Targeted Treatment of PCOS within the Brain

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Targeted treatment of PCOS within the brain

Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome

doi.org/10.1210/clinem/dgab320

Background

Current treatment of PCOS involves the use of hormonal contraceptives, spironolactone, cyclic administration of progesterone and metformin for women presenting with glucose intolerance or type 2 diabetes. These treatments correct the biochemical imbalance of PCOS and improve symptoms but not the central cause of hormonal dysregulation.

Neurokinin 3 (NK3) is a receptor involved in the positive and negative feedback loops of the hypothalamic-pituitary-gondal (HPG) axis. The HPG axis coordinates the release of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, progesterone and androgens.

Previous studies in premenopausal women found that NK3 receptor antagonism (blockers) decreased secretion of LH, lowered LH/FSH ratios and suppressed follicle development. An exploratory study using NK3 antagonist, MLE4901 in women with PCOS, showed a decrease in LH pulse frequency causing a statistically significant reduction in blood (serum) levels of LH and testosterone compared to placebo.

MLE4901 has since been discontinued due with elevated transaminase levels (causing liver disease) found in a small group of women. Fezolinetant is another NK3 antagonist which is structurally different to MLE4901 and shown no effect on transaminase levels to date.

Aim

To evaluate the effects of fezolinetant on the biochemical features of PCOS.

Methodology

In this multicenter placebo controlled trial 72 eligible women were randomly allocated to receive 60mg fezolinetant, 180mg fezolinetant or identical placebo, once a day (after breakfast), for a total of 12 weeks.

PCOS was defined according to the Rotterdam criteria with normal thyroid function, FSH, estradiol, prolactin and 17-hydroxyprogesterone levels required for study eligibility. Women also needed to have a negative cervical cytology (pap smear), negative urine test for drug abuse and negative pregnancy test.

To minimise potential bias in the results women with evidence of diabetes, bariatric or ovarian surgery (within 6 months), hysterectomy or bilateral oophorectomy, Cushing’s syndrome, pelvic inflammatory disease, malignancy, drug allergy or intolerance, liver disease or jaundice, elevated alanine aminotransferase or aspartate aminotransferase levels, elevated total bilirubin or creatine levels, hemoglobin <10g/dL, hepatitis positive, psychological disorder, acute or chronic illness, significant blood loss or transfusion (within 3 months), abnormal ECG (electrocardiogram) and antiandrogen treatment (within 3 months) were excluded from the study.

Assessments were carried out every 3 weeks, up to week 12, with a final follow up visit on week 18.

Primary study outcome was mean change in testosterone, after 12 weeks of treatment. Secondary outcomes of interest were changes in LH, FSH, progesterone and estradiol levels, menstrual cycles, PCOS syndromes and ultrasound parameters (endometrial thickness, ovarian volume, number of follicles/cysts and size of dominant follicle).

Safety assessments were also carried out and various pharmacokinetic parameters measured to monitor the absorption, distribution, metabolism and excretion of fezolinetant from the body.

Results

Of the initial 73 women who began the trial, 64 completed the study (placebo = 26, 60mg fezolinetant = 21, 180mg fezolinetant = 17). Baseline clinical characteristics did not differ significantly other than BMI which was higher in the placebo group (31.2 vs 26.7 vs 26.3).

Analysis of total testosterone levels showed a dose-dependent effect of fezolinetant on the reduction of total testosterone. The change in total testosterone at weeks 3, 6 and 12 was -19%, -14% and -17% with 60mg fezolinetant, and -32%, -31% and -33% with 180mg fezolinetant. Pharmacokinetic analysis suggested the higher concentration of fezolinetant suppressed androgen levels for the entire day.

Similarly fezolinetant also decreased levels of LH (more than FSH), causing a significant dose-dependent decrease in the LH/FSH ratio, compared to placebo, by week 12. Other hormone levels, estradiol and progesterone, did not change in either fezolinetant dosage group.

Interestingly 12 weeks of fezolinetant treatment failed to improve PCOS syndrome questionnaire scores, ultrasound parameters or menstrual cycles.

A slight but statistically insignificant decrease in AMH levels was noted, with a similar trend in ovarian volume, for the 180mg treatment group. The authors suggested this may be an early sign of improved clinical outcomes with longer studies required to confirm.

Safety wise headaches, paresthesia, rash, nausea, nasopharyngitis, superficial thrombophlebitis and depression were recorded as adverse events. The most common of these was headaches and paresthesia occurring in 39.1% and 17.1% of women respectively in the 180mg treatment group.

No change in vital signs, ECG values or bone density markers was seen however a dose-related increase in creatinine was observed in 3.7% of placebo patients, 4.3% of women taking 60mg fezolinetant and 18.2% of women taking 180mg fezolinetant.

SUMMARY: TREATMENT OF PCOS

Neurokinin 3 receptor antagonist (blocker) medication, targets the central cause of hormone dysregulation in women with PCOS, the KNDy neurons within the hypothalamus region of the brain, by decreasing the secretion of LH, improving LH to FSH ratios and reducing total testosterone levels.

Limitations

  1. Small study size and heterogeneity of women with differences in BMI, SHBG, metabolic markers and incidence of oligomenorrhea not adjusted for in the results.
  2. Short trial period (3 instead of 6-9 months) limited clinical outcomes requiring further studies to evaluate the long term benefits of fezolinetant

Funding

This study was sponsored by OGEDA S.A. (Gosselies, Belgium), a wholly owned subsidiary of Astellas Pharma, Inc.

Glossary

Dose-dependent
The response to a drug varies with the quantity administered.

Nasopharyngitis
Common cold (virus) diagnosed by swelling of the nasal passages and back of the throat (pharynx).

Parethesia
A burning or prickling sensation that usually felt in the hands, arms, legs or feet and can also occur in other parts of the body.

Pulse frequency
Number of secretions per a specific unit of time (hour, day).

Receptor
Chemical structures, composed of protein, that receive and transduce signals within a biological system.

Superficial thrombophelbits
Blood clot in the superficial vein just under the skin.

Transaminase
A group of enzymes that catalyze the interconversion of amino acids and oxoacids by transfer of amino groups.

Similar studies

Skorupskaite K, et al. (2020). Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome. https://doi.org/10.1093/humrep/deaa104

Fraser G L, et al. (2016). The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. https://doi.org/10.1210/jc.2015-3621

George J T, et al. (2016). Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. https://doi.org/10.1210/jc.2016-1202

Fraser G L, et al. (2015). The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. https://doi.org/10.1210/en.2015-1409


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