dose will be maintained at the final dose level.

Peter Tam, vice president of product and corporate development for Vivus, said during a conference call with investors that the purpose of the program is to "bracket the entire dose range of Qnexa." Patients already are being screened for the second trial, called CONQUER, which is "really the primary pivotal study of 2,500 patients" and will test mid-dose and high dose Qnexa. Enrollment is expected to start in the next few weeks.

"We don't know if the low dose is going to be ultimately a very effective maintenance dose or not, and that's why we're testing it in one of our Phase III studies," Tam said, adding that the program "is designed in such a way to allow patients dosing flexibility," so they can titrate downward if a dose is too high.

Phentermine, first approved by the FDA in 1959 as an appetite suppressant, is used for weight loss and available generically. Topiramate (Topamax, Johnson & Johnson) prevents epilepsy and migraine but carries such side effects as depression, insomnia, memory trouble, somnolence, paresthesia (tingling or numb skin), psychomotor slowing, dizziness, and nausea.

The once-per-day controlled-release topiramate reduced the peak plasma concentration by 20 percent and delayed the time to maximum plasma concentration by six hours, while maintaining total exposure similar to the twice-daily version, which could mean better compliance by patients and a milder side effect profile.

The co-primary endpoints for all the Phase III studies will evaluate the differences between treatments from baseline to the end of the treatment period in mean percent weight loss and in the percentage of subjects achieving weight loss of 5 percent or more.

Obesity therapies that do not affect such accompanying disorders as hypertension and dyslipidemia will be judged as "cosmetic in nature," said Leland Wilson, president and CEO of Vivus, pointing out that about 75 percent of obese patients have high blood pressure, and most will develop it eventually.

"In the future, drug-induced weight loss, I believe, will functionally become first-line therapy because of the ineffectiveness of diet and exercise," he said, adding that Vivus aims to "treat the heaviest and sickest of obese patients."

During the third quarter, the company recognized a $14 million deferred license payment from St. Louis-based KV Pharmaceutical Co., which bought Evamist, a transdermal estradiol spray for moderate to severe menopause symptoms in a potential $180 million deal. (See BioWorld Today, July 31, 2007, and April 2, 2007.)

The KV arrangement included $140 million upon FDA approval, which took place in late July, and that money has been recorded as deferred income and will be recognized as license revenue ratably over the remaining 21.5-month term of the agreement for improvements to the drug's applicator.

Revenue rose $19.1 million for the third quarter, compared to $4 million for the same period last year, and Vivus earned $1.3 million, or 2 cents per share, compared with a loss of $6.2 million, or 13 cents per share, last year. Thomson Financial analysts expected Vivus to report $12.5 million in revenue and break even.

Shipments of Muse, the company's applicator-delivered alprostadil for erectile dysfunction, increased, bumping revenues to $4.1 million from $3.9 million for the same period last year.

Vivus' pipeline includes Testosterone MDTS (metered dose transdermal spray), which has completed a Phase II trial for female hypoactive sexual desire disorder, and the ED drug avanafil, which also has undergone a Phase II study. At the end of the third quarter, the company had cash and cash equivalents of about $161 million.

"We remain neutral on Vivus shares pending improved visibility on the future of Testosterone MDTS and the clinical profile of Qnexa," wrote Sanderson in a research report Friday.

Cowen's quarterly report declared the Vivus story "all about Qnexa," and noted the firm's management continues to "go back and forth with the FDA" on an SPA for the Phase III program of Testosterone MDTS, which deploys the same device as Evamist, designed by Acrux Ltd., of Melbourne, Australia. Vivus is looking for a development partner for that product and for avanafil, licensed from Tanabe Seiyaku Co. Ltd., of Osaka, Japan, in March 2001.

Like Viagra (sildenafil, Pfizer Inc.), avanafil is a PDE5 inhibitor, but may act quicker and leaves the system faster, providing dual benefits - especially for heart attack patients, who risk interaction with nitrates, often given as emergency therapy. Vivus finished a 284-patient, 12-week Phase II dose-ranging study in mid-2005, and Cowen speculated a deal for the product could come next year.