New PCOS Treatment Undergoing Clinical Trials

Guest post by Dr. Rashmi Kudesia, MD MSc

Earlier this month, it was reported that Millendo Therapeutics, Inc., a pharmaceutical company focused on endocrine disorders, had obtained the rights to develop and commercialize a compound currently being called MLE4901, for the treatment of polycystic ovary syndrome (PCOS). Though the thought of a novel PCOS treatment is very exciting, let’s examine the current state of this compound.

My first question upon reading this report was: how is this compound supposed to work? PCOS is the most common hormonal disorder among reproductive-aged females, affecting somewhere between 5-15% of women. The hallmarks of the syndrome include irregular or absent ovulation, excess of male hormones (androgens) leading to hair overgrowth and other troublesome symptoms, and a strong association with insulin resistance and metabolic disease, such as type 2 diabetes, heart disease and so forth. To date, treatment options have all focused on managing these individual components, but we have never had a therapy that is truly curative. This is very frustrating for not only fertility patients, who often express their frustration over ovulation induction medications only working for the current menstrual cycle and not “fixing” the fundamental issue, but truly for all PCOS women who struggle with its associated symptoms, especially difficulty losing weight.

Though much remains unknown about PCOS, one of the common hormonal patterns observed in PCOS women is a high level of luteinizing hormone (LH). This hormone, which comes from the pituitary gland in the brain, is stimulated by another part of the brain, the hypothalamus, via a hormone called gonadotropin-releasing hormone (GnRH). A number of previous studies have shown that GnRH seems to be released more frequently and in greater amounts in women that have PCOS, possibly causing the elevated LH levels that drive the excess androgen levels and other symptoms. Though it is not conclusively established that this pattern is the root cause of PCOS for all women, it would stand to reason that normalizing GnRH release could also balance other hormone levels and perhaps treat PCOS! And, indeed, MLE4901 is designed to decrease GnRH (and LH) levels by reducing the frequency of secretion. It does this by blocking (or antagonizing) a receptor for a protein known as neurokinin 3 (NK3). NK3 antagonists were initially undergoing trials as treatment for schizophrenia, when the potential connection to human reproduction through GnRH was discovered.

So, next question: what has this compound been shown to do so far? Well, it was originally developed by another, much larger pharmaceutical company, AstraZeneca, as compound AZD4901. In the development of new potential medications, once a compound shows promise in non-human research, there are typically three phases of trials that are undertaken before a drug is approved. Phase I studies are small studies on healthy volunteers to explore the safety of a drug. Once it has been shown to be safe in this initial testing, one can move on to Phase II. A Phase IIa study, such as the one done by AstraZeneca, tries to establish the drug’s efficacy when compared to placebo and to assess what the appropriate dose might be. The AZD4901 Phase IIa study included 65 women, aged 18-40, with PCOS. Each participant was randomly assigned to one of four different groups – one group that received only placebo (no active compound) and three treatment groups (increasing doses of compound). The study was double-blinded, meaning that neither the participants nor the researchers knew which regimen any participant was on until after all the data had been collected.

The primary outcome of the study was to look at the ratio of LH concentrations after 7 days of treatment, compared to baseline. So, if the LH levels went down after taking this compound, the ratio would be less than 1. The placebo and lower two treatment doses showed no significant difference from baseline to day 7. The third arm, though, with 40mg AZD4901 twice daily, demonstrated a statistically significant 46.4% decrease in the LH concentration. To say it was “statistically significant” essentially means that the study indicated that with this dose, there appeared to be a decrease in LH that was unlikely to be due to chance. The study also looked at testosterone levels, and though this data has not been made available in the NIH Clinical Trials Registry, the press reports on MLE4901 report that testosterone levels were also decreased. In the whole group, only one participant was reported to have a serious adverse event, appendicitis, which may well have been unrelated to the compound. A variety of other non-serious adverse events were reported.

So, what’s next? To move this compound forward, Millendo will need to conduct Phase III trials, which will include larger groups of women over a longer period of time, with more clinically-relevant outcomes. This trial will help to establish whether MLE4901 will actually hold any treatment potential. In other words, it will address the question of whether the same decrease in LH and testosterone levels are seen when the compound is tested in larger, more diverse, groups of women. Other questions the trial would presumably attempt to address would include: whether those levels stay low over an extended treatment period, whether women stick to this regimen over time without significant side effects and whether there are measurable improvements in either self-reported or measured signs and symptoms of PCOS. Unfortunately, many drugs that seem promising in Phase II don’t end up making the cut in Phase III testing. Nonetheless, to try and treat PCOS as an entire condition, rather than just chipping away at its manifestations, is a whole new way of thinking, and one with hopefully a lot of promise. We’ll certainly be looking out for these results, with fingers crossed!

*Dr. Kudesia is not involved in any manner with the research study associated with the development of MLE4901 nor has she any affiliation with AstraZeneca.

Dr. Kudesia is a board-certified Reproductive Endocrinology and Infertility specialist, practicing at Houston IVF in Houston, Texas. She joined Houston IVF in 2018 after practicing in New York City, where she was named a “New York Super Doctors Rising Star” in 2016 and 2017.

After completing her Baccalaureate degree in Biology & Medicine magna cum laude from Brown University, she received her M.D. with honors from the Duke University School of Medicine, where she was selected into a clinical research training program co-sponsored by the National Institutes of Health. Her residency training in Obstetrics & Gynecology at the New York Hospital-Weill Cornell Medical Center was followed by subspecialty training in Reproductive Endocrinology and Infertility (REI) at the Albert Einstein College of Medicine-Montefiore Medical Center, alongside a Masters’ of Science degree in Clinical Research Methods. She subsequently served as a Clinical Assistant Professor at the Icahn School of Medicine at Mount Sinai, as well as the Research Rotational Director for the REI fellowship, and Medical Director of the Brooklyn office of the Reproductive Medicine Associates of New York.

Dr. Kudesia is a Fellow of the American College of Obstetricians and Gynecologists, and an active member of the American Society for Reproductive Medicine (ASRM), Society for Reproductive Endocrinology and Infertility, Androgen Excess & Polycystic Ovary Syndrome Society, and American Medical Association (AMA). She has served in multiple local and national leadership roles in organized medicine, including her current positions as Secretary of the ASRM Women’s Council Executive Board and the ASRM delegate to the AMA Young Physicians’ Section.

Dr. Kudesia has also presented scientific research at national and international conferences, and has received multiple awards and grants for her work. She has published peer-reviewed articles and book chapters, including in leading journals such as Fertility & Sterility and the American Journal of Obstetrics & Gynecology, as well as editing a theme issue on reproductive medicine for the American Medical Association Journal of Ethics. Her current areas of focus include improving in vitro fertilization cycle prognosis, polycystic ovary syndrome, LGBT fertility, and fertility awareness, counseling, and access to care. She actively promotes women’s health and wellness on social media via Twitter, Facebook, and Instagram.