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ABBOTT’s HYTRIN IS SAFE AND EFFECTIVE FOR RELIEF OF SYMPTOMS OF BENIGN PROSTATIC HYPERPLASIA, IMPROVEMENT OF URINARY FLOW RATE -- FDA ADVISORY COMMITTEE

Executive Summary

Abbott's alpha blocker Hytrin (terazosin) is safe and effective for treating symptoms of benign prostatic hyperplasia (BPH) and improving urinary flow rate, FDA's Endocrinologic & Metabolic Drugs Advisory Committee concluded at its March 1 meeting. The advisory committee, along with its invited guests, voted unanimously that the demonstrated improvement in symptom score and urine peak flow rate caused by Hytrin is clinically significant. The committee also concluded from study data that 10 mg Hytrin once-daily is the most effective dose for relieving BPH symptoms and increasing urinary flow rate. Hytrin's BPH NDA (20-223) was filed in December 1991. Abbott Director of Medical Affairs David Pizzuti, MD, presented details of the Hytrin BPH clinical program, which consists of 1,392 patients enrolled in 13 trials including three U.S. double-blind, placebo-controlled studies which were the focus of his presentation. A total of 671 patients were given a once-daily dose of Hytrin or placebo at bedtime in the three U.S. trials. Clinical trials M87-012 and M89-377 were both 24-week, titration-to-response studies, and M87-005 was a 12-week, titration-to-fixed-dose study. The primary efficacy parameters for the three studies were peak urine flow rate and symptom scores based on the Boyarsky symptom questionnaire with scores from 0-27. In study M87-012, patients were titrated up to 2, 5, 10 or 20 mg of terazosin until they reached a predefined response or were sham titrated on placebo. The dose was escalated unless there was a 30% improvement in peak flow rate (PFR) from baseline and some improvement in the symptom score. Symptom scores and peak flow rates were recorded every four weeks. The study randomized 199 men with BPH who were over 40 years old and were normotensive or controlled hypertensives. Of the 175 evaluable patients, 153 completed the trial. The evaluable patients on terazosin "achieved a statistically significantly greater reduction in symptoms compared to the placebo group" with a 5.3 point change on the Boyarsky score, Pizzuti said. "At the very first observation point at four weeks, there was already a statistically significant difference between the terazosin and the placebo group in the degree of change in their symptoms," Pizzuti explained. "This improvement continued and was maintained at approximately between a five and six point mean change throughout the remainder of the 24 weeks of the trial." Looking at the percentage of patients achieving at least a 30% improvement in symptoms, "there was a statistically significantly greater percentage of terazosin patients that achieved this degree of response compared to placebo." As for change in PFR, Pizzuti said, "we see a statistically significantly greater response in the terazosin group corresponding to a mean change of almost 3 ccs" compared to 1.4 ccs per second in the placebo group, which translates into a 35% change for the terazosin group and a 16% change for the placebo group. In the individual visit analysis of PFR, "there appears to be a treatment benefit at approximately eight weeks, which became statistically significant at 16 weeks," he noted. Summarizing results of the three trials, Pizzuti stated that "for all three top trials, the symptoms and peak flow were statistically significantly greater [with terazosin] than seen with placebo." He continued: "With respect to time of onset, again we see evidence of a rapid response particularly for symptoms shown at the first observations at two and four weeks." PFR "varied from six to 16 weeks in terms of the time it took to achieve a statistically significant response," Pizzuti said. With respect to the percentage of patients with at least a 30% improvement, he reported that "approximately two-thirds of the terazosin group [perceived] this degree of response in symptoms and approximately one-half in all three trials [had] this degree of response in peak flow rate." In the meeting agenda, FDA said that "in men with BPH, both symptom scores and maximum flow rates improve more rapidly in the terazosin trials as compared to the finasteride [Merck's Proscar] trials." The agency said: "there was a 1.2 to 1.4 improvement of symptom scores in the finasteride trials versus 1.4 to 3.5 in the terazosin trials, [and] there was a 0.9 to 1.3 increase in peak flow rate in the finasteride trials versus 1.4 to 1.9 in the terazosin trials." In a five-to-two vote with one abstention, the committee and the invited guests concluded that the benefits of Hytrin therapy outweigh the risks. Several committee members were concerned about the increased incidence of some adverse events including dizziness, postural hypotension and asthenia seen in clinical trials in patients receiving Hytrin compared to patients taking placebo. Pizzuti noted that "when we consider the incidence of some of these adverse events, particularly headache and dizziness in the placebo group, the attributable risk is never greater than 5%." Committee member Lewis Kuller, MD, University of Pittsburgh, said: "We have no data really on standing blood pressures and really very little data on large numbers of patients, especially normotensive patients, who have been followed for any length of time, especially for patients who are older -- [who] may have other comorbidity, which, I think, is the place where this drug is going to be widely used." Committee member Ethel Siris, MD, Columbia University, said: "I thought the patients at greater risk were the ones who were hypertensive [and] on other hypertensive therapies. I mean they're the ones most susceptible to hypotensive episodes." Siris voted that the benefits of Hytrin outweigh any risks, but added that "I'd love to see more data." Commenting on the benefit/risk question, committee member Robert Harrison, MD, University of Rochester, said "It seems to me that this whole issue is being blown out of proportion." He added: "I think this is [an] effective drug...and I think that the syncopal episodes are relatively minor." All the committee members and guests agreed that Abbott should follow patients treated with terazosin in the studies for a longer period, such as five years, to determine the outcome of treatment, maintenance of effectiveness and development of complications associated with BPH, such as infection, acute retention, kidney damage, development of prostate cancer and surgical complications. Based on conversations with FDA, Abbott may plan to extend its ongoing four-year study of terazosin's use for BPH out to five years. The study is Abbott's largest long-term, uncontrolled trial and includes 232 patients from the placebo-controlled trials. At the time of NDA filing, there were 484 patients enrolled, of whom 443 were evaluable, Pizzuti said. In December 1992, Abbott submitted to FDA data on patients who had been treated for up to 30 months. Symptom response was maintained over this time and change in peak flow rate stayed "between 2.5 and 3 ml per second." Further data on Hytrin use will also come from a one-year, double-blind study being conducted by the Department of Veterans Affairs that involves 1,200 men receiving one of four therapies: Hytrin, Proscar, a combined Hytrin/Proscar regimen, and placebo. Hytrin relaxes smooth muscle in the prostate and bladder neck and provides quick relief of symptoms, while Proscar inhibits the 5- alpha reductase enzyme and reduces prostate size. Abbott is also sponsoring a one-year study of Hytrin called the Hytrin Community Assessment Trial (HYCAT). The objective of the study is to enroll 2,500 patients, randomize them to Hytrin 10 mg or placebo, and assess symptom score, peak flow and whether the drug therapy is cost effective.
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