Uterine fibroids

Overview

Uterine fibroids are common fibrous or muscular growths of the uterus. While the exact cause of fibroid development is not fully understood, lifestyle, environment, and inherent, though currently poorly understood, biological factors are all believed to play a role. Prevalence ranges enormously, with estimates ranging from 45% to 69% of women, with the highest rates seen in women of African descent. Around 20-40% of women with fibroids experience pelvic pain, often caused by pressure on pelvic organs or fibroid deterioration, along with abnormal uterine bleeding, such as heavy periods or bleeding between periods. Fibroids can also affect fertility, cause pregnancy-related complications, lead to urinary problems, and contribute to anaemia.

Unmet needs

Despite the significant clinical impact of uterine fibroids on women’s health and well-being, there is currently very limited understanding of their basic pathogenesis. Better basic biological research is needed to guide the development of novel diagnostics and treatments. Diagnosis is typically achieved through ultrasound or MRI, with current treatment options including anti-inflammatory drugs for pain and bleeding management, and hormone therapy or surgery. Diagnosis and treatment are also generally expensive – costs range from USD $11,000 to $25,000 per patient annually in the United States – and are out of reach in most LMICs, where access to high-tech diagnostic tools and surgical treatments is limited. Currently, repurposed hormone medications, like gonadotropin-releasing hormone (GnRH) agonists and ulipristal acetate, are the only FDA-approved treatments, but all have limited efficacy, and access to them in LMICs remains a challenge. Current research is focused on repurposing additional hormonal therapeutics, anti-inflammatories (N-acetylcysteine) and cancer drugs, such as letrozole, as potential treatments to reduce fibroid size.

Funding

Funding for uterine fibroids totalled $12m in 2023, the first year in which it was included in the G-FINDER scope. As with most other gynaecological conditions, the vast majority of this funding was for basic research ($11m, 86%), reflecting the difficulties presented for product development by the lack of a thorough understanding of these conditions. Drugs received the next largest share ($1.7m, 14%), while diagnostics accounted for only 1% of the total funding ($0.1m). There was no funding reported for either biologics or devices & combinations.

Of the $1.8m devoted to product development for uterine fibroids, a little under half was US NIH support for post-registration studies of the drug letrozole, which can shrink fibroids by reducing estrogen production within the fibroid cells. Almost all of the remainder went to a Phase II study on fertility improvement with epigallocatechin gallate (EGCG), which was also entirely funded by the NIH. The tiny amount of funding for diagnostics came from a combined grant exploring the use of stress strain ultrasound imaging for the detection and characterization of endometriosis and uterine fibroids.

The NIH was responsible for essentially all the global funding for uterine fibroid R&D in 2023 (99.7%), the sole exception being a small, $40k, grant from the UK Medical Research Council for basic research.

Funding for Uterine Fibroids

Product landscape & pipeline

The landscape of biomedical products in use or in development for uterine fibroids is very limited, despite the high prevalence of the condition. In cases of symptomatic fibroids where medical treatment is needed, surgical removal, preceded by hormonal treatment to shrink their size, is the current standard of care. However, alternatives to surgical treatment for this condition are limited, and the R&D landscape is not very diverse, offering few options to disrupt its diagnosis and treatment. With just 42 medicines (including 36 repurposed), four devices and only three iterations of imaging approaches for diagnosis, there doesn’t appear to be the same level of dynamism as other gynaecological conditions

The medicines landscape for uterine fibroids includes 14 marketed products and 28 candidates in development – bearing in mind marketed products cover symptomatic treatment of fibroids and their size over any novel approaches to address their underlying cause.

Indeed, 12 of the 14 medicines marketed for the treatment of uterine fibroids are repurposed drugs, including a number of contraceptives (four) or GnRH antagonists (seven) whose hormonal impact can reduce fibroid-related bleeding and anaemia, uterine volume and fibroid size. The latter includes five repurposed drugs and two new chemical entities or combinations that have been developed specifically for uterine fibroids: relugolix combined tablet and linzagolix. Contraceptive drugs include combined contraceptive pills and progesterone-only contraceptive pills, which can help control heavy menstrual bleeding without affecting fibroid size. Progesterone receptor modulators are also used: ulipristal acetate and mifepristone can reduce mean blood loss and the size of fibroids.

Non-hormonal treatments include NSAIDs for the management of fibroids-related pain, and with a potential beneficial impact on blood loss. The antifibrinolytic agent tranexamic acid is also a first-line non-hormonal therapy for heavy menstrual bleeding, but its use is potentially associated with an increased risk of venous thromboembolism.

Candidates in development include one biologic, the repurposed injectable collagenase clostridium histolyticum developed to treat collagen-related conditions and currently in Phase I studies for its effects on fibroids’ stiffness, and 27 drugs, with ten novel biological entities. The latter includes several new chemical entities initially investigated for cancer treatment, such as 2-methoxyestradiol, currently in discovery and preclinical for their potential impact on fibroids. Most other NCEs under investigation follow traditional (hormonal) therapeutic avenues explored for uterine fibroids, which signals limited innovation.

Similarly, eight of the 27 drug candidates are repurposed hormonal treatments routinely used in gynaecology, including for cancer treatment, with a potential impact on menstrual bleeding, pelvic pain and fibroid volume.

Other avenues explored to reduce fibroid size include anti-inflammatory drugs, such as N-acetylcysteine (NAC); anti-cholesterol drugs like simvastatin (Phase II); and prolactin-lowering agents marketed for hyperprolactinemia and neuropathic conditions for both uterine fibroids and endometriosis (Phase III).

Two antihypertensive drugs and the beta-blocker propranolol have also been associated with reduced uterine fibroid incidence in retrospective nested case-control studies, suggesting a protective role and potential therapeutic applications.

Overall, the R&D space for uterine fibroids seems to suffer from a general lack of interest and investment, leading researchers to try out existing drugs, but devoid of truly innovative and ambitious research investigating and treating the root cause. None of the therapeutics used or investigated have the ability to prevent fibroid growth or resurgence, with the only option for removal remaining surgical treatment, albeit with no guarantee against recurrence. Women suffering from symptomatic uterine fibroids are only offered options that might marginally improve their symptoms, but cannot hope for a complete resolution of the condition.

Devices used and developed for uterine fibroids have the same limitations as mere symptomatic treatment. Two devices originally developed for contraception and hormone-dependent cancers are approved for the treatment of uterine fibroids: the levonorgestrel IUS can reduce heavy menstrual bleeding and improve pain symptoms, and the goserelin (GnRH agonist) implant is specifically recommended as pretreatment for women undergoing surgical removal of uterine fibroids. Two additional devices are in discovery and preclinical: a raloxifene-loaded drug-eluting insert for intrauterine administration has been tested in rabbits for enhanced targeting efficiency; and the Womed Leaf intrauterine device, designed to prevent adhesions and developed conjointly for endometriosis and uterine fibroids, with two specific drugs: Fibroid for preoperative fibroid treatment and ReLeaf for alleviating uterine fibroids pain. abnormal bleeding and improving fertility.

There are only three diagnostics currently in use or in development for uterine fibroids, all based on imaging techniques: ultrasound is the gold standard, and MRI is a tool for more precision. Additionally, an AI-supported diagnostic tool is being developed by researchers from Huazhong University of Science and Technology to support ultrasound interpretation and uterine fibroids diagnosis. No alternative technical approaches seem to be explored for diagnosing uterine fibroids, including biomarkers, meaning that there is very little hope of revolutionary diagnostic approaches to this condition being available in the near or long-term future.

Uterine fibroids pipeline