The Search For Better Endometriosis Treatments Continues

Women’s pain is something that has historically been overlooked, dismissed, and stigmatized. It is an awkward topic and is often avoided. While menstrual pain is accepted as part of being a woman, for some, it can significantly impact quality of life. This is because behind this pain is a serious condition called endometriosis.

Why should we care about endometriosis?

Approximately 10% of women suffer from endometriosis, and for these women, menstrual pain can be much more serious than mild cramping. Endometriosis can also have significant negative effects on fertility, leaving many families unable to have children or making it very difficult and expensive to do so.

Although the numbers reveal how common endometriosis is, it still remains a somewhat little-known disease that is not well studied, and as a result, women with the disease do not have many treatment options.

What is endometriosis?

Endometriosis is a disorder that arises from the endometrium, the tissue that lines the womb, or uterus. The endometrium is where a fertilized egg is implanted and where the placenta develops during pregnancy. Under normal conditions, it thickens every month to prepare for implantation. This thickening occurs in response to increased estrogen, produced by the ovaries to begin the process of ovulation. Ovulation occurs once every month and is the process by which one of the two ovaries releases an egg that travels through the associated fallopian tube (one fallopian tube connects each ovary with the uterus) to the uterus, where it waits to be fertilized. If fertilization does not occur, the endometrium is shed during the process of menstruation.

Endometriosis occurs when endometrial tissue is found outside the uterus in the body cavity (endometrial lesions or attachments), often attached to the outside of the ovaries, bowel, or bladder. Endometrial lesions outside the uterus continue to respond to estrogen, and when estrogen levels increase prior to ovulation, these lesions behave as though they were still in the uterus, by thickening and bleeding. This time though, the blood has nowhere to go and is released into the body cavity.

Although it is debated, the primary cause of endometriosis is thought to be retrograde menstruation, which occurs when instead of exiting the body, menstrual fluid flows backward through the open-ended fallopian tubes into the body cavity, bringing with it endometrial tissue, which attaches to the internal organs and results in endometriosis.

Endometriosis not only causes chronic pain but can have significant effects on fertility. In fact, 30–50% of women with endometriosis are infertile, illustrating the significant impact this disease has on women worldwide.

How is endometriosis diagnosed and treated?

Because pelvic pain is the primary symptom of endometriosis, and pain is extremely difficult to quantify, a definitive diagnosis can take years. In fact, the average time for an endometriosis diagnosis can be over six years. Given the impact of endometriosis on quality of life (endometriosis can significantly affect work productivity) and potential effects on fertility, improving diagnostic methods for this disease is a serious unmet clinical need.

Endometriosis is currently only definitively diagnosed by laparoscopic surgery, a surgical procedure in which a small camera is inserted into the abdomen to visualize internal organs. During this process, endometrial lesions in the body cavity can be removed by a surgeon, by either burning them off or cutting them out. However, this only treats the lesions present at the time of surgery and does not prevent more from forming.

If the diagnosis of endometriosis is difficult, treatment is even more so. Although endometrial attachments can be removed during laparoscopic surgery, continual monthly menstruation will inevitably lead to the development of new endometrial lesions. Therefore, women with endometriosis may have to undergo multiple surgeries to remove lesions that continually arise over time.

With the goal of reducing retrograde menstruation and subsequent development of endometrial lesions, women are often prescribed contraceptives, such as a birth control pill or an intrauterine device, which are thought to both help with pain and reduce menstruation, lowering the chances that further lesions will form. To treat the pain without oral contraceptives, women have few options other than over-the-counter analgesics, such as Motrin® or Advil®. In very severe cases, a hysterectomy (complete surgical removal of the uterus and/or ovaries) may be performed, which effectively removes the endometrium altogether.

However, contraceptives and hysterectomy are not reasonable options for women who would someday like to have children. Contraceptives have incredibly variable effects in individual women and are associated with a myriad of side effects. In extreme cases, even hysterectomy is not a total cure; if endometrial lesions that are present in the body cavity before the procedure are not thoroughly removed, they will still grow, bleed, and cause pain.

So, what now?

The source of endometriosis pain associated is unknown, but is thought to be due to the swelling and bleeding caused by the attachments, which cause localized inflammation. Many of the treatments for endometriosis have focused on removing the lesions (e.g. surgery) or preventing more lesions from forming (e.g. oral contraceptives or hysterectomy). However, there are few treatments, other than over-the-counter painkillers, that relieve the pain from which women with endometriosis suffer.

At the end of July this year, the FDA approved a new drug to treat endometriosis-associated pain, called ORILISSA^TM. ORILISSA was developed by AbbVie in collaboration with Neurocrine Biosciences, Inc. and is also known by its generic name, elagolix. ORILISSA’s effects on endometriosis-associated pain were evaluated in two phase 3 clinical trials that included almost 1,700 women with moderate or severe endometriosis-related pain.

ORILISSA is a gonadotropin-releasing hormone (GnRH) antagonist that targets the hormonal changes that cause endometrial thickening and bleeding, namely, the high estrogen levels prior to ovulation that “feed” the growth of endometrial lesions. The female hormonal cycle is tightly regulated by the cycling of multiple hormones, many of which are produced by different organs. The ovary produces estrogen in response to increased levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are both made by the pituitary gland. LH and FSH levels are in turn stimulated by increased levels of GnRH, which is secreted by the hypothalamus.

ORILISSA targets the first step of this cycle: the release of GnRH. Its behavior as an antagonist means that it blocks GnRH activity by binding to the GnRH receptor and shutting down the cascade of hormones leading to estrogen production.

During the phase 3 clinical trials, which preceded FDA approval, women with moderate to severe endometriosis-associated pain were treated with ORILISSA at two different doses for six months. In just one month, ORILISSA significantly reduced both menstrual pain and non-menstrual pelvic pain and this was sustained over the six months of the study.

In the time since FDA approval of ORILISSA, a number of concerns about the study have surfaced. A July report by the Institute for Clinical and Economic Review (ICER), “an independent and non-partisan research organization that objectively evaluates the clinical and economic value of prescription drugs, medical tests, and other health care and health care delivery innovations,” suggested that ORILISSA may not have the significant health benefit that was advertised. The report stated that “evidence was not adequate to determine whether elagolix offers a net health benefit compared to no treatment, or compared to treatment with either a GnRH agonist (leuprorelin acetate) or a hormonal contraceptive (depot medroxyprogesterone), due to limited and mixed evidence on clinical effectiveness and potential risks.”

These concerns are related to the limited treatment time evaluated in the study (only six months) and the reported side effects, which included hot flushes, increased LDL cholesterol levels (the “bad” cholesterol), as well as bone loss, a symptom of osteoporosis. These are all symptoms of low estrogen levels and mimic menopause, which is simulated with ORILISSA treatment.

Although ORILISSA was the first drug in decades to be approved for endometriosis pain, whether it will be an effective long-term treatment option remains to be seen.

In the same report, the ICER stated, “Patient organizations should band together to seek commitments from government research funding agencies and manufacturers to increase research for common conditions affecting women’s health such as endometriosis.”

Clearly, the need to develop better treatment options for women with endometriosis is great.