Orilissa (elagolix) can provide greater relief over existing alternatives for women with moderate-to-severe pain due to endometriosis, a clinical benefit that’s reflected in better quality of life, an AbbVie executive affirmed.
The recent U.S. approval of Orilissa represents the first oral therapy given regulatory favor in a decade for endometriosis, a condition estimated to affect 1 out of 10 women of childbearing age. The treatment – developed by AbbVie and Neurocrine Biosciences – proved its worth in “the largest clinical [program] in endometriosis to date,” Dawn Carlson, MD, AbbVie’s vice president of general medicine development, said in a recent interview with Endometriosis News.
“I’m very proud of a company that seeks to find solutions for significant unmet needs, and for women that have been suffering from endometriosis without a lot of different treatment options,” she added.
This disorder affects multiple aspects of a woman’s life, from work and interactions with family to social relationships, but it also carries heavy healthcare costs, frequent emergency hospital visits, and a need for repeated surgeries to either remove lesions growing outside the uterus or to establish a diagnosis. Each women deals with pain differently‚ but moderate-to-severe is generally on a scale that’s significant and life-altering.
“Pain is very individualized, how a woman will experience it … but I think it’s an underestimated impact,” Carlson said. “I’m hopeful that Orilissa will be able to make a difference.”
Orilissa is now available in retail pharmacies at a monthly list price of almost $845, or $10,140 a year, for both doses, a company spokeswoman said. This price falls within the range recommended by Institute for Clinical and Economic Review (ICER) — $8,800 and $12,800 per year — and its estimates of therapy cost matched to perceived added benefit for patients.
“We’ve been very thoughtful and responsible in our approach to pricing Orilissa, really, with the goal of optimizing patient access,” Carlson said.
Easing ‘fairly significant pain’
The Food and Drug Administration (FDA) based Orilissa’s approval on positive results of two Phase 3 studies (NCT01620528 and NCT01931670) in almost 1,700 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 were then invited to continue — or start — treatment for six months in respective extension studies (NCT01760954) and (NCT02143713).
Moderate-to-severe pain, Carlson explained, meant a score of at least four out of 10, and an average of around seven, in the numerical rating scales frequently used to measure pain. “I think that’s fairly significant pain,” she said.
Findings had three out of four patients on the higher dose reporting a significant and clinically meaningful reduction in the three most common types of pain linked to this disease — daily menstrual pelvic pain, non-menstrual pain, and pain during sex. Women taking the lower dose also reported significant pain amelioration.
The FDA favored both doses, the higher for up to six months and the lower for up to 24 months of continuous treatment.
“We’re very pleased Orilissa has been approved in multiple dosing options, which does allow the physician to individualize that treatment based on the specific type and severity of endometriosis pain that a woman has,” Carlson said.
The 200 mg dose also reduced endometrial tissue proliferation after six months. Whether this may contribute to Orilissa’s pain relief is not yet known, Carlson said.
But women taking Orilissa in the trials needed fewer painkillers, and clearly expressed favorable responses to treatment — with evidence of lesser pain and better life quality holding throughout the extension studies.
AbbVie is now conducting two multi-center Phase 3 trials (NCT03213457 and NCT03343067) comparing Orilissa as a stand-alone treatment to its combination with hormonal add-back therapy consisting of estrogen and progesterone — estradiol/norethindrone acetate — in nearly 1,600 premenopausal women (up to age 49) with endometriosis-associated pain. The first of these two studies includes a placebo arm, and is due to end in December 2020.
Both trials — actively recruiting or preparing to do so across the U.S. and Canada (for contact information, click on their NCT numbers) — will primarily assess the proportion of women with lower menstrual and non-menstrual pain over six months. The second of the two (NCT03343067) also has as a main goal changes in bone mineral density over 24 months. It expects to conclude in November 2021.
Bone mineral density and other safety issues
Orilissa blocks the gonadotropin-releasing hormone (GnRH) receptor in the pituitary gland, leading to less estrogen and progesterone production in the ovaries. The higher the dose, the greater the suppression of sex hormones.
As reflected in its prescribing information, related adverse events can be serious, including liver changes, reduction in bone mineral density (BMD), and suicidal thoughts — although the most common, not surprisingly, is hot flashes.
“All of these safety concerns are related to the mechanism of action,” Carlson said. “There are things that could be predicted based on how elagolix (Orilissa) is known to work.”
Concerns with liver changes led to the FDA’s decision to push back its initial decision date, after it granted Orilissa priority review in October 2017. “Liver safety is always something that’s looked at with new drugs, so it’s not surprising that they might ask for additional presentations of the data,” she added.
