OrilissaTM, a "significant advancement" for endometriosis patients - or another obstacle to quality care?

 Photo Credit: Casey Berna

Photo Credit: Casey Berna

Last week, the FDA approved OrilissaTM (elagolix), an orally administered GnRH antagonist that has been developed by AbbVie, an Illinois-based company in cooperation with Neurocrine Biosciences, Inc., to treat moderate to severe endometriosis pain. With the approval of this drug, many articles were published calling OrilissaTM an ‘exciting game-changer’ and 'a huge thing in women's health.’ But, not everyone is excited and serious concerns exist regarding whether this treatment is truly a significant advancement in care - or something that will further delay the gold standard, multidisciplinary care patients need.

As a GnRH antagonist, OrilissaTM works to suppress normal ovarian function, reducing estrogen in the body. GnRH (gonadatropin releasing hormone) is produced in the hypothalmus and stimulates the pituitary gland to release hormones which, in turn, stimulate the production and release of estrogen by the ovaries and placenta (and in males, testosterone). GnRH agonists and antagonists are synthetic, highly potent drugs that work to suppress estrogen (or androgen) synthesis. 

AbbVie also manufactures Lupron®, a GnRH agonist. This drug, which is also used to treat endometriosis symptoms by suppressing ovarian function, stimulates the release of GnRH until the pituitary is exhausted, ceasing gonadotropin production and putting the ovaries to sleep.

OrilissaTM, is being promoted as a better option to Lupron® to be used as a second line of treatment after NSAID’s and birth control pills can no longer manage symptoms.

Medical “treatments” for endometriosis symptoms are not new, and have long focused on minimizing estrogen in the body. For example, low dose birth control pills, which also reduce estrogen production by the ovaries, are often used as the first line of treatment for endometriosis pain. As most patients will confirm, however, medical treatments can minimize symptoms for a period of time for some, but often do not remain effective, especially after they are discontinued. Side effects from medical treatments vary. Lupron®, for example, has been known to have devastating, long-term effects for many. OrilissaTM is being promoted as a better option to Lupron®, to be used as a second line of treatment after NSAIDs and birth control pills can no longer manage symptoms.

Today, the Institute for Economic and Clinical Review (ICER) came out with their final report on OrilissaTM.  The report is the result of nearly a year's worth of data mining and stakeholder discussion, which culminated in a presentation of the research and a panel discussion where a group of varied medical professionals heard the available, current evidence on the drug. The council also heard invited public commentary, which included testimonies from subject matter experts and patient advocates Dr. Martin Robbins, an endometriosis specialist and surgeon, Heather Guidone, the Program Director of the Center for Endometriosis Care, and Casey Berna, the Director of Program and Partnerships at Endo What, who also helped inform the research and were a part of the roundtable discussion after the vote.

There were more questions asked than answers given during the ICER review, which AbbVie elected not to attend, and even confusion among the voting panel. What are the long-term side effects of this drug, especially for those patients taking it for 24 months, or taking the high dosage? Is the low dose of this drug more effective than taking a low dose birth control pill, which has lesser side effects? Why was this drug not compared to other medical treatments? Is it safe for teenagers?  How does this drug compare to multidisciplinary treatments for endometriosis, which have no side effects?  Why, after first line treatment fails, does it make sense for patients to go on another medical treatment that will simply allow recurrence of symptoms upon cessation of therapy? Heather Guidone recalled that, “Several in the room, in fact, expressed actual shock and outrage at how little progress has been made in endometriosis and how they were supposed to vote using extremely limited data."

After hearing all of the evidence, the New England CEPAC voted that "the evidence was not adequate to determine whether elagolix (OrilissaTM) 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." Furthermore, the council could not vote on long-term value for money, "due to their finding that evidence is inadequate to determine that the clinical benefits of elagolix (OrilissaTM) outweigh its unknown long-terms risks. "(ICER Report). 

