Hoechst's Cariporide MI Program Stalls Following Phase III Results

Hoechst Marion Roussel is debating the future development of its NHE-inhibitor cariporide (HOE 642) for myocardial infarction following results from a Phase III trial that "did not confirm a statistically significant effect of the drug," HMR reported March 2.

The firm noted that while "preliminary analysis demonstrated a favorable safety profile" and "efficacy results of the five week observation period differed in subgroups," the efficacy of cariporide was not confirmed in the overall patient population.

HMR's GUARDIAN (Guard During Ischemia Against Necrosis) study investigated cariporide in over 11,500 patients suffering from unstable angina pectoris or undergoing percutaneous transluminal coronary angioplasty or coronary artery bypass grafting.

The company's decision whether to pursue an NDA for cariporide will follow the release of data from the GUARDIAN trial at the upcoming annual meeting of the American College of Cardiology in New Orleans March 9, HMR said.

The company had previously planned to file for cariporide approval in the U.S. and Europe during the second quarter of 1999, and anticipated over $400 mil. in peak annual sales for the product. The development of cariporide has been somewhat slower than Hoechst projected when it acquired Marion Merrell Dow in 1995. At that time, the company was targeting a 1998 filing date ("The Pink Sheet," Dec. 22, 1997, p. 15).

The GUARDIAN study was a double blind, placebo controlled multinational trial in which patients with ischemia were given cariporide three times daily for a period between two and seven days ("The Pink Sheet," Dec. 22, 1997, p. 15).

The goal of the trial was "to decrease the number of patients who will proceed to develop acute MI" and "to minimize the extent of irreversible left-ventricular damage" and mortality, the U.K.' s National Research Register clinical trials database notes.

The National Research Register notes that the benefits of NHE inhibition for the limitation of infarct size in acute myocardial infarction may be restricted. This limitation is due to "possibly impaired penetration of the drug in the area of ischemia" and "advanced necrosis because of the complete coronary obstruction to blood flow."

"Further analyses are ongoing to better understand preliminary findings [of the GUARDIAN trial] and to examine opportunities for further studies," HMR said.

A discontinuation of the cariporide program by HMR may mean that the first cardiovascular therapy to emerge from the post-merger pipeline with Rhone-Poulenc Rorer could be RPR's thrombin inhibitor Revasc (desirudin), which it licenses from Novartis. At a December press briefing Hoechst and Rhone-Poulenc reported that the combined company, Aventis Pharma, would have three Phase III cardiovascular candidates post-merger ("The Pink Sheet" Dec. 7, 1998, p. 17).

Another Hoechst compound suffering late-stage development difficulties is the glial cell modulator Savian (propentofylline) for Alzheimer's disease.

Hoechst appealed the negative opinion rendered on the drug by the Committee on Proprietary Medicinal Products in October, and has provided a re-analysis of trial data. Hoechst expects the CPMP to issue a second opinion on Savian later this year. Savian has been marketed in Japan as Hextol since 1988.

Hoechst AG's 1998 net sales fell 16% to $24.2 bil. (DM 43.7 bil.), the firm reported March 3. The company attributed the decline to "the deconsolidation of the specialty chemicals and the polypropylene businesses as of July 1, 1997, and the formation of the diagnostics company Dade Behring on Oct. 1, 1997."

Hoechst net income increased 32% to approximately $1.05 bil., an increase the company attributed primarily to lower taxes and minority interests.

The Aventis merger ran into a potential snag during the week of Feb. 22, when Hoechst's largest shareholder, Kuwait Petroleum Company, expressed concerns about whether the merger would serve shareholder interests ("The Pink Sheet" March 1, In Brief). The Kuwaiti firm owns a 24.5% stake in Hoechst.

Hoechst is currently in discussions with KPC aimed at clarifying the terms of the Aventis merger. Hoechst remains confident that the merger will be approved by shareholders at the annual general meeting on May 4. Rhone-Poulenc's shareholders will vote on the merger on May 26. Both firms established global integration teams for their pharmaceutical business in January, and have named over 500 senior executives to the combined entity.