Trial data showed that Orilissa may increase the level of the enzyme alanine aminotransferase (ALT) — a sign of potential liver damage. But Carlson said these increases were mostly modest and transient. “The FDA assessment noted the benefits exceeded the potential risks to the patient, and the precautions that are in the label adequately warn about those liver changes,” she added.
Women with moderate hepatic impairment are advised to use the treatment at 150 mg once daily, and for no longer than six months. According to Carlson, this is due to a different metabolism in these women, leading to Orilissa concentrations in their body more in line with the 200 mg dose.
As for bone mineral density loss, both trials and their extension studies showed a dose-dependent reduction in the lumbar spine, hip, and femoral neck — measured using dual-energy X-ray absorptiometry — in treated patients. Specifically, 12 months of continuous use led to a greater than 8% BMD loss in 2% of women taking the 150 mg once-daily dose, and in 21% of those on 200 mg twice-daily, a likely explanation for the shorter treatment duration given that higher dose.
FDA recommendations were based on its assessment of tolerable changes in BMD, Carlson said, adding “Orilissa isn’t really prescribed as a course of treatment in a manner analogous to, say, antibiotics,” but rather on a as-needed basis.
Decreases in bone mineral density, or bone mass — which can risk osteoporosis — are consistent with Orilissa’s-mediated lowering of estrogen levels. Although such BMD losses are “largely modest,” she said, some women may not fully regain that lost to treatment and, in consultation with a physician, might consider a scan to assess bone health.
Lower estrogen levels are also associated with suicidal thoughts, Carlson said, noting the established link between estrogen changes and depression. She recommends physicians be aware of patients with depressive symptoms.
Favoring a lowest effective dose, as the FDA did, is “fairly common,” she added. “As physicians, we always try to use what we need, not the maximal dose,” with symptom severity guiding treatment goals.
Whether patients may return to Orilissa after a “washout” period has not been addressed, she added. Also unexplored are possible improvements in bone health with supplements like calcium and vitamin D. Their need is best left to a woman and her physician, based on her overall health.
A faster-working alternative and future steps
Prior GnRh receptor-targeting medications were agonists, meaning they initially stimulate production of GnRh, as well as of estrogen and progesterone. Feedback between the brain and peripheral organs to this stimulation then causes a complete suppression of these hormones.
Orilissa, an oral and non-peptide GnRH antagonist, suppresses these hormones more quickly, which translates to faster relief and a faster return to baseline levels after stopping treatment, allowing menstruation to restart and hot flashes to ease. Agonists, in contrast, take several months for “feedback mechanisms to rev the system back up,” Carlson said. “That’s a difference.”
She added: “We do know that the level of suppression is different, again, between the agonists and antagonists. With complete suppression, some of the symptoms are much more severe than we’ve seen with elagolix [Orilissa].”
Painkillers will still have a role in treating endometriosis-associated pain, but Orilissa’s approval followed “the largest clinical program specifically designed to address the three types of endometriosis-associated pain” Carlson said, adding that means, in her opinion, “it’s the best studied option.”
AbbVie is also exploring Orilissa as a potential treatment for uterine fibroids, also known as myoma. Orilissa is being tested in a higher dose – 300 mg twice daily – either alone or in combination with low-dose sex hormone therapy.
The company announced top-line results of a second six-month trial (ELARIS UF-II; NCT02691494) in March, showing that the combo met its primary efficacy goal of reducing menstrual bleeding — with 76.2% of treated women achieving clinical response in comparison to 10.1% for placebo — and a 50% or greater decrease from study start, which she called “a very stringent endpoint.” Safety results were “as expected,” she added.
According to AbbVie and Neurocrine, these results were consistent with those of the first Phase 3 study (ELARIS UF-I trial; NCT02654054), reported in February.
AbbVie is now conducting a six-month extension study (NCT02925494) to evaluate Orilissa’s long-term efficacy and safety in 433 women with uterine fibroids who completed the prior six months of treatment.
It plans to report full results, once available and analyzed, at an upcoming scientific meeting, and to explore if Orilissa might treat other diseases mediated by sex hormones.
Overall, AbbVie, which acquired Orilissa from Neurocrine in 2010, has been conducting a broad clinical program aiming at new options for women with endometriosis. “A lot of thought and work has gone into this,” said Carlson, who has been with AbbVie since 1998.
“It’s really gratifying to be part of a company that’s been able to provide the first and only GnRh antagonist specifically developed for women with moderate-to-severe endometriosis pain, and with such a well-studied program,” she added.
And bring greater recognition to a disease long overlooked or dismissed outright.
“I think that’s one of the exciting things that is coming out of this [Orilissa’s approval] – that people are starting to talk about endometriosis,” Carlson concluded. “Women have not always shared the depths of what they’re experiencing.”