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Endometriosis specialists also have many reservations about this drug.  In a letter applauding ICER’s research, Dr. David Redwine, a pioneer in endometriosis care, states that “[a]fter subtracting patients who stopped therapy due to adverse events and subtracting placebo effect, over 50% of women did not respond to the medicine-hardly impressive. ICER found that elagolix was incrementally effective and expensive, but clearly not the homerun that AbbVie wished it were.”  Dr. Jeff Arrington, of the Center of Endometriosis Care in Atlanta, worries about endometriosis patients having all information available regarding the unknowns about this drug and other available options before deciding a treatment plan. He warns, “[d]octors are going to present this drug as the latest and greatest treatment for endometriosis, when it is not! It is palliative in nature and as far as they have studied it, it serves the same role that birth control and pain pills do. These drugs attempt to make the patient comfortable, while leaving the actual disease.”

Dr. Sallie Sarrel, a pelvic floor therapist in the NY/NJ area who specializes in endometriosis and is a patient advocate, warns that, “people with endometriosis need to treat the source of their pain and all of the associated conditions, like pelvic floor dysfunction, instead of masking the disease with drugs and hormones.” Dr. Iris Orbuch, an endometriosis specialist in NYC and LA points out that, “OrilissaTM does not cure endometriosis, melt away endometriosis implants, cause these implants to disappear or reverse the progression of endometriosis implants. What’s the plan for a woman once she stops OrilissaTM, and is still in ‘moderate to severe pain’? This medicine will ultimately delay necessary excision of endometriosis surgery while subjecting her to a whole host of side effects, not to mention a hefty price tag to boot.” 

Concerning side effects of the drug include potentially irreversible bone mineral density loss; potential increased risk for coronary heart disease; possible liver damage; and anxiety and depression. Among the most concerning potential side effects are suicidal ideation, suicidal behavior, and exacerbation of mood disorders, which have all been linked to the drug. Among the most concerning potential side effects that came up at the ICER meeting was the question of what happens to patients who get pregnant while taking OrilissaTM? Patients who take this drug are advised to use a non-hormonal form of birth control while on it. Some patients who took OrilissaTM during the clinical trials did get pregnant. Because OrilissaTM can lighten menstruation, patients are at risk for not being aware of their pregnancy and continuing to take this drug while pregnant. Some patients who took OrilissaTM during the clinical trials did, in fact, get pregnant. Some suffered miscarriages, and some babies born with birth defects were reported. While, it is uncertain if this was due to OrilissaTM, there are no studies demonstrating the impact OrilissaTM can have on a fetus or the possible long-term effects on the baby, when taking this medication while pregnant.

Over 40% of patients with infertility have endometriosis. The clinical research did not study the drug’s impact on fertility or if suppressing the ovaries could have a lasting effect on ovarian reserve and/or function. Dr. Andrea Vidali, a reproductive endocrinologist and endometriosis expert in NYC is concerned that “the availability of an oral formulation will induce physicians to lazily condemn patients to a lifetime of hormonal treatments prior to exploring the option of a potentially curative surgical excision. Additionally, we are facing the possibility that treatment would be initiated empirically without proper diagnosis. This is particularly concerning for patients with repeated pregnancy losses or IVF failures in which treating endometriosis is of paramount importance.”

Having already invested several hundreds of millions of dollars in OrilissaTM, AbbVie is set to make billions from selling this drug to patients - indeed, market watchers speculate that OrilissaTM will ultimately achieve more than a billion in sales annually from the endometriosis market as well as from additional market opportunities planned for the drug (i.e. fibroids). Dr. Orbuch feels passionately that, “Money would be much better spent creating multi-specialty, multidisciplinary centers to treat endometriosis and pelvic pain, rather than this medicine, which at best, may be a temporary band-aid while ultimately delaying proper treatment for patients.”

Dr. Allyson Shrikhande, a board certified Physician Medicine and Rehabilitation specialist and a leading expert on chronic pelvic pain feels that, "Endometriosis is a complicated disease that affects many organ systems as well as muscles, peripheral and central nervous system, and hormones. Given this scenario a multidisciplinary approach is often necessary focusing on early diagnosis and improving the quality of life of the patient. This is where I would put the money, early diagnosis, finding a definitive treatment and managing symptoms and quality of life for our patients."

Endometriosis specialists and patient advocates alike recognize the need for more medical treatments for patients. However, the endometriosis population is a vulnerable one that has endured much suffering. Drugs offered to patients need to be well researched, including all long term effects,  and patients also need to be made aware of all treatment options, including being referred to an endometriosis specialist and multidisciplinary care to have informed consent. 

 

Shannon Cohn