By Eliana Kosova
For some, finding the right medication to treat their medical condition is as simple as consulting a doctor and picking up a prescription. For many others, it’s a waiting game. Unfortunately, for those with uterine fibroids, the situation is more often the latter than the former.
Although anywhere from 20 to 80 percent of U.S. women will develop fibroids by the time they reach age 50, no medication to treat uterine fibroids has ever been approved by the U.S. Food and Drug Administration (FDA). This lack of approved medication is in no way due to a lack of demand for less-invasive uterine fibroids treatments. So, when the pharmaceutical company Allergan submitted its uterine fibroids drug, Esmya, for FDA review, it sparked a new sense of hope. The NWHN has been tracking Esmya every step of the way, and is eager to provide accurate information about the drug, even as unexpected complications began to emerge among Esyma’s users.
First, some background. Uterine fibroids are tumors found within the uterine walls, often resulting in a change to the uterus’ size and/or shape. Fibroids are made of muscle and fibrous tissue and vary in size from as small as a pea to as large as a melon. It is important to note that the presence of fibroids does not increase the risk of developing uterine cancer later on. In fact, fewer than 1 in 1,000 cases of fibroids are cancerous.
Research shows that there are different factors that increase the risk of developing fibroids. Women who are around age 30 to 50; have a family history of fibroids; are obese; are taking hormonal medication; or have experienced early menstruation are more likely to develop fibroids. When it comes to race, women of African or Caribbean descent are more likely to develop fibroids than women of other races and ethnicities. Other factors can decrease the risk; women who have had children or who consume a diet rich in green vegetables and fruit (rather than large amounts of beef and pork) have lower risks of developing fibroids.
Currently, surgery is the only treatment for uterine fibroids. Some surgical procedures target the fibroids themselves: myomectomy, myolysis, and uterine artery embolization. A myomectomy is a surgery in which fibroids are removed through the vagina and cervix, small incisions in the abdomen, or open abdominal surgery. By contrast, both myolysis and uterine artery embolization first shrink and then destroy fibroids. The myolysis procedure utilizes medications that affect the production of sex hormones, Gn-RH agonists, while uterine artery embolization cuts off the fibroids’ access to the blood supply.
Other procedures, such as endometrial ablation and hysterectomy, are even more invasive, directly impact fertility, and prevent patients from being able to conceive. Endometrial ablation is the removal of the uterine lining in order to control abnormal bleeding. Around half of the women who undergo this surgery stop menstruating, while another third have much lighter bleeding. Hysterectomy is the total removal of the uterus.
Patients who do not want to have surgery can manage the pain and bleeding that often occur from fibroids. Options include overthe-counter pain relievers, such as ibuprofen and aspirin; low-dose or progesterone-like birth control methods, to control bleeding; iron supplements, to help prevent anemia associated with heavy bleeding; and tranexamic acid, a non-hormonal medication that eases menstrual periods and should only be used on heavy bleeding days. Unfortunately, these non-invasive methods may not provide patients with long-term relief.
Esmya & Other Treatments
Recently, however, there has been a surge in the development of new uterine fibroid medications to help patients manage and treat the condition. In addition to Allergan, other pharmaceutical companies are working on drugs, as well. Bayer’s drug vilaprisan, a selective progesterone receptor modulator, is currently in Phase III trials. (Phase III trials test a new treatment alongside of a treatment that is currently in use.) Abbvie’s drug elagolix, an oral gonadotropin-releasing hormone receptor antagonist, is simultaneously in Phase III trials for treating uterine fibroids and pending FDA approval for treating endometriosis.
Allergan’s Esmya, or ulipristal acetate, is the first of these medications to be evaluated by the FDA for the treatment of uterine fibroids. Esmya 5 mg was approved by the European Medical Association (EMA) in 2012 for short-term, preoperative use, and again in 2015 for longer-term, intermittent use among patients not seeking surgery. In August, the FDA rejected the application for Esmya’s use to treat uterine fibroids, citing safety concerns about Esmya’s use in other countries.
Esmya, like other selective progesterone receptor modulators, works by blocking the progesterone receptors that are located within the uterus and throughout the human body. Progesterone is a hormone released by the ovaries that helps regulate the growth of the lining of the womb (the endometrium). In some cases, uterine fibroids can be spurred by higher levels of progesterone. When the progesterone receptor is blocked, fibroids that have previously been “fed” by progesterone start to shrink. In many women, fibroids’ related side effects, such as heavy menstrual bleeding and pelvic discomfort, also diminish.
In Europe and the U.S., two major studies have been conducted to determine Esmya’s efficacy. A European series of trials called the PGL4001 (Ulipristal Acetate) Efficacy Assessment in Reduction of Symptoms Due to Uterine Leiomyomata (PEARL) trials used a double-blind, randomized study model (the gold standard in clinical trials) to assess Esmya’s impact. PEARL 1 and PEARL 2 demonstrated Esmya’s efficacy when compared to a placebo, and highlighted its fewer side effects in comparison to leuprolide acetate, a synthetic gonadotropinreleasing hormone that has been used preoperatively in uterine fibroids patients. The subsequent trials, PEARL 3 and PEARL 4, explored the safety of Esmya for repeated use. The PEARL studies also revealed that patients taking Esmya experienced some uncommon, non-life-threatening side effects, such as drug hypersensitivity. The EMA used these trials to evaluate and approve Esmya for short-term and long-term use in Europe.
Allergan also gave the FDA access to data from the VENUS trials, another set of double-blind randomized trials of Esmya’s safety and efficacy. The VENUS studies have been completed, but the detailed findings have not been released to the public.
Recently, however, cases of Esmya patients suffering from post-treatment liver damage have begun to surface. So far, eight women have reportedly suffered serious liver damage, four of whom had to have a liver transplant. In light of these complications, the EMA launched an investigation into Esmya and its potential health risks. On May 18, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) issued a statement concluding that “Esmya may have contributed to the development of some cases of serious liver injury.” PRAC also issued a number of precautionary recommendations intended to protect patients from liver injury, including a warning to patients with liver problems not to use Esmya, and the implementation of regular checks on the liver health of patients currently taking the drug. Since then, the EMA’s Committee for Medicinal Products for Human Use (CHMP) has endorsed these guidelines, and sent them to the European Commission to be finalized legally.
After the EMA investigation began, the FDA adjusted its own review process in order to spend more time assessing the drug’s approval. That assessment concluded with the FDA deciding that the agency would not approve Esmya at this time, due to safety concerns. Although Allergen has stated that it will work with the FDA to address safety concerns, the company recently sold off its women’s products division. Allergen may, in fact, be abandoning Esmya. For now at least, Esmya won’t be an option for U.S. women.
Despite these setbacks, the NWHN is encouraged by the number of companies investing in the creation of medications for uterine fibroids. Each new development brings researchers one step closer to a potential solution, and brings patients one step closer to receiving the care they deserve. There is no doubt that patients’ access to different varieties of treatment is crucial. This variety must never come at the expense of safety, however. We must continue to critically examine emerging uterine fibroids medications so that we can empower patients with the information they need to make the best decisions about their own health.
Eliana Kosova is a former Policy Fellow who worked predominantly on the Challenging Dangerous Drugs and Devices Campaign during her time at the NWHN.
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