Prominent gynecologist Hugh S. Taylor is such a fan of the new endometriosis therapy Orilissa (elagolix) that, within 48 hours of its U.S. approval, he was already prescribing it for his patients — even filling out paper prescriptions because Orilissa hadn’t yet been added to his clinic’s electronic database.
“It’s a wonderful new additional choice for those women for whom an oral contraceptive doesn’t work, or those with moderate to severe pain who want a more rapid therapy but don’t want to risk the failure of birth-control pills,” said Taylor, chief of obstetrics, gynecology and reproductive services at Yale School of Medicine in New Haven, Connecticut.
“In the past, we often started women with endometriosis on an oral contraceptive,” said Taylor, a consultant to AbbVie who led several key studies of Orilissa. “Unfortunately, that therapy often fails for a high percentage of women. So, the options for second-line therapy often included a GnRH agonist — which is very effective, but fully suppresses estrogen levels — or surgery. Women now have a choice of something that is not as extreme but still very effective.”
James Simon, a gynecologist with IntimMedicine Specialists in Washington, D.C., concurs.
Simon says that Orilissa — jointly developed by AbbVie and Neurocrine Biosciences — “works extremely well in getting patients pain relief,” with “the advantage …. [of] fewer side effects than the injectable GnRH [gonadotropin-releasing hormone receptor] agonist like Lupron, and it’s oral, so it appears that we may be able to use it for a longer time.”
The two doctors, who spoke separately by phone with Endometriosis News, both see Orilissa as a crucial step in treating a painful disease that affects 10 percent of all women of childbearing age, and that for far too long has been neglected as a healthcare priority.
The U.S. Food and Drug Administration (FDA) based its July 24 approval of Orilissa on positive results of two Phase 3 studies (NCT01620528 and NCT01931670) in 1,686 women with moderate-to-severe endometriosis-related pain.
Two doses of Orilissa — 200 mg twice a day and 150 mg once daily — were compared to placebo over a six-month period. Patients then were invited to continue — or start — treatment for six months in respective extension studies (NCT01760954) and (NCT02143713).
Both doctors also agree that concerns about possible liver damage, a reason the FDA postponed its decision by a few months to fully analyze the studies’ liver data, are minimal.
“I think that just comes from an abundance of caution by the FDA,” Taylor said. “Liver toxicity was not a concern that showed up in our studies, and it’s nothing we expect to see with elagolix.” For women with moderate hepatic impairment, the recommended dosage of Orilissa is 150 mg once daily for up to six months.
Simon, who treated about 30 patients with Orilissa — then elagolix — in clinical trials, said “we did not see liver injury in my patients during the trial, or any suggestions thereof. But because the liver is the common pathway where all drugs get broken down and metabolized, I suspect the FDA is concerned about it in a theoretical way.”
Bone loss could be an issue
A bigger problem appears to be the possible loss of bone mineral density, which in studies was more pronounced among women on elagolix than on placebo.
“Bone loss was minimal on the lower dose [of 150 mg once a day], and not enough to be clinically concerned about. On the high dose [of 200 mg twice daily], everyone stayed within the normal range for bone density, but there was a decrease among women on that higher dose,” Taylor said — a likely reason 200 mg use is limited to six months, and the lowest effective dose for a person specified as the preferred dose.
“It’s a good principle, with any medication, not to use more than you need, and to use the lowest effective dose,” Taylor said. “If the 150 mg is effective, there’s no need to use the higher dose. Some patients will find the higher dose is more effective, and some may want to start on a high dose and get the disease under control as soon as possible, and then taper down.”
Likewise, Simon said bone loss is “a real possibility, but it’s one for which we have excellent technology to assess it and monitor any progression while on treatment.”
“I plan to start almost everybody on the lower dose to see if it’s adequate to stop their periods and relieve their pain, and use the higher dose only as needed,” said Simon, a clinical professor at George Washington University. Earlier this year, he was elected president of the International Society for the Study of Women’s Sexual Health.
Both Taylor and Simon favor calcium and vitamin D supplements to counteract the risk of bone loss — even among women not taking this medication.
“I recommend that to most of my patients, especially during the reproductive years,” Taylor said.
Added Simon: “Regardless of any guidelines, I personally will be monitoring my patients’ skeletal health to make sure they’re not losing bone, and that they’re getting adequate calcium and vitamin D, and, as needed, some kind of estrogen-progesterone add-back therapy if they need it — and many of them will require some.”
Safety and efficacy
The way Orilissa works is actually quite simple, Taylor said.
“Endometriosis is fueled by estrogens, and this drug indirectly turns off estrogen production in the ovaries,” he said. “The signal the ovaries receive comes from the pituitary gland, which is regulated by GnRH made in the hypothalamus of the brain. It blocks production of GnRH coming from the hypothalamus.
“The pituitary makes less of the hormone, the ovary makes less estrogen, and the endometriosis doesn’t grow,” Taylor said.
That Orilissa is effective in relieving patients’ pain does not seem to be in doubt.
Simon, suggesting there is always a possible placebo effect, said his patients have told him they get relief immediately. To be sure, he said Orilissa normally takes “a couple of weeks” to kick in, with relief evident by the time of a woman’s first or second missed menstrual cycle.
Taylor said that even though Orilissa is a new therapy, it has proven its efficacy and safety in large-scale clinical trials where the most common side effect was “mild hot flashes.”
“Over 1,600 women were followed for over a year in three clinical trials, and the safety profile was exceptional,” he said. “There were really no worrisome safety events — nothing that would say to me as a physician not to use this medication.”
A better treatment, but not a cure
A treatment benefit is that it’s an alternative to surgery, Taylor said, and a more effective medication for moderate-to-severe endometriosis pain than anything now on the market.
“Surgery isn’t a long-term cure; it’s a short-term removal of the endometriosis,” he said. “Even after surgery, a woman will need to be on medications to prevent this from recurring — unless they’re approaching menopause — because the same things that cause endometriosis to begin with are still there.”
In fact, for roughly half of all women who undergo surgery, the pain recurs within two years, Taylor said.
“Endometriosis is a very common disease, and there are a lot of women out there who aren’t adequately treated now,” he said. “Birth-control pills frequently fail, but they don’t want to take that next step. And some of them have significant mood changes and bloating, which they tolerate when they don’t need to. They were hesitant to do something as invasive as surgery or an injectable drug that would drop their estrogen level to essentially zero. Here we have an oral medication that lets us find the appropriate dose. It then becomes a much easier decision to go to a second-line therapy.”
Simon stressed that Orilissa — which costs $845 every four weeks without insurance — won’t cure endometriosis.
“We have other examples of medications like Lupron [Depot, also by AbbVie] were used for long periods of time and then stopped. The symptoms of endometriosis — and presumably the endometriosis as well — came back when the woman’s menstrual cycles returned,” he said. “We don’t have that kind of long-term data on this product [Orilissa], but there’s no reason to believe — given its mechanism of action — that its long-term use, once it’s stopped, will have cured as opposed to simply suppressed the endo.”
His reasoning: “Whether you turn off the woman’s menstrual cycle with an injectable GnRH agonist like Lupron, or you turn off her cycle with an antagonist like elagolix, the turning-off part is the same.”