Efficacy concerns surrounding GlaxoSmithKline's Xenical (orlistat) may prove to be a bigger hurdle to overcome than safety or self-selection issues as the firm pursues an Rx-to-OTC switch of the drug.

Although the proposed OTC dose of 60 mg shows statistically significant weight loss, "there is no evidence presented that a modest, transient weight loss due to orlistat will afford any long-term clinical benefit through either a change in behavior or a reduced risk of serious clinical diseases manifested by being overweight," an FDA review of studies on the drug finds.

The FDA documents, released Jan. 20, question whether GSK's proposed six-month treatment - submitted under the trade name Alli - would be beneficial for a "chronic" condition such as obesity.

The documents were released in advance of a Jan. 23 review of the switch proposal by the agency's Nonprescription Drugs and Endocrinologic & Metabolic Drugs advisory committees.

GSK filed the Xenical switch application in June after purchasing licensing rights to the drug's OTC version from Roche in July 2004 (¹ Also see "GSK Sees Big Opportunity In OTC Diet Aids: Xenical Switch NDA Filed" - Pink Sheet, 1 August, 2005., p. 5 and ² Also see "Xenical Rx-To-OTC Switch In The Works, GSK/Roche Announce" - Pink Sheet, 26 July, 2004., p. 5).

According to the agency, drug treatment for chronic conditions "must be maintained long-term or chronically" to result in clinical benefit. "It is difficult to define the clinical benefits of short-term treatment with orlistat," FDA states.

"Although not studied by [GSK], it is well known that once weight-loss treatment is stopped, lost weight is quickly regained and improvements in co-morbidities become undone."

Efficacy of orlistat use in "mildly overweight" people with a Body Mass Index of 25-28 also was questioned.

Comparing studies conducted for Xenical's Rx approval and proposed switch "raise[s] the possibility that orlistat may be less effective in mildly overweight individuals than in obese subjects," the agency states.

The prescription NDA study was conducted in individuals with a BMI of at least 28. A 5% or greater weight loss was achieved by 42% of subjects who took 60 mg, 45% taking 120 mg and 23% taking placebo.

In a more recent study conducted to support a Xenical switch, participants had a BMI of 25-28. A 5% or more weight loss was achieved in 36% of those taking the 60 mg dose and 28% taking placebo.

The difficulty in determining the benefits of short-term use is "further complicated," FDA states, because "evidence suggests that the overweight BMI range of 25-<30 is="" not="" associated="" with="" increased="">

Addressing factors such as diet and exercise, an FDA comparison of the studies finds that "greater weight loss was seen for patients whose diet diaries were monitored...than for patients not monitored regardless of treatment group."

FDA took issue with GSK's placement of data on serum lipid concentrations and blood pressure levels in the safey portion of the NDA rather than the efficacy section.

The agency quotes the sponsor as stating that the OTC indication "is to promote weight loss...all other benefits achieved from orlistat would be most appropriately handled under the supervision of a physician."

By drawing attention away from comorbidity reduction, GSK "appears to be saying that overweight individuals with weight-related co-morbidities such as type 2 diabetes, hypertension, or dyslipidemia are inappropriate candidates" for the drug, the agency states.

Orlistat's interference with the absorption of fat-soluble vitamins is among FDA's highest safety concerns for product users.

Studies showing a lower incidence of vitamin deficiency in the orlistat 60 mg group versus the 120 mg groups is "not reassuring given that the proposed label will allow patients to take up to 120 mg," FDA says.

Further, the review concludes that despite a recommended six-month use, it is "possible that some individuals will prolong use of this drug, potentially without appropriate vitamin supplementation."

The agency anticipates a "more detailed discussion" to take place at the advisory committee meeting on orlistat use and risk of pancreatitis.

Despite a 2003 review by Roche finding no relationship between the two, FDA states that a review of the Adverse Event Reporting System "identifies a sizable imbalance" in the number of pancreatitis incidents associated with orlistat and those linked to Abbott's weight-loss drug Meridia (subtramine).

- Bridget Behling

Short-Term Xenical Treatment Benefits “Difficult To Define,” FDA Says

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