−Removed: Unless otherwise provided in this Annual Report, references to the “Company,” “we,” “us,” and “our” and similar references refer to Celcuity Inc., a Delaware corporation.
−Removed: We own various unregistered trademarks and service marks, including our corporate logo.
−Removed: Solely for convenience, the trademarks, trade names and service marks in this Annual Report, including those owned by third parties, may be referred to without the ®, TM or SM symbols, but such references should not be construed as any indicator that the owner of such trademarks, trade names and service marks will not assert, to the fullest extent under applicable law, their rights thereto.
−Removed: We do not intend the use or display of other companies’ trademarks, trade names and service marks to imply an endorsement or sponsorship of us by any other companies.
−Removed: We are developing companion diagnostic tests designed to expand the eligible patient populations for targeted therapies by discovering new cancer sub-types molecular-based approaches cannot detect.
−Removed: Our proprietary CELsignia diagnostic platform is the only commercially ready technology we are aware of that uses a patient’s living tumor cells to identify the specific abnormal cellular process driving a patient’s cancer and the targeted therapy that best treats it.
−Removed: We believe our CELsignia platform provides two important improvements over traditional molecular diagnostics.
−Removed: First, molecular diagnostics can only provide a snapshot of the genetic mutations present in a patient’s tumor because they analyze cell fragments.
−Removed: Using cell fragments prevents molecular diagnostics from analyzing the dynamic cellular activities, known as cell signaling, that regulate cell proliferation or survival.
−Removed: Cancer can develop when certain cell signaling activity becomes abnormal, or dysregulated.
−Removed: Since genetic mutations are often only weakly correlated to the dysregulated cell signaling activity driving a patient’s cancer, a molecular diagnostic is prone to providing an incomplete diagnosis.
−Removed: CELsignia tests overcome this limitation by measuring dynamic cell signaling activity in a cancer patient’s living tumor cells.
−Removed: When a CELsignia test detects abnormal signaling activity, a more accurate diagnosis of the patient’s cancer driver is obtained.
−Removed: Second, molecular diagnostics can only estimate the probability of a patient’s potential drug response based on a statistical analysis of the drug’s clinical trial results.
−Removed: Instead of this indirect estimate of drug response, CELsignia tests confirm that a targeted therapeutic matches the patient’s cancer driver, which significantly increases the likelihood of a positive clinical outcome.
−Removed: Our first analytically validated and commercially ready test using our CELsignia platform is our CELsignia HER2 Pathway Activity Test for breast cancer, which diagnoses two new sub-types of HER2-negative breast cancer that traditional molecular diagnostics cannot detect.
−Removed: Our internal studies show that approximately 15%-20% of HER2-negative breast cancer patients have abnormal HER2 signaling activity similar to levels found in HER2-positive breast cancer cells.
−Removed: As a result, these HER2-negative patients have undiagnosed HER2-driven breast cancer and would be likely to respond to the same anti-HER2 targeted therapies only HER2-positive patients receive today.
−Removed: Our CELsignia HER2 Pathway Activity Test is targeting HER2-negative breast cancer patients receiving drug treatment.
−Removed: Our second CELsignia test for breast cancer evaluates independent c-Met signaling activity and its involvement with HER family signaling in HER2-negative breast cancer tumor cells.
−Removed: Our internal studies have found that approximately 20%-25% of HER2-negative breast cancer patients have abnormal c-Met signaling activity that is co-activated with abnormal HER family signaling.
−Removed: These studies suggest that this sub-group of HER2-negative breast cancer patients may best respond to treatment with a combination of HER family and c-Met inhibitors.
−Removed: Our third CELsignia test for breast cancer evaluates PI3K signaling in HER2-negative breast cancer tumor cells.
−Removed: Our internal studies demonstrate how measurement of PI3K-involved signaling may provide a more sensitive and specific method of identifying patients most likely to benefit from PI3K inhibitors than current genetic tests that measure PI3K mutations.
−Removed: We intend to combine these three tests to create the CELsignia Multi-Pathway Activity Test, or CELsignia MP Test.
−Removed: With this next generation CELsignia test, we plan to provide an analysis of EGFR/HER1, HER2, HER3, c-MET, and PI3K-node involved signaling activity for each patient tumor specimen received.
−Removed: We completed development of our first CELsignia test for ovarian cancer in 2020.
−Removed: This test identifies a new sub-group of ovarian cancer patients with tumors that have abnormal c-Met and HER2 signaling activity.
−Removed: These findings suggest that a significant sub-group of ovarian cancer patients may respond to treatment with a combination of ErbB and c-Met inhibitors.
−Removed: Nearly 15,000 women a year die from ovarian cancer, a disease that has less than a 50% five-year survival rate and a limited range of targeted therapy options.
−Removed: There is thus a significant unmet need for additional therapeutic options for ovarian cancer patients.
−Removed: As a companion diagnostic, our CELsignia test for ovarian cancer will be intended to help pharmaceutical companies obtain new drug indications and expand treatment options for this challenging tumor type.
−Removed: We initiated discussions with pharmaceutical companies about collaborating on clinical trials in late 2020.
−Removed: We also made significant progress in 2020 developing a new CELsignia test intended to diagnose breast and ovarian cancers driven by dysregulated RAS signaling.
−Removed: Dysregulation of RAS signaling, which includes the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, is estimated to drive 30%-40% of all cancers.
−Removed: Pharmaceutical companies have developed numerous drugs that target RAS-involved pathways.
−Removed: However, the number of interactions amongst RAS-regulated pathways has made it extremely difficult to use molecular tests to identify patients with dysregulated RAS signaling tumors.
−Removed: The challenge of diagnosing a cancer driven by a dysregulated RAS signaling network is magnified because two or more different pathways are typically involved.
−Removed: Recent research has also found that RAS mutations play a much less important role in dysregulated RAS signaling than previously thought.
−Removed: Our CELsignia platform is uniquely suited to untangle the complexity of dysregulated RAS signaling tumors and identify the targeted therapy combination capable of treating it.
−Removed: Once development of the new RAS test is completed, we intend to add it to our current CELsignia Multi-Pathway Activity tests for breast and ovarian cancer.
−Removed: This next generation CELsignia test would provide an analysis of EGFR/HER1, HER2, HER3, c-MET, PI3K, and RAS-involved signaling activity for each patient tumor specimen received.
−Removed: Our current CELsignia tests have the potential to diagnose oncogenic signaling activity undetectable by molecular tests in up to one in three HER2-negative breast cancer patients and one in five ovarian cancer patients.
−Removed: If our efforts to develop a RAS dynamic signaling test are successful, the percentage of cancer patients who could benefit from a CELsignia test would further increase.
−Removed: In addition to the new breast cancer sub-types our CELsignia test diagnoses, we discovered eight new potential cancer sub-types in lung, ovarian, kidney, and bladder cancers.
−Removed: Approved or investigational drugs are currently available to treat each of these new potential cancer sub-types.
−Removed: CELsignia tests for these additional cancer sub-types are in various stages of development, and we expect them to become commercially ready on a staggered basis over the next few years.
−Removed: The development process for these additional CELsignia tests includes completion of internal animal, verification, training set, and validation studies.
−Removed: As new CELsignia tests become commercially ready, we expect to initiate collaborations with pharmaceutical companies to help them obtain new drug indications for the new cancer sub-types our tests identify.
−Removed: In addition, we will continue our research to identify additional new cancer sub-types and to develop the corresponding CELsignia tests to diagnose them.
−Removed: Our overall commercialization strategy is to develop companion diagnostics that expand the patient population eligible for targeted therapies.
−Removed: We expect to collaborate with pharmaceutical companies to advance the clinical development of their targeted therapies with the eventual goal of obtaining FDA approval of a new drug indication.
