MERCK AND ABBOTT TO CO-SPONSOR PROSCAR/HYTRIN COMBINATION TRIAL; PROSCAR PHASE III RESULTS SHOW "SOME" SYMPTOM IMPROVEMENT IN 70% OF PATIENTS

Merck and Abbott have agreed to co-sponsor a study measuring the efficacy of combination Hytrin/Proscar therapy for the treatment of benign prostatic hyperplasia, clinical researcher Herbert Lepor, MD, Medical College of Wisconsin, announced at a June 1 session of the American Urological Association's annual meeting in Toronto. The combination study, which will be conducted by the Department of Veterans Affairs, will enroll 1,200 patients at 30 V-A medical centers. The randomized, placebo-controlled comparison study will include four arms: Proscar (finasteride) alone, Hytrin (terazosin) alone, a combined Proscar/Hytrin regimen, and placebo. The protocol for the study is still awaiting V-A approval, Lepor reported. The possibility of using the two BPH therapies in combination was raised last year by Merck Chairman and CEO Roy Vagelos at a meeting with analysts last winter ("The Pink Sheet" Nov. 19, p. 8). Vagelos suggested that Proscar and Hytrin might complement each other since Proscar is intended to treat the underlying causes of prostate disease, while alpha blockers like Hytrin alleviate symptoms. "If an alpha blocker is doing some good and can be well tolerated, it would be taken along with Proscar," Vagelos predicted. Once approved, Merck's Proscar and Abbott's Hytrin will be competing not only against each other but against transurethral prostate surgery, which is currently about 90% effective in curing BPH. Single agent drug therapy appears to be effective in improving BPH symptoms in about three-fourths of patients in clinical trials. Given the high recovery rate with surgery and the anticipated resistance to pharmaceutical approaches for BPH by urologists, showing an additive efficacy effect with the concomitant regimen would help the drug companies make a good case for pharmaceutical treatment. The V-A study also will provide the two firms with their first opportunity for a head-to-head comparison of Proscar and Hytrin. Phase III data presented at the convention by Abbott and Merck appear to indicate that patients receiving the optimal dose of Hytrin experienced greater overall improvement in urine flow and symptom score than patients enrolled in the study of Merck's 5- alpha reductase inhibitor Proscar. However, researchers and consultants for both firms noted that differences in the design of the Hytrin and Proscar trials make it very difficult to compare the two drugs' relative efficacy. "Many people will be tempted to compare these two drugs, and I would warn that that is not a good thing to do," cautioned John McConnell, associate professor of urology at the University of Texas. "They have different baseline evaluations, exclusion criteria, and different patient populations." Speaking before the convention's first plenary session on June 2, Elizabeth Stoner, MD, head of Merck's Proscar development project, reported that over 70% of the patients receiving 5 mg of Proscar in Phase III trials experienced "at least some improvement in clinical symptoms...... [and] 33% of all patients had an excellent clinical response." A total of 1,645 patients were enrolled in Merck's year-long, international Phase III study. After a placebo run-in, patients in the study were randomized into one of three treatment arms: a placebo control arm with 555 patients: a 1 mg a day Proscar arm with 547 patients; and a 5 mg daily Proscar arm with 543 patients. The study monitored reduction in prostate size and overall improvements in urine flow and general symptoms for 12 months. An NDA based on the trial results was submitted to FDA on April 15 ("The Pink Sheet" April 22, T&G-2). Merck's presentation to the urologists focused on the 5 mg arm of the study, which is the dose awaiting FDA approval. In that patient group, about one-half of the patients experienced a reduction in prostate size of 20% or more. One-third of the patients receiving 5 mg Proscar had an increase in urine flow of 3 cc per second or greater and 57% had an increase of 1 cc or more. Mean improvement in urinary flow was approximately 20-35%, increasing from a baseline flow of 8-9 cc per second to a trial- end flow of 11-12 cc per second. Clinical trials with alpha blockers have demonstrated 30-45% increases in mean urine flow after only two months of therapy. However, Merck downplayed the limited symptomatic improvement with Proscar, noting that reduction in "urine flow and symptom relief was not [the Proscar study's] goal." Stoner said that Proscar "is really targeted to address the underlying mechanism of the disease, and not to improve the urinary flow rates over the short-term." Proscar's success in reducing prostate size an average of 20% per patient, stemming from the drug's ability to suppress the hormone dihydrotestosterone (DHT), led Stoner to hypothesize that Proscar will be effective not only at treating the symptoms of mild-to-moderate BPH, but may also play a role in actually "reversing the natural history of the disease." At a June 1 symposium sponsored by Abbott, Lepor presented the results of his recently completed Phase III study of Hytrin. The three-month, multicenter, randomized trial involved 313 patients with mild-to-moderate BPH at 12 treatment centers. After a placebo run-in, patients were randomized into four treatment arms consisting of a placebo group and active control groups receiving 2 mg, 5 mg, or 10 mg of Hytrin daily. Patients receiving 10 mg of Hytrin daily experienced a 41% increase in urine flow, compared to 9% in the placebo group, and a 79% increase in total symptom score improvement, compared to 38% in the placebo group. Merck consultant Roger Kirby, MD, St. Bartholomew's Hospital in London, pointed out at a Merck press briefing for Proscar that the Abbott study provided no long-term data on the continued efficacy of Hytrin. Historically, he maintained, "most alpha blockers will give you about a 30% flow rate improvement within the first few days of starting, but the problem is, because of the side-effect profile, patients don't want to take the drug long term." Long-term alpha blocker therapy for BPH has been associated with a relatively high incidence of asthenia and dizziness. Lepor noted that there was a "statistically insignificant but growing" trend towards these side-effects in the Abbott trial. A randomized, well-controlled trial of the drug's long-term efficacy has not yet been conducted, but Abbott says plans for a follow-up trial are now in the works. Hytrin is already commercially available for the treatment of hypertension. A supplemental NDA filing based on the BPH clinical trials is expected to be submitted in early 1992. Pfizer is also planning to file a BPH indication for its alpha blocker antihypertensive Cardura (prazosin). Phase III clinical trial data from the Cardura trials were not available for presentation at the AUA convention, but Pfizer says it remains on track for a late 1992 filing. Pfizer said it currently has no plans for studying Cardura in combination with other BPH drugs.