Aeterna Zentaris Inc. (TSX: AEZ; NASDAQ: AEZS) today disclosed additional positive top line Phase 1 results for its cytotoxic conjugate AN-152 in patients with gynaecological and breast cancers. Further data showed the compound?s good safety profile and established the maximum tolerated dose (MTD) at 267 mg/m? which will be the recommended dose for a Phase 2 trial. In addition to good safety data, the trial provided a hint of efficacy as disease stabilization and regression of lesions were observed at the 160 mg/m? and 267 mg/m? dose levels.
Dr. J?rgen Engel, Executive Vice President, Global R&D and Chief Operating Officer at Aeterna Zentaris, stated, “This additional data provides further proof of concept that the chemical linkage of doxorubicin and the luteinizing hormone-releasing hormone part of the drug molecule is stable in human blood. Most importantly, we witnessed a good safety profile and a hint of efficacy enabling us to establish a suitable dose for further development of AN-152 in the treatment of various cancers.”
Gilles Gagnon, President and Chief Executive Officer at Aeterna Zentaris added, “We are very pleased and now even more encouraged with the latest Phase 1 results for AN-152 which lend further credibility to our very promising oncology platform. By targeting patients suffering from ovarian and endometrial cancer with confirmed LHRH receptor status, we believe we may increase our chances of success for our Phase 2 program in these indications. This targeted approach is an additional example of personalized therapy which is becoming more and more the way of the future.”
About the AN-152 Phase 1 Trial in Gynaecological and Breast Cancers
This ongoing Phase 1 open-label, multi-center, dose-escalation, safety and pharmacokinetic study conducted in Europe, includes 17 patients suffering from breast, endometrial and ovarian cancers with proven luteinizing hormone-releasing hormone (LHRH) receptor status. Patients were administered AN 152 by intravenous infusion over two hours at dosages of 10, 20, 40, 80, 160 and 267 mg/m?. Patients received at least two treatment courses, 21 days apart.
Results
Dose escalation was stopped at 267 mg/m? , which is equimolar to a doxorubicin dose of 77 mg/m?, and declared as maximum tolerated dose (MTD) due to dose-limiting although rapidly reversible hematoxicity (CTC grade 4 leucocytopenia/neutropenia) in two out of six patients. Pharmacokinetic (PK) analyses showed dose-dependent plasma levels of AN-152 and only minor (10%-30%) release of doxorubicin. One complete response (TBC by forthcoming CT scan) and two stable disease out of six patients at the 160 mg/m? dose level were reported, while at the 267 mg/ m? dose level, one partial response and three stable disease were observed from this group of seven patients.
Conclusion
Infusion of AN 152 is well tolerated in female patients. Disease stabilization and regression of lesions are promising signals for therapeutic activity of the cytotoxic LHRH analog, most probably through receptor-mediated uptake by tumor tissue. Because of the rapid reversibility of the potentially dose-limiting hematoxicity even in patients with multiple prior therapies, the dose of 267 mg/m? is going to be recommended for Phase 2 trials with ovarian and endometrial cancer as targeted indications. Ovarian and endometrial cancers are two forms of cancer where LHRH receptors are highly expressed.
Background
Human breast, endometrial and ovarian cancers commonly express receptors for luteinizing hormone-releasing hormone (LHRH-R). High-affinity binding sites for LHRH are found in 52% of human breast cancers, as well as in 80% of human ovarian and endometrial cancers. LHRH-R can be used for targeted chemotherapy with AN 152, in which doxorubicin is linked to [D-Lys(6)]-LHRH. Safety pharmacology and toxicity studies in mice, rats and dogs demonstrated a significantly reduced cardiotoxic potential of AN-152 compared with doxorubicin, e.g. no QT prolongation, myocarditis or fibrosis in the appropriate models. The Phase 1study assessed dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of AN-152 given once every three weeks in patients with gynaecological and breast cancers.
About Cytotoxic Conjugate AN-152
Targeted cytotoxic peptide conjugates are hybrid molecules composed of a synthetic peptide carrier and a well-known cytotoxic product. The design of these products allows for the specific binding and selective uptake of the cytotoxic conjugates by the LHRH receptor-positive tumors. The binding of cytotoxic conjugates to cancerous cells that express these receptors results in an accumulation of the antiproliferative agent in the malignant tissue. This binding is followed by internalization and retention of the cytotoxic drug in the cells. Therefore, since they target specific cells, cytotoxic conjugates are much less toxic, have less side-effects and are more effective in vivo than the respective radicals in inhibiting tumor growth.
About Aeterna Zentaris Inc.
Aeterna Zentaris Inc. is a growing global biopharmaceutical company focused on endocrine therapy and oncology, with proven expertise in drug discovery, development and commercialization.