First Patient Dosed in China Phase III Trial of Linzagolix, a Novel Oral GnRH Antagonist Offering Flexible Dosing for Long-Term Management of Uterine Fibroids

December 16, 2022Shanghai Baozheng Pharmaceutical Technology Co., Ltd. (hereinafter referred to as “Baozheng Pharma”) announced that the first subject has been enrolled in its China Phase III clinical trial of BG2109 (Linzagolix) for the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women (Drug Clinical Trial Registration Platform: CTR20221747).Linzagolix is a novel, oral, non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist originally developed by KISSEI PHARMACEUTICAL CO., LTD. in Japan and exclusively licensed to Baozheng Pharmaceutical for development in the Greater China region. Linzagolix will fill the gap in the clinical treatment of uterine fibroids in China by providing a safe and effective long-term non-surgical management option for clinical practice.

Linzagolix is administered orally once daily. By binding to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland, it inhibits the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby reducing estrogen levels and treating estrogen-dependent conditions. In June 2022, Linzagolix tablets (brand name Yselty^®) Approved in the European Union and the United Kingdom for the treatment of moderate to severe symptoms of uterine fibroids in women of reproductive age, available in 100 mg and 200 mg doses, which can be used as monotherapy or in combination with add-back therapy (ABT) using estrogen and progestin. Except for the 200 mg monotherapy, which is approved for short-term use (<6 months) to reduce uterine and fibroid volume, the other regimens have no duration limits and allow for long-term use by patients.^[1，2]. Therefore, Linzagolix has becomeThe World's First Approvedand isOnlyGnRH antagonists offering flexible dosing options. Currently, similar drugs marketed overseas for the treatment of moderate to severe symptoms of uterine fibroids include Elagolix (brand name ORIAHNN^®) and Relugolix (brand name MYFEMBREE^®), both are fixed-dose formulations containing the hormone ABT, with a maximum treatment duration of no more than 24 months.^[3，4]. In contrast, Linzagolix forAlso applicable to patients who are unwilling or unsuitable for hormone ABT therapy., the target population is broader, and it can provide multiple regimens for short-term use and/or long-term maintenance therapy, thereby better meeting the individual needs of patients.

The world’s leading medical journal, The Lancet, recently published the results of two pivotal global Phase III clinical trials (the PRIMROSE 1 and 2 studies) evaluating linzagolix for the treatment of uterine fibroids.^[5]。In all once-daily oral linzagolix dose groups, the proportion of patients who achieved the primary clinical trial endpoint for reduction in menstrual blood loss at 24 weeks (i.e., ≤80 mL and ≥50% reduction from baseline) was significantly higher than that in the placebo group (P≤0.003), with the highest response rates observed in the 200 mg monotherapy and combination therapy groups, at 75.5% and 93.9%, respectively.Linzagolix 200 mg group alsoSignificantly reduces the volume of the uterus and fibroidsAt 24 weeks of treatment, the mean uterine volume in participants from two studies was reduced by 31% and 43%, respectively, and the mean fibroid volume was reduced by 45% and 49%, respectively. Linzagolix demonstrated a favorable overall safety and tolerability profile, with no unexpected serious adverse events observed.

Professor Xu Congjian, Dean of the Obstetrics and Gynecology Hospital of Fudan University and Principal Investigator of the Phase III clinical trial of linzagolix for uterine fibroids in China, pointed out:Symptomatic uterine fibroids severely impair reproductive health in women of childbearing age and reduce work productivity and quality of life; pharmacological therapy should therefore be a key option in their clinical management. In obstetrics and gynecology practice, a patient-centered approach should be adopted to continuously explore individualized, safe, effective, cost-effective, convenient, and long-term pharmacological regimens for symptomatic uterine fibroids. Baozheng Pharmaceutical has introduced linzagolix, an overseas originator GnRH antagonist, into the Chinese market. International literature reports that linzagolix is not only highly effective in treating heavy menstrual bleeding associated with uterine fibroids, but also contributes to pain relief, reduction in uterine and fibroid volume, improvement of anemia, and enhancement of quality of life.^[5]. As the only oral GnRH antagonist currently available worldwide that offers flexible dosing regimens, it enables physicians to select individualized treatment plans based on the specific clinical conditions of different patients, with the potential to address an unmet clinical need. We look forward to the smooth conduct of the Phase III clinical trial in China and its expedited approval for marketing, thereby benefiting a broad population of patients with uterine fibroids.

