DotEndo

• Prevalent, debilitating disease: Over 10% of all women from ages 18-49 are affected by endometriosis, with 15M US women experiencing symptoms. The timeline for diagnosis averages 10 years today because there is no test other than invasive surgery, but symptoms are nonspecific. 

• Urgent need for a test: Endometriosis creates a high burden of illness for women who suffer from it, and has been described as “nothing short of a public health emergency.” Many provider types are tasked with evaluating pelvic pain, but only a small subset of OB/GYNs bear the burden of most endometriosis diagnoses. Providers need a way to elicit symptoms from women and objectify pain, but without a quantitative tool or test today, most patients remain undiagnosed or misdiagnosed. 

• Clinical context: Surgery - laparoscopy under general anesthesia - is the standard for diagnosis today. It is impractical to offer surgery, biopsy, or another invasive method to the millions of women seeking diagnosis. Today, endometriosis patients face an average of a decade-long diagnostic odyssey with five medical doctors until surgical confirmation. This delay in diagnosis is plagued with unnecessary pain, poor quality of life, unnecessary disease progression, and avoidable medical testing and procedures to rule out other conditions.  Clinical diagnosis of endometriosis, when it occurs, has the potential to open the door to empirical treatment, proper referral, and an end to the diagnostic odyssey well ahead of this ten-year time point.
  
  The impact of having a clinical diagnosis is such that the European Society for Human Reproduction and Embryology (ESHRE) recently published updated guidelines where “laparoscopy is no longer the diagnostic gold standard.”  While many provider types are tasked with evaluating pelvic pain, today only a small subset have a high level of endometriosis education. This wide range of provider types needs a way to elicit symptoms from women and objectify pain. Without a quantitative tool or test to establish the parameters for clinical diagnosis, most patients will remain undiagnosed or misdiagnosed. 

  A standardized clinical diagnostic test must be developed from data generated in a rigorously designed clinical study - such as DotLab’s EMPOWER trial - to create and train the algorithm based on well-characterized clinical samples collected at the time of surgical confirmation. Additionally, it must be usable in all types of provider offices as endometriosis specialists and surgeons alone cannot evaluate the one in seven women with pelvic pain. 
  
  Estimates of direct and indirect costs of endometriosis in the US alone range from $22 billion to $69 billion. The availability of non-invasive tools to aid in the diagnosis of endometriosis could reduce the time to diagnosis, years of discomfort, disease progression, and associated co-morbidities and healthcare costs. 
  

DotEndo is a non-invasive test intended to be used in women of reproductive age - 18 through 49 years of age - with unexplained pelvic pain and/or suspected endometriosis. The test, performed in a laboratory (or laboratories), incorporates the levels of biomarkers and EMPOWER clinical data as validated in surgically-confirmed patients into an algorithm that generates a test result that, if high risk, is suggestive of the presence of endometriosis. This information, in conjunction with standard clinical assessment, may be used to evaluate for endometriosis.

DotEndo is designed to be deployed around the world-- in developing markets as a saliva-based test, and as a blood-based test where blood tests are easily accessed.

DotEndo‘s ML algorithm is trained on data from DotLab’s EMPOWER clinical study, the most robust trial ever performed for the diagnosis of endometriosis. EMPOWER is the first and only study to receive FDA protocol concurrence in this space, and ran at over two dozen top academic institutions. Baseline characteristics and biomarker expression levels in blood were used to develop the diagnostic model. The DotEndo test is low-cost to run and highly scalable, and performs 20 points higher (AUC) than the next-best markers.

EMPOWER stands on the shoulders of a decade of prior research and IP owned by DotLab. DotLab’s patent portfolio started with an exclusive license from the Yale School of Medicine, and today spans >60 patents. The rigorous design of EMPOWER is such that:

Only trained MIGS (minimally invasive gynecological surgery) providers, or other specialized endometriosis surgeons enroll patients.

Samples and correlating EMPOWER clinical data were collected within 8 weeks of surgery to reflect the current state of disease.

All outcomes were confirmed via visual assessment on laparoscopy and >90% have histopathological assessment as well.

