New Test Brings Hope and New Answers for Unexplained Infertility, Failed IVF and Miscarriage

Couple at Appointment

Infertility has touched many people’s lives; sometimes there are no answers as to why it occurs. Research towards uncovering the cause of otherwise unexplained infertility has led to some large research initiatives recently and has discovered that undiagnosed endometriosis may be the culprit in many cases. Endometriosis is a condition in women that causes uterine tissue to grow outside of the uterus, creating scar tissue over time (called adhesions) that can cause severe pain, heavy periods, and infertility. While it is a common problem affecting 1 in 10 women of reproductive age, confirming its diagnosis used to rely on laparoscopic surgery to physically see the adhesions inside the woman’s abdomen.

Now, research has identified biomarkers specific to endometriosis and is working towards the development of less invasive tests to help identify women likely to have endometriosis, even if they don’t have any symptoms. These tests can also have meaningful impact on women struggling with unexplained infertility by giving them an answer to their infertility and providing treatment options to aid in getting pregnant. One of these tests is called ReceptivaDx offered through CiceroDx.

BioSpace spoke to Christopher Jackson, CEO and President of CiceroDx, to get more information.

Can you briefly summarize CiceroDx?

Christopher: “We are a company focused on women’s reproductive health with an emphasis on developing testing modalities to detect conditions such as endometriosis that are difficult to diagnose yet have a huge impact on the ability to start a family or to enjoy a normal healthy lifestyle.”

What is ReceptivaDx?

Christopher: “ReceptivaDx is a test that helps women who are struggling to get pregnant and have a baby either naturally or through in vitro fertilization (IVF). Even in the best IVF centers in the US, at least 40% of women still cannot get pregnant. While endometriosis has always been suspected as the primary cause in these unexplained failures, detecting endometriosis via laparoscopic surgery is an invasive and expensive procedure that has all but vanished. It’s now typically reserved for patients with heavy bleeding or major pelvic pain. ReceptivaDx is the first test to provide a non-invasive means for detecting inflammation of the uterine lining often without symptoms.

ReceptivaDx has been commercially available since February of 2017. Before the end of 2019, CiceroDx will have analyzed over 3,000 samples.”

What are the limitations of ReceptivaDx testing?

Christopher: “Infertility is a complex issue, so many potential areas of concern need to be addressed. Although we are a new and important piece of the puzzle, we are still just one piece. Our data suggests we can help 6 out of 10 women with unexplained infertility. While that is exciting, we still can’t provide answers for everyone. But we take that as a challenge.”

What does the process of getting ReceptivaDx testing look like?

Christopher: “A simple discussion with a woman’s healthcare provider to get the ball rolling is all that’s required. The endometrial biopsy is done during the ‘window of implantation’ 7-10 days after ovulation (days 20-24 of the menstrual cycle). Most women will use an ovulation kit to detect their luteinizing hormone (LH) surge, which occurs right before ovulation. If you detect your LH surge on a Monday for example, your biopsy window would start the following Monday for four days. Fertility doctors can also control cycles, referred to as “mock” cycles, with medications like progesterone. In these instances, a biopsy is taken during days 5-10 of progesterone administration.

An endometrial biopsy, which is not considered a surgical procedure, can be performed during a regular visit to either an Ob-Gyn or fertility center. While there is temporary pain and discomfort, the procedure is over in minutes and has fewer potential risks or side effects when compared to laparoscopy. Other than the office visit time, most women take less than a half day before returning to normal activities.

Once collected, the biopsy tissue sample is placed in a vial with preservative (formalin) and the vial is shipped via FedEx overnight to one of our two US lab locations for analysis. The endometrial tissue sample is processed by a pathology lab and slides are prepared for a pathologist to review. Pathologists look for a protein marker called BCL6 in the tissue, which is highly associated with endometriosis. In addition to applying a special stain that recognizes the presence of BCL6, each biopsy gets a full review by a pathologist to rule out everything from infection to even the presence of cancer or pre-cancerous cells. Results are available in about a week.”

Who is the ReceptivaDx test recommended for?

Christopher: “For women working with a fertility center, most referrals come from women who have failed IVF at least once or who have suffered multiple pregnancy losses either naturally or through IVF. Many women with limited or no fertility coverage from their health insurance will use the test upfront to see what their risks are before IVF. Statistically, less than 15% of families in the US have the financial ability or means to pursue a family through IVF. About 60% of women seeking assistance from fertility centers do not have fertility benefits coverage.

ReceptivaDx is an affordable option for families that have all but given up on their dream of having children. Women who test positive are five times less likely to conceive than women who test negative. If they test positive, treatment options can be applied to potentially allow them to conceive on their own without any further help.”

What does a positive test result mean? What about a negative result?

Christopher: “A positive result indicates the presence of inflammation in the uterine lining most commonly associated with endometriosis. The test measures the levels of a certain marker called BCL6 in endometrial tissue. We can’t decipher the extent or location of the disease based on the result, but we know the presence of inflammation due to the body’s immune response to endometriosis. Once identified, women testing positive can be treated with hormone suppression medications to tame the inflammation, allowing for a more receptive uterine lining. Laparoscopy to remove the adhesions caused by endometriosis is also a treatment choice. However, more women are opting for hormone suppression due to lower cost and avoiding invasive surgery, unless they have other major symptoms of endometriosis like extreme pain.