−Removed: Collaborations are expected to involve initially Phase I or Phase II interventional clinical trials to evaluate the efficacy of our collaboration partners’ targeted therapies patients selected with one of our CELsignia tests.
−Removed: We are currently evaluating, or expect to evaluate, a variety of targeted therapies in combination with other targeted therapies, hormonal therapies, of chemotherapies, including:
−Removed: i) pan-HER and c-Met inhibitors;
−Removed: ii) pan-HER inhibitors and endocrine therapy;
−Removed: iii) pan-HER inhibitors and chemotherapies;
−Removed: and iv) PI3K inhibitors and endocrine therapy.
−Removed: The FDA has approved three c-Met inhibitors, six HER-family inhibitors, and four PI3K inhibitors for cancer treatment.
−Removed: Additional c-Met, HER-family, and PI3K inhibitors are being evaluated in on-going clinical trials.
−Removed: We have four collaborations underway that rely on a CELsignia Pathway Activity Test to select breast cancer patients for treatment with targeted therapies.
−Removed: For the first one of these collaborations, we are fielding a prospective open-label Phase II clinical trial with Genentech, Inc.
−Removed: (“Genentech”) and NSABP Foundation, Inc.
−Removed: (“NSABP”) to evaluate the efficacy and safety of Genentech’s HER2 targeted therapies, Herceptin and Perjeta, in early-stage HER2-negative breast cancer patients with hyperactive HER2 signaling tumors.
−Removed: We expect interim results from this trial in either the fourth quarter of 2021 or first quarter of 2022 and final results approximately nine months later.
−Removed: For the second of these collaborations, we are fielding a prospective open-label Phase II clinical trial with Puma Biotechnology, Inc.
−Removed: (“Puma”) and West Cancer Center to evaluate the efficacy and safety of Puma’s drug, Nerlynx, and chemotherapy in early-stage triple-negative breast cancer patients selected with our CELsignia HER2 Pathway Activity Test.
−Removed: We expect to obtain interim results in either the fourth quarter of 2021 or first quarter of 2022 and final results approximately nine months later.
−Removed: For our third collaboration, we are fielding a prospective open-label Phase II clinical trial with Puma Biotechnology, Inc.
−Removed: (“Puma”), Massachusetts General Hospital, the UCLA Jonsson Comprehensive Cancer Center and the Vanderbilt-Ingram Cancer Center to evaluate the efficacy and safety of Puma’s drug, Nerlynx, and Faslodex, an AstraZeneca drug, in previously treated metastatic HR-positive, HER2-negative breast cancer patients selected with our CELsignia HER2 Pathway Activity Test.
−Removed: For our fourth collaboration, we are fielding a prospective open-label Phase II clinical trial with Pfizer Inc.
−Removed: and Sarah Cannon Research Institute to evaluate the efficacy and safety of two Pfizer targeted therapies, Vizimpro, a pan-HER inhibitor, and Xalkori, a c-Met inhibitor, in previously treated metastatic HER2-negative breast cancer patients selected with our CELsignia Multi-Pathway Activity Test.
−Removed: An additional collaboration to evaluate tissue samples from a Phase II study evaluating Puma’s pan-HER inhibitor, Nerlynx, Genentech’s HER2 antibody, Herceptin, and Bristol-Myers Squibb’s EGFR inhibitor, Erbitux, in metastatic colorectal cancer patients is expected to be completed in late 2022.
−Removed: Unlike the four clinical trial collaborations, our CELsignia test will be used solely to evaluate tissue samples after they have been enrolled in this trial.
−Removed: We will not receive payment for the testing we perform.
−Removed: We expect our CELsignia test will provide critical insight after the trial is completed about the patient characteristics most correlative to drug response.
−Removed: While molecular tests identify increasing numbers of genetic variants in tumor tissue, determining the dysfunction driving most patient’s cancer using molecular tests remains elusive.
−Removed: Less than 20% of Americans who died of cancer in 2018 were eligible for a molecular targeted therapy because they lacked what are currently considered actionable genetic or proteomic mutations.
−Removed: This reflects the limitations of using static measurements of proteins or genetic mutations in cell fragments to characterize the dynamic and complex cell signaling activity that may be driving a patient’s cancer.
−Removed: Directly measuring dynamic cell signaling activity is an alternative diagnostic approach to identify the cancer driver in patient tumors lacking actionable genomic or proteomic mutations.
−Removed: This approach requires the use of living patient tumor cells as well as technology to quantify signaling activity levels.
−Removed: Efforts to obtain patient tumor cells have previously been limited by the lack of reliable methods to extract and culture cancer cells from patient tumors.
−Removed: Lack of access to living patient tumor cells, in turn, hampered development of technology to analyze dynamic signaling activity.
−Removed: Our CELsignia platform addresses the need for better cancer diagnostic tests using two complementary technologies that represent a significant departure from molecular-based analyses.
−Removed: Unlike molecular tests that use cell fragments and can only measure the static composition of a cell, our CELsignia platform measures real-time signaling activity in a patient’s live tumor cells.
−Removed: This enables us to (1) identify the cellular signaling dysfunction driving a patient’s cancer;
−Removed: and (2) identify the targeted therapy that matches the dysfunction in the patient’s cells.
−Removed: Our CELsignia tests are performed in our laboratory in Minneapolis, Minnesota that is certified under the Clinical Laboratory Improvement Amendments of 1988, or CLIA, and accredited by the College of American Pathologies, or CAP.
−Removed: Our platform, comprised of our internally developed cell microenvironment and cell signaling quantification technologies, allows for more accurate diagnoses and the discovery of new cancer sub-types.
−Removed: We believe our CELsignia platform will fundamentally change the standard-of-care many cancer patients receive.
−Removed: Patients with the newly identified cancer sub-types we have discovered have oncogenic pathways that are signaling abnormally, and, we believe, may respond positively to a matching targeted therapy.
−Removed: By identifying patients with a new cancer sub-type, each CELsignia test will create, in effect, a proprietary patient population that molecular diagnostics cannot identify.
−Removed: Our initial commercial strategy is to partner with pharmaceutical companies to provide companion diagnostics for the pharmaceutical partners’ existing or investigational targeted therapies.
−Removed: We expect such partnerships to involve collaboration on clinical trials, regulatory submissions, and commercialization activities.
−Removed: We will initiate activities to pursue partnerships as our CELsignia tests become commercially ready and can be matched with a potential partner’s targeted therapies.
−Removed: Our commercial-related efforts to date have focused on seeking partnerships for our CELsignia tests, the first of which became commercially ready as a laboratory developed test (“LDT”) in 2016.
−Removed: We expect to seek pharmaceutical partnerships for a variety of different targeted therapies in other solid tumor types as we are conducting our initial clinical trials with Genentech’s, Pfizer’s, and Puma’s targeted therapies.
−Removed: We believe our CELsignia tests will expand the matching drug’s market size because they can facilitate approval of new drug indications that a pharmaceutical company would not otherwise be able to obtain.
−Removed: We expect that successful pharmaceutical company partnerships will generate significant revenue from the sale of tests to identify patients eligible for clinical trials, from milestone payments, and, potentially, from royalties on the incremental drug revenues our tests enable.
−Removed: A key requirement for success of these partnerships will be clinical trial results that demonstrate the advantages of using a CELsignia test as a companion diagnostic.
−Removed: Once a new drug indication is received that requires use of the CELsignia test to identify eligible patients, we will offer our tests directly to treating physicians and coordinate go-to-market strategies with our partner.
−Removed: This coordination of commercialization strategies will allow us to significantly leverage the sales, marketing and reimbursement resources of our pharmaceutical partner, unlike traditional molecular diagnostic companies.