The subjects in EMPOWER represent a broad spectrum of endometriosis patients across multiple races and ethnicities, ages, stages of disease, and symptom presentations.

As a blinded study, the disease status was not known before surgery, and the blood sampling protocol was identical for all subjects.

After data lock, subjects were divided into two categories, endometriosis (case) and non-endometriosis (control).

Truth regarding endometriosis disease status of the subjects (cases versus control) was determined via surgical diagnosis.

Study investigators performed visual assessment at time of surgery to determine whether endometriosis was present.

Post-surgery, subjects were assigned a case or control status.

Availability of DotEndo, a clinical test that combines a requisition form and a blood draw, has the potential to put the ability to clinically diagnose endometriosis that top-tier surgeons have, into the hands of any provider. This would be transformative for patients around the world with pelvic pain; given the lengthy delay in diagnosis that exists today, the availability of a clinical diagnostic could greatly reduce the diagnostic odyssey and time to treatment, dramatically improving quality of life. 

Endometriosis is a common condition affecting 10% of all women of child-bearing age, translating to approximately 190 million women worldwide, in which endometrium-like tissue is found outside of the uterus, primarily on pelvic organs and more rarely in other tissues. Endometriosis creates a high burden of illness for women who suffer from it and has been described as “nothing short of a public health emergency”. The vast majority (80%) of women with endometriosis exhibit symptoms.

This chronic, progressive, and debilitating disease can plague women from adolescence, into their reproductive years, and even later in the post-menopausal period of their lives. However, asymptomatic women with endometriosis may still have significant and serious ongoing pathology, such as bowel or other visceral structure involvement. Endometriosis-related symptoms may be incorrectly attributed to other disorders. Different disease phenotypes and the difficulty associated with diagnosing endometriosis can contribute to a long diagnostic journey for some women that can lead to delayed or missed treatment opportunities. 

Women who endure the symptoms of the disease suffer from a poor quality of life during their peak years with repercussions to career and relationships, increased hospitalizations, and if not treated early surmount to organ adhesion, pain sensitization, and infertility. Women with disease affecting ovarian structures may also be at increased risk for ovarian cancers.6 According to the American Society for Reproductive Medicine (ASRM), “Endometriosis should be viewed as a chronic disease that requires a lifelong management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures.”

Endometriosis can have a significant impact in a multitude of areas including but not limited to infertility, maternal and fetal risks during pregnancy, the impact of chronic pain and pain sensitization, the risks of surgical interventions and the use of opioids, the effect of endometriosis on quality of life, extra-pelvic lesions and comorbidities, and associated cancer risks. The understanding of endometriosis has grown tremendously thanks to the preponderance of evidence regarding the disease process and its far-reaching debilitating and irreversible effects.

The operators of DotLab have lived experiences with women's health and infertility. For example, Heather Bowerman is active in the NYC women's health communities and is committed to filling research & development gaps of underserved areas of women's health. She has been recognized as a Top 35 Global Innovator by the MIT Technology Review, a World Technology Award Finalist for Health & Medicine, and as one of the 100 Most Intriguing Entrepreneurs by Goldman Sachs. She was previously a management consultant at McKinsey & Company in healthcare and technology, Harvard’s nanotechnology teaching fellow, and an associate in the Obama White House’s Office of Science & Technology Policy. She is a graduate of the UC Berkeley College of Engineering and Harvard University. DotLab has been named as an “Amazing Medical Breakthrough” by Reader’s Digest and as one of the “Fierce 15” companies of 2019 by FierceMedTech.

