Will the first in a new round of diet drugs win FDA approval? The briefing documents released by the agency this morning reveal that Qnexa, which will be reviewed on Thursday by an agency panel, may cause psychiatric and cardiovascular side effects. FDA medical reviewers also believe the pill should have undergone more testing in pregnant women and they recommend warnings to avoid the possibility of fetal deformities. Why? There were 34 pregnancies during a clinical trial, despite recommendations for using two forms of birth control.

For those who may not recall, Qnexa is a combo treatment - it includes phentermine, which was part of the fen-phen cocktail that was yanked in 1997, and topiramate, which is marketed as the Topamax seizure med. But phentermine can be habit forming and is contraindicated for people with advanced arteriosclerosis, cardiovascular disease, or moderate to severe hypertension (see more about this below), while topiramate includes warnings about suicide and requires a patient pregnancy registry.

Nonetheless, Vivus has been a hot stock lately, partly because clinical trial data released last fall showed Qnexa helped moribdly obese patients lose an average of 14.7 percent of their body weight, compared with 2.5 percent on placebo. Another study of patients with high blood pressure, high cholesterol or diabetes found Qnexa yielded average weight loss of 13.2 percent, compared with 2.4 percent on placebo (see our recent post). Meanwhile, concerns about revisiting the fen-phen debacle appear muted.

Consequently, the initial reaction of one Wall Street analyst to the FDA documents released this morning is upbeat. “Overall, we believe the language in the FDA briefing documents to be fairly benign,” wrote Leerink Swann’s Steve Yoo, in a note distributed a short while ago, “but the FDA is requesting a pregancy category X label that would include contraindication in pregnant women and a warning/ precaution for females of childbearing potential.” Indeed, the FDA notes that “if approved, the person-years of exposure to (Qnexa) among women of child-bearing potential will be enormous.”

Vivus, by the way, is proposing a large outcomes trial if its drug is approved. Please continue reading below for some key points in the FDA documents…

The majority of the study subjects were middle-aged white women. The elderly, which was defined as those older than 65, represented less than 8 percent of the total study population. Overall, 12 percent of low-dose and mid-dose subjects, and 18 percent of high-dose subjects withdrew from the studies due to an adverse event.

The incidence of depression-related adverse events in clinical trials was 3.4 percent in the placebo group, 5 percent in the low-dose group, 3.8 percent in the mid-dose group, and 7.7 percent in the high-dose group. Anxiety-related adverse events were reported with frequencies similar to those observed for depression, with nearly three times as many reports in high-dose versus placebo. Sleep-related adverse events were reported by approximately 6 percent, 7 percent, 7 percent, and 11 percent of subjects randomized to the placebo, low-dose, mid-dose, and high-dose groups.

In Phase III clinical trials, subjects randomized to Qnexareported more cognitive-related adverse events compared with subjects randomized to placebo. When the attention, memory, language, and other cognitive disorders not otherwise specified subclasses were pooled, the incidence rates were 1.7 percent, 2 percent, 5.6 percent, and 7.8 percent in the placebo, low-dose, mid-dose, and high-dose groups, respectively. The clinical significance of these imbalances is unknown.

In categorical analyses, the Qnexa patients had greater frequencies of increases in baseline heart rate of 5, 10, 15, and 20 beats per minute compared with the placebo group. The clinical significance of the increases in heart rate is unknown. The incidence of arrhythmia-related adverse events was 1.8 percent, 1.3 percent, 4.2 percent, and 4.7 percent in the placebo, low-dose, mid-dose, and high-dose groups, respectively. Palpitations comprised the majority of these adverse events and occurred in 12 (0.8 percent) placebo subjects and 27 (1.7 percent) high-dose subjects.

Relatively few elderly individuals or subjects with a history of myocardial infarction or stroke were enrolled into the phase 3 clinical trials. Not surprisingly, then, the overall number of ischemic cardiovascular-related adverse events in the development program was very low.

Another issue is metabolic acidosis. The percentages of individuals from the placebo, low-dose, mid-dose, and high-dose groups who experienced two consecutive or an endpoint bicarbonate value below 21 mEq/L were 2.1 percent, 8.8 percent, 6.4 percent, and 12.8 percent, respectively.

And what about efficacy? The mean weight loss for patients on the high-dose was 10.6 percent, 8.6 pecent for the mid-dose and 5.1 percent for thos on the low-dose and 1.7 percent for patients given a placebo.

pic thx to alan cleaver on flickr