NEW YORK – While endometriosis is a common cause of debilitating menstrual pain, the few options for noninvasive diagnostic testing remain out of reach for many patients, and the disease can remain unidentified for years or more than a decade.
Endometriosis is known to affect roughly 10 percent of women of reproductive age and involves the growth of tissue that is similar to the lining of the uterus in other locations including on or under the ovaries, on the fallopian tubes, and on the bowels or bladder. It can cause pelvic pain, inflammation, and infertility as well as nonspecific symptoms such as bloating or fatigue and is associated with increased risk of ovarian cancer and autoimmune diseases. Treatment can involve pain relief, hormone therapy, and surgery to remove affected tissue or sever certain nerves.
The gold standard for endometriosis diagnosis is laparoscopic surgery with histological confirmation, yet those methods are unavailable for many patients due to regional shortages of surgeons who are trained to identify lesions from the disease. The disease also is often overlooked because of a normalization of menstrual pain by both patients and healthcare providers.
Idhaliz Flores, a professor and endometriosis researcher at Ponce Health Sciences University in Puerto Rico, said study results suggest that the disease is diagnosed anywhere from five to 12 years following the onset of symptoms. Physicians are increasingly reaching a diagnosis without surgery through the clinical presentation that is characteristic for endometriosis, including severe menstrual pain that is unresponsive to over-the-counter medications, pain during intercourse, and infertility, but diagnosis remains delayed in most cases.
In an effort to address these issues, the US National Institutes of Health's Rapid Acceleration of Diagnostics Technology (RADx Tech) program recently announced it will give $3 million in prizes to fund the development of noninvasive tests that could be used to modernize the diagnosis of endometriosis. The top three entries in the RADx Tech ACT ENDO Challenge will receive $600,000, $500,000, and $400,000 each and runners-up will receive $100,000 each.
In addition to those prizes, the NIH also plans to spend $1 million to support test development by those teams.
Candace Tingen, chief of the Gynecologic Health and Disease Branch of the NIH's National Institute of Child Health and Human Development, said that primary care providers often think that the symptoms of endometriosis are "just a painful period" or they attribute them to other conditions such as irritable bowel syndrome or interstitial cystitis. Family members who have experienced similar pain tend to minimize it as a normal part of menstruation.
The NIH hopes to spur the development of a test that could give more patients answers without surgery, perhaps even through home-based sample collection.
"We're looking for something that could really be used in all women, accessible to all women, no matter where they live, no matter who their clinician is, to really be able to cut down on that diagnostic delay," Tingen said.
Earlier treatment could help reduce the risks of ovarian cancer and autoimmune disease, alleviate pain, and help to prevent the neurological changes that result in increasing sensitivity to pain following long-term suffering, Tingen said. That process, known as central sensitization, is believed to be the connection between endometriosis and migraines or increased jaw, back, and genital pain.
"This is pain that is so severe that it is immensely impacting these women's quality of life, and this happens from when they're 12 to when they're 51," she said.
The challenge is intentionally open to a broad range of diagnostic technologies, Tingen said. In addition to the developers of blood-based tests, entrants have included teams with expertise in developing imaging-related probes, algorithms to assess data from an MRI, wearable devices that could be used to detect contractions in the uterus or gut, and applications to analyze electronic health records for reports that are consistent with endometriosis.
When a primary care physician or gynecologist suspects endometriosis, expertise is needed to find the often small and hidden lesions that are characteristic of the disease, Flores said. Even if a patient has adequate insurance coverage for the surgery, the procedure still may be unavailable due to a shortage of local gynecologists with training to perform it.
Some cases may be diagnosed, however, through ovarian cysts and lesions that are visible through ultrasound or MRI, Flores said. Radiology experts have shown that, with training, even superficial lesions can be identified through imaging. Researchers also have been developing artificial intelligence-based software to better identify those lesions.
Flores has been researching endometriosis biomarkers for more than 20 years with a focus on a blood-based signature of the disease and she is the chief scientific officer for the firm Nura Health, which is developing a blood-based endometriosis test. Her work has involved studies on RNA targets and circulating antibodies, and she noted that some companies in the space have seen promise in microRNAs and blood-based metabolites.
