Baozheng Pharma Files IPO Prospectus for Linzagolix: The World’s First Orally Administered, Flexible-Dose GnRH Antagonist Addressing Pain in Over 30 Million Women

If you are a patient with endometriosis (hereinafter referred to as “endometriosis”), you may experience severe dysmenorrhea, chronic pelvic pain, and even infertility, depression, and anxiety. More distressingly, these symptoms may persist from menarche (the first menstrual period) until menopause.

According to WHO data, endometriosis affects approximately 10% (190 million) of women of reproductive age worldwide. Currently, there is no cure; the condition is commonly referred to as "benign cancer." Existing treatment modalities primarily aim to control symptoms and include surgical intervention and long-term pharmacological management. The postoperative recurrence rate shows a year-on-year upward trend, reaching up to 50% within five years after surgery.

If you are a patient with uterine fibroids, you may also experience dysmenorrhea and menstrual changes, which can lead to secondary anemia and infertility. According to the Chinese Expert Consensus on the Diagnosis and Treatment of Uterine Fibroids (2017), the prevalence among women of reproductive age can reach 25%, while autopsy statistics indicate an incidence rate of up to 50%.

Uterine fibroids and endometriosis rank as the top two contributors to the disease burden among women of childbearing age in China. However, the pharmaceutical market for these conditions continues to remain sluggish.Common therapeutic agents include nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal medications, combined oral contraceptives (COCs), and GnRH agonists. Issues such as suboptimal efficacy, impairment of daily activities, difficulty in individualized dose adjustment, and adverse reactions associated with long-term use often lead patients to discontinue treatment, resulting in disease recurrence and diminished quality of life.

On December 16, 2022, and July 14, 2023, Linzagolix, a GnRH receptor antagonist exclusively licensed by Baozheng Pharma, completed the enrollment of the first patient in its Phase III clinical trials for uterine fibroids and endometriosis. The drug is indicated for the treatment of moderate to severe symptoms of uterine fibroids and endometriosis-associated pain in adult women of reproductive age.As the first orally administered GnRH antagonist with flexible dosing, Linzagolix will provide a novel long-term management solution for uterine fibroids and endometriosis.

Gonadotropin-releasing hormone (GnRH) is a peptide secreted by the hypothalamus that acts on GnRH receptors to stimulate the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This subsequently induces the gonads to produce various hormones, playing a crucial role in reproductive regulation and forming the hypothalamic-pituitary-ovarian axis.

In recent years, highly active GnRH analogs have been extensively synthesized and introduced into clinical practice, primarily categorized into injectable GnRH agonists and GnRH antagonists.

Injectable GnRH agonists are regarded as the “gold standard” for pharmacological management of endometriosis in the Chinese Expert Consensus on Long-term Management of Endometriosis. Once GnRH agonists take effect, exogenous GnRH-a occupies GnRH receptors, rendering the pituitary gland unresponsive to GnRH, suppressing ovarian function, and reducing estrogen secretion to postmenopausal levels. In clinical practice, GnRH agonists can effectively alleviate endometriosis-associated pain symptoms and reduce lesion size to a certain extent.

Although GnRH agonists are highly feasible hormone replacement drugs, they present numerous challenges in clinical application:

1. The current route of administration is subcutaneous or intramuscular injection, with one dose every four weeks, resulting in poor patient convenience and accessibility.

2. After binding to GnRH receptors, GnRH agonists initially cause a transient surge in the release of FSH and LH, leading to a rapid increase in estrogen levels and exacerbating symptoms in patients over the short term, a phenomenon known as the “flare effect.” Therefore, patients using GnRH agonists must endure an initial worsening of their condition and wait several weeks before the therapeutic effects take place.

3. After 2–3 weeks of continuous administration, the receptors become fully occupied or depleted, leading to desensitization of pituitary GnRH receptors and loss of sensitivity to GnRH agonists. This results in a significant decrease in FSH and LH levels, thereby suppressing estrogen production.However, women with normal menstrual cycles typically require approximately three months after discontinuation of the medication to resume ovulation. Patients attempting to conceive must endure a prolonged waiting period for the recovery of pituitary function, while the extremely low estrogen levels can lead to significant perimenopausal symptoms, including hot flashes, vaginal dryness, mood instability, and sleep disturbances.

GnRH antagonists, characterized by the absence of a flare effect, rapid onset of action, and swift recovery of pituitary function, have rapidly entered this arena as strong competitors, addressing clinical dilemmas.

GnRH antagonists competitively bind to GnRH receptors, directly inhibiting the hypothalamic-pituitary-gonadal axis, resulting in a rapid decline in FSH and LH levels after administration.Unlike agonists, GnRH antagonists can be administered at any time during the follicular phase and produce an immediate inhibitory effect, andPituitary function recovers within 2 to 4 days after discontinuation of the medication.。

Linzagolix, a non-peptide GnRH receptor antagonist introduced by Baozheng Pharma, is the world’s first orally administered small-molecule GnRH antagonist with adjustable dosing.

Based on the dose-dependent characteristics of its inhibitory effects, Linzagolix has introduced adjustable dosing regimens, including 100 mg and 200 mg, which can be used either as monotherapy or in combination with add-back therapy (ABT) using estrogen and progestin.

