AEterna Zentaris Inc. today reported Phase 3 results for its North American efficacy trial Z-033 and the safety trial Z-041 in benign prostatic hyperplasia (BPH), with its lead endocrinology compound for urology, cetrorelix pamoate. As announced on March 6, 2009, sanofi-aventis U.S. LLC entered into an agreement with AEterna Zentaris for the development, registration and marketing of cetrorelix in BPH for the U.S. market.
Study Z-033
The first multi-center efficacy trial Z-033 was conducted in 53 sites in the United States and Canada, with 8 additional sites in Europe. The study involved 667 patients under the supervision of lead investigator, Herbert Lepor, M.D., Professor and Chairman, Department of Urology, at NYU School of Medicine, New York. Patients entered a 1- to 4-week screening period to confirm severity and stability of voiding symptoms based on the International Prostate Symptom Score (IPSS). Patients were then randomly allocated to cetrorelix or placebo in a double-blind fashion. Patients were administered cetrorelix by intra-muscular (IM) injection at Week 0, 2, 26 and 28 (for treatment Arm A, those in Arm B received IM injection at week 0, 2 and 26 followed by placebo at Week 28). Patients in treatment Arm C received placebo injections at Week 0, 2, 26 and 28. All patients were followed up to Week 52.
The study Z-033 demonstrated no clear differences in overall efficacy with all 3 groups showing an improvement in IPSS of approximately 4 points that was maintained throughout the 52 weeks. There was a slight advantage in favor of the main active treatment arm (Arm A) up to Week 46 of the follow-up, which was no longer demonstrated at Week 52. These differences did not achieve statistical significance. Furthermore, a favorable trend on the IPSS, as compared to placebo, was seen in a sub-group of patients with large prostate glands (greater than 50 cm3) on entry to the study.
Tolerability of cetrorelix in study Z-033 was very good, as evidenced by the absence of major differences to placebo with regard to both clinical adverse events or changes in laboratory parameters. The most frequently reported adverse experiences included hot flushes, nasopharyngitis, injection site pain, and headache, which is what was seen in the safety study Z-041. In particular, the incidence of hot flushes was lower than was seen in study Z-041 (see below), and they were also reported by patients randomized to placebo.
Study Z-041
In the safety study Z-041, all patients received cetrorelix by intra-muscular (IM) injection at Weeks 0 and 2, and were followed up to Week 26. The primary endpoint was the incidence of possibly drug-related adverse events; efficacy parameters were evaluated as secondary endpoints. The study was conducted in 68 sites in the United States and Canada.
Cetrorelix was generally well tolerated. Adverse events were mostly mild and transient in intensity. Serious adverse events occurred in 12 patients, but none of these was assessed as possibly drug-related. The most frequently reported adverse experiences included hot flushes, nasopharyngitis, injections site pain, and headache. Hot flushes were reported by 49 patients and were mild and of short duration in the majority of patients. Only one patient experienced a severe episode. A questionnaire was used to assess the local tolerance of the IM injection and affirmed the acceptability of this route of administration.
Efficacy was assessed using the IPSS which showed an improvement from a mean score of 21.2 at baseline to 15.6 at Week 26. In 63% of the patients, the improvement was by at least 3 points. Notably, the 46% of patients who had received previous treatment for BPH showed an important mean improvement of 5 points, which is only slightly less than the 6 point improvement seen in treatment-naive patients. Maximum uroflow improved by 25%, from 10.3 to 12.5 ml/sec, and also the mean uroflow showed similar improvement.
Juergen Engel, Ph.D., AEterna Zentaris President and CEO stated, "Although the data received for the open-label safety study Z-041 with a nearly 6 point reduction in IPSS are in line with what we had observed in our Phase 2 program, we are disappointed by the failure to achieve the primary endpoint in the efficacy study Z-033. We remain committed to the ongoing Phase 3 program with cetrorelix in BPH and are working towards receiving the results of the second pivotal efficacy study Z-036 in November."
Herbert Lepor, M.D., Professor and Chairman, Department of Urology, at NYU School of Medicine, New York and Lead Investigator of the Z-033 trial added, "These findings are unexpected in light of the previous Phase 2 experience. Those data and the strength of the safety data available to date had given us confidence in this potential new treatment for BPH. It is now important to await results of the other placebo-controlled efficacy study Z-036."
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