−Removed: Our Value Proposition
−Removed: We believe we offer a clear and compelling value proposition to the key healthcare stakeholders:
−Removed: Patients & Providers-Improved patient outcomes.
−Removed: Our CELsignia tests provide a more accurate diagnosis of a patient’s cancer driver.
−Removed: This will enable physicians to match more precisely the targeted therapy they use to treat their patients, which we believe will increase the percentage of patients responding to the drug, improving overall patient outcomes significantly.
−Removed: Pharma-Increased revenue & optimized clinical trials.
−Removed: CELsignia tests can significantly increase the revenue potential for many existing targeted therapies by identifying entirely new pools of patients potentially responsive to their therapy.
−Removed: For some targeted therapies, we estimate a CELsignia test could double the number of patients approved to receive treatment, thus driving billions of dollars in incremental sales.
−Removed: Also, by providing more precise selection of patients, our CELsignia tests can increase the odds a clinical trial meets its trial endpoint, greatly enhancing the likelihood the drug will obtain FDA approval for a new indication.
−Removed: In addition, according to an ARK Invest publication dated August 2016, companion diagnostics that increase the response rates of a drug can reduce Phase 3 clinical trial size as much as ten-fold and costs as much as 60%.
−Removed: Payors-Lower costs per responsive patient.
−Removed: By providing more precise cancer diagnoses and driving higher drug response rates, we will significantly reduce the money spent on drugs that do not benefit patients.
−Removed: Many targeted therapies cost more than $50,000 per treatment and only benefit a small fraction of patients receiving them.
−Removed: Calculating drug costs on a cost-per-responsive patient, and not just cost-per-treated patient, highlights the true cost of targeted therapies and the expense associated with low drug response rates.
−Removed: For instance, a $50,000 targeted therapy with a 30% response rate costs $167,000 per responsive patient;
−Removed: however, that same drug would only cost $83,000 per responsive patient if the response rate was 60%.
−Removed: Our Competitive Strengths
−Removed: We have a number of key strengths that enhance our ability to achieve our mission and build a successful company:
−Removed: We are the first company that we are aware of to launch diagnostic tests that measure the signaling pathway activity in a patient’s live tumor cells, which we believe gives us a significant first mover advantage.
−Removed: High barriers to entry.
−Removed: Our issued and pending patents, as well as our proprietary information and trade secrets, give us a strong intellectual property position that we believe creates a significant barrier to entry for potential competitors.
−Removed: Broad range of applications for our platform.
−Removed: We can develop tests for a wide range of signaling pathways and a wide range of cancer types.
−Removed: This allows us to build a deep new product pipeline that creates multiple paths to build a large and profitable business.
−Removed: Diverse revenue streams including pharma partnerships.
−Removed: We anticipate generating significant revenue from companion diagnostic pharmaceutical partners, including revenue from the sale of tests to identify patients eligible for clinical trials, milestone payments, and potentially, from royalties on the incremental drug revenues our tests enable.
−Removed: Our most significant revenue opportunity comes from ongoing sales of CELsignia tests to physicians during the commercialization stage of the companion diagnostic.
−Removed: Strong senior leadership team.
−Removed: Our founders and senior leaders have a proven track record of success building, operating and selling several successful companies.
−Removed: We have deep and highly relevant and complementary diagnostic, scientific, product development, and commercialization experience that has enabled us to establish market leadership positions for the companies we previously led.
−Removed: Our Platform Advantages
−Removed: Our unique and proprietary CELsignia functional cellular analysis technology represents a major shift from the diagnostic industry’s reliance on molecular profiling to characterize a patient’s cancer sub-type.
−Removed: Our goal is to leverage our technology to build a durable competitive advantage that enables us to improve outcomes for a significant percentage of cancer patients.
−Removed: Our CELsignia platform advantages include:
−Removed: Powerful cancer sub-type discovery tool.
−Removed: We have already discovered 16 new potential cancer sub-types that are not currently diagnosed and treated with a matching targeted therapy.
−Removed: These sub-types are characterized by the dysregulated signaling pathway activity our CELsignia tests identify.
−Removed: By identifying new cancer sub-types, we are creating new patient populations to which pharmaceutical companies can offer new and existing drug therapies.
−Removed: Direct patient-specific assessment of disease status.
−Removed: Even though the response rates for many targeted therapeutics are low, for those patients who do respond, their outcomes can be improved significantly.
−Removed: The problem is matching the patient to the right drug.
−Removed: Our platform overcomes this problem by directly identifying whether an oncogenic signaling pathway is abnormally active in a patient’s cells.
−Removed: This provides the most complete assessment available today of the intracellular activity driving a patient’s cancer.
−Removed: Existing genomic tests typically can only provide a determination whether cancer is present and an assessment of molecular mutations that may or may not be associated with the patient’s cancer driver.
−Removed: Direct measurement of matching drug effectiveness.
−Removed: An important advantage of the CELsignia platform is its ability to quantify the amount of signaling dysfunction that a matching targeted therapy can inhibit in an individual patient’s cancer cells.
−Removed: This allows us to evaluate whether there are inherent drug resistance mechanisms that would prevent the therapy from functioning in the patient’s tumor cells.
−Removed: Molecular tests cannot provide this evaluation.
−Removed: Improved response rates.
−Removed: We believe a patient population will have a higher response rate to a matching targeted therapy when it is diagnosed with a CELsignia test than with a molecular biomarker.
−Removed: By first identifying whether dysregulated signaling is present and then confirming that a matching targeted therapy can inhibit the dysfunction, a CELsignia test eliminates the two primary variables that confound patient response to targeted therapy signaling:
−Removed: the presence or absence of the disease and the drug not functioning as intended.
−Removed: A molecular test provides insight on neither of these variables in most cases.
−Removed: Identified drug responsive proprietary patient cohorts.
−Removed: Approximately 80% of cancer patients lack a genetic biomarker to guide treatment.
−Removed: For these patients, the cellular dysfunction driving the cancer goes undiagnosed, thus excluding such patients from receiving a potentially beneficial targeted therapy.
−Removed: We believe our CELsignia tests will enable us to identify new proprietary patient populations not currently diagnosable with molecular tests and increase the number of patients likely to respond to a matching targeted therapy.
−Removed: Moreover, we will be the only partner a pharmaceutical company can work with to develop a companion diagnostic for a new indication of a targeted therapy addressing these new patient populations.
−Removed: By contrast, most molecular diagnostic tests are undifferentiated and have little proprietary value, which gives pharmaceutical companies a wide range of companies to select from when choosing a molecular-based companion diagnostic partner.
−Removed: Streamlined FDA approval of targeted therapeutics.
−Removed: CELsignia tests will enable our pharmaceutical partners to enroll patients in their clinical trial with the same cellular dysfunction their targeted therapy is designed to inhibit.
−Removed: We believe this will improve patient response rates, increasing the likelihood the trial meets its endpoint target and thus the likelihood the drug receives FDA approval.
−Removed: Improved patient response rates would also help reduce the size, cost, and length of our partner’s clinical trials.
−Removed: According to the Centers for Disease Control and Prevention, cancer was the second-leading cause of death in the United States in 2019, responsible for nearly one of every four deaths.
−Removed: There are many types of cancer treatment options, including surgery, radiation therapy, chemotherapy, immunotherapy, hormone therapy, stem cell transplant, and targeted therapy.
−Removed: Targeted therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecular targets involved in the progression of cancer.
−Removed: Targeted therapies differ from standard chemotherapy drugs in that they are often cytostatic (block tumor cell proliferation) rather than cytotoxic (kill tumor cells).
