Sanofi-Aventis is positioning its two late-stage antidepressant candidates as potential components of combination regimens.

"Virtually all of the drugs on the market have similar mechanisms, so...combinations of drugs may heighten efficacy," Sanofi Senior VP-Global Marketing Pierre Chancel said during a year-end investor presentation Feb. 13.

During the presentation Sanofi highlighted two Phase III depression compounds: the NK2 antagonist saredutant (SR 48968) and the beta 3 agonist ambigron (SR 58611).

With saredutant and ambigron, "you have two separate mechanisms here which enable potentially new approaches to depression management," Chancel noted.

One reason Sanofi may be highlighting potential use of the two compounds in combination regimens is that nearly all of the selective serotonin reuptake inhibitor antidepressants are available as generics. Positioning ambigron and saredutant as add-ons to existing therapies could allow the firm to ensure the compounds receive broad coverage despite the availability of generics.

Chancel said new treatment mechanisms and regimens are needed because the rates of relapse seen with current antidepressant medications remain high.

"What is most important ... is that after the first episode, the risk of a second is 50 percent. After a second, however, the risk of a third is 70 percent and after a third, the risk of a fourth is 90 percent in terms of relapses into depression," he explained.

"We are looking at a disease, which is insufficiently managed, perhaps too late in the game, and not in an adequate fashion."

[Editor's note: During the call, Le Fur spoke in French. Sanofi provided an English translation for the presentations, which is used in the article.]

An Agency for Healthcare Research & Quality report on antidepressants also recommended that combination antidepressant regimens may help address recurrent depression (¹ Also see "AHRQ Antidepressant Report May Put Pressure On CMS Formulary Guidelines" - Pink Sheet, 22 May, 2006., p. 24).

In addition, Chancel pointed out that most patients receiving antidepressant medications fail to achieve complete remission either due to inadequate response or intolerable side effects. "About 50 percent of patients do not respond to a ... treatment. Only 30 percent achieve a full response," he noted.

"In terms of safety and compliance, more than one in three patients stop treatment during the first month either because of adverse events or because of lack of symptom relief, so there is room for therapeutic improvement."

Sanofi Senior VP-Science and Medical Affairs Marc Cluzel said that a saredutant/SSRI combination regimen may be particularly effective at inducing disease remission.

"Until now, when we looked at depression issues, we tended to exclusively base our judgement on positive changes in the Hamilton [depression rating] scale, but increasingly the question is becoming 'Has the patient returned to normal or not?'" he said.

"Perhaps with NK2 antagonists and inhibitors of serotonin or other combined products we will probably have a solution to that," he said.

The exec cited a Phase IIb study comparing saredutant 100 mg with fluoxetine 20 mg (Lilly's Prozac and generics) and placebo in which 36.7 percent of saredutant and 38.9 percent of fluoxetine patients achieved remission (defined as exhibiting a HAM-D score of <8), compared to 28.7 percent of placebo patients.

However, Cluzel acknowledged that Sanofi has seen "mixed" results in Phase III trials of saredutant in depression.

In two of four completed pivotal trials comparing saredutant with paroxetine (GlaxoSmithKline's Paxil and generics) and placebo, saredutant failed to show a statistically significant benefit relative to placebo.

"That is fairly standard because in most instances, in fact with all antidepressant agents, you have got about half of these studies that are statistically significant and the other half that are not statistically significant," he maintained.

However, Cluzel also acknowledged that the fact that "paroxetine was statistically significant versus placebo" in the trials could be a "slight" barrier to registering the product.

"Nonetheless, with a meta-analysis of the four studies, you see high positivity," he emphasized.

Cluzel said the "perfect" tolerability profile seen with saredutant in pivotal trials also makes the compound a strong candidate for combination use. "When you are looking for a combination treatment, it is important to have products that are tolerated very well since the side effects can add up," he said.

In the pivotal trials, incidences of nausea, dry mouth, diarrhea, headache, somnolence and dizziness for saredutant were similar to placebo and numerically lower than paroxetine.

Cluzel also highlighted saredutant's sexual side effect profile. In a meta-analysis of the pivotal, saredutant demonstrated a statistically significant benefit relative to placebo with regard to the changes in sexual functioning questionnaire.

"You can see positive activity versus placebo, so you can imagine the activity versus paroxetine, which does cause sexual function problems," he said.

Sanofi has not determined whether saredutant's lead indication will be GAD or MDD, but the firm expects to submit an application to FDA in late 2007 or 2008.

The firm has a similar filing time frame for ambigron and expects results from two Phase III depression trials in the "very near future," Cluzel said.

In a completed Phase III trial in 317 in- and out-patients with recurrent major depression, ambigron 700 mg/day patients exhibited a mean change of -13.3 from baseline in the HAM-D scale after 42 days, compared to -13.2 for paroxetine 20 mg/day and -11.1 for placebo.

Cluzel said ambigron demonstrated "really spectacular" efficacy in the subset of patients with severe depression (HAM-D >25 at baseline). Severe patients receiving ambigron had a mean decrease in the HAM-D of 15.6 compared to 11.9 for placebo and 14.9 for paroxetine.

As was the case with saredutant, Cluzel said ambigron's safety profile makes it a strong candidate for combination regimens. There are "no metabolism problems," Cluzel said. "This is important if you are going to to be using two products jointly."

In pivotal trials, ambigron patients had twice the rate of nausea versus placebo (9.4% vs. 4.5%), though still less than paroxetine (10.5%). Headache occurred at a higher rate for ambigron (11.0%) than for both paroxetine (8.1%) and placebo (9.8%).

Sanofi is conducting Phase III trials of both ambigron and saredutant in GAD and MDD in the elderly. Chancel noted that 9 percent of individuals >70 years of age have depressive disorders compared to 6 percent of patients ages 25 to 69 and 4 percent of patients ages 15 to 24.

The studies in the elderly reflect the company's strategy of targeting its central nervous system products to older patients.

"Understanding more and more about these diseases, such as sleep or depression or, indeed, Alzheimer's, this is enabling us to work towards better management," Chancel said. "What is really at stake [is] epidemiology that increases with age."

"When you project the population forward with aging populations, well mechanically, inexorably there is an increase ... in these disorders," he said.

Sanofi is focusing the development programs for its Phase III insomnia treatment eplivanserin (SR 46349) on the elderly. The firm plans to file the 5-HT2A antagonist in 2008.

Cluzel explained that as patients age, they tend to wake up more frequently during the night and have shorter periods of slow wave sleep and rapid eye movement sleep, which has a detrimental effect on sleep quality. Consequently, Sanofi is conducting three Phase III trials of eplivanserin evaluating the compound's effect on wake time after sleep onset.

Sanofi's lead candidate in Alzheimer's disease is the neurotrophic xaliproden (SR 57746), which the firm expects to file in 2008. Sanofi is developing xaliproden as a potential disease modifying agent. The firm has two ongoing Phase III, randomized, placebo-controlled studies evaluating xaliproden's impact on cognitive function and global decline and hippocampal volume.

- Andrew Kasper (a.kasper@elsevier.com)

Sanofi Touts Late Stage Antidepressants’ Tolerability As Key For Combo Use

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