Sanofi-Synthelabo plans to move two new molecular entities into Phase III during 2004.

The company reported positive Phase IIb results for the antidepressant saredutant and the aquaretic SR 121463 at a London-Paris business briefing Feb. 16.

SR 121463, a vasopressin V2 receptor antagonist to treat sydrome of inappropriate anti-diuretic hormone secretion (SIADH), was successful at reducing serum sodium levels after five days of treatment and showed "good safety and tolerability" in a 22-month open-label extension study.

Phase III trials for SIADH (also known as hyponatremia) will begin in the second quarter. The aquaretic has also completed Phase IIa for treatment of cirrhotic ascites.

If the Phase III trials are successful, the drug will potentially compete with Yamanouchi's pending dual V1 and V2 receptor antagonist conivaptan; a conivaptan NDA for hyponatremia was filed in January.

Sanofi's second Phase III candidate, the neurokinin-2 receptor antagonist saredutant, demonstrated results comparable to fluoxetine (Lilly's Prozac and generics) for control of depression and anxiety and as depression maintenance therapy after six weeks of treatment. Pivotal trials are slated to commence later this year. The drug is also in Phase IIb for irritable bowel syndrome.

Saredutant would be the second neurokinin receptor antagonist to enter Phase III for depression. Development of the first agent, Merck's substance P NK-1 receptor antagonist aprepitant, was discontinued in November after Phase III trials failed to demonstrate efficacy (¹ Also see "Merck Discontinues Substance P Depression Compound After Failed Trial" - Pink Sheet, 17 November, 2003., p. 34).

The NK-1 receptor antagonist category is also being widely explored for depression and anxiety in earlier-stage research: GlaxoSmithKline has two NK-1 antagonists for the indications in Phase I and one in Phase II; Roche has an NK-1 antagonist in Phase II.

Another Sanofi Phase IIb agent, the NK-3 receptor antagonist osanetant, had been in clinical trials for phobias/anxiety and depression, but is now apparently being evaluated only for schizophrenia.

Central nervous system drugs dominate Sanofi's Phase IIb pipeline. Besides osanetant and saredutant, the Phase IIb CNS portolio comprises two Alzheimer's disease agents, SR 57667 and SL 65.0155 (also being studied for Parkinson's disease); the anxiety and muscular contracting agent SL 65.1498; and the sleep disorder agent eplivanserin.

Rounding out Phase IIb are two oncology agents, SR 31747 for prostate cancer and SR 48692 for small cell lung cancer.

Upon advancing to the next stage of development, saredutant and SR 121463 will join the company's seven current Phase III NMEs. The NMEs include another antidepressant, the beta-3 agonist SR 58611.

During the Feb. 16 presentation, Sanofi touted its successful Phase III trials for amiodarone analog dronedarone for maintenance of sinus rhythm in atrial fibrillation, and for the central cannabinoid 1 (CB1) receptor antagonist rimonabant ( Acomplia ) for smoking cessation and obesity. Rimonabant is completing seven pivotal trials for the two indications (² Also see "Sanofi Chews The Fat: Rimonabant Anti-Obesity NDA To Be Filed By 2005" - Pink Sheet, 15 September, 2003., p. 25).

Successful dronedarone results should be welcome news for the company: a European Phase III trial for treatment of arrhythmias/fibrillation in high-risk patients with congestive heart failure and ventricular dysfunction was discontinued in January 2003 due to a potential increase in the risk of death in actively treated patients. Sanofi says the incidence of adverse events in the maintenance trials is similar to placebo.

Sanofi's existing total of seven novel Phase III agents is impressive. Only Pfizer rivals that total with 12 novel agents in Phase III development; GlaxoSmithKline ties Sanofi with seven (including new vaccine combinations), according to FDC Reports' The NDA Pipeline (³ Also see "Phase III Pipelines Running Dry; Bristol Looks Relatively Flush In 2004" - Pink Sheet, 29 December, 2003., p. 22).

Combined with its merger target Aventis, Sanofi would currently have 12 novel Phase III compounds.

The strength of Sanofi's pipeline was a major theme of the investor presentation in the hopes of attracting Aventis shareholders. Sanofi stressed increased resources for R&D as a key driver for the potential merger (see ⁴ Also see "Aventis Would Provide Critical Mass For Sanofi’s Mid-Term R&D – Sanofi CEO" - Pink Sheet, 23 February, 2004. ).

Sanofi To Move Two NMEs Into Phase III In 2004, For Total Of Nine

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