−Removed: According to the National Cancer Institute, there are currently more than 90 approved targeted oncology therapies, some of which cost more than $100,000 per treatment course.
−Removed: Diagnostic tests to detect single biomarkers are now widely used by pathologists to determine the molecular sub-type of a cancer.
−Removed: When a molecular biomarker test is used to support the choice of therapy to prescribe, it is often referred to as a “companion diagnostic.” Increasing numbers of targeted therapeutics are prescribed based on the results from a companion diagnostic test to detect the presence of a molecular biomarker.
+Added: otherwise provided in this Annual Report, references to the “Company,” “we,” “us,” and “our”
+Added: and similar references refer to Celcuity Inc., a Delaware corporation.
+Added: We own various unregistered trademarks and service marks, including
+Added: our corporate logo.
+Added: Solely for convenience, the trademarks, trade names and service marks in this Annual Report, including those owned
+Added: by third parties, may be referred to without the ®, TM or SM symbols, but such references should not be construed
+Added: as any indicator that the owner of such trademarks, trade names and service marks will not assert, to the fullest extent under applicable
+Added: law, their rights thereto.
+Added: We do not intend the use or display of other companies’ trademarks, trade names and service marks to
+Added: imply an endorsement or sponsorship of us by any other companies.
+Added: are a clinical-stage biotechnology company seeking to extend the lives of cancer patients by pursing an integrated therapeutic (Rx) and
+Added: companion diagnostic (CDx) strategy.
+Added: Our therapeutic efforts are focused on developing potential first-in-class or best-in-class molecularly
+Added: targeted therapies that address the same cancer driver a CELsignia companion diagnostic can identify.
+Added: CELsignia is uniquely able to analyze
+Added: live patient tumor cells to identify new groups of cancer patients likely to benefit from targeted therapies.
+Added: This enables a CELsignia
+Added: CDx to support advancement of new indications for already approved targeted therapies.
+Added: We believe this integrated Rx and CDx strategy
+Added: will maximize the impact our drug development efforts have on the treatment landscape for cancer patients.
+Added: first drug candidate we are developing internally is gedatolisib, a potent, well-tolerated, small molecule dual inhibitor, administered
+Added: intravenously, that selectively targets all class I isoforms of PI3K and mammalian target of rapamycin (mTOR).
+Added: In April 2021,
+Added: we obtained exclusive global development and commercialization rights to gedatolisib under a license agreement with Pfizer, Inc.
+Added: initial clinical development program for gedatolisib will focus on the treatment of patients with hormone receptor positive (HR+),
+Added: HER2-negative, advanced or metastatic breast cancer.
+Added: Additional clinical development programs are expected to focus on other tumor
+Added: types that involve a hormonal signaling pathway, such as prostate, endometrial, or ovarian cancer.
+Added: the development of a potential first-in-class targeted therapy for breast cancer, like gedatolisib, with our CELsignia platform is a
+Added: natural extension of our strategy to use our CELsignia CDx to enable new indications for other companies’ targeted therapies.
+Added: combining companion diagnostics designed to enable proprietary new drug indications with targeted therapies that treat signaling dysregulation
+Added: our CDx identifies, we believe we are uniquely positioned to improve the standard-of-care for many early and late-stage breast cancer
+Added: Our goal is to play a key role in the multiple treatment approaches required to treat breast cancer patients at various stages
+Added: of their disease.
+Added: (Rx) Product Development
+Added: is a potent, reversible dual inhibitor that selectively targets PI3K and mTOR.
+Added: Gedatolisib was originally developed by Wyeth and clinical
+Added: development was continued by Pfizer after it acquired Wyeth.
+Added: We exclusively licensed global rights to gedatolisib from Pfizer in April
+Added: A Phase 1b trial evaluating patients with HR+/HER2- metastatic breast cancer was initiated in 2016 and subsequently enrolled
+Added: 138 patients.
+Added: January 13, 2022, gedatolisib was granted Fast Track designation for the treatment of patients with HR+/HER2- metastatic breast
+Added: cancer after progression on CDK4/6 therapy.
+Added: Fast Track designation is granted by the FDA for products that are intended for the treatment
+Added: of serious or life-threatening disease or conditions and which demonstrate the potential to address an unmet medical need.
+Added: The designation
+Added: offers the opportunity for frequent interactions with the FDA to discuss the drug’s development plan and to ensure collection of
+Added: appropriate data needed to support drug approval, as well as eligibility for rolling submission of a New Drug Application.
+Added: on the favorable preliminary results reported to date from the Phase 1b trial, we are preparing to initiate a Phase 3 clinical trial
+Added: (VIKTORIA-1) evaluating gedatolisib and fulvestrant with or without palbociclib in patients with HR+/HER2-
+Added: advanced or metastatic breast cancer whose disease progressed on prior treatment with a CDK4/6 therapy and an aromatase inhibitor.
+Added: expect to initiate the (VIKTORIA-1) study in the first half of 2022.
+Added: cancer is the most prevalent cancer in women, accounting for 30% of all female cancers and 13% of cancer-related deaths in the United
+Added: The National Cancer Institute estimated that approximately 281,000 new cases of breast cancer would be diagnosed in the United
+Added: States in 2020, and approximately 43,600 breast cancer patients would die of the disease.
+Added: Approximately 190,000, or 70%, of these new
+Added: cases are for HR+/HER2- breast cancer.
+Added: different breast cancer subtypes are currently identified using molecular tests that determine the level of ER and HER2 expression.
+Added: 70% of breast cancers are HR+/HER2-, which is indicative of hormone dependency.
+Added: Despite progress in treatment strategies, metastatic
+Added: HR+/HER2- breast cancer (MBC) remains an incurable disease, with a median overall survival (OS) of three years and a five-year
+Added: survival rate of 29%.
+Added: different classes of targeted therapies are currently used to treat HR+/HER2- tumors:
+Added: endocrine-based therapies, CDK4/6 inhibitors,
+Added: PI3K inhibitors and mTOR inhibitors.
+Added: Each of the CDK4/6 inhibitors, PI3K inhibitors and mTOR inhibitors are generally used to respond
+Added: to the related mechanisms of resistance to endocrine therapy, namely, activation of the CDK4/6, PI3K and mTOR pathways.
+Added: specifically relates to gedatolisib, activation of the PI3K/mTOR pathway has been implicated in a wide variety of human cancers, involving
+Added: either activating mutations, or other unknown drivers of pathway amplification.
+Added: These include cancers of the breast, prostate, endometrial,
+Added: colon, rectum, and lung, among others.
+Added: associated with PI3K involve complex essential cell regulatory mechanisms including feedforward and feedback signaling loops.
+Added: Overactivation
+Added: of the pathway is frequently present in human malignancies and plays a key role in cancer progression.
+Added: Four catalytic isoforms of class
+Added: I PI3K preferentially mediate signal transduction and tumor cell survival based on the type of malignancy and the genetic or epigenetic
+Added: alterations an individual patient harbors.
+Added: Due to the multiple subcellular locations, activities, and importance of the different PI3K
+Added: complexes in regulating many types of cancer cell proliferation, control of PI3K activity is an important target in cancer therapy.
+Added: is a critical effector in cell-signaling pathways commonly dysregulated in human cancers.
+Added: The mTOR signaling pathway integrates both
+Added: intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation, and survival.
+Added: is a serine/threonine protein kinase, a downstream effector of PI3K, and regulated by hormones, growth factors, and nutrients, that is
+Added: contained in two functionally distinct protein assemblies – mTORC1 and mTORC2:
+Added: In cancer, dysfunctional signaling leads to various
+Added: constitutive activities of the mTOR complexes, making mTOR a good therapeutic target.