According to the results of the global Phase III clinical trials (PRIMROSE 1 and 2) on uterine fibroids published in The Lancet, all four dosing regimens of linzagolix (100 mg monotherapy, 200 mg monotherapy, and each combined with ABT) demonstrated significant efficacy in reducing menstrual blood loss in patients. The highest response rates were observed in the 200 mg plus ABT group, reaching 75.5% and 93.9%, respectively.

Secondly, the 200 mg monotherapy group significantly reduced uterine and fibroid volumes. In two pivotal Phase 3 studies, the mean uterine volume decreased by 31% and 43% from baseline, respectively, while the mean fibroid volume was reduced by 45% and 49%, respectively.

For patients who are not suitable for hormonal add-back therapy, a monotherapy regimen of either 200 mg or 100 mg can also meet treatment needs.This means that linzagolix allows for the selection of individualized dosing regimens based on the condition of patients with uterine fibroids.

In June 2022, Linzagolix tablets were approved for marketing in the European Union and the United Kingdom for the treatment of uterine fibroids with moderate to severe symptoms in adult women of reproductive age. On December 16, the first subject was enrolled in the Phase III clinical trial of Linzagolix in China.

In addition to treating menstrual bleeding caused by uterine fibroids, Linzagolix tablets also provide a long-term pharmacological management option for endometriosis. Phase 2 EDELWEISS clinical trial results in the treatment of endometriosis demonstrated that Linzagolix significantly alleviates endometriosis-associated pain. Doses of 75 mg, 100 mg, and 200 mg all significantly improved dysmenorrhea, overall pelvic pain, defecation pain, and patients’ health status (Quality of Life).

“As an oral medication, Linzagolix tablets offer greater portability and patient accessibility, more diverse usage scenarios, and enhanced privacy. This is truly a convenience for our female patients,” said Ji Baohua, founder of Baozheng Pharma, in an interview with VCBeat.

In the European Union, except for the 200 mg monotherapy regimen, which is approved for short-term use of less than 6 months to reduce uterine and fibroid volume, other regimens of Linzagolix tablets have no duration limits, allowing for long-term patient use.

“In recent years, topics such as medical aesthetics and reproductive health have gained increasing traction, with many women willing to spend on consumer healthcare. However, when these women actually develop diseases that impair their quality of life, they often find a lack of effective medications available in hospitals. This is a significant concern,” stated Ji Baohua. He pointed out that gynecological diseases remain severely under-prioritized globally, and the gap in innovative drug R&D represents another major challenge.

Domestic innovative gynecological drugs face the same issue: there is a huge clinical demand, but a lack of novel drugs.Ji Baohua stated, “This gap is being filled by hormone preparations and contraceptives derived from Chinese patent medicines, generic drugs, and active pharmaceutical ingredients (APIs). However, clinical needs have not been directly met, leaving substantial room for future development.”

Leveraging this potential, Baozheng Pharma is driving growth through a dual strategy of independent R&D and license-in partnerships, establishing clinical and commercialization platforms for the development of pharmaceuticals, health supplements, and medical devices. Ji Baohua emphasized,“A true product is one that addresses clinical pain points by developing clinical drugs.”

Baozheng Pharma’s first in-house R&D pipeline targets the field of assisted reproduction for women. According to response data from the National Health Commission, the total number of treatment cycles for various assisted reproductive technologies exceeded 1 million in 2022, with over 300,000 live births. Meanwhile, Beijing and Liaoning have successively incorporated assisted reproductive technologies into their medical insurance coverage. As a highly sought-after niche segment within the assisted reproduction industry, in vitro fertilization (IVF) is garnering increasing attention.

However, in clinical practice, more subtle needs remain unaddressed. IVF patients often suffer from endogenous progesterone deficiency and thus rely heavily on exogenous hormonal support for luteal phase maintenance during the transfer cycle. The traditional method of luteal support is intramuscular injection of progesterone. However, as progesterone is formulated in an oil-based vehicle, its absorption by tissues is slow, frequently leading to muscle induration, pain, redness, and swelling, causing significant distress to women undergoing IVF treatment.

In addition to intramuscular injection, a novel approach for progesterone supplementation is the administration of vaginal gel. This method offers greater convenience and reduced pain; however, it has certain limitations, including the propensity for residual medication to cause vaginitis, contraindication in patients with uterine bleeding, and patient concerns regarding potential adverse effects on the fetus.Baozheng Pharma is independently developing a novel progesterone delivery system designed to enhance safety and tolerability while ensuring therapeutic efficacy. The project is currently being advanced with full momentum.

“After sharing at a conference, I received a friend request that read, ‘I am that one in ten patients with endometriosis.’ It was truly inspiring,” mentioned Ji Baohua. “Therefore, Baozheng Pharma is committed to providing Chinese women with more accessible, high-quality, and convenient solutions.”

Addressing the pressing clinical needs in gynecology, Baozheng Pharma will next target conditions such as menopausal syndrome and preterm birth syndrome. VCBeat will continue to monitor these developments closely.