Myovant Sciences’ gonadotropin-releasing hormone (GnRH) antagonist relugolix may suffer from limited acceptance in endometriosis-related pain due to lack of dosing options compared to its competitors. 

While efficacy differences between the GnRH antagonists are tough to determine based on available trial data, the convenience that comes from being able to choose a dose and consequently use add-back therapy will likely be an important factor for uptake.

While a once-daily schedule is a significant advantage for relugolix compared to AbbVie’s approved twice-daily Orilissa (elagolix), it is one that ObsEva’s Phase III linzagolix also possesses. Relugolix is being evaluated at one high dose with add-back therapy, but Orilissa is available in two dosage strengths and linzagolix is being trialled at two doses with or without add-back therapy.

Add–back therapy is the addition of a small amount of the hormones estrogen and progesterone or progesterone alone. 

Topline results from relugolix’s Phase III SPIRIT 2 (NCT03204331) and SPIRIT 1 (NCT03204318) trials are expected in 1Q20 and 2Q20, respectively, as per a 21 October press release. The data release is expected to trigger a share price movement of 15–20%, according to an analyst report. Myovant’s market cap is $1.25bn.

In endometriosis-related pain, relugolix sales are estimated to reach $850m in 2025, as per GlobalData. Orilissa is estimated to reach $750m in 2024, according to a second analyst report.

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By GlobalData

Phase III (NCT03992846 and NCT03986944) linzagolix data is expected by year end 2021, as per the first analyst report. Its sales are estimated to reach $603m in 2025, as per GlobalData.

Myovant did not respond to a request for comment.

Dose flexibility offers convenience

All the GnRH antagonists seem effective in suppressing hormone levels as per the intended mechanism, said Orilissa investigator Dr Hugh Taylor, chief of Obstetrics and Gynecology, Yale-New Haven Hospital, Connecticut. While there may be some subtle differences among them, the absence of long-term data makes it difficult to fully assess the distinction, added a relugolix investigator.

The main differences between the GnRH antagonists are based on the dose and presence or lack of add-back therapy, noted Taylor and the investigator. Add-back therapy is used to counter side effects due to GnRH antagonists’ action, such as loss of bone mineral density.

Relugolix’s strategy is not amenable to titration, as the trial appears to evaluate high-dose suppression with add-back therapy with no other options, said Taylor. SPIRIT1 and SPIRIT2 are evaluating a 40mg relugolix dose with 1mg estradiol/norethindrone acetate for 24 weeks versus relugolix alone for 12 weeks followed by relugolix with add-back therapy for another 12 weeks versus placebo.

Having a treatment option without the presence of add-back therapy is beneficial, said the investigator. Multiple options allow physicians to increase or decrease a dose based on a patient’s response, said Dr David Archer, professor of obstetrics and gynecology for the Jones Institute for Reproductive Medicine, Norfolk, Virginia, US. While a physician could consider off-label dosing, the responsibility in relation to safety and efficacy then lies with the prescriber rather than manufacturer, added the investigator. Furthermore, dosing flexibility helps patients feel more in control, noted Dr Susan Khalil, director, Sexual Health, Mount Sinai Hospital, New York.

It may be beneficial to use the lowest effective dose first with no additional hormones, Taylor said. Some physicians may also prefer to start at the highest dose and then step down, said Archer. For example, a patient who is started on the Orilissa high dose can usually be switched to the lower dose once pain control is sufficient, Taylor noted.

Orilissa is approved at two doses: 150mg once daily and 200mg twice daily. An ongoing Phase III endometriosis-related pain study (NCT03213457) is evaluating Orilissa/add-back therapy. The trial recruited patients until April 2019, after which its status was changed to “active, not recruiting” on the website. 

Since antagonists are absorbed better than agonists, the ability to titrate-up a dose is an advantage over agonists used to treat endometriosis pain, like leuprorelin acetate, Archer said,

While the safety, tolerability and efficacy of a GnRH antagonist/add-back approach are generally good, cost-effectiveness remains a challenge, said Dr Paolo Vercellini, professor of obstetrics and gynaecology with the department of clinical sciences and community health at the Università degli Studi, Milan. However, low-dose GnRH antagonist monotherapy can have reduced clinical effectiveness compared with full-dose treatment and still requires barrier contraception, he explained. Depending on the level of ovarian suppression, add-back therapy may be needed in any case, said Vercellini.

Once-daily aids uptake considerations

Relugolix’s once-daily schedule is attractive compared to Orilissa’s twice-daily regimen, said Taylor. Patients do not need to carry the drug with them during the day and the compliance rate is better, added the investigator. Furthermore, Myovant’s add-back strategy allows for a higher dose to be given for a longer time, said the investigator. With long-term therapy, physicians can try a few different options, like incorporating oral contraceptives or hormone replacement drugs as add-back therapies, the investigator added.

Linzagolix is also attractive because of its longer-acting half-life compared to Orilissa, which allows once-daily dosing, said Taylor, adding studies are exploring linzagolix with or without add-back therapy.

Usage will boil down to a physician’s comfort level and whether they have used a particular drug, said Archer. Orilissa is the first drug has that advantage, Archer added. Orilissa was FDA-approved on 24 July 2018. AbbVie reported $59m Orilissa revenues for 1Q19–3Q19 in its 3Q financials.

Efficacy expected to be in line with Orilissa

Orilissa, relugolix and linzagolix have largely comparable efficacy based on existing trial data, experts noted. Nonetheless, trial outcomes depend on patient perspectives, said Khalil. It will be easier to see the impact of the pharmacokinetic differences between the drugs once they have all been used in the real-world setting for longer than just clinical trials, she added. The relugolix studies measure the primary endpoint over six months, which will give better data on response sustainability, said the investigator. The primary endpoint in the Phase III linzagolix study is at three months, while six-month Orilissa data is available.

Relugolix may be more potent than Orilissa, since it is active at 40mg compared to the latter’s highest dose of 200mg, said Archer. However, there has been no data to show how potency impacts pituitary secretion of follicle-stimulating hormone, he noted.

Relugolix’s 487-patient Phase II study was conducted in Japan by Takeda Pharmaceutical, which licensed certain rights to Myovant in 2016, and showed that a change in baseline visual analog scale score for pelvic pain during last four weeks of treatment in a 12-week period was -3.222 with placebo, -11.924 with 40mg relugolix and -12.552 with leuprorelin, a GnRH agonist (Osuga et al; Endocrine Abstracts (2017) 49 GP134). SPIRIT 1 and SPIRIT2 are using the Numeric Rating Scale to measure the proportion of responders for dysmenorrhea and nonmenstrual pelvic pain based on a daily assessment.

The two scales are comparable and relatively sensitive in quantitating pain, albeit largely subjective, Archer said. It can be difficult for patients to report on a daily basis, the investigator said. The trials will give a good idea about efficacy, but the rest will have to come from real-world experience, noted the investigator. It is difficult to compare the Orilissa data to relugolix in terms of responses as pain assessment can be subjective even with the same patient, said Archer. Orilissa was approved based on an improvement in the percentage of responders who reported a change in the Dysmenorrhea pain scale and Non-Menstrual Pelvic Pain scale.

by Manasi Vaidya in New York

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.