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WARNER-LAMBERT's QUINOLONE ENOXACIN NDA COVERS FIVE SEPARATE INDICATIONS, FIRM SAYS; R&D PROGRAM FEATURING CNS, CARDIOVASCULAR AND ANTICANCER PRODUCTS

Executive Summary

Warner-Lambert is initially seeking five indications for its first quinolone antibiotic, Comprecin (enoxacin). The company's NDA, which was filed in October, covers infections of the skin as well as the genital, urinary and upper and lower respiratory tracts. "Across the board, enoxacin has been proven to be a highly efficacious antibiotic . . . with an overall clinical response of 92%," Warner-Lambert researcher Clifford Sipporin, PhD, told security analysts at a Nov. 6 presentation at the firm's R&D facility in Ann Arbor, Michigan. "Oral doses of enoxacin result in high and sustained serum, tissue and fluid levels beyond anything that's currently available or in development." In chronological terms, Warner-Lambert is already behind in the race to market products in the new quinolone class. Merck's Noroxin (norfloxacin) was approved by FDA on Nov. 3. However, the Warner-Lambert entry could prosper on the basis of broader indications. Noroxin's initial approval was limited to urinary tract infections. Among other firms in the quinolone race, Miles and Johnson & Johnson are still in clinicals with ciprofloxacin and ofloxacin, respectively. Sterling has an NDA pending for Eradacil (rosoxacin) and another quinolone, amifloxacin, in clinicals. Enoxacin product characteristics compared to other quinolones were emphasized at the meeting. Sipporin referred to a U.K. study in which enoxacin reached maximum serum concentration levels almost twice that of norfloxacin and 50% higher than ciprofloxacin. "Norfloxacin reaches no achievable blood levels to make it useful as a systemic antibiotic," Sippporin asserted. He noted that enoxacin's half life is twice that of the other two, thus supporting a twice-daily dosing regimen. Enoxacin has recently been deemed approvable in West Germany and New Zealand, where it will be launched in January, the company said. Licensed from the Japanese firm Dainippon, enoxacin will eventually be marketed in areas covering roughly half of the nearly $8 bil. world antibiotic market. Warner-Lambert noted that development is under way of an I.V. form of the drug, and that work is proceeding on other oral forms and ophthalmic uses. The parenteral filing is targeted for 1988. In addition, the company has trials planned for new indications including chronic osteomyelitis, chronic prostatitis, treatment and prophylaxis of immune compromised patients, and surgical prophylaxis. Further back in the pipeline, three promising second generation quinolone compounds are being developed with a focus on staphylococcus and anaerobic infections. Discussing its research activities with central nervous system durgs, the company highlighted its anticonvulsant, antipsychotic and cognition activator development programs. With an established $80 mil. a year anticonvulsant market position in Dilantin, the firm said it will submit an NDA for zonisamide in the next 30-60 days as add-on therapy in patients with partial epileptic seizures. Warner-Lambert researcher Donald Maxwell, MD, noted that the drug's advantages include once-a-day dosing, fewer side effects than existing therapeutics and activity against grand mal or tonic-clonic seizures. During 1986, zonisamide studies as therapy for grand mal seizures were initiated in refractory patients. The company said it intends to submit a supplemental NDA for that indication in 1988. Warner-Lambert, which licenses zonisamide from Dainippon, has exclusive U.S. and Canadian rights and non-exclusive rights for all other countries except Japan. The company estimates the world anticonvulsant market at over $300 mil., $200 mil. in the U.S. Three other anticonvulsants are also under development -- gabapentin, currently in Phase II, and CI-946 and CI-953, both in Phase I/early Phase II. An NDA filing for gabapentin is projected for 1990, according to the firm, with filings for CI-946 and CI-953 scheduled for 1992. The latter filings will roughly coincide with the company's development timetable in the antipsychotic area, where the focus is on chronic and acute schizophrenia. Maxwell identified two Phase I compounds, CI 943 and CI-936, which have shown an absence of neurological side effects in primates and an ability not to block dopamine receptors. In the area of cognition activators, Warner-Lambert is pursuing three compounds aimed at memory loss disorders in the elderly. Pramiracetam, currently in Phase II, is being investigated to prevent memory loss associated with electroconvulsive therapy, a treatment for chronic depression. Maxwell noted that U.S. Phase III trials could begin early in 1987. A 1987 European Phase III trial is scheduled for 1987 to evaluate the drug's efficacy in senile dementia and memory loss in geriatric patients. In addition, the company plans to study pramiracetam in the U.S. for pediatric dyslexia beginning in the fall of 1987. Two other cognition activators, CI-844 and CI 933, are about to start Phase II trials in the U.S., Maxwell noted. Warner-Lambert's interest in lipid-regulation therapies, combined with its experience in the area of confectionary manufacturing, has resulted in a product aimed at expanding the current market for cholystyramine. Cholybar is a chewable, flavored bar formulation of the lipid-lowering agent that the company believes will increase patient compliance. A mid-1987 ANDA filing is planned, and the product could be on the market by the end of the year, according to the company. Warner-Lambert noted that its current lipid research thrust is on two types of enzyme inhibitors -- HMG-CoA reductase inhibitors, which facilitate the removal of low-density lipoproteins from the blood, and ACAT inhibitors, which prevent absorption of dietary cholesterol. Further along is CI-924, which is envisioned as a "backup compound" to Lopid (gemfibrozil). The company said the product is comparable to Lopid in efficacy at half the dose, once daily. CI-924 is currently undergoing Phase II evaluation in the U.S. In the cancer area, the company continues to concentrate its research efforts on chemotherapeutic agents and will start, beginning in 1987, a yearly submission of at least one anti-cancer NDA until 1992. Amsidine (amsicrine), will be the first such filing. The drug is currently approved for acute leukemia outside the U.S. Warner-Lambert identified trimetrexate as one of its most promising compounds. In Phase II studies for small cell lung cancer, which accounts for 75% of total lung cancer cases, the drug showed a nearly 20% response rate. A 1987 filing for that indication in foreign countries is expected, and in anticipation of a U.S. submission, the company will begin further clinical evaluation of the drug in combination with currently approved agents such as cisplatin and doxyrubicin. Other potential applications for trimetrexate, Warner-Lambert noted, are in treating opportunistic infections such as toxoplasmosis and Pneumocystis Carinii. In early experimental studies in AIDS patients at NIH, the drug achieved a 70% success rate with patients suffering from pneumocystis carinii when treated in combination with leucovorin, the company said. An IND filing is planned in the near future. Warner-Lambert also noted that two research teams at its Cambridge, England facility are pursuing basic research in the neuropeptide area, with one team focusing on compounds for suppressing appetite, and the other looking at compounds with the ability to produce an analgesic effect as strong as the opiates without their concomitant side effects.
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