Endometriosis

Overview

Endometriosis is a chronic, estrogen-dependent condition that causes endometrial-like tissue to grow outside of the uterus, commonly affecting organs such as the ovaries, bladder, and bowel. It leads to debilitating symptoms such as chronic pelvic pain, painful periods, and infertility.  Over 60% of women with endometriosis experience persistent pain. The condition is estimated to affect at least 10% (190 million) of reproductive-aged women globally, with prevalence varying significantly, particularly between LMICs. However, these figures are likely to represent a significant underestimate, due to challenges in diagnosing the condition, a historical tendency to dismiss women’s pain, and a paucity of consistent health data on this issue globally. A recent systematic review estimated prevalence at 18% globally. In LMICs, especially, data on endometriosis is sparse or unavailable due to diagnosis relying on specialised surgical care, which is often unavailable.

Unmet needs

Endometriosis is poorly understood, hard to diagnose (without invasive procedures), and has no cure. Current treatments primarily focus on managing symptoms, such as pain relief and hormonal therapies like contraception. However, these approaches do not address the underlying causes of the condition. As a result, the disease may continue to progress, potentially leading to chronic complications, including infertility. Diagnosis can take years due to the lack of non-invasive options, with definitive diagnosis ultimately requiring surgery. The challenge this condition presents to women is even greater in LMICs, where limited diagnostic tools and specialised care, along with stigma and financial barriers, contribute to delays in obtaining treatment. There is an urgent need globally for more accessible diagnostics, including biomarker-based and non-invasive tools suitable for low-resource settings, as well as research into targeted therapies that address the underlying causes of endometriosis, for example by preventing tissue migration and reducing lesions’ size. Promising candidates include FOR-6219, an inhibitor of 17β-Hydroxysteroid Dehydrogenase 1, which blocks the formation of estradiol, reducing endometriotic lesions and pain, and HMI-115, a prolactin receptor monoclonal antibody, which showed beneficial impact on pain in a Phase II study.

Funding

Global funding for endometriosis totalled $28m in 2023, the first year in which it was included in the G-FINDER survey. This is far below the R&D funding received by other conditions with similar prevalence, as outlined in our recent report on women’s pain. Over half of all endometriosis R&D funding in 2023 was for basic research ($17m, 59%), reflecting a gradually awakening interest in filling gaps in our knowledge of the disease’s basic pathology.

Drugs received the next largest share of funding ($6.5m, 23%), including $0.6m from the NIH for the use of heated nanoparticles to destroy lesions, alongside other NIH-backed projects like a $20k Phase II study into repurposing botulinum toxin for pain management, and $0.9m for a Phase III study of repurposing GnRH antagonist.

Despite the urgent need for diagnostics beyond laparoscopic surgery, just 11% ($3.2m) of funding was dedicated to diagnostic development.

Apart from a small grant ($0.02m) from the Society for the Advancement of Gynecologic Excellence, a Canadian philanthropic organisation, all endometriosis funding came from the public sector, with 90% of all funding originating from the US NIH ($25m). Contributions from the eight other funders lagged far behind, headlined by the European Commission’s $1.1m (4% of total funding, for diagnostic development), the French National Research Agency ($0.7m, 2%, for basic research) and the Australian National Health and Medical Research Council ($0.4m, 2%, for basic research and drug development).

With funding coming mostly from high-income country research organisations – as they begin to acknowledge the scale of endometriosis’s burden following high profile advocacy in this area – two LMICs also funded research for endometriosis: the Argentinian National Council for Scientific and Technical Research (CONICET) contributed $20k, and the Indian Department of Biotechnology, Ministry of Science and Technology (DBT) contributed $200k.

Just 7% ($1.9m) of endometriosis funding went specifically to clinical development, all of it from the NIH for drug trials, partly reflecting the big share of funding still devoted to basic research, and implying that sufferers face a long wait for approved products.

Funding for endometriosis

Product landscape & pipeline

As with several other women’s health conditions, a poor understanding of the pathology of endometriosis is limiting the development of biomedical products to diagnose and treat it. The landscape of therapeutics available or in development for endometriosis is limited to symptomatic treatments rather than medicines to treat and ultimately cure the underlying cause. This is alongside a heavy reliance on repurposed drugs, common to many gynaecological conditions, reflecting a rational need to leverage existing approaches to treat symptoms and alleviate women’s suffering now, albeit at the expense of innovation. Promisingly, diagnostics research focuses on biomarkers, which have the dual potential to offer non-invasive, precision testing while also elucidating much-needed insights into the disease itself. Only one has made it to market, though, and two-thirds are still in early development.