+Added: addition, the PI3K/mTOR pathway, like other mitogenic pathways, can also promote the activities of cyclin D and CDK4/6 to drive proliferative
+Added: cell cycling.
+Added: The available evidence indicates that resistance to CDK4/6 inhibition in patients with HR+/HER2- advanced breast cancer
+Added: is a transient adaptive mechanism, most likely involving the PI3K/mTOR pathway.
+Added: This data indicates that CDK4/6 signaling is restored
+Added: in CDK4/6 resistant tumors when PI3K/mTOR inhibitors are applied.
+Added: Thus, continuing CDK4/6 inhibitor treatment in combination with a PI3K/mTOR
+Added: inhibitor in patients who progressed on their prior CDK4/6 inhibitor, would both blockade the reactivated CDK4/6 pathway and prevent
+Added: adaptive activation of the PI3K/mTOR pathway.
+Added: This suggests the limited efficacy induced by current standard-of-care (SOC) therapies
+Added: in patients who have progressed on a CDK4/6 therapy reflects the mechanistic inadequacy of relying on partial PI3K/mTOR inhibition (e.g.,
+Added: alpelisib or everolimus) and no CDK4/6 inhibition to address this complex disease mechanism.
+Added: believe the complex connection between PI3K/mTOR and CDK4/6 regulated cell cycling can enable gedatolisib to adaptively reactivate CDK4/6
+Added: signaling that reportedly occurs in CDK4/6 resistant tumors when the PI3K/mTOR pathway is completely blockaded.
+Added: By re-activating CDK4/6
+Added: signaling, we believe gedatolisib can restore the therapeutic effect of CDK4/6 inhibition when it is combined with a CDK4/6 inhibitor.
+Added: The contributory effect of a CDK4/6 inhibitor when combined with gedatolisib would thus largely reflect the interaction between the two
+Added: therapies that gedatolisib initiates.
+Added: of gedatolisib anti-tumor in vivo activity was provided in a study evaluating the combination of gedatolisib and a CDK4/6 inhibitor in
+Added: cell-line xenograft model where response to endocrine therapy was improved and tumor regressions were induced.
+Added: In a study evaluating
+Added: the MCF7 xenograft model (ER+/HER2-/PIK3CA mutant), the combination of gedatolisib with palbociclib and fulvestrant caused 90% tumor
+Added: regression with no tumor regrowth observed for more than 60 days after the final dose.
+Added: of Gedatolisib over Other PI3K and mTOR Inhibitors
+Added: important role the PI3K/mTOR pathway plays in cancer has led to significant investment in the development of many different PI3K and
+Added: mTOR inhibitors for solid tumors.
+Added: However, developing efficacious and well-tolerated therapies that target this pathway has been challenging.
+Added: This reflects the inherent adaptability and complexity of the PI3K pathway, where numerous feedforward and feedback loops, crosstalk
+Added: with other pathways, and compensatory pathways enable resistance to PI3K inhibition.
+Added: Another major hurdle for the development of PI3K
+Added: pathway inhibitors has been the inability to achieve optimal drug-target blockade in tumors while avoiding undue toxicities in patients.
+Added: believe there is significant potential for gedatolisib to address previously treated breast cancer tumors and has the potential to be
+Added: used in other tumor types where the PI3K/mTOR pathway is either:
+Added: i) driving tumorigenesis directly;
+Added: ii) cooperating with other dysregulated
+Added: signaling pathways;
+Added: or iii) a mechanism of resistance to other drug therapies.
+Added: a result, we believe gedatolisib’s unique mechanism of action, favorable pharmacokinetic properties, and intravenous formulation
+Added: offer distinct advantages over currently approved and investigational therapies that target PI3K or mTOR alone or together.
+Added: limitations of therapies that only inhibit a single class I PI3K isoform or only one mTOR kinase complex
+Added: is a pan-class I isoform PI3K inhibitor with low nanomolar potency for the p110α, p110β, p110γ, and p110δ
+Added: Because gedatolisib inhibits all four PI3K isoforms and both mTOR complexes, it prevents the confounding effect of isoform
+Added: interaction that may occur with isoform-specific PI3K inhibitors and the confounding interaction between PI3K isoforms and mTOR.
+Added: This compares to therapies that only inhibit a single class I isoforms (e.g., alpelisib, a PI3K-α inhibitor)
+Added: or only one mTOR kinase complex (e.g., everolimus, an mTORC1 inhibitor), which cross-activate uninhibited sub-units due to numerous
+Added: feedforward and feedback loops between the PI3K isoforms and mTOR, which in turn induces compensatory resistance that reduces the
+Added: efficacy of isoform specific PI3K or single mTOR kinase complex inhibitors.
+Added: tolerated by patients than oral PI3K and mTOR drugs.
+Added: is administered intravenously (IV) on a four-week cycle of three weeks-on, one week-off, in contrast to the orally administered pan-PI3K
+Added: or dual PI3K/mTOR inhibitors that are no longer being clinically developed.
+Added: Oral pan-PI3K or PI3K/mTOR inhibitors have repeatably
+Added: been found to induce significant side effects that were not well tolerated by patients.
+Added: This typically leads to a high proportion
+Added: of patients requiring dose reductions or treatment discontinuation, despite showing promising efficacy.
+Added: By contrast, gedatolisib
+Added: stabilizes at lower concentration levels in plasma compared to orally administered PI3K inhibitors, resulting in less toxicity, while
+Added: maintaining concentrations sufficient to inhibit PI3K/mTOR signaling.
+Added: Isoform-specific
+Added: PI3K inhibitors administered orally were developed to reduce toxicities in patients.
+Added: While the range of toxicities associated with
+Added: isoform-specific inhibitors is narrower than oral pan-PI3K or PI3K/mTOR inhibitors, administering them orally on a continuous basis
+Added: still leads to challenging toxicities.
+Added: The experience with an FDA approved oral p110-α specific inhibitor, Piqray, illustrates
+Added: the challenge.
+Added: In its Phase 3 pivotal trial Piqray was found to induce a Grade 3 or 4 adverse event (AE) related to hyperglycemia
+Added: in 39% of patients evaluated.
+Added: In addition, 26% of patients discontinued alpelisib due to treatment related adverse events.
+Added: in the 103-patient dose expansion portion of the Phase 1b clinical trial with gedatolisib, only 7% of patients experienced Grade
+Added: 3 or 4 hyperglycemia and less than 10% discontinued treatment.
+Added: Experience with Gedatolisib
+Added: of December 31, 2021, 492 patients with solid tumors have received gedatolisib in eight clinical trials sponsored by Pfizer.
+Added: patients, 129 were treated with gedatolisib as a single agent in three clinical trials.
+Added: The remaining 363 patients received gedatolisib
+Added: in combination with other anti-cancer agents in five clinical trials.
+Added: Additional patients received gedatolisib in combination with other
+Added: anti-cancer agents in nine investigator sponsored clinical trials.
+Added: January 13, 2022, gedatolisib was granted Fast Track designation for the treatment of patients with HR+/HER2- metastatic breast
+Added: cancer after progression on CDK4/6 therapy.
+Added: Fast Track designation is granted by the FDA for products that are intended for the treatment
+Added: of serious or life-threatening disease or conditions and which demonstrate the potential to address an unmet medical need.
+Added: The designation
+Added: offers the opportunity for frequent interactions with the FDA to discuss the drug’s development plan and to ensure collection of
+Added: appropriate data needed to support drug approval, as well as eligibility for rolling submission of a New Drug Application.
+Added: Gedatolisib’s
+Added: safety, tolerability and pharmacokinetic profile were determined in a Phase 1 First-in-Human study.
