Myovant Sciences Inc.'s kickoff to 2017 with a phase III trial testing its oral gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix in uterine fibroids (UFs) signaled a year of tighter focus on the condition, with a group of heavyweight drug developers involved in that indication as well as endometriosis.

"They crop up together for two reasons – they're both benign diseases that occur in women of reproductive age and they're both driven by estrogen, and UFs more so by progesterone as well," Myovant CEO Lynn Seely told BioWorld Insight. As a targeted therapy that lowers both, relugolix is "perfectly poised to be evaluated" as the dual remedy, she said. "Millions of women are suffering from UFs and endometriosis, and there really has been little in the way of innovation" for the last two decades, so they represent a "wide-open space with a lot of patient need."

hysterectomy burden cited

Hamilton, Bermuda-based Myovant's program involves two international trials, LIBERTY 1 and LIBERTY 2, to evaluate the safety and efficacy of relugolix in women with heavy menstrual bleeding associated with UFs. Relugolix will be tested with and without low-dose hormonal add-back therapy. Among drug classes, GnRH antagonists are "clearly are in the lead," Seely said. "Previously, GnRH agonists have tried to treat this disease but are belabored by side effects" and, unlike the antagonists, were injected. Relugolix is given orally, once per day, and can "beautifully suppress estrogen and progesterone levels in by far the majority of women. We're going to add back just a small amount of hormone replacement therapy to help minimize any side effects" such as bone mineral density or hot flashes – conditions for which the hormone therapy is prescribed to postmenopausal women, she noted, and is known to work.

Also in the UF game is Neurocrine Biosciences Inc., of San Diego, with a GnRH antagonist testing elagolix in two phase III studies and expecting top-line data by the end of the year. In the meantime, the company aims to submit an NDA for the drug in endometriosis during the third quarter of this year with partner Abbvie Inc., of North Chicago.

Obseva SA, of Geneva, has GnRH therapy OBE2109, licensed in 2015 from Tokyo-based Kissei Pharmaceutical Co. Ltd., bound for two phase III experiments as well in the first half of this year. The treatment started a phase IIb trial in endometriosis last fall. Meanwhile, Allergan plc, of Dublin, and Gedeon Richter plc, of Budapest, Hungary, in late January turned up encouraging results deploying a different mechanism of action in the phase III study with ulipristal acetate, a selective progesterone receptor modulator (SPRM), for bleeding due to UFs.

Neurocrine's candidate, though it's ahead of Myovant's, "has a short half-life, and they've been trying to find the right level of estrogen suppression" to avoid side effects, Seely said. "That's proven to be quite difficult to do. They started [in endometriosis by] trying to have a very personalized approach. With UFs, they're using a maximum estrogen suppressive dose, which is 300 mg twice a day, with and without the hormonal add-back therapy." Obseva's oral GnRH is "a little bit farther behind" and also takes a personalized approach where "you start with one dose and if it's not enough, [the patient comes] back and adds more" – a process that's complicated and time-consuming for patients as well as busy doctors, she said.

Regarding SPRMs, Seely pointed out they are approved in Europe and Canada, and probably will become another option in the U.S., although they have to be given cyclically and can bring about "some endometrial changes," which means patients must "resume bleeding for two cycles and can go on the medication again. It requires a lot more monitoring to ensure the endometrium remains safe, whereas our drug is just one pill once a day consistently."

Piper Jaffray analyst Charles Duncan, covering Neurocrine, urged investors not to overlook endometriosis, where the company also has its candidate in phase III testing (and where Myovant's relugolix is slated to begin in the first half of this year). "Our key opinion leaders' diligence in the endometriosis space suggests that regulators and prescribers view this as one of the highest unmet needs in women's health, and likely a bigger need than UF," he wrote in a research report at the end of January. "The first reason for this is the burden of disease, both in terms of patient pain and loss of productivity, as well as costs to the health care system. Endometriosis is the most common reason for hysterectomy in young women under 35, and costs associated with [the condition] are higher than many other chronic" problems, such as migraine.