In total, 107 medicines are in use or development for the treatment of endometriosis. Of these, 27 products are approved or adopted in clinical practice and recommended in clinical guidelines (25%). While this would suggest a reasonable number of therapeutic options, most of them (24, 89%) are repurposed medicines, initially developed for either general pain management (3) or hormonal therapies (hormone-dependent cancers, contraception, 21). Although both approaches have a beneficial effect on pain, and with hormonal therapy, endometrial lesion size and growth, they are not a cure. Thirteen of the hormonal therapy treatments comprise existing combined oral contraceptives or progestogens (recommended as first-line treatment for endometriosis-related pain), with an additional nine gonadotropin-releasing hormone (GnRH) analogues, antagonists or agonists, originally developed for the management of hormone-dependent cancers and which can slow down the progression of endometriosis. Three GnRH-impacting drugs are new chemical entities developed specifically for endometriosis and uterine fibroids: relugolix alone, relugolix combined tablet (with estradiol, and norethindrone acetate) and SHR7280. Additionally, danazol, a synthetic steroid with anti-gonadotropic and anti-estrogenic properties and was the first FDA-approved treatment for endometriosis, but its use is currently restricted due to safety concerns (particularly liver toxicity). In general, the use of GnRH agonists/antagonists presents risks in terms of bone mineral density loss and side effects. As a result, clinical guidelines recommend limiting their use to 6 to 12 months and adding hormone replacement therapy, such as the synthetic steroid Tibolone, to minimise risks and side effects.

The pipeline of endometriosis medicines in development is also characterised by a high proportion of repurposed drugs and biologics, with 34 new chemical entities out of the 80 candidates (43%). Among the 46 repurposed drugs, nine are drugs developed to decrease estrogen production for hormone-dependent conditions, either GnRH agonists/antagonists or analogues, estrogen receptor modulators (raloxifene) or aromatase inhibitors (letrozole). Other types of repurposed drugs are those marketed for psychiatric and neurological indications (such as epilepsy, Parkinson’s or neuropathic pain), mainly investigated for pain management in the context of endometriosis. Anti-inflammatory drugs, such as prednisolone and quercetin, are also being explored, as well as general class antibiotics, the latter used to treat infections of endometrial tissue, but also explored for their potential impact on lesions and pain symptoms. New chemical entities (31) are generally less advanced than repurposed drugs in their development, with no candidates in Phase III, albeit with a handful in Phase II (10). While several of them follow traditional hormonal therapeutic avenues, some are more innovative, such FOR-6219, a novel small molecule inhibitor of 17β-Hydroxysteroid Dehydrogenase 1 developed by Organon, which blocks the formation of estradiol, reducing endometriotic lesions and pain without affecting natural hormone or ovarian function.

Thirteen biologics are under investigation, with the most advanced being repurposed products routinely used in fertility treatments (two in Phase III). Novel biologics are either in the discovery and preclinical phase or in Phase II, the latter including HMI-115, a prolactin receptor monoclonal antibody, AMY109, targeting inflammation and pain, and MT 2990, a monoclonal antibody targeting interleukin-33 for treating pain associated with endometriosis.

Both available therapeutics and medicines in development reflect a stab-in-the-dark approach, where numerous (mostly existing) drugs are tried out to address multiple symptoms and issues and find what works. There is also very little innovative research. This probably reflects decades of underfunding, leaving researchers with limited means and leading them to explore existing options rather than develop ambitious approaches to elucidate and treat the root cause of endometriosis. While the medicines used and investigated provide some improvements for patients, their efficacy is limited and variable, and most women have to keep experiencing debilitating pain and disease progression, even when diagnosed and treated.

Devices are also explored and used for the treatment of endometriosis, with three hormonal repurposed implants already used in a clinical context: the contraceptive levonorgestrel IUS and the etonogestrel-based implant, and the goserelin (GnRH agonist) implant, usually used for hormone-dependent cancers. Devices in development include three drug delivery systems, such as a progestin vaginal ring (human safety and efficacy) and the anastrozole vaginal ring (discovery and preclinical). and four devices developed for homecare with pain management as their main indication, such as the Angel Touch device (magnetic field irradiation). Devices – also then – don’t appear to be following innovative research avenues for the treatment of endometriosis beyond its symptoms. 

Current surgical diagnostic options for endometriosis are invasive and not always accessible. So, although the diagnostic landscape appears small – there are just 14 candidates in the pipeline and one marketed product - it is largely biomarker-based, and as such rather interesting. The single-marketed test is Ziwig’s Endotest, a saliva-based diagnostic which detects a signature of 109 miRNAs identified through artificial intelligence. The majority of diagnostics in development (11) are also biomarker-based, with four having reached late development studies evaluating their diagnostic performance, including Aspira Women's Health’s EndoCheck and MDNA Life Sciences’ Mitomic Endometriosis Test (MET), both using serum protein biomarkers. Only two diagnostic tests in development are based on imaging technologies, both in early development: the MRI contrast agent Spagopix developed for tumour-selective MRI, and 3D/4D transperineal ultrasound for the detection of deep infiltrating endometriosis via measurements of the pelvic floor muscle. Two tests are based on visual examination of the anogenital distance (AGD), also a parameter used in a multiparametric screening tool developed by the University of Melbourne to rule out endometriosis based on AGD and medical history.

While diagnostic R&D appears to be a more innovative field than the medicine pipeline, the small number of candidates and their level of advancement reflect limited investment and suggest delays before non-invasive tests reach the market. Considering current issues in diagnosing endometriosis and the severe consequences they have for women, including years of delay in obtaining answers, the landscape and pipeline for endometriosis diagnostics suggest an institutional and historical neglect that is yet to be truly compensated.

Endometriosis pipeline

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