Geneva-based Obseva SA’s phase III Primrose 2 trial with gonadotropin-releasing hormone (GnRH) antagonist linzagolix in heavy menstrual bleeding (HMB) due to uterine fibroids (UFs) hit the primary endpoint in 94% of patients, and the company in the second quarter of 2020 will report six-month data from the Primrose 1 study, which is also a phase III experiment, in the same indication.

The setup has Wall Street speculating about the compound’s odds against Orilissa (elagolix), the GnRH drug from Abbvie Inc., of North Chicago, and relugolix, in the same class, from Basel, Switzerland-based Myovant Sciences GmbH. The latter said an 87.7% one-year response rate in its Liberty open-label extension study supports submission of an NDA for the relugolix combination tablet (relugolix 40 mg plus estradiol 1 mg and norethindrone acetate 0.5 mg) for women with UF-related HMB in April 2020. On March 9, the company made known its submission of a marketing authorization application to the EMA for the combo tablet.

Abbvie put in the NDA for Orilissa in the UF indication in August 2019. In July 2018, the FDA cleared Orilissa under priority review for moderate to severe endometriosis pain. The compound was discovered and advanced through the clinic by Neurocrine Biosciences Inc., of San Diego, and then co-developed from phase III to approval in partnership with Abbvie in a $575 million deal inked in the summer of 2010 that provided Abbvie with global commercialization rights.

Obseva, during its March 5 pipeline update, pointed to positive results for the six-month primary endpoint and all ranked secondary endpoints for both doses from Primrose 2, which enrolled about 500 women. The efficacy and safety of two oral doses of linzagolix are being evaluated, including 100 mg once daily without hormonal add-back therapy (ABT) and 200 mg once daily with ABT. Phase III trials Edelweiss 2 (in the U.S.) and Edelweiss 3 (in the U.S. and Europe) continued to enroll. Each will sign up about 450 women with endometriosis-associated pain, and will test two oral doses of linzagolix, 75 mg once daily without ABT and 200 mg once daily with ABT. The company said it was pursuing a commercial partnership, too. Looking ahead, Obseva said that in the second quarter it would also roll out 12-month data from Primrose 2 and get feedback from U.S. and European regulators on filing strategies for the UF indication.

H.C. Wainwright analyst Raghuram Selvaraju was optimistic. “We anticipate data from [the Edelweiss] studies in late 2020 or early 2021,” he wrote in a March 9 report. “In our view, linzagolix could be launched in the U.S. for UF in late 2021 and obtain a label extension for endometriosis-associated pain in late 2022. We feel that Obseva ought to be able to consummate a U.S. licensing deal on linzagolix later this year, either following the release of data from the Primrose 1 trial or after the release of data from both the Primrose 1 study and the Edelweiss trials.”

Adoption slow process

During its March 5 earnings call, Obseva officials provided insight on the important differences between Primrose 2 and the trials conducted by competitors. Patient populations were not the same (only 5% African-American in Primrose 2 vs. 50% to 70% in studies with Orilissa and relugolix), and there were disparities in body mass indices. On the subject of bone loss seen in Primrose 2, management noted that the FDA specifically asked that the Primrose effort prohibit the use of vitamin D and calcium supplements, since the phase II study in UF was done in a Japanese population only, and gatekeepers wanted to check out the standalone effect in Caucasians. SVB Leerink analyst Ami Fadia zeroed in on that aspect in her March 6 report. “While we do not know whether the Liberty trials for relugolix allowed concomitant use of vitamin D and calcium, the protocol of the Elaris UF trials for Orilissa did not prohibit their use,” she wrote. In the endometriosis work with Orilissa, 83% of patients in the six-month analysis and 86% of patients in the 12-month extension analysis took one or both supplements. The subgroup analysis suggested that the patients taking them turned up 0.48% to 0.65% less bone mineral density (BMD) loss, although the group that didn’t take the supplements was small and the analysis was post-hoc. So “the real-world experience on bone loss of linzagolix, if approved, could be much more benign, as most patients will be recommended to take the supplements,” in Obseva’s view, she said. “On the other hand, the exclusion of these supplements in Primrose 1 means that it may still be difficult to compare the BMD data to the competitors’ trials.”

In February, Fadia’s firm hosted a “fireside chat” with Myovant CEO Lynn Seely and Chief Financial Officer Frank Karbe, who believe the GnRH antagonist class “will continue to grow with time.” They pointed to the treated population of 5 million patients in the U.S. for endometriosis and 4 million for UF, which together suggest “a large potential opportunity,” though adoption won’t happen right away. Myovant plans to partner its product in order to launch with a sales force large enough to address the 36,000 obstetrician-gynecologists available for targeting, and discussions with would-be collaborators are ongoing.

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