A negative test allows providers to rule out endometriosis as a concern and assures families that future IVF attempts have a higher likelihood of success. In a study conducted in an IVF center in South Carolina, women testing negative for the BCL6 marker had a 59% success rate on their next IVF transfer compared to 11% in women who were positive for BCL6.”

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What is BCL6? And how is it related to endometriosis?

Christopher: “BCL6 is a protein marker of inflammation highly associated with endometriosis when found in endometrial tissue. BCL6 is normally controlled by progesterone, an important hormone in pregnancy. However, it has been shown to be overexpressed in women with endometriosis. This inflammatory response causes a disruption of the uterine lining, enough to block implantation or dislodge an embryo, leading to miscarriage.

In a study of 119 women with unexplained infertility who were undergoing fertility treatment, 105 women (88%) tested positive for high BCL6 levels. Sixty-five of the women with high BCL6 levels underwent laparoscopy to look for signs of endometriosis, of which 61 women (94%) were confirmed to have endometriosis. This data showed that ReceptivaDx testing accurately predicts uterine inflammation (with 93% sensitivity and 96% specificity) and led to further studies to show how BCL6 could be used in a fertility setting to reliably predict success or failure in future IVF attempts.

One of our most recent papers showed that 10 women receiving hormone suppression therapy (depot leuprolide acetate, a gonadotropin-releasing hormone (GnRH) agonist, for two months) after a positive BCL6 test had similar pregnancy and birth success rates to 21 women who had laparoscopic surgery (the standard for treating women with endometriosis to help increase fertility). A control group of 54 women without any treatment after a positive BCL6 test did not fare as well in the study (15% or less pregnancy and live birth rates compared to over 50% for both treated groups) and were at much higher risk of miscarriage (50% miscarriage rate in women untreated compared to less than 20% in both treated groups of women). This demonstrates a less costly and less involved treatment pathway to pregnancy.”

BCL6, which stands for B-cell lymphoma 6, has also been found in lymphoma tissue (hence its name). The BCL6 protein is often measured via flow cytometry to monitor the progression of treatment in patients with lymphoma. There is no proven correlation between lymphoma and endometriosis in women.”

Do you have any ongoing or upcoming clinical trials? If so, can you talk about the data so far?

Christopher: “We have more than a half dozen peer-reviewed papers supporting the role of BCL6 in infertility. In late 2018, we were granted a Small Business Innovation Research (SBIR) grant from the National Institutes of Health (NIH). Getting this grant was no small feat and speaks to the need for markers like ours and the rigorous approach we take in our scientific process. The grant’s primary goals are to validate previous research in much larger populations, test different treatment protocols, identify additional markers, and see if we can use these markers in other sample types, such as saliva, blood and cervical mucous, that may help more women gain access to this test.

We just concluded and submitted our initial results from the grant-funded research which look very promising. Although we are excited about our results, the information is preliminary, and we can’t disclose or discuss them until it is published.

The next set of studies will include prestigious university-based fertility research programs such as Stanford, Wake Forest and the University of North Carolina. As part of the next phase of the grant, we are applying for a clinical trial using a well-known and FDA approved drug associated with endometriosis pain. Our goal will be to show how this treatment provides a pathway to resolve infertility in patients with a positive ReceptivaDx test result.”

How can a woman who is interested in the test obtain ReceptivaDx?

Christopher: “We encourage patients to coordinate directly with our office to assist in getting a ReceptivaDx collection kit sent to their doctor’s office if their current provider does not have any.

The ReceptivaDx test biopsy can be performed by any Ob-Gyn or a fertility doctor during a routine office visit. If a woman’s Ob-Gyn does not routinely perform endometrial biopsies, physicians can refer to a local specialist with more biopsy experience. Collection kits are provided at no charge to physician offices by CiceroDx.

Because our published clinical data was based on women undergoing IVF or other forms of assisted reproductive technologies (ART), most of our referring providers are based in fertility centers. We now have about 300 fertility centers that stock our collection kits and refer samples routinely.

With that data now in hand, we are beginning to focus more on women’s health centers and Ob-Gyn offices, specifically for recurrent pregnancy loss, an area that has provided little or no new answers to women in the past 30 years.”

Do you have plans to use ReceptivaDx for general endometriosis diagnosis not associated with pregnancy or fertility issues?

Christopher: “Part of our current research is in pain patients where fertility is not an issue or the reason the woman sought medical attention. To date, all of our published research is in the fertility sector. We are currently confirming the presence of our markers in endometrial tissue of pre-menopausal women that underwent hysterectomies that were later confirmed by pathology to have endometriosis. Once the markers are validated, the goal is to find these markers in less invasive sample types, such as pap smear, blood or saliva. Although not surgery, an endometrial biopsy is considered quite invasive for a young woman simply trying to understand pelvic pain or heavy menses.”

How much does the test cost? And can insurance cover it?

