Aventis To Continue Cariporide Development In Coronary Artery Bypass

Aventis Pharma will focus its late-stage cariporide development efforts on treating patients undergoing coronary artery bypass grafting, instead of the original indication for acute coronary syndrome, Hoechst Marion Roussel reported in a July 22 announcement on priority pipeline candidates for the merged HMR/Rhone-Poulenc Rorer.

A Phase III study with the sodium-hydrogen exchange inhibitor in patients undergoing CABG is likely to begin in early 2000, following the conclusion of ongoing dose-optimization studies in CABG patients.

HMR had put the development of the NHE inhibitor on hold in March, following preliminary results from the Phase II/III GUARDIAN trial showing that the drug did not reach a statistically significant reduction in the risk of death and new heart attacks in patients with acute angina pectoris, or in patients undergoing percutaneous transluminal coronary angioplasty or CABG (¹ (Also see "Hoechst's Cariporide MI Program Stalls Following Phase III Results" - Pink Sheet, 8 Mar, 1999.)).

Preliminary subgroup data from the GUARDIAN study "reflected varying efficacy rates, with the most promising among CABG patients who received the highest dose (120 mg) of cariporide." Final trial results "support further investigations of the 120 mg dosage or higher dosages in patients undergoing CABG."

Aventis' plans for cariporide also involve the initiation of European Phase II trials in acute myocardial infarction; Phase II trials in this indication are ongoing in Japan. The cariporide launch is targeted for 2003, with HMR expecting peak sales to exceed $400 mil.

HMR has also decided to continue the development of its glial cell modulator propentofylline (Viviq) for Alzheimer's disease.

Phase III development of propentofylline in the U.S. was put on hold when European regulators recommended against approving the compound in October. HMR appealed the decision, and the Committee for Proprietary Medicinal Products determined that an additional Phase III trial would be required (² (Also see "Novo Nordisk Prepares For European NovoRapid Launch" - Pink Sheet, 7 Jun, 1999.)).

The dossier submitted to CPMP in 1998 focused on a successful European Phase III study and an unsuccessful U.S. trial, HMR noted. The firm plans to commence another U.S. Phase III study in early 2000 that will have the same design as the European trial.

Hoechst believes that the disparity in results between the two trials stemmed from interactions between propentofylline and food. In the European trial, patients received the drug one hour before meals, while the U.S. trial allowed for therapy to be administered either one hour before meals or two hours after.

The 12-month European study randomized 260 patients with mild-to-moderate Alzheimer's or vascular dementia to 300 mg propentofylline or placebo one hour before meals three times daily.

The study reported statistical significance in favor of Viviq in global and cognitive measures of dementia: Gottfries-Brane-Steen scale, Symptom Short Test and Mini-Mental State Examination.

Hoechst is also conducting a series of Phase I propentofylline trials "to further investigate potential food and drug interactions that may impact the bioavailability of the drug." A launch for the compound could take place in 2003, HMR said.

Aventis will not pursue the development of the serotonin 5HT2A receptor antagonist (M100907) for an acute schizophrenia indication, but will consider further development of the compound for chronic schizophrenia and chronic psychoses, HMR said.

Hoechst has completed three Phase III studies in over 1,000 schizophrenia patients with M100907. A panel of outside experts concluded that the drug has an adverse event profile similar to placebo, HMR said.

Data from two U.S. studies "indicate that the drug's effect in acute schizophrenia, although better than placebo, is inferior to haloperidol," HMR said. A four-month European study in patients with predominantly negative symptoms "did not demonstrate statistically significant effects compared to placebo."

The decision whether to continue development of M100907 will depend on interim analysis of an ongoing European Phase III trial slated to last for 12 months. If the trial "demonstrates superiority of M100907, compared to haloperidol, HMR will consider further development of M109907 for the long-term treatment of chronic psychoses."