+Added: The favorability of preliminary results
+Added: from our most recently completed clinical trial, a Phase 1b study which evaluated 138 patients with HR+/HER2- advanced breast
+Added: cancer, led us to focus our initial clinical development program on advanced breast cancer.
+Added: 1 First-in-Human Study
+Added: 2013, Pfizer completed a Phase 1, open-label, dose-escalation first-in human study of single-agent gedatolisib in patients with advanced
+Added: solid tumors.
+Added: The primary objective of Part 1 of the study was to determine the safety, tolerability, and maximum tolerated dose (MTD)
+Added: of single-agent gedatolisib administered once weekly as an intravenous (IV) infusion.
+Added: Seventy-seven patients with advanced solid tumors
+Added: received doses of gedatolisib and the MTD was determined to be 154 mg IV once weekly (n = 42).
+Added: Subsequent analysis determined that the
+Added: recommended Phase 2 dose could be increased to 180 mg IV once weekly.
+Added: the MTD, the majority of patients enrolled in the MTD group experienced only grade 1 treatment-related adverse events (AEs).
+Added: 3 treatment-related adverse events were noted in 23.8% of patients, and the most frequently reported included mucosal inflammation and
+Added: stomatitis (7.1%), increased alternative lengthening of telomeres (ALT) (7.1%), and increased aspartate aminotransferase (AST) (4.8%).
+Added: Only 2% of patients experienced Grade 3 hyperglycemia.
+Added: No treatment-related AEs of grade 4 or 5 severity were reported at any
+Added: 1b HR+/HER2- MBC Clinical Trial Results (preliminary)
+Added: 2016, Pfizer initiated a Phase 1b trial dose-finding trial with an expansion portion for safety and efficacy to evaluate gedatolisib
+Added: when added to either the standard doses of palbociclib plus letrozole or palbociclib plus fulvestrant in patients with HR+/HER2- metastatic
+Added: breast cancer.
+Added: PI3K mutation status was not used as an eligibility criterion.
+Added: Patient enrollment for the trial is complete.
+Added: total of 138 patients with HR+/HER2- metastatic breast cancer were dosed in the clinical trial.
+Added: Twelve patients from this
+Added: study continue to receive study treatment, as of December 31, 2021, ten of whom have received study treatment for more than three
+Added: patients were enrolled in two dose escalation arms to evaluate the safety and tolerability and determine the MTD of gedatolisib when
+Added: used in combination with the standard doses of palbociclib and endocrine therapies.
+Added: The MTD was determined to be 180 mg administered
+Added: intravenously once weekly.
+Added: patients were enrolled in one of four expansion arms (A, B, C, D) to determine if the triplet combination of gedatolisib plus palbociclib
+Added: and letrozole or gedatolisib plus palbociclib and fulvestrant produced a superior objective response (OR), compared to historical
+Added: control data of the doublet combination (palbociclib plus endocrine therapy).
+Added: All patients received gedatolisib in combination with
+Added: standard doses of palbociclib and endocrine therapy (either letrozole or fulvestrant).
+Added: In Arms A, B, and C, patients received an
+Added: intravenous dose of 180 mg of gedatolisib once weekly.
+Added: In Arm D, patients received an intravenous dose of 180 mg of gedatolisib on
+Added: a four-week cycle of three weeks-on, one week-off.
+Added: Objective response was determined using Response Evaluation Criteria in Solid
+Added: Tumors v1.0, or RECIST v1.0.
+Added: MBC with progression and no prior endocrine-based systemic therapy or a CDK4/6 inhibitor in the metastatic setting.
+Added: endocrine-based therapy for metastatic disease (CDK4/6 treatment naive).
+Added: MBC with progression during one or two prior endocrine-based systemic therapy in the metastatic setting, with no prior therapy
+Added: with any CDK inhibitor.
+Added: Second- or third-line endocrine-based therapy for metastatic disease.
+Added: MBC with progression during one or two prior endocrine-based systemic therapies in the metastatic setting and following prior
+Added: therapy with a CDK inhibitor.
+Added: Second- or third-line endocrine-based therapy for metastatic disease.
+Added: MBC having progressed on a CDK inhibitor in combination with endocrine therapy as the most recent regimen for metastatic disease.
+Added: Second- or third-line endocrine-based therapy for metastatic disease.
+Added: preliminary analysis for the 103 patients enrolled in the expansion portion of the Phase 1b clinical trial, as of the database cutoff
+Added: date of May 10, 2021, showed:
+Added: analysis for all arms in aggregate:
+Added: objective response rate (ORR)
+Added: clinical benefit rate (CBR)
+Added: responses, as measured by RECIST v1.0, are shown in the following chart for Arm A (1 st line patients) and Arm D (2 nd /3 rd
+Added: line patients who received recommended dosing regimen).
+Added: The dotted line represents the cutoff for partial response (PR), defined
+Added: as a 30% reduction from the baseline tumor assessment.
+Added: safety analysis:
+Added: all arms in aggregate, all patients experienced at least one Grade 1 or Grade 2 treatment-emergent adverse event.
+Added: The most commonly
+Added: reported adverse events regardless of grade and occurring in at least 30% of patients included stomatitis (81%), neutropenia (80%),
+Added: nausea (75%), fatigue (68%), dysgeusia (46%), vomiting (45%), anemia (40%), diarrhea (34%), decreased appetite (32%), leukopenia
+Added: all arms in aggregate, the Grade 3 and 4 treatment-emergent adverse events occurring in at least 20% of patients were neutropenia
+Added: (67%), stomatitis (27%) and rash (20%).
+Added: Neutropenia is a known class effect of CDK4/6 inhibitors.
+Added: Stomatitis was reversible in most
+Added: patients with a steroidal mouth rinse.
+Added: All grades of treatment-related adverse events related to hyperglycemia was reported in 22%
+Added: Grade 3 or 4 hyperglycemia was reported in 7% of patients.
+Added: Gedatolisib was discontinued in 10% of patients.
+Added: the patients in Arm D, who received the Phase 3 dosing schedule, Grade 3 and 4 treatment-emergent adverse events occurring in at
+Added: least 20% of patients were neutropenia (67%) and stomatitis (22%).
+Added: All grades of treatment-related adverse events related
+Added: to hyperglycemia was reported in 22% of patients;
+Added: Grade 3 or 4 hyperglycemia was reported in 7% of patients.
+Added: Gedatolisib was discontinued
+Added: in 4% of patients.
+Added: best overall response and progression free survival data for each arm is presented in the table below:
+Added: CDKi-pretreated
+Added: CDKi-pretreated
+Added: represents PR, except in Arm A, which had 1 CR.
+Added: Responses per RECIST 1.1
+Added: 2 unconfirmed PR
+Added: Abbreviations:
+Added: CBR = clinical
+Added: benefit rate;
+Added: NR = not reached
+Added: Layman 2021 SABCS
+Added: Gedatolisib Clinical Trials
+Added: 2 Pilot Clinical Trial for HER2+/PIK3CA+ Patients
+Added: Korean Cancer Study Group sponsored a Phase 2 pilot clinical trial to evaluate gedatolisib combined with a trastuzumab biosimilar (Herzuma®),
+Added: in patients with HER2+/PIK3CA+ metastatic breast cancers whose disease had progressed after treatment with three or more prior HER2 targeted
+Added: therapy regimens.
+Added: The clinical trial commenced in December 2019 and interim efficacy data from the first 16 patients enrolled was presented
+Added: at the San Antonio Breast Cancer Symposium in December 2020.
+Added: Patients received a trastuzumab biosimilar (8 mg/kg IV for 1st cycle loading
+Added: dose, and then 6 mg/kg IV every 3 weeks) plus gedatolisib (180 mg, weekly IV).
+Added: The primary endpoint was objective response, a reduction
+Added: of at least 30% in tumor volume by RECIST v1.1.