Baozheng Pharma focuses on women’s health in China, deeply cultivating the fields of gynecology and reproductive health that have significant unmet clinical needs. With a profound understanding of women’s needs and clinical challenges, it is committed to providing comprehensive solutions for issues in the field of women’s health. Currently, through a dual-drive strategy of promoting independent research and development as well as introducing external innovations, Baozheng has established clinical and commercialization platforms for the R&D of drugs, health supplements, and medical devices. Uterine fibroids and endometriosis account for two of the top three diseases contributing to the disease burden among women of childbearing age in China.^[6]. Therefore, by first introducing the core product Linzagolix, Baozheng Pharma will provide better treatment options for female conditions such as uterine fibroids, endometriosis, and assisted reproduction (for infertility treatment). Baozheng Pharma will remain committed to addressing clinical pain points, actively responding to and implementing the State Council’s Outline for the Development of Chinese Women (2021–2030) and the Outline for the Development of Chinese Children (2021–2030), thereby enhancing the sense of gain, happiness, and security among women nationwide.

Uterine Fibroids Are the Most Common Benign Tumors in Women, with an Estimated Prevalence of Up to 25% Among Women of Reproductive Age^[7], in addition to genetic factors, estrogen levels are a key regulator of fibroid growth. Uterine fibroids can cause abnormal uterine bleeding and severe menorrhagia, which may lead to secondary anemia that can be life-threatening in severe cases. They are also associated with abdominal and pelvic pressure symptoms, abdominal pain, and may result in infertility.^[7，8]. Currently, the primary treatment modality in China is surgery; however, the postoperative recurrence rate approaches 50%, and approximately one-third of patients require reoperation.^[7], whereas radical total hysterectomy results in the loss of fertility. Clinically commonly used medications primarily include Chinese proprietary medicines, as well as symptomatic treatments such as hormonal contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs), and tranexamic acid. Subcutaneously administered GnRH agonists exhibit a "flare-up" effect, characterized by an exacerbation of pre-existing symptoms during the early phase of treatment. Due to significant risks such as bone mineral density loss, their use is limited to short-term therapy (3–6 months). Upon discontinuation, uterine fibroids often "rebound" to their pre-treatment size.^[7], it is therefore often used as an adjunctive measure to reduce fibroid volume prior to surgery.

[1] ObsEva Press Release,  “ObsEva Announces European Commission Marketing Authorization for Yselty^® (linzagolix), an Oral GnRH Antagonist, for the Treatment of Uterine Fibroids.” June 17, 2022. [Online]. Available: https://www.obseva.com/pressrelease-detail/?pr=5038. [Accessed 14 NOV 2022].

[2] ObsEva Press Release,  “ObsEva Announces UK MHRA Marketing Authorization for Yselty^® (linzagolix), an Oral GnRH Antagonist, for the Treatment of Uterine Fibroids.” June 28, 2022. [Online]. Available: https://www.obseva.com/pressrelease-detail/?pr=5089. [Accessed 14 NOV 2022].

[3] FDA Approved Label for ORIAHNN^® . Revised: 05/2020.

[4] FDA Approved Label for MYFEMBREE^®. Revised: 05/2021.

[5] J. Donnez and H. S. Taylor, Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials. Lancet. 2022 Sep 17;400(10356):896-907.

[6] Ji N, Liu SW, Zeng XY, et al. Study on the disease burden of gynecological diseases in China in 2016. Chinese Journal of Obstetrics and Gynecology. 2018;53(5):313-318.

[7] Chinese Expert Consensus Group on the Diagnosis and Treatment of Uterine Fibroids. Chinese Expert Consensus on the Diagnosis and Treatment of Uterine Fibroids. Chin J Obstet Gynecol. 2017;52(12).

[8] Al-Hendy A, Myers ER, Stewart E. Uterine Fibroids: Burden and Unmet Medical Need. Semin Reprod Med. 2017;35(6):473-480.