Oncology & Endocrine Therapy

Multiple cancers, benign prostatic hyperplasia (BPH) and endometriosis

Preclinical development

Luteinizing hormone-releasing hormone (LHRH) peptidomimetics represent a new class of LHRH antagonists with the potential advantages obtainable from oral administration. A drug based on these substances could be especially useful for the treatment of BPH, breast cancer and prostate carcinoma. Æterna Zentaris’ lead compound, AEZS-115, is a peptidomimetic molecule with good selectivity and stability as well as an excellent safety profile in orienting toxicity and safety pharmacology studies.

A major benefit of LHRH antagonists as opposed to agonists is their immediate, direct action and effectiveness in dose-dependently blocking gonadotropin secretion which allows for a modulated intervention into the release of sex steroids. This avoids the necessity to reach castration levels of sex hormones and leads to far less side effects and considerably better tolerability. 

AEZS-115 decapeptide-like binding mode to the LHRH receptors is similar to that found with the binding of the native LHRH linear decapeptide molecule. Due to this mode of binding and AEZS-115 structure, it exhibits moderate species selectivity and high target selectivity. Furthermore, AEZS-115 promises to have an exceptionally advantageous safety profile and orally bioavailable.

Apart from receptor binding studies and functional reporter gene assays, LHRH antagonism is supported by the inhibition of luteinizing hormone (LH) secretion from vital rat pituitary cells treated with AEZS-115 and stimulated by LHRH. Immediate testosterone suppression in rats was observed after oral application of AEZS-115, confirming the mode of action as well as in vivo studies.

AEZS-115 given once orally in doses of 20mg/kg to male rats, leads to testosterone suppression within 2-4 hours. Testosterone suppression and corresponding plasma levels of AEZS-115 are evident for 8-12 hours. After three consecutive doses of 10mg/kg of AEZS-115 given in 8 hours intervals, plasma levels of testosterone remained suppressed up to 16 hours after the last application. Accumulation of AEZS-115 was not observed after the three dosages. Excellent correlation between testosterone suppression and plasma compound level was shown. In orienting toxicity and safety studies in rats, AEZS-115 was very well tolerated.

Lead candidates are in preclinical development.

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