Christopher: “The test costs $690, which includes free shipping via FedEx to our nearest laboratory testing center. The patient pays their provider separately for the biopsy procedure. Additional markers for endometritis (CD138) and uterine receptivity (beta3 integrin) can also be added to the test for $125 each. Endometritis is an infection causing the same inflammatory conditions as endometriosis and is treated with antibiotics. Centers often add this test to rule out this condition.

ReceptivaDx is a ‘fee for service’ test, meaning we don’t contract or bill insurance and the patients pay upfront at the time of sample submission. We did this to keep pricing in reach for everyone, especially since most women don’t have specific coverage for fertility testing or procedures beyond routine testing. In many cases, insurance will reimburse patients, although it depends on the type of plan, deductible and whether or not fertility related testing is a covered benefit. CiceroDx provides the patient with a detailed receipt and everything they need to submit to their insurance or healthcare spending account.

For reference, the cost of an endometrial biopsy ranges from $150 to $1,100, whereas the cost of laparoscopy ranges from $1700 to $15,700 and involves a much longer recovery period. In terms of insurance coverage, getting pre-authorization for laparoscopy without signs or symptoms of endometriosis is often difficult.”

What made you look into and develop this technology?

Christopher: “We have always had a research interest in diagnostic testing involving fertility. Most studies in pre-clinical research have focused on molecular genetics to identify potential gene sequences that might play a role in infertility. We saw little in the current science to prove the direct association of these thousands of gene sequences, so we focused our attention on markers that could be detected by immunohistochemistry (IHC) on endometrial tissue, a more direct and easier path to clinical availability. Once BCL6 was identified as an accurate marker, defined scientifically as very sensitive and very specific, we negotiated an exclusive licensing arrangement with the University of North Carolina at Chapel Hill.

We have since licensed a second marker called SIRT-1. Although very preliminary, we believe we will have technology that will soon allow us to collect biopsies on patients at any time, not just in the 4- to 5-day window of implantation.”

What makes ReceptivaDx different than other infertility testing?

Christopher: “The way we look at our test is not what makes it different than other infertility tests but what it adds to the work-up for those patients who are not getting pregnant. However, there are some unique advantages to our test. First, ReceptivaDx can be offered to women outside of the IVF setting and to those without fertility coverage. It’s also the only test that detects endometriosis in women with unexplained infertility and recurrent pregnancy loss without requiring laparoscopy surgery. This is extremely relevant given the diminished use of laparoscopy today.

Without insurance coverage for laparoscopy, endometriosis has gone undetected in the US for a long time. This silent epidemic means it takes the average woman 7-9 years before getting properly diagnosed. A typical woman seeking care will either be ignored or misdiagnosed, then mistakenly treated for conditions like IBS. That’s just absurd. Right now, we have 18- and 20-year-olds who are brave enough to discuss their heavy menses and cramping, only to be told “Well, that’s just your period, everyone’s different.” Those same young women will be the next fertility patients due to 7-9 years of scarring caused by endometriosis. In addition, we know that there are thousands of women who are asymptomatic who continue to experience recurrent pregnancy loss without any idea why. CiceroDx wants to end that and find easier ways to detect endometriosis in a woman’s annual visit with their Ob-Gyn. It’s just a shame that it’s taken this long to address a problem that healthcare providers simply stopped looking for.”

What does the landscape for infertility testing and tests like ReceptivaDx look like right now?

Christopher: “In many ways, we are in the wild west of medicine. Every time you turn around someone has a new test to offer. However, I think it comes down to clinical data; making sure there is data to back up the testing is vital. We have strong data about the efficacy of ReceptivaDx and on treatments given to women who test positive for ReceptivaDx.

Everybody is searching for a way to diagnose endometriosis in a variety of sample types and so are we. Right now, I consider it to be healthy competition that is addressing a major issue that has been overlooked for quite some time.”

(For more information about other endometriosis and infertility research, check out this article.)

What are the knowledge gaps that still need to be addressed in infertility research?

Christopher: “More needs to be done for women who can’t afford to seek advanced fertility care or IVF. For example, miscarriage is very common, but repeat miscarriages are not. Women deserve to know what is causing them to have multiple miscarriages.

There is also a business side to the fertility industry that sometimes gets in the way of advancements. Don’t get me wrong, there has been amazing progress in this industry over the last 20 years in terms of success rates, but 40% of women seeking help from a fertility center will still not be successful and give up. We can be proud of the current success rates, but nobody wants to discuss those who fail. The most challenging patients are left behind. The research and validations we have conducted prove that we can help this subset of women.”

Is CiceroDx exploring other causes of infertility, such as polycystic ovary syndrome (PCOS), in the hopes of developing a test for that?

Christopher: “If we can find markers that offer great certainty of a diagnosis, we will continue to validate them. PCOS is on our radar screen, but we have yet to see anything that we feel confident would provide accurate information. We are a data-driven company and we won’t offer a test if it has the same confidence factor as flipping a coin. There also must be a companion treatment; identifying something and not providing a treatment pathway just frustrates the patient. We can’t be satisfied with just identifying conditions.”

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