Sanofi-Aventis Pares Pipeline, Ditches Antidepressant Amibegron

In light of clinical setbacks and a broader overhaul, Sanofi-Aventis has ended some once-promising advanced development programs, while the fates of others hang in the balance, pending study results and strategic reviews.

Sanofi's progress with its pipeline can be measured by a couple of regulatory submissions. Multaq , an atrial fibrillation drug with a troubled history, was resubmitted in the U.S. and Europe at the end of June, the firm noted during a second-quarter earnings call July 31. Its sleep disorder therapy eplivanserin is set to follow with filings in the last quarter of this year.

However, Sanofi has discontinued a pair of programs - the antidepressant amibegron and gastric cancer agent S-1. It's also unclear whether aflibercept in refractory ovarian cancer and saredutant for major depression will survive to make it to filing, according to the latest call. Yet the firm had indicated all four compounds would be filed this year as recently as March 2008, during a presentation at a Cowen Health Care conference in Boston.

Pipeline changes are partly related to general belt-tightening, Hanspeter Spek, Executive VP of pharmaceutical operations, explained during the earnings call, pointing to market conditions that led the firm to cut 4,000 staff in North America and Western Europe between 2006 and 2008, while boosting personnel elsewhere in the world.

"We have adapted our collaboration between marketing and research in redefining what our future products will present in terms of the value proposition," Spek said, introducing an R&D update during the call.

Disappointments In Depression

Though late-stage beta 3 agonist amibegron (SR 58611) was "strongly positive" in terms of maintenance in late-stage research, it also had a signal of hepatic toxicity.

Unable to clear this problem, the firm decided it would be "very difficult to market this drug," given expectations for demand, Senior VP-R&D Marc Cluzel said.

Sanofi had been banking on amibegron and the NK2 antagonist saredutant (SR 48968), another late-stage compound, as novel entrants to the crowded anti-depressant space that could serve as add-on therapies to selective serotonin reuptake inhibitors (¹ (Also see "Sanofi Touts Late Stage Antidepressants’ Tolerability As Key For Combo Use" - Pink Sheet, 26 Feb, 2007.) p. 6). But neither product's development program has gone as hoped.

This spring, saredutant missed statistical significance against placebo in the INDIGO trial in elderly patients (² (Also see "Sanofi’s Lovenox Weathers Heparin Storm; Pipeline Faces Some Setbacks" - Pink Sheet, 5 May, 2008.) p. 3).

Then in the placebo-controlled MAGENTA study, discussed during the second-quarter earnings call, saredutant did not significantly reduce the relapse rate in patients who had responded to an initial three-month saredutant course and were treated for one year. However, the firm noted, the antidepressant did show good tolerability in longer-term use.

Sanofi is awaiting the completion of two other trials before it determines whether to continue saredutant development. Results of the studies, which combine saredutant with the SSRIs paroxetine ( Paxil ) and escitalopram ( Lexapro ), are due in the first half of 2009.

Oncologics Also An Area Of Setbacks

Another drug that has experienced setbacks is aflibercept (VEGF-Trap) in advanced refractory ovarian cancer. Sanofi says the regulatory strategy for the product is under review. In a Phase II study, the fusion protein, partnered with Regeneron, missed its primary endpoint but it did show evidence of activity based on RECIST and CA-125 criteria (³ (Also see "Sanofi/Regeneron’s Aflibercept Misses Mark In Phase II Ovarian Cancer Trial" - Pink Sheet, 21 May, 2008.)).

Cluzel said discussions about aflibercept continue with FDA, adding that it's difficult to predict the outcome at this point. "We are continuing to make our case," he said.

Meanwhile, he reported, enrollment is "moving ahead robustly" in four pivotal Phase III studies in the following indications: first-line metastatic prostate cancer; second-line metastatic non-small cell lung cancer; second-line colon cancer; and first-line pancreatic cancer.

Sanofi is planning a head-to-head comparison with Genentech's VEGF agent Avastin (bevacizumab), and is starting a pilot study in the first-line setting to assess the "respective advantage of Avastin versus VEGF Trap."

Sanofi has pulled the plug on another oncologic, the oral pyrimidine fluoride-derived S-1. On July 18, Sanofi announced it was terminating a 2006 agreement with Taiho for ex-Asia rights to S-1, due to disappointing new trial results. The anticancer agent failed to meet its primary endpoint of superior overall survival in a trial of more than 1,000 treatment-naïve patients with advanced gastric cancer, Tokyo-based Taiho reported July 18.