Melissa Stosic, COO, was an early pioneer of non-invasive prenatal testing, which went from lab to market at breakthrough speed. Melissa has been working in various arenas of women's healthcare and genetics for the past 15 years. She began her career working with patients as a prenatal genetic counselor and coordinator at Columbia University. While there, she transitioned into research as lead coordinator on several hallmark studies focused on validating new technology to improve prenatal diagnosis. Melissa then spent 5 years at Natera in multiple roles including Director of Medical Education. There, she was responsible for clinical input and signoff for non-invasive prenatal testing (NIPT) product development and expansion, created and led a scientific advisory board and speakers bureau, lectured to providers across the globe about NIPT and expanded carrier screening, and led the medical science liaison team including reporting of high risk and atypical results to providers. Melissa then returned to Columbia to lead a reproductive genetics service providing prenatal and cancer counseling and genetic testing guidelines within OBGYN. She currently coordinates an online genetics course for MFM fellows and is an active member of ClinGen’s CaDRe (Consent and Disclosure Recommendations) committee. Melissa received her BS in Biology from Rowan University and her MS in Genetic Counseling from Arcadia University.

DotLab already has top-tier Research Use Only customers and major commercial contracts, and will expand to broad commercial availability. DotLab’s globally differentiated EMPOWER trial provides data and the sample repository for DotEndoTM and additional, future products. 

DotLab’s team includes experienced bioengineers, data scientists, medical affairs leaders, and operators in women’s health. The Scientific Advisory Board is composed of the top Key Opinion leaders in the field. DotLab is proud to be backed by leading life science investors, institutional funds such as Morgan Stanley, and the NIH.

DotLab’s DotEndoTM test opens up the endometriosis market; 1.3M tests (<10% US market) in 2028 achieves >$250M revenue

• Med societies declared urgency for an endo test. Reports revealed an OB/GYN  workforce shortage; 36% of US counties are “care deserts”
• New wave of tx (GnRH analogs, such as AbbVie’s Orilissa) failed commercially without a test. R&D spend tops $1B+/drug

For therapeutic innovations to succeed commercially, a broadly-used, non-invasive diagnostic test is desperately needed. This has been the limiting factor for adoption of therapeutic innovations to date.

While peer-reviewed publications serve as the key means of provider communication about DotEndo, the content below is meant to offer simplified answers to FAQs.

Why is there a clinical need for DotEndoTM? There are numerous, long-standing hurdles for diagnosing endometriosis in today’s world.

1. No quantitative test exists to establish parameters for clinical diagnosis, therefore, clinical diagnosis is not happening often or early.

   1. Many patients remain undiagnosed.

   2. When clinical diagnosis occurs, it is often not timely due to the referral path that patients face prior to laparoscopy.

2. There is currently a decade-long diagnostic odyssey until eventual surgical confirmation.

   1. The American College of Obstetrics and Gynecology (ACOG) agrees that “the differential diagnosis for chronic pelvic pain is extensive.”

   2. Overlapping conditions and broad symptomatology make interpretation of pelvic pain difficult.

3. Unnecessary disease progression and avoidable medical testing often occur while trying to rule out other conditions or rule in endometriosis. These include: 

   1. Unnecessary pain;

   2. Poor quality of life;

   3. Risk for medical complications; & 

   4. Disease progression.

How does DotEndo address this need? 

DotEndoTM is a broadly accessible way to solve the existing hurdles and triage patients toward the appropriate treatment and/or specialists early in the diagnostic journey.

1. DotEndoTM provides a way to standardize clinical diagnosis.

   1. It gives all providers a way to elicit symptoms from women and objectify pain.

   2. It could open the door to empirical treatment, proper referral, and an end to the 10 year diagnostic odyssey.

2. DotEndoTM has the potential to drive a paradigm shift for endometriosis patients. It may:

   1. Identify endometriosis prior to significant disease progression;

   2. Minimize unnecessary procedures & referrals to rule out other conditions; & 

   3. Lessen the symptomatic burden.

3. DotEndoTM provides a way to democratize access to a top-caliber clinical diagnosis.

   1. The test could narrow disparities in pelvic pain care for underserved populations.

How might a provider utilize DotEndoTM to change patient care? 

DotEndoTM utilizes a wealth of clinical data, biomarkers, and ML in a first-of-its kind test, giving providers confidence in a clinical diagnosis and guiding treatment options.

