ObsEva makes case for hormone suppressive therapy in uterine fibroid study, but safety qualms vex investors
About a month after the Swiss biotech disclosed a failed late-stage study in its IVF program, ObsEva on Monday unveiled positive pivotal data on its experimental treatment for heavy menstrual bleeding triggered by uterine fibroids, but the therapy’s safety profile irked investors.
ObsEva in-licensed the drug, linzagolix, from Japan’s Kissei Pharmaceutical in 2015. Two doses of the drug (100 mg and 200 mg) were tested against a placebo in the 535-patient Phase III study, dubbed PRIMROSE 2, in patients who were both on and off hormonal add-back therapy (ABT).
The aim of the therapy was to reduce the rate of heavy menstrual bleeding. Patients with menstrual blood loss volume of ≤ 80 mL and ≥ 50% reduction from baseline at 24 weeks were categorized as responders.
The responder rate was 93.9% for women receiving 200 mg of the drug with ABT (p < 0.001), and 56.7% for women receiving 100 mg without ABT (p < 0.001), compared to 29.4% in the placebo group. Both doses also induced statistically significant rates of amenorrhea (the absence of menstruation), pain reduction and quality of life.
“We believe positive data from the low-dose without ABT cohort (40-50% response rate) could differentiate Linzagolix from competitors, with a competitive market position as a potential first-line treatment for patients unable to receive ABT (women predisposed to high BMI, CV risk and diabetes),” BMO Capital Market’s Do Kim wrote in a note last month.
Linzagolix is an oral GnRH receptor antagonist, a substance that causes the ovaries to stop making estrogen and progesterone, being developed for use in heavy menstrual bleeding triggered by uterine fibroids and pain associated with endometriosis. GnRH drugs, which typically come in the form of injections or nasal sprays, have been around for decades and are administered in tandem with ABT to ameliorate the menopausal-type side effects and the thinning of bones.
The clinical impact of linzagolix at 75 mg and 100 mg doses without hormonal ABT are being assessed in ObsEva’s late-stage endometriosis (EDELWEISS 2/3) trials. The drug is also being investigated in a separate uterine fibroids trial — PRIMROSE I — that is set to read out in the second quarter of next year. If data from the other PRIMROSE study are also positive, the company expects to submit a marketing application to the EU by the end of next year and to the FDA by early 2021, it said.
“A substantial amount of data released to date supports use of linzagolix without ABT in pre-menopausal women with these conditions, avoiding known risks of ABT while providing symptom relief and bone preservation,” H.C. Wainwright’s Raghuram Selvaraju wrote in a note last week. “In our view, linzagolix’s potential as an effective GnRH receptor antagonist that can be used without ABT could confer best-in-class status within this category of compounds.”
AbbVie and Neurocrine Biosciences’ twice-daily GnRH agonist therapy elagolix (branded as Orilissa), which was approved last year to treat endometriosis, is also under FDA review for use in uterine fibroids.
The companies have reported data from two pivotal six-month studies — in one late-stage study, 68.5% (p<0.001) of elagolix-treated women with uterine fibroids achieved clinical response compared to placebo (8.7%), in the second trial 76.2% (p<0.001) did compared to placebo (10.1%). However, the drug’s side effect profile has caused pause — in addition to the loss of bone density, some patients also experienced hot flashes and night sweats.
Meanwhile, Vivek Ramaswamy’s Myovant also has GnRH agonist, relugolix, that has performed well in late-stage uterine fibroid studies, and the drug’s safety profile appears to be better than elagolix.
In the ObsEva trial, the most frequently observed adverse events, occurring in > 5% of patients, were headaches, hot flushes, and anemia. Mean percentage change from baseline in bone mineral density (BMD) was consistent with previous clinical data, it added.
That implies BMD reductions were under 2% across all treatment groups, Credit Suisse’s Martin Auster said. “(A)nd only 2.5% of women (9/367 with BMD data for all anatomic sites) had a >8% BMD decrease (OBSV is blinded to the data so associated dose arms are not known), an important FDA threshold. ”
Jefferis analyst Biren Amin noted that that the “BMD loss appears to be slightly higher than competitors, (1.31% with high-dose linzagolix vs 0.13-0.75% for competitors).”
The company’s shares $OBSV closed down more than 29% at $3.23 on Monday.
Uterine fibroids are almost always benign tumors that emerge in or on the muscular walls of the uterus. They can cause symptoms such as abnormal uterine bleeding, heavy or painful periods, anemia, abdominal pain, backache, increased abdominal girth and bloating, urinary frequency or retention, constipation or painful defecation, pregnancy loss, painful intercourse and, in some cases, infertility. Between 20% to 80% of women develop fibroids by the time they reach age 50, according to HHS estimates.
In November, ObsEva’s oxytocin receptor antagonist, nolasiban, failed to differentiate from placebo in key study, forcing the company to abandon the program. The drug, in-licensed from Germany’s Merck KGaA, was engineered to enhance the receptivity of the endometrium to embryo implantation to augment the chances of a successful pregnancy and live-birth among patients undergoing embryo transfer following assisted reproductive technology.