"Most likely it will be a mix of different molecules that could … with enough accuracy, differentiate patients from non-patients," Flores said.
Ongoing efforts
Flores noted that even outside the NIH RADx program, some firms have made promising progress on improving endometriosis diagnosis.
For instance, California-based DotLab has been developing its DotEndo test to identify microRNA biomarkers in blood samples using testing methods licensed from the Yale University School of Medicine. DotLab CEO Heather Bowerman said that the firm is not yet ready to disclose details about the methods or targets that will be used in a commercial version of the test but noted that some of the biomarkers have been described in a validation study in the American Journal of Obstetrics & Gynecology, and the firm has determined that testing for more than a few dozen microRNA targets provided minimal increases in test accuracy.
Bowerman said that developing and evaluating the performance of a test for endometriosis is challenging because of the complexity of the disease and the lack of funding for studies related to women's health issues. Research into endometriosis has been underfunded, and collecting a meaningful number of well-characterized samples during laparoscopy is not feasible for most teams.
"Unlike other areas of medicine, there's no biorepository where these samples can be obtained and examined or analyzed in a novel way," she said.
She said that it is also critical to evaluate the performance of an endometriosis test with surgical confirmation in patients with suspected disease and controls.
Bowerman said that only a small subset of healthcare providers is highly educated on endometriosis, so education will be a part of her company's strategy to drive adoption of DotEndo. The firm hopes to first target expert Ob/Gyns who have experience with endometriosis and whose use of the test can inspire confidence more broadly.
Bowerman declined to say whether DotLab is participating in the RADx Tech endometriosis challenge. She said, however, that the firm is seeking US Food and Drug Administration de novo marketing authorization and payor coverage for the test when it comes to market.
Meanwhile, in Europe, French biotech firm Ziwig has developed a CE-marked next-generation sequencing-based assay called the Ziwig Endotest to identify microRNA biomarkers of endometriosis in a saliva sample with the aid of AI-based software. The test is available in Europe, the Middle East, and a few other markets for use in patients ages 18 to 43 years with symptoms of endometriosis and normal or equivocal imaging results.
Lina Fakhoury, international markets director for Ziwig, said in a statement that Ziwig is working to secure US FDA approval for its test but is ineligible to participate in the RADx Tech challenge because it is not US-based.
Other companies exploring the space include Proteomics International, which inked a deal this year to acquire and use about 600 patient plasma samples from the University of Oxford to validate its PromarkerEndo proteomic test for endometriosis; and Aspira Women's Health, which signed a material transfer agreement last year to obtain from Oxford serum samples to support the development of its blood-based EndoCheck protein biomarker test.
Meanwhile, Predica Diagnostics said earlier this year that it is also conducting research to identify potential biomarkers in the vaginal microbiome for endometriosis. Also within the last year, Aditxt subsidiary Pearsanta acquired a blood-based mitochondrial DNA test that had been in development by MDNA Life Sciences, while Hera Biotech acquired the endometriosis assets of Swiss firm Scailyte and announced plans to develop tissue-based molecular assays as an alternative to laparoscopy.
The European Union and US NIH also have been funding biomarker discovery studies in recent years as well as test development.
As for the RADx Tech challenge, Tingen said that the NIH is supporting teams with access to imaging, commercialization, and regulatory experts, among others. The agency will announce in December which eight teams will pitch their ideas to a judging panel of experts in January 2025.
The NIH plans to announce in March which four teams will be selected for one year of support and development assistance, and the winners will be judged based on their progress during that year.
In presentation materials provided by Tingen, the agency further explains that it is placing a high priority on noninvasive biomarker-based tests, point-of-care tests, technologies that can distinguish between malignancies and nonmalignant endometriomas, tests that could be used to address the disease in adolescents, and tests that could be used in diverse and understudied populations. All entries need to have a reasonable likelihood of entering the market within the following 10 years.
Flores said that the NIH contest is the type of initiative that is needed for progress on endometriosis testing.
"I think we're going to be pleasantly surprised to see a lot of new companies or unknown … companies and research groups that will come up with solutions," she said.