1. Information for patients

   1. Answer the “why?”

   2. Lessen diagnostic odyssey

   3. Support decision-making

   4. Add confidence

2. Intervention potential (treatment)

   1. Hormonal contraception

   2. Medical therapy, e.g, GnRH antagonist therapy such as elagolix (Orilissa)

   3. Referral to mental health specialist

   4. Referral to endometriosis specialist or REI

3. Insight for providers

   1. Complete the clinical picture

   2. Prevent unnecessary referrals

   3. Impact on how patient is counseled

Endometriosis is prevalent, can impact a female’s quality of life and- until today- has been difficult to diagnose for patients ranging in age from adolescence to menopause. The difficulty in diagnosis of the disease is multifactorial: as a) the symptoms of endometriosis are not specific to the disease and b) historically, the only reliable way to diagnose the disease has been with laparoscopic surgery- an invasive, expensive surgery, requiring multiple days for recovery limiting the accessibility of surgery for the diagnosis of endometriosis. The implications of the delay in diagnosis can be paramount as endometriosis is a chronic and progressive disease. 

The disease is associated with several symptoms- including pelvic pain, infertility, painful periods, painful intercourse- to name a few.  These symptoms significantly reduce a woman's quality of life, causing some women to stay home from work and for young females to stay home from school.  General awareness of endometriosis is low, and speaking about its associated symptoms is taboo; this applies to developed western nations but is especially the case in developing nations. For this reason, many women are unable to advocate for themselves and suffer from the consequences of the disease in silence. An accessible modality to diagnose endometriosis is the first step to take women with endometriosis’ concerns seriously.

Enter DotEndo. DotEndo is the first and only Non-Invasive Test for Endometriosis. WIth a simple blood draw, females and providers can determine if the source of a patient’s symptoms is from endometriosis. DotEndo looks at novel biomarkers and can determine if its pattern is consistent with endometriosis.

DotEndo is truly a paradigm shift and its potential is vast.. The noninvasive modality makes identifying endometriosis highly accessible. Once endometriosis is identified, females can get the treatments they need. Hormonal therapies have been shown to alleviate symptoms and improve a female’s quality of life.  A first line treatment for endometriosis is Oral Contraceptives (OCPs), a highly accessible treatment.  In instances where OCPs do not work, there are other hormones that can be considered to manage the disease. 

While DotEndo is currently offered via a blood sample, DotLab owns the international intellectual property for a saliva based version of the product which will further broaden the potential when its development is complete. A saliva based version of DotEndo will allow DotLab  to better serve international markers and expand reach to underserved populations in expanding markets.

DotEndo unlocks broad accessibility to females across the world- in both developed and developing nations- in the diagnosis of endometriosis and subsequent management of the disease. In other words, DotEndo will give a voice to the 400 million women suffering in silence and whose concerns were previously dismissed. But our ambitions with DotEndo go beyond this, we hope that DotEndo will create a global conversation about painful periods and remove the taboos that were once associated with these female-specific-symptoms.

DotEndo's AI/ML is developed and trained on data from DotLab's pivotal trial, EMPOWER. 

The EMPOWER clinical study was meticulously designed in partnership with the FDA and Key Opinion Leaders in endometriosis, as previously described on this application.

Prior to EMPOWER, the following studies served as the foundational data in support of our test and study design. DotLab exclusively holds all associated intellectual property: 

1. Pre-clinical work (Linked), Cosar et al. 2018: This is the first report showing serum miRNA expression in primates induced with endometriosis normalized in response to treatment, supporting the potential for this class of biomarkers to be used both to diagnose and to monitor its progression and response to therapy.

2. Cosar et al. 2016 (Linked): Specific biomarker panel shown to have high sensitivity and specificity in blood serum (AUC = 1.00).

3. Moustafa et al. 2020 (Linked): In a “real world” scenario of patients with various disease stages, DotLab trained a strong 6-marker algorithm and validated against Cosar/Cho (AUC = 0.94).