Looking For The Silver Lining

A slimmed-down portfolio, Sanofi-Aventis says, allows the firm to focus on six key late-stage programs, including the immunomodulator teriflunomide for multiple sclerosis, the anti-thrombotic compound AVE5026, and the GLP-1 agonist AVE0010 for diabetes.

The firm is also playing up its resubmission of Multaq (dronedarone) - an atrial fibrillation drug that was previously rejected by FDA - and the coming submission of the insomnia agent eplivanserin.

Around the last week in June, Multaq was resubmitted to FDA and filed with EMEA. On Aug. 8, Sanofi announced FDA is giving the application a priority review and that the review period begins July 31.

"We [expect] both agencies will come to a decision during 2009 and are in intensive preparations of pre-marketing for this product," Spek said.

The firm says it is targeting a market of approximately six million patients, focusing first on the estimated 68 percent of the total having their first episode and then secondarily on the remainder, made up of "permanent patients."

Multaq was previously declared "not approvable" for atrial fibrillation/atrial flutter by FDA in 2006 (⁴ (Also see "Sanofi Dronedarone Re-Filing Anticipated In 2008 After FDA “Non Approvable” Letter" - Pink Sheet, 31 Aug, 2006.)).

Full results of the ANDROMEDA study, which examined dronedarone in patients with congestive heart failure and ventricular dysfunction, were published in the New England Journal of Medicine in June. That trial, which was stopped in 2003, showed a risk of death with the drug (8.1 percent versus 3.8 percent for placebo).

But the new application is supported by results from the ATHENA trial, which was expanded and redesigned after the "not approvable" letter. In that study, Multaq showed a 24 percent reduction in heart-related hospitalization or death from any cause, the study's primary endpoint (⁵ (Also see "Sanofi-Aventis Heart Drug Multaq Back To FDA In Third Quarter" - Pink Sheet, 15 May, 2008.)).

Additional results from ATHENA showing the drug's effect on cardiovascular outcomes and stroke in patients with atrial fibrillation will be presented at the upcoming European Society of Cardiology meeting, held from Aug. 30 to Sept. 3 in Munich, Germany.

Though Sanofi-Aventis envisions Multaq as a big breakthrough, the delay in submission allowed other firms to get ahead. And while Spek reiterated Sanofi's claim that Multaq will be "the first real breakthrough in this indication since the introduction of amiodarone 25 years ago," other atrial fibrillation drugs will likely make it to the market first.

Astellas and Cardiome's Kynapid (vernakalant) and Solvay's Pulzium (tedisamil) are both pending at FDA, past their original user fee dates (⁶ (Also see "A Tale Of Two Drugs: Atrial Fibrillation Reviews Draw Focus On RiskMAPS" - Pink Sheet, 7 Jan, 2008.), p. 7).

This year also should see the U.S. filing of Sanofi's sleep disorder therapy eplivanserin, a 5-HT2A antagonist. Execs affirmed during the call that submission is slated for in the fourth quarter.

Insomnia is an important category for Sanofi. The firm markets the leading Ambien (zolpidem) franchise.

Eplivanserin has been touted as a new concept for insomnia; the firm is positioning it as improving sleep quality, instead of merely inducing sleep (⁷ (Also see "Sanofi-Aventis Pipeline Includes Sleep Quality Aid, Depression Therapy" - Pink Sheet, 5 Sep, 2005.) p. 18). The drug previously performed well in the Phase III placebo-controlled GEMS study, significantly reducing wake time after sleep onset and night-time awakenings (⁸ (Also see "Sanofi’s Lovenox Weathers Heparin Storm; Pipeline Faces Some Setbacks" - Pink Sheet, 5 May, 2008.), p. 3).

Sanofi has another 5-HT2A antagonist, volinanserin, also in Phase III development for insomnia.

Vaccine Unit Offers Rays Of Light

Sanofi also has some upcoming vaccines submissions. The firm is set to file an application with FDA for a two-dose infant/toddler version of its meningitis vaccine Menactra in the first half of 2009, having already completed enrollment in a Phase III trial in this age group.

Also in development is a high-dose flu vaccine designed to boost immune response in elderly people. This product will be filed in the "next several months" with a planned launch in the second half of 2009.

- Emily Hayes ([email protected])