HOECHST MARION ROUSSEL MUST CHOOSE BETWEEN TRENTAL OR BERAPROST UNDER FTC AGREEMENT; BIOVAIL WILL HAVE RIGHT-OF-REFERENCE TO DILTIAZEM PHARM/TOX DATA

Hoechst Marion Roussel must divest either Trental (pentoxifylline) or a research program for beraprost to preserve competition in the intermittent claudication market, according to a proposed consent agreement with the Federal Trade Commission approving the merger of Hoechst and Marion Merrell Dow announced Sept. 18.

Trental was a $180 mil. product in the U.S. for Hoechst Roussel in 1994, according to the FTC complaint. The compound is patented through early 1997. The company has reported research efforts for new dosage forms and new indications for the xanthine derivative, including treatment of AIDS and dementias. Beraprost is a platelet aggregating inhibitor/oral prostacyclin licensed by Marion Merrell Dow in the U.S. and Canada from Toray Industries, which markets the drug in Japan.

"MMD is one of only a few companies engaged in advanced stages of research and development of drugs for use in the treatment of intermittent claudication that would have competed against Hoechst's Trental franchise," the FTC complaint states. Beraprost is in Phase I/II clinical trials.

The agreement calls for two additional divestments, both involving generic versions of Marion Merrell Dow products under development by Hoechst.

Specifically, the agreement states that Hoechst Marion Roussel must divest either Marion's Pentasa mesalamine brand or Hoechst/Copley's generic formulation in development; and either Marion's Rifadin (rifampin) or the Hoechst generic. The market for mesalamine was about $70 mil. in 1994, FTC said, while rifampin sales were about $18 mil.

"Prior to the merger, Hoechst had begun research and development of a generic oral dosage form of mesalamine that would have competed against MMD's Pentasa," the complaint states. Marion's exclusivity for the Pentasa mesalamine formulation expires May 10, 1996, and the company has use patents that protect the ulcerative colitis indication that expire in 2002 and 2007. Competing brands of mesalamine are marketed by Solvay (Rowasa) and Procter & Gamble (Asacol).

"Prior to the merger, Hoechst was one of only a few companies that had begun research and development of a generic rifampin product that would have competed against MMD's Rifadin," the complaint adds. Rifadin loses orphan drug exclusivity on May 25, 1996. The mesalamine and rifampin divestments are designed to ensure that Hoechst's version and Marion's version will compete "in the same manner in which these compounds would compete absent the merger," the consent order states. The agreement does not appear to preclude the introduction of an "authorized" generic through Marion, a strategy MMD has employed for other products.

For all three divestments, Hoechst has nine months from the date the agreement is made final to comply. The purchasing company and the manner of the acquisition must be approved by the commission. A trustee will be appointed to oversee the divestments. In the event the divestments have not been completed within nine months, the trustee may be ordered to complete them for Hoechst.

Hoechst also agreed to grant Biovail "the right of reference to the pharmacology, toxicology and animal reproductive toxicology data contained in MMD's NDA 18-602 for diltiazem on file with FDA" within seven days of finalization of the agreement.

The stipulation relates to Biovail's once-daily diltiazem brand Tiazac, which will compete with Marion's top-selling product Cardizem CD. Hoechst had been working on development of Tiazac in conjunction with Biovail, but the company terminated its agreement during its negotiations to buy MMD. Hoechst's action, however, "fails to remedy the anticompetitive effects of the merger, because it leaves Biovail as a less effective competitor than it would have been absent the merger," FTC charges in the complaint.

Prior to its merger agreement with MMD, Hoechst agreed to pay Biovail $7.5 mil. to resolve litigation between Biovail and MMD over the product ("The Pink Sheet" May 8, p. 3). The FTC agreement includes stipulations that Hoechst withdraw the citizen petitions and patent suits filed by MMD over the issue and that it refrain from filing any subsequent patent infringement actions against Biovail. Hoechst must also return all non-public information to Biovail and must refrain from using the information.

The timing of the consent agreement ensures that the direct impact of the diltiazem provisions will be limited: Biovail's Tiazac was approved Sept. 11 and has been licensed to Forest for marketing. FTC noted, however, that the toxicology data would be available "to secure additional FDA approvals for Tiazac."

The agreement "will allow Biovail to continue the development of additional forms of diltiazem on a clear, unobstructed path, unencumbered by baseless patent litigation," the Toronto-based firm declared. Biovail announced Sept. 19 that it has acquired the Puerto Rican firm Galephar P.R., Inc., which codeveloped Tiazac. The asset purchase brings to Biovail Gelephar's 22,000 sq. ft. Carolina, P.R. manufacturing plant, additional territorial rights to Tiazac and technology for development of future controlled-release products.

The real impact of the FTC order may be to prevent Hoechst Marion from pursuing litigation against the marketed product. MMD entered into numerous suits against the first challenger in the once-daily diltiazem category, Rhone-Poulenc Rorer (Dilacor XR), to stop alleged claims of bioequivalence.

Biovail indicated following approval of Tiazac that it would emphasize the potential to switch patients from other diltiazem brands to Tiazac ("The Pink Sheet" Sept. 18, T&G-2). Given the administrative record established under the consent agreement, Marion may be less willing to challenge those marketing campaigns in court. The Federal Trade Commission has stated its interest in alleged "abuse of process" by innovators in combating subsequent market entrants.

Final approval of the agreement will allow Hoechst Marion Roussel to proceed with its worldwide integration.

The $7.1 bil. acquisition was completed under a "hold separate" agreement in July that required Hoechst to continue operating Marion separately ("The Pink Sheet" July 3, T&G-7). Hoechst Marion Roussel will be headquartered at the old Marion headquarters in Kansas City, with other North American sites in Montreal, Cincinnati and Somerville, N.J. Former MMD President Richard Markham will move to Frankfurt to assume his new position as deputy head of HMR.

The company already has begun the process of paring its research pipeline. On Sept. 15, Hoechst Marion Roussel announced that it has licensed the rights to diflouromethylornithine (DFMO) to San Antonio-based ILEX Oncology. ILEX was founded in 1994 with the mission of speeding commercialization of anti-cancer agents.

DFMO is involved in numerous studies for both cancer prevention and therapy being sponsored by the National Cancer Institute, according to NCI's FY 1997 Bypass Budget. Ongoing studies include Phase II trials in colon and prostate chemoprevention, and Phase II/III trials for chemoprevention in breast cancer, cervical cancer, prostate cancer, bladder cancer, oral cavity cancers, skin cancer and colon cancer.

DFMO "irreversibly inhibits ornithine decarboxylase, a key enzyme in the biosynthesis of polyamines," the NCI document states. "ODC enzyme activity and the resulting polyamines are essential for cellular proliferation of normal mammalian cells and, on the other hand, are overexpressed in various cancer cells. Thus, agents that inhibit polyamine synthesis may be good candidates for use in cancer chemotherapy and chemoprevention."

The consent agreement was approved for public comment by the FTC commissioners 5-0 on Sept. 15. It will be open for comment for 60 days.