+Added: of a data cutoff date of October 30, 2020, nine of 16 patients achieved a partial response, an ORR of 56%, and four patients had stable
+Added: Thirteen of 16 patients thus received either a partial response or stable disease, resulting in a clinical benefit rate of 81%.
+Added: Best responses are shown in the following chart.
+Added: The dotted lines represent the cutoff for progressive disease (>20% tumor growth)
+Added: and for partial response (>30% tumor regression).
+Added: Patient whose target lesion decreased by 63% but a new leptomeningeal seeding occurred.
+Added: duration of treatment for the 16 patients evaluated is shown in the chart below.
+Added: As of the October 30, 2020 data cutoff, 16 patients
+Added: (80%) remained on therapy.
+Added: Four patients discontinued treatment, one due to disease progression, one due to an adverse event of Grade
+Added: 1 diarrhea, one participant decision, and one patient being unable to undergo the required MRI imaging due to a titanium rod implant
+Added: from non-treatment related worsening of scoliosis.
+Added: At the time of data cut-off, the median time on treatment for these 20 patients was
+Added: 10.1 cycles (approximately 10 months) and all 10 patients who had achieved an objective response remained on therapy assessment.
+Added: time of the analysis, nine patients had a continuing response.
+Added: The dashed lines show the response at 3 months and 6 months.
+Added: 1 Clinical Trial in Patients with Solid Tumors
+Added: phase 1 study conducted at the Indiana University Simon Cancer Center evaluated the safety, tolerability, pharmacokinetics and preliminary
+Added: activity of gedatolisib combined with carboplatin and paclitaxel in patients with advanced solid tumors previously who were treated with
+Added: two or more prior chemotherapies.
+Added: Seventeen patients were enrolled (10 clear cell ovarian, one low-grade serous ovarian, four endometrial,
+Added: and two lung cancers).
+Added: The ORR was 65% in all patients (11/17 patients:
+Added: eight partial responses and three complete responses) and stable
+Added: disease was 17% (3/17).
+Added: Among patients with clear cell ovarian cancer, the ORR was 80%, with three patients achieving a complete response.
+Added: Gedatolisib Clinical Trials
+Added: Planned Phase 3 HR+/HER2-
+Added: MBC Clinical Trial (VIKTORIA-1)
+Added: are preparing to initiate VIKTORIA-1, a Phase 3, open-label, randomized clinical trial to evaluate the efficacy and safety of gedatolisib
+Added: in combination with fulvestrant with or without palbociclib in adults with HR+/HER2- advanced breast cancer whose disease has progressed
+Added: after prior CDK4/6 therapy in combination with an aromatase inhibitor.
+Added: This multi-center, international trial is expected to enroll 651 total subjects at approximately 175 clinical sites
+Added: across the U.S., Europe, and Asia.
+Added: We expect to initiate the VIKTORIA-1 clinical trial in the first
+Added: half of 2022.
+Added: clinical trial will enable separate evaluation of subjects according to their PIK3CA status.
+Added: who meet eligibility criteria and do not have confirmed PI3KCA mutations (WT) will be randomly assigned (1:1:1) to receive
+Added: a regimen of either gedatolisib, palbociclib, and fulvestrant (Arm A), gedatolisib and fulvestrant (Arm B), or fulvestrant (Arm C).
+Added: Up to 351 subjects who are PIK3CA WT will be enrolled.
+Added: The three-arm design will also show the contribution of gedatolisib.
+Added: Subjects who meet eligibility criteria and have confirmed PI3KCA mutations (MT) will be randomly assigned (1:1) to
+Added: receive a regimen of either gedatolisib, palbociclib, and fulvestrant (Arm D) or alpelisib and fulvestrant (Arm E).
+Added: subjects who are PIK3CA MT will be enrolled.
+Added: clinical trial primary endpoints are progression free survival (PFS), per RECIST 1.1 criteria, as assessed by blinded independent
+Added: central review (BICR).
+Added: Two primary endpoints will be evaluated in subjects who are PI3KCA WT, and one primary endpoint will be
+Added: evaluated in subjects who are PI3KCA MT.
+Added: In subjects who are PI3KCA WT, the PFS of gedatolisib in combination with palbociclib and
+Added: fulvestrant (Arm A) will be compared to fulvestrant monotherapy (Arm C), and the PFS in gedatolisib in combination with fulvestrant
+Added: (Arm B) will be compared to fulvestrant monotherapy (Arm C).
+Added: In subjects who are PI3KCA MT, the PFS of gedatolisib in combination
+Added: with palbociclib and fulvestrant (Arm D) will be compared to alpelisib combined with fulvestrant (Arm E).
+Added: subjects will receive treatment according to the assigned study arm until objective progressive disease, unacceptable toxicity, death,
+Added: or withdrawal of consent, whichever occurs first.
+Added: Subjects in Arm C will have the option to receive the treatment regimen provided in
+Added: Arm A or Arm B upon radiographically confirmed disease progression.
+Added: Subjects will be followed for AEs, safety laboratory testing, tumor
+Added: assessment by RECIST v1.1, quality of life, and overall survival.
+Added: Phase 2 Gedatolisib Clinical Trials
+Added: expect to use the CELsignia PI3K Activity Test to help support development of gedatolisib for breast cancer indications.
+Added: studies demonstrate how measurement of PI3K-involved signaling may provide a sensitive and specific method of identifying patients most
+Added: likely to benefit from PI3K inhibitors.
+Added: We believe CELsignia tests uniquely enable us to pursue indications simultaneously for unselected
+Added: patient populations and CELsignia selected patient sub-groups.
+Added: This approach can greatly reduce the risk of pursing an indication for
+Added: a large, but unselected patient population, as we plan to do for the initial gedatolisib indication.
+Added: By combining the capabilities of
+Added: CELsignia PI3K Activity Test with a potent pan-PI3K/mTOR inhibitor like gedatolisib, we believe we are uniquely suited to maximize the
+Added: probability of obtaining regulatory approval to market gedatolisib.
+Added: we plan to initiate two Phase 2 clinical trials to evaluate gedatolisib in HR+/HER2- breast cancer patients selected with a CELsignia
+Added: PI3K Pathway Test.
+Added: One trial is expected to evaluate gedatolisib in combination with fulvestrant in up to 25 patients with metastatic
+Added: breast cancer.
+Added: The second trial is expected to evaluate up to 15 patients with early-stage breast cancer with gedatolisib in combination
+Added: with palbociclib and letrozole.
+Added: These clinical trials are expected to be initiated at sites which are already participating in a trial
+Added: that is screening patients with the CELsignia HER2 Pathway Test.
+Added: Screened patients who provide a tumor biopsy will receive a CELsignia
+Added: HER2 and PI3K Test.
+Added: Patients found to have hyperactive HER2 signaling will be eligible to receive treatment with an anti-HER2 therapy
+Added: and those with hyperactive PI3K signaling will be eligible to receive gedatolisib in combination with other targeted therapies.
+Added: enrollment is expected to begin for the two trials in late 2022.
+Added: License Agreement
+Added: April 2021, we entered into a license agreement, or the Gedatolisib License Agreement, with Pfizer pursuant to which we acquired exclusive
+Added: (including as to Pfizer) worldwide sublicensable rights to research, develop and manufacture, and commercialize gedatolisib for the treatment,
+Added: diagnosis and prevention of all diseases.
+Added: Pursuant to the Gedatolisib License Agreement, we are obligated to use commercially reasonable
+Added: efforts to develop and seek regulatory approval for at least one product in the U.S.
+Added: and if regulatory approval is obtained, to commercialize
+Added: such product in the U.S and at least one international major market.
