A Novel Aromatase Inhibitor, Leflutrozole, for Treatment of Non-Obstructive Azoospermia

Non-obstructive azoospermia (NOA) is the most severe form of male factor infertility and reflects a profound impairment of spermatogenesis. Men with NOA typically require surgical sperm retrieval procedures, such as testicular sperm aspiration (TESA), testicular sperm extraction (TESE), or micro-TESE, followed by intracytoplasmic sperm injection (ICSI). Even with surgical retrieval, sperm recovery rates remain limited and live birth rates are modest. At present, no pharmacological treatments are approved for male infertility, underscoring a substantial unmet clinical need.

Aromatase inhibitors reduce the conversion of testosterone to estradiol by inhibiting the CYP19A1 enzyme, thereby increasing the testosterone-to-estradiol ratio and stimulating gonadotropin secretion. Letrozole and anastrozole have been used off-label in infertile men, including selected patients with NOA, with small studies demonstrating that aromatase inhibition may induce the appearance of spermatozoa in the ejaculate. Leflutrozole is a novel, non-steroidal aromatase inhibitor and a derivative of letrozole with an extended half-life, allowing once-weekly oral dosing at substantially lower doses than conventional daily aromatase inhibitor regimens. Previous clinical studies in men with obesity-associated functional hypogonadism have demonstrated that once-weekly leflutrozole improves serum testosterone concentrations and semen parameters with an acceptable safety profile.

The NOVA-NOA trial is a single-center, prospective, interventional study designed to evaluate the efficacy and safety of leflutrozole in men with non-obstructive azoospermia. The study investigates whether 20 weeks of treatment with oral leflutrozole 0.3 mg administered once weekly can induce the presence of spermatozoa in the ejaculate and thereby potentially reduce the need for surgical sperm retrieval.

Following informed consent and confirmation of azoospermia at screening and baseline, eligible participants receive oral leflutrozole 0.3 mg once weekly for a total treatment duration of 20 weeks. Semen samples are collected prior to treatment and during therapy at predefined visits (Weeks 12, 16, and 20) to evaluate spermatogenic response. If spermatozoa are identified in any semen sample during treatment, participants are offered repeat semen sampling and referral to a fertility clinic for cryopreservation according to standard clinical practice. Participants continue study treatment until Week 20 irrespective of early detection of spermatozoa.

Blood and urine samples are collected longitudinally to characterize changes in reproductive hormones, metabolic parameters, mineral homeostasis, bone turnover markers, and circulating concentrations of leflutrozole. Seminal fluid is additionally analyzed for leflutrozole concentrations when sufficient ejaculate volume permits. These assessments are intended to describe the endocrine and systemic effects of sustained aromatase inhibition in men with NOA and to support mechanistic interpretation of any spermatogenic response.

Safety is evaluated throughout the study using repeated clinical assessments, laboratory monitoring, and systematic recording of adverse events. Key safety measures include monitoring of hematocrit, hemoglobin, prostate-specific antigen, liver biochemistry, and cardiovascular parameters. Participants are followed until Week 24 for on-site safety assessments, corresponding to more than five half-lives of the investigational medicinal product, and complete an additional safety and pregnancy outcome follow-up by telephone at Week 36.

Statistical analyses are conducted on an intention-to-treat basis. The primary efficacy analysis evaluates whether treatment with leflutrozole induces the presence of spermatozoa in the ejaculate, using an exact binomial testing framework under the assumption that untreated men with NOA would not spontaneously develop spermatozoa during the observation period. Secondary analyses describe within-participant changes in hormonal, metabolic, and exploratory semen parameters over time.

The overall objective of the NOVA-NOA trial is to determine whether, once-weekly leflutrozole administered without concomitant medication can induce spermatogenesis sufficient for the appearance of spermatozoa in the ejaculate of men with non-obstructive azoospermia, thereby offering a potential non-surgical pathway to biological fatherhood for a subset of this patient population.

• Change in serum reproductive hormones [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in seminal fluid reproductive biomarkers [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in reproductive hormone ratios [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in body mass index [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in glycemic and insulin resistance markers [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in lipid profile [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in hematocrit [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in markers of bone turnover [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in urinary mineral homeostasis [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in serum mineral homeostasis [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in seminal fluid mineral concentrations [Time frame: Change from baseline to week 20 (end-of-treatment)]
• Change in calciotropic hormones [Time frame: Change from baseline to week 20 (end-of-treatment)]