"The second reason is the lack of acceptable treatment options for endometriosis: while birth control and over-the-counter pain medication work for milder cases, there is a lack of 'second-line' type treatments to use before advancing to surgical procedures or options with higher side effect profiles, such as Lupron [leuprolide, Abbvie Inc.]," he pointed out. Duncan called elagolix "well-positioned to enter as a chronic, oral option in this second-line market by offering a flexible regimen with or without add-back therapy vs. Lupron, a different efficacy and side effect profile vs. birth control," and none of the complications that can come with surgery. "Currently, our model for elagolix is split approximately 60/40 on value from endometriosis and UF," he said.

surgery easier, when necessary

Jefferies analyst Biren Amin, also covering Neurocrine, pointed out that elagolix will have to compete with SPRMs in UFs, such as the one from Allergan and Gedeon and another, vilaprisan, from Leverkusen, Germany-based Bayer AG. At the meeting of the American Society for Reproductive Medicine (ASRM) meeting in Salt Lake City in October, phase II data with the latter and phase III results with the former rolled out. "The studies each showed an efficacy of more than 95 percent in controlling bleeding caused by UF," Amin reported. "Importantly, as SPRMs do not suppress estradiol, common side effects seen with GnRH antagonists (e.g., hot flushes and bone mineral density loss) were not observed.

"However, ulipristal acetate has been shown to alter the endometrium," he said, echoing Seely, which is why its treatment is restricted to intermittent use in the EU where it is approved. Forty percent of patients experienced treatment-related endometrium changes with vilaprisan as well. "We had a chance to speak to physicians at ASRM about this and most were not concerned, as these changes appear to be transient and are most likely mediated through SPRMs' effect on collagen and the extracellular matrix. To support this, one expert highlighted that more than 100 births from ex-U.S. ulipristal-treated patients have yielded no reproductive issues," Amin wrote in a report. "Surgeons did note the difficulty of using ulipristal as a pretreatment to reduce the size of UF, as the structural changes make UFs more 'squishy' and thus more difficult to excise. This does not appear to be the case for GnRH antagonists," which may be one reason for companies' interest in the class.

Prostate cancer, too

Myovant went public last October with a $217 million offering, cash that the company said would last through the phase III results to at least 2019. In June 2016, Osaka, Japan-based Takeda Pharmaceutical Co. Ltd. and Bermuda's Roivant Sciences Ltd. formed Myovant around relugolix and another compound, RVT-602, to treat female infertility as part of assisted reproduction. RVT-602, a peptide analogue of kisspeptin, had gone as far as phase II in men's health indications. (See BioWorld Today, Oct. 4, 2016, and Oct. 28, 2016.)

As CEO, Seely has an impressive track record: She spent a decade as the chief medical officer at San Francisco-based Medivation Inc., where she led the development of prostate cancer drug Xtandi (enzalutamide). The compound pulled in sales of $1.9 billion in 2015 and drew a $14 billion acquisition by Pfizer Inc., of New York. (See BioWorld Today, Aug. 23, 2016.)

Cowen and Co. analyst Phil Nadeau enthusiastically started coverage of Myovant in November. Relugolix "has produced strong proof-of-concept data in a number of large indications," he wrote in a report, citing how the drug "successfully reduced menstrual blood loss associated with uterine fibroids in a phase II study of 216 women. In endometriosis, daily administration of relugolix significantly decreased pelvic pain in a phase II study of 487 women."

The candidate has possibilities in prostate cancer as well. A phase II trial in 228 men showed that the treatment suppresses testosterone to castration levels, reducing levels of prostate-specific-antigen. Phase III trials in that indication also are scheduled to begin in the first half of this year. "We expect all to complete in 2019, with worldwide regulatory filings following shortly after," Nadeau said. "We project a 2021 launch, and that relugolix will achieve more than $2 billion in sales by 2025." Myovant in-licensed relugolix from Takeda "on attractive terms," he recalled, and Myovant owns global rights to relugolix outside of Asia, obligated to Takeda for only a high single-digit royalty on sales. "Our analysis suggests that Myovant is undervalued based on the potential of relugolix alone," he said.

As for RVT-602, the kisspeptin drug, it's bound for the clinic this year as a treatment for infertility. The approach is designed to safely induce a surge of luteinizing hormone during assisted reproduction, without a risk of ovarian hyperstimulation syndrome. A phase I study in healthy female volunteers is expected to begin in the second half, followed by a phase II program in women in need of assisted reproduction.

Frank Karbe, Myovant's chief financial officer, said that "while a lot of the focus and attention at the moment is on our lead asset, we have a broader vision." Women's health needs an industry leader, he said. "We would like to believe we will become that company."