4. Press release (Linked): DotLab’s press release is linked for the publication of Moustafa et al., 2020 in the American Journal of Obstetrics & Gynecology as the first to validate biomarkers that reliably differentiate between endometriosis and other gynecologic pathologies with high accuracy

More information on the EMPOWER study is below: 

DotLab Press Release (Linked): “Multi-center cohort study for DotLab’s non-invasive test for endometriosis: EMPOWER Study being conducted at centers at the vanguard of endometriosis care”

This is a preview of an unpublished manuscript and is subject to change. This information will be published in a peer-reviewed journal. Do not distribute. This information is exclusively the intellectual property of Dot Laboratories, Inc.

Title: 

Development and validation of a non-invasive clinical diagnostic test for endometriosis

Condensation: 

Blood samples and clinical information from subjects undergoing laparoscopy for benign gynecological conditions were utilized to develop and validate a clinical diagnosis algorithm for endometriosis.

Clinical Trial Information:

The trial was registered on ClinicalTrials.gov with identifier NCT04598698 on October 22, 2020. The recruitment period for this cohort was November 2, 2020 to September 21, 2021. This study involved 16 locations including the following: The Advanced Gynecologic Surgery Institute, Park Ridge, Illinois, United States; MedStar Health, Washington, DC, United States; Stanford University, Stanford, California, United States; Academia Women’s Health, Atlanta, Georgia, United States; University of Louisville, Louisville, Kentucky, United States; Johns Hopkins University, Baltimore, Maryland, United States; University of Pennsylvania, Philadelphia, Pennsylvania, United States; Northwestern Medicine, Chicago, Illinois, United States; University of Pittsburgh, Pittsburgh, Pennsylvania, United States; University Hospitals, Mayfield Heights, Ohio, United States; Columbia University, New York, New York, United States; NorthShore University, Evanston, Illinois, United States; University of South Florida, Tampa, Florida, United States; University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States; RADfertility, Newark, Delaware, United States; Seattle Reproductive Medicine, Seattle, Washington, United States.

DotLab takes safety and compliance seriously, and retains a world class Security Officer. We work with world-class data scientists, held to the highest ethical standards and regulations. Below, we are sharing example FAQs for DotEndo.

FAQ: How are the identity of the users of your product/platform verified/authenticated? For our current pharma customers, DotLab is a contract service provider for the CRO/ Therefore, DotLab does not have access to the applicable systems, subjects, or sites. For our FDA-facing pivotal trial, EMPOWER, DotLab works with two well-known vendors for data collection and maintenance. As the study sponsor, DotLab is not provided with any identifying information.

FAQ: Does your company collect users’ Personal Identifiable Information (PII)? No, DotLab does not do this for pharma partnerships or our pivotal trial. PII would be required for the future clinical test (to be ordered by medical providers). However, DotLab itself would not collect or store PII on the subjects – all PII is removed. For our future commercial test, the PII would be stored by DotEndo’s LIMS provider.

FAQ: Other than PII, what types of data does your business collect and/or process? Molecular data: Blood and saliva specimens analyzed by DotLab generate molecular data of interest (e.g., miRNA differential expression levels). DotLab maintains the specimens per our study protocols. DotLab has IRB approval as the study sponsor, and each recruitment site has IRB approval to protect subject safety as well. All specimens are stored with unique identifiers that do not include any PII.

DotLab does not have access to the link between the identifiers and PII. Molecular data is stored off-premises, and only certain vendor-approved individuals have access to the systems. For example, separate computers and security protocols are utilized by clinical and research teams, so research does not have access to clinical reports. 

FAQ: How does the company train the phlebotomists to handle and ship blood samples to ensure quality? For our current pharma customers, DotLab has strict protocols for all lab staff. Research and clinical protocols are stored in a software system called Media Lab. For our FDA-facing pivotal trial, DotLab maintains a detailed laboratory manual with specific instructions for the collection, processing, and storage of specimens. DotLab also trains each study staff member at all sites on the lab manual. DotLab collects Case Report Forms (CRFs), on which answers to questions verify compliance with the protocol.

FAQ: Where does the liability lie in the event of a misdiagnosis? DotLab includes sensitivity and specificity on all reports, so it is clear that DotEndo is not meant to be a 100% accurate diagnosis. DotEndo is meant to offer a report with clinical value for the provider within the parameters of CLIA and CAP. For example, here is some of the daft language approved by DotLab’s Medical Director for the sample results report. The test results are meant to be used in combination with other factors (e.g., medical history) at the discretion of the provider; in other words, the test is not meant to be used in isolation, but with full medical context.

