Abbvie’s Elagolix Looks Set To Stake Claim In Endometriosis

Abbvie plans 2017 filing for elagolix, licensed from Neurocrine, after second Phase III trial leaves the oral drug with a competitive profile.

AbbVie Inc. is set to file elagolix for endometriosis in 2017, after the gonadotropin-releasing hormone antagonist met co-primary endpoints in a second large Phase III trial.

Abbvie reported Feb. 10 that two different doses – 150 mg once daily and 200 mg twice daily – of the oral agent met all efficacy endpoints in the Phase III M12-671 study of 815 premenopausal women with endometriosis. The trial had two co-primary endpoints related to reduction in scores of menstrual pain (dysmenorrhea) and non-menstrual pelvic pain associated with endometriosis, at month three and month six, as measured by the Daily Assessment of Endometriosis Pain scale.

Abbvie has been touting the drug as among the promising pipeline candidates that could help fill the gap left by its best-selling anti-inflammatory drug Humira (adalimumab), which eventually will face biosimilar competition ( (Also see "AbbVie Sets Out To Win Over Investors In Its First Financial Call" - Pink Sheet, 30 Jan, 2013.).

Abbvie’s injectable gonadotropin-releasing hormone agonist peptide Lupron (leuprolide), now available as a generic, has been a standard treatment for endometriosis but has some troublesome side effects, notably amenorrhea and loss of bone mineral density. Oral contraceptives may also be prescribed.

Elagolix represents an alternative to Lupron that could offer a better side effect profile on top of the convenience of oral dosing (Also see "Making A Market In Women’s Health: Endometriosis, Fibroids Emerge As Rx Targets" - Pink Sheet, 16 Apr, 2013.). GnRH agonists are given in multi-month depot formulations, which means it is harder to stop treatment due to adverse events.

The safety and efficacy in the M12-671 study were similar to a previously reported and similarly designed Phase III trial – M12-665 – of 872 women with endometriosis pain. The results are also in line with Phase II data.

AbbVie touted that the Phase III pivotal studies, in nearly 1,700 women with moderate to severe endometriosis-associated pain, "represent[ed] the largest prospective randomized endometriosis trials conducted to date.”

Elagolix was generally well-tolerated in M12-671, but caused statistically significant changes in bone mineral density at the lumbar spine compared to placebo.

The company needs to compile safety data from a six-month extension study to characterize effects on BMD for regulatory purposes, which will push the new drug application (NDA) submission to 2017.

As the first milestone in what will be a busy year, the news is great for Abbvie, although the filing date in 2017 is disappointing compared to expectations, UBS Equities analyst Marc Goodman said in a Feb. 10 note.

The drug is also now in Phase III for uterine fibroids.

Interviews with clinical consultants suggest elagolix has potential to displace GnRH agonists and take share from oral contraceptives in the endometriosis market, Cowen & Company analysts noted in their 2015 Therapeutic Categories Outlook Report.

Elagolix was initially developed by Neurocrine Biosciences Inc.Abbott Laboratories Inc. licensed worldwide rights to the drug for all indications in 2010, for $75m upfront and milestones worth up to $500m and generous sales royalties (Also see "AbbVie’s Gaps Are Neurocrine’s Gains" - Pink Sheet, 11 Feb, 2013.).

The company estimates that endometriosis affects an estimated 176 million women worldwide.

Elagolix is the only new candidate in Phase III for endometriosis. Phase II therapies include Bayer AG’s contraceptive BAY98-7196 and Repros Therapeutics Inc.’s progesterone receptor modulator Proellex.

Breaking Down The Data

Abbvie’s M12-671 study examined treatment effects at three-month and six-month time points (see table). Efficacy for pelvic pain at the 150 mg dose was in line with performance of Lupron and better at the 200 mg dose, BioMedTracker analyst Edny Inui noted.

“While the improvement in dysmenorrhea was less than observed on GnRH agonists after six months, elagolix does not cause amenorrhea throughout treatment in all patients, and few patients report side effects,” she noted.

The most common side effects for elagolix in the trial were hot flush, headache and nausea. Discontinuation rates were 25.3% for placebo, 21.2% for 150 mg QD and 19.7% for 200 mg BID.

The mean percent change from baseline in bone mineral density at the lumbar spine after six months compared to placebo was 1.2% for the 150 mg QD dose and 2.95% for the higher dose.

Lupron causes bone density loss by an average of 3.2% at six months of treatment, according to labeling, so the lower dose of Elagolix provides similar efficacy with reduced side effects (1.2% reduction in bone density at six months) and the higher dosing provides greater efficacy on pelvic pain with similar effects on bone density compared to Lupron, Inui pointed out.

UBS Equities’ Goodman concluded that the safety profile was consistent with the first Phase III trial and that while changes in bone mineral density “are always somewhat concerning,” this wouldn’t be enough to hinder approval.

Elagolix Study Results, M12-671: Co-primary Endpoints
Endpoints	Proportion of Responders at Month 3 and Month 6
	Menstrual pain		Non-menstrual pelvic pain
	Month 3	Month 6	Month 3	Month 6
Placebo	22.7%	25.4%	36.5%	40.6%
Elagolix 150 QD	43.4%*	46.2%*	49.8%*	51.6%*
Elagolix 200 BID	72.4%*	76.9%*	57.8%*	62.2%*
*Statistically significant result vs. placeboSource: AbbVie