+Added: paid Pfizer a $5.0 million upfront fee upon execution of the Gedatolisib License Agreement and issued to Pfizer $5.0 million of our common
+Added: We are also required to make milestone payments to Pfizer upon achievement of certain development and commercial milestone events,
+Added: up to an aggregate of $335.0 million.
+Added: We will pay Pfizer tiered royalties on sales of gedatolisib at percentages ranging from the low
+Added: to mid-teens, that may be subject to deductions for expiration of valid claims, amounts due under third-party licenses and generic competition.
+Added: Unless earlier terminated, the Gedatolisib License Agreement will expire upon the expiration of all royalty obligations.
+Added: period will expire on a country-by-country basis upon the later of (a) 12 years following the date of First Commercial Sale of such Product
+Added: in such country, (b) the expiration of all regulatory or data exclusivity in such country for such Product or (c) the date upon which
+Added: the manufacture, use, sale, offer for sale or importation of such Product in such country would no longer infringe, but for the license
+Added: granted herein, a Valid Claim of a Licensed Patent Right.
+Added: Capitalized terms in this paragraph have the meanings set forth in the Gedatolisib
+Added: License Agreement.
+Added: have the right to terminate the Gedatolisib License Agreement for convenience upon 90 days’ prior written notice.
+Added: Pfizer may not
+Added: terminate the agreement for convenience.
+Added: Either we or Pfizer may terminate the Gedatolisib License Agreement if the other party is in
+Added: material breach and such breach is not cured within the specified cure period.
+Added: In addition, either we or Pfizer may terminate the Gedatolisib
+Added: License Agreement in the event of specified insolvency events involving the other party.
+Added: Manufacturing
+Added: rely on third parties to manufacture gedatolisib.
+Added: We expect to enter into agreements with contract manufacturing organizations, or CMOs,
+Added: to produce drug substance for gedatolisib.
+Added: We require all of our CMOs to conduct manufacturing activities in compliance with current
+Added: good manufacturing practice, or cGMP, requirements.
+Added: We anticipate that these CMOs will have the capacity to support both clinical supply
+Added: and commercial-scale production, but we do not have any formal agreements at this time to cover commercial production.
+Added: We may also elect
+Added: to enter into agreements with other CMOs to manufacture supplies of drug substance and finished drug product.
+Added: and Marketing
+Added: any of our product candidates are approved, we intend to market and commercialize them in the U.S.
+Added: and select international markets,
+Added: either alone or in partnership with others.
+Added: Cancer patients are managed by oncologists, medical geneticists and neurologists, and therefore
+Added: we believe can be reached with a targeted sales force.
+Added: for Gedatolisib
+Added: pharmaceutical industry is characterized by rapid evolution of technologies and intense competition.
+Added: While we believe that our product
+Added: candidates, technology, knowledge, experience and scientific resources provide us with competitive advantages, we face competition from
+Added: major pharmaceutical and biotechnology companies, academic institutions, governmental agencies and public and private research institutions,
+Added: among others.
+Added: Any product candidates that we successfully develop and commercialize will compete with approved treatment options, including
+Added: off-label therapies, and new therapies that may become available in the future.
+Added: Key considerations that would impact our ability to effectively
+Added: compete with other therapies include the efficacy, safety, method of administration, cost, level of promotional activity and intellectual
+Added: property protection of our products.
+Added: Many of the companies against which we may compete have significantly greater financial resources
+Added: and expertise than we do in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory
+Added: approvals and marketing approved products.
+Added: are several PI3K and mTOR inhibitors approved by the FDA, including Piqray and Afinitor from Novartis AG, Aliqopa from Bayer Corporation,
+Added: Copiktra from Verastem, Inc.
+Added: Zydelig from Gilead Sciences, Inc.
+Added: and we are aware that other companies are, or may be, developing products
+Added: for this indication, including AstraZeneca plc, BridgeBio Inc., Eli Lilly and Company, F.
+Added: Hoffmann-La Roche Ltd, Kazia Therapeutics Limited,
+Added: Infinity Pharmaceuticals, Inc., Revolution Medicines Inc., and Takeda Pharmaceutical Company Limited.
+Added: There may be additional companies
+Added: with programs suitable for addressing these patient populations that could be competitive with our efforts but that have not yet disclosed
+Added: specific clinical development plans.
+Added: Smaller or early-stage companies, including oncology-focused therapeutics companies, may also prove
+Added: to be significant competitors, particularly through collaborative arrangements with large and established companies.
+Added: These companies
+Added: may also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites,
+Added: enrolling patients in clinical trials and acquiring technologies complementary to, or necessary for, our programs.
+Added: The availability of
+Added: reimbursement from government and private payors will also significantly impact the pricing and competitiveness of our products.
+Added: competitors may obtain FDA or other regulatory approvals for their products more rapidly than we may obtain approvals for our product
+Added: candidates, which could result in our competitors establishing a strong market position before we are able to commercialize our product
+Added: Development and CDx Programs
+Added: proprietary CELsignia diagnostic platform is the only commercially ready technology we are aware of that uses a patient’s living
+Added: tumor cells to identify the specific abnormal cellular process driving a patient’s cancer and the targeted therapy that best treats
+Added: This enables us to identify patients whose tumors may respond to a targeted therapy, even though they lack a previously associated
+Added: molecular mutation.
+Added: By identifying cancer patients whose tumors lack an associated genetic mutation but have abnormal cellular activity
+Added: a matching targeted therapeutic is designed to inhibit, we believe our CELsignia CDx can expand the markets for a number of already approved
+Added: targeted therapies.
+Added: Our current CDx identifies breast and ovarian cancer patients whose tumors have cancer drivers potentially responsive
+Added: to treatment with human epidermal growth factor receptor 2-negative (HER2), mesenchymal-epithelial transition factor (c-MET), or phosphatidylinositol
+Added: 3-kinases (PI3K) targeted therapeutics.
+Added: CELsignia platform provides an important advantage over traditional molecular diagnostics.
+Added: Current molecular diagnostics analyze fragmented
+Added: cells to obtain a snapshot of the genetic mutations present in a patient’s tumor.
+Added: Using cell fragments prevents molecular diagnostics
+Added: from analyzing the dynamic cellular activities, known as cell signaling, that regulate cell proliferation or survival.
+Added: Cancer can develop
+Added: when critical cell signaling, regulating physiologic activity such as cell proliferation, becomes abnormal or dysregulated.
+Added: Since genetic
+Added: mutations are often only weakly correlated to the dysregulated cell signaling activity driving a patient’s cancer, a molecular
+Added: diagnostic is prone to providing an incomplete diagnosis.
+Added: CELsignia tests overcome this limitation by measuring dynamic cell signaling
+Added: activity in a cancer patient’s living tumor cells.
+Added: When a CELsignia test detects abnormal signaling activity, a more accurate diagnosis
+Added: of the patient’s cancer driver is obtained.
+Added: are supporting the advancement of new potential indications for four different targeted therapies, controlled by other pharmaceutical
+Added: companies, that would rely on a CELsignia CDx to select patients.
+Added: Our first analytically validated and commercially ready test using
+Added: our CELsignia platform, the CELsignia HER2 Pathway Activity Test for breast cancer, diagnoses two new sub-types of HER2-negative breast
+Added: cancer that traditional molecular diagnostics cannot detect.
+Added: Our internal studies show that approximately 15-20% of HER2-negative breast
+Added: cancer patients have abnormal HER2 signaling activity similar to levels found in HER2-positive breast cancer cells.
+Added: As a result, these
+Added: HER2-negative patients have undiagnosed HER2-driven breast cancer and would be likely to respond to the same anti-HER2 targeted therapies
+Added: only HER2-positive