Our goal over coming years with DotEndo is to directly impact endometriosis treatment decisions, thereby transforming patient lives. 

Once a clinical diagnosis is made, the next steps for treatment– per the most recent guidelines from eight professional societies1, – and referral, fall under a variety of treatment types. Of note, the majority of guidelines support empiric treatment of endometriosis prior to laparoscopic confirmation. The DotEndoTM test can assist with arriving at this clinical diagnosis and identifying women with endometriosis quickly upon symptom presentation, opening the door to treatment initiation. 

All relevant professional society guidelines agree that the combined oral contraceptive pill (COC) or progestins are recommended for patients with endometriosis. Progestin-only treatments include oral contraceptives, intrauterine devices, and injected options. 

COCs are most common in the US. “The…COC is a widespread contraceptive method which is also used widely by clinicians empirically in patients with dysmenorrhea [pelvic pain during menstruation].” Most of the included guidelines propose combined oral contraceptives as a first empirical medical treatment in endometriosis associated pain before performing diagnostic laparoscopy, although the reported level of evidence differs.”1 

For many patients with pelvic pain secondary to endometriosis, hormonal contraception relieves symptoms and suffice as treatment. However, 1 in 3 women with endometriosis do not respond to hormonal contraception, in which cases providers may proceed to treatment #2 or #4 below. 

Many provider subtypes may be comfortable with treating a woman with endometriosis using the first-line treatment, hormonal contraception. If upon follow-up, the pelvic pain persists, second-tier therapy becomes an option. Many provider types will refer to an endometriosis specialist for further evaluation at this juncture.

Four out of five women with endometriosis suffer from mental health issues, likely secondary to the effects that long-term unresolved pain can have on quality of life. For this reason, considering a referral to a mental health specialist for women with endometriosis is important.

Gonadotropin-releasing hormone (GnRH) agonists and antagonists are two classes of commercially-available, second-line therapies to treat endometriosis-associated pelvic pain, particularly when COCs fail as a first-line therapy. GnRH agonists are preferred over GnRH antagonists due to the lesser side-effect profile.

“GnRH agonist use in endometriosis patients is reserved for patients with persistent symptoms after the use of first line therapy [such as those in Use Case 1]. All the…societies agree that GnRH agonists can reduce the endometriosis associated pain.”1 For GnRH antagonists, the professional society ESHRE “supports their use as an additional (second line) treatment option.”2 

The long delay to excision surgery may be reduced by a positive DotEndo test result, especially for patients who do not respond to medical therapy. This may also be true for second or third laparoscopies in the probable event of recurrence, or prior to IVF. Pelvic pain is not a reliable proxy for disease burden. Commercial payers may be able to standardize surgery coverage decisions with DotEndo as a triage test.

12 part time, 4 full time, not counting our two dozen clinical sites and partners. 

Leadership: 
Heather Bowerman. CEO & Founder. Bioengineering, ex-McKinsey, ex-White House science policy. 10 years in health + AI/ML.

Melissa Stosic. COO. Helped to pioneer Non-Invasive Prenatal Testing (NIPT) at Natera. Medical Affairs leader.

Hugh Taylor, MD. Principal Investigator, Clinical Development. Yale Med Dept Chair. Recent President, ASRM. 

Robert Taylor, MD PhD. Principal Investigator, EMPOWER pivotal trial. UCSF research career. endometriosis key opinion leader.

Incorporated in May 2016. Seed financing in June 2017. Full time ever since, with decades of prior experience depending on the team member.

DotLab takes DEI seriously, and has been recognized for its efforts in this area by Morgan Stanley Inclusive Ventures Lab.

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Commercial reimbursement in progress. Detailed reports are available.

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$2M over the next 24 months to fund broad launch ($1M/year). Burn is much lower through 2024.

$100K for clinical utility pilot, a key post-marketing study

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