On November 14th, at the 47th American Association of Gynecologic Laparoscopists (AAGL) Global Congress on Minimally Invasive Gynecology in Las Vegas, Chicago-based AbbVie and Neurocrine Biosciences presented for the first time, additional results from two replicate pivotal Phase 3 clinical trials evaluating the efficacy and safety of elagolix in women with uterine fibroids.
The approval of elagolix in July by the FDA – to be sold as Orilissa for a list price of $845 per month – was a significant step forward for AbbVie, since it provides women suffering from endometriosis with the first new drug in 10 years.
What are fibroids and their symptoms?
Fibroids are muscular tumors, usually located in the wall of the uterus (womb). Another medical term for fibroids is leiomyoma or just “myoma”. Rarely cancerous (benign), fibroids can develop as a single tumor, or there can be more of them in the uterus. As is the case with foetuses during a pregnancy, fibroids are compared to fruits, to create an image of how big they are. Dimensions vary from as small as an apple seed or as big as a grapefruit, but there have been cases of very large, watermelon sized tumors.
Most women who have fibroids do not experience any symptoms, but some of them can have really serious ones:
- Bleeding, sometimes heavy enough to cause anemia or painful periods
- A very heavy feeling lower stomach area
- Enlargement of the lower abdomen
- Frequent urination
- Pain during sex
- Lower back pain
- Complications during pregnancy and labor, including a six-time greater risk of cesarean section
- Reproductive problems, such as infertility, is very rare, but can occur due to the position of the fibroids (blocking the fallopian tubes or preventing the embryo from attaching itself to the womb wall, etc)
According to the Office on Women’s Health’s estimates, between 20 and 80 percent of all women will have fibroid tumors by the time they turn 50. Despite these huge numbers, many women don’t know anything about fibroids. Even worse, since symptoms are related to the menstrual cycle, most women tend not to discuss symptoms, perpetuated as “normal” through generations.
What treatments are available?
There are distinct ways to deal with fibroids, once women find out they have them. In the case of no symptoms, treatment might not be needed, but the doctor will check any growth during regular exams.
If symptoms are present, treatment will be decided depending on their severity and impact on the woman’s quality of life, and especially on whether she wants to have children.
For mild symptoms associated with fibroids, the physician might suggest taking medication. Mild pain can be controlled with over-the-counter drugs such as ibuprofen or acetaminophen. In the case of heavy bleeding during periods, an iron supplement can prevent anemia or correct it if the patient has already lost too much blood.
Drugs that could be used to deal with fibroid related symptoms are usually taken for birth control. Low-dose birth control pills and progesterone-like injections (e.g., Depo-Provera®) do not make fibroids grow and can help control heavy bleeding. An IUD (intrauterine device) called Mirena® can be used to control heavy bleeding.
Other drugs used to treat fibroids are “gonadotropin releasing hormone agonists” (GnRHa), such as Lupron®. Sometimes they are used before surgery to make fibroids shrink, so they are easier to remove. Side effects include hot flashes, depression, difficulty sleeping, decreased sex drive, and joint pain. GnRHas can cause bone mineral loss, so their use is generally limited to six months or less. These drugs are very expensive, and certain insurers will only cover them partially, if at all.
Myomectomy – Fibroids are removed without taking out the healthy tissue of the uterus, a method used in women who want to have children.
Hysterectomy – The uterus is removed, so having children is no longer possible. This type of surgery is the only way to completely cure uterine fibroids.
Endometrial ablation – The lining of the uterus is removed or destroyed to control very heavy bleeding. Results are good, but the woman can’t have children.
Myolysis – A laparoscopy guided needle is inserted into the fibroids, and electric current or freezing is used to destroy them.
Uterine Fibroid Embolization (UFE) or Uterine Artery Embolization (UAE) – a thin tube is inserted into the blood vessels which feed the fibroid, making it possible for tiny plastic or gel particles to be injected into them, thereby blocking the blood supply to the fibroid and shrinking it.
Almost 800 premenopausal women with heavy menstrual bleeding associated with uterine fibroids were evaluated in two pivotal studies at approximately 100 sites in the United States and Canada, during the elagolix Phase 3 uterine fibroid program. For six months, the replicate studies measured safety, tolerability and efficacy of elagolix alone (300 mg twice daily) and in combination with low-dose hormone (add-back) therapy (estradiol 1.0 mg / norethindrone acetate 0.5 mg) in women with uterine fibroids.
How did Abbvie’s new drug affect symptoms?
Over the next six months the drug and placebo, respectively, were administered, results demonstrated that elagolix (300 mg twice daily), in combination with low-dose hormone (add-back) therapy (estradiol 1.0 mg / norethindrone acetate 0.5 mg), reduced heavy menstrual bleeding associated with uterine fibroids compared to the placebo.
Numbers look good for Abbvie, since 68.5 percent of women with uterine fibroids achieved a clinical response compared to the placebo (8.7 percent) In ELARIS UF-1, with percentage rising even more in ELARIS UF-2, where 76.2 percent of patients achieved a clinical response compared to the placebo (10.1 percent).
“Many women in the United States suffer from uterine fibroids, yet symptoms often go unresolved and can have significant impact on day-to-day activities,” said William D. Schlaff, MD, Chair, Department of Obstetrics & Gynecology, Thomas Jefferson University. “These findings provide objective data demonstrating the potential value of elagolix as a future treatment for women with uterine fibroids.”
Significant symptom alleviation and better quality of life
In both studies, clinical response was considered to be less than 80 mL menstrual blood loss during the last of the six months and reduction by half or more of the menstrual blood loss volume from baseline to final month.
The aim was to prove alleviated symptoms and a better quality of life for the women with symptomatic uterine fibroids. Positive results were recorded based on the disease-specific Uterine Fibroids Symptom and Health-Related Quality of Life questionnaire (UFS-QoL).
“More non-invasive treatment options are needed for women with uterine fibroids who experience symptoms,” said Dawn Carlson, M.D., M.P.H., Vice President, General Medicine Development at AbbVie. “The results support AbbVie’s continued efforts to pursue regulatory filing of elagolix and its potential to help women manage heavy menstrual bleeding associated with uterine fibroids.”
Side effects and contraindications
According to Abbvie, the overall safety profile for elagolix was consistent with results from Phase 2 studies in uterine fibroids; no new safety issues were observed. Side effects included hot flushes and reduction in bone mineral density, but these were less frequent in women who received elagolix in combination with add-back therapy compared to elagolix alone. The most frequent adverse events reported during the treatment period for elagolix (300 mg twice daily), in combination with add-back therapy, were hot flush, nausea, headache, night sweats and fatigue.
Data from the Phase 3 clinical trial program will support regulatory submission for elagolix in uterine fibroids, anticipated in mid-2019.
Elagolix is an orally-administered, nonpeptide, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Elagolix is currently being investigated in diseases that are mediated by ovarian sex hormones, such as uterine fibroids and endometriosis. To date, elagolix has been studied in over 40 clinical studies, totaling more than 3,700 subjects. U.S. regulatory submission for elagolix in uterine fibroids is anticipated in mid-2019.
About ORILISSA™ (elagolix)
ORILISSA is approved by the U.S. Food and Drug Administration (FDA) for the management of moderate to severe pain associated with endometriosis. The recommended duration of use for ORILISSA is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months. ORILISSA is recommended to be taken orally at approximately the same time each day, with or without food.