A long half-life, high bioavailability and no food affect – plus the prospect for add-back hormone therapy or not – may distinguish Geneva-based Obseva SA's gonadotropin-releasing hormone (GnRH) therapy for uterine fibroids (UF) and endometriosis, CEO Ernest Loumaye told BioWorld Today. "The beauty of this class is its capacity to suppress estradiol in a dose-dependent manner," he said. "Where we are different is in the pharmacokinetic [PK] profile of OBE2109 and how we are developing it."

The Geneva-based firm has OBE2109, licensed in 2015 from Tokyo-based Kissei Pharmaceutical Co. Ltd., bound for two phase III experiments in the first half of this year, one of three new chemical entities in the pipeline. OBE001 (nolasiban) is an oral oxytocin receptor antagonist to be used with in vitro fertilization and OBE022, an oral PGF2α receptor antagonist is "early stage but very interesting," he said.

Results from the phase II IMPLANT trial with nolasiban showed a statistically significant relationship between the dose of drug and the ongoing pregnancy rate at week 10 and increased live-birth rates of women with normal serum progesterone levels (patients with higher levels of estradiol and progesterone, associated with reduced pregnancy rates, were excluded from analysis) at the time of embryo implantation by 67 percent vs. placebo, or 20.4 percent absolute (51 percent vs 30 percent, respectively). Obseva plans to start a European phase III trial with nolasiban for patients undergoing assisted reproductive technology (ART) in the first half of this year.

Phase I-stage OBE022 is a potential first-in-class, once-daily therapy antagonist designed to control preterm labor by reducing inflammation, decreasing uterine contractions and preventing cervical changes and membrane ruptures. Today, only treatments with limited efficacy or restrictive safety issues are available, such as tocolytics used off label, which offer limited efficacy in suppressing uterine contractions and delaying birth.

"For all three drugs, we have exclusive rights and there are no buy-back, opt-in options for the licensors," Loumaye said, adding that the company is "well-covered from an intellectual property standpoint, to between 2030 and 2035" for the batch. Of particular interest has been OBE2109. "The beauty of this class is its capacity to suppress estradiol in a dose-dependent manner," he said, unlike standbys in fibroid therapy such as Lupron Depot (leuprolide, Abbvie Inc.). "There is no way to have a more subtle or moderate suppression of estradiol [with Lupron]" whereas with OBE2109, "if you give a moderate dose, you have a partial suppression of estradiol. If you give a high dose, you have full suppression." A woman with a regular menstrual cycle has estradiol between 60 and 300 pg/mL. After menopause, it's in the middle 20s. "What has been shown – and this is the method of elagolix development – is that if you give the right dose of GnRH antagonists, you can bring estradiol [down to between] between 20 and 60 pg/mL," he said. Neurocrine Biosciences Inc., of San Diego, has the GnRH antagonist elagolix undergoing UF tests 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, of North Chicago. (See BioWorld Insight, Feb. 27, 2017.)

Neurocrine's candidate, though it's ahead of Hamilton, Bermuda-based Myovant Sciences Inc.'s GnRH bid relugolix, boasts a short half-life, and the company has been working to find the right level of suppression to avoid side effects. In UFs, Neurocrine is using a maximum estrogen suppressive dose, which is 300 mg twice a day, with and without hormonal add-back therapy. Obseva takes a more personalized approach, trying two doses – one with full suppression and add-back, plus one providing partial suppression without add-back. "Not all patients will be fully controlled with moderate suppression," Loumaye said. "A group of patients may need a more severe suppression for controlling systems. But you cannot just suppress estradiol. You have to have some add-back therapy, [and] that means bringing back some estrogen and progestin in order to protect bones. Here we diverge from elagolix development."

ANALYST: MAY BE 'TITRATABLE TO EFFECT'

UF and endometriosis are often targeted together because "both conditions are estrogen-dependent, and both are well-known to resolve after menopause," Loumaye said. "But then we come to the trade-off. If you [medicate] too severely, you lose bone-mineral density [BMD] and that's unacceptable." Add-back therapy, he noted, "is actually hormone-replacement therapy that has been developed for menopause," commonly Activella (estradiol/norethindrone, Gemini Laboratories Inc.), which brings cardiovascular and thromboembolic risks, as well as – this is "more speculative," he allowed – a potentially increased chance of breast cancer.

"Women treated with endometriosis are usually in their 30s," Loumaye said, where as those treated for UF are typically in their 40s, with a median age of 42, and may be overweight, have hypertension along with glucose intolerance and other problems. "We know there will be a population both for UF and endometriosis for which you will have either contraindications or side effects preventing the use of add-back therapy," he said. "That's why we want to have both options. What Abbvie has shown us is that there is a subset of the population in which hormonal replacement therapy actually reversed the efficacy, reduced the efficacy of suppression. That's not a surprise, because [you are adding] back estradiol and progestin. The difference is not major but there is definitely a difference and, again, this is a population which would face a choice. What would we do if add-back reversed control of the symptoms?" The add-back patients represent a significant portion, he said, pointing to data with elagolix that showed patients got 150 mg per day with no damage to bone and about 60 percent defined as responders.

More companies are busy with drug development in women's health these days because innovation until recently had slowed, with therapies decades old still being used, such as oral contraceptives in endometriosis, Loumaye said. He cited an article in Fertility and Sterility, published by the American Society for Reproductive Medicine that hailed OBE2109 and the GnRH class. "Indeed, OBE2109 has a consistent PK profile and low variability thanks to its high bioavailability and low volume of distribution, enabling personalized dosing that can be 'tailored' according to individual estradiol values and symptoms," the article noted. UF, for its part, is the leading cause of hysterectomy, though fibroids tend to spontaneously regress after menopause. "We are not saying that surgery will disappear," Loumaye said, "but there is a fraction of this population [that can] be treated medically, avoid surgery, and go quietly through menopause." Obseva will start a phase III trial in UF during the coming weeks.

Nolasiban in ART may arrive just in time. The mean age of first pregnancy is 32-34 years, whereas a generation ago first pregnancies turned up about 10 years earlier on average. In China, with the release of the one-child policy, a huge population of women in their 40s is wanting second children, Loumaye said. As for OBE022, no drug exists to treat preterm labor, although Makena (hydroxyprogesterone caproate, Amag Pharmaceuticals Inc.) is marketed for prevention. "People are using non-steroidal inflammatory drugs and the like," with their limited activity and side effects, Loumaye said.

Piper Jaffray analyst Charles Duncan covers Neurocrine. In a research report at the end of January, he found it "worth revisiting the competitors for elagolix, as early last week Myovant initiated two phase III U.S./EU trials for relugolix in UF, and another player, Obseva, completed its IPO to fund an ongoing phase IIb in endometriosis, as well as upcoming phase III starts in UF. From the phase II data, we see relugolix as a potent GnRH antagonist; however, it appears the PK/pharmacodynamic profile of the drug requires add-back therapy at all dose levels – this was confirmed by the recently announced phase III UF trial design. From our recent key opinion leader diligence, we believe patients and prescribers will prefer the option to use a drug with or without add-back, depending on how high a dose is needed for symptom relief. [Regarding] Obseva's OBE2109, we think this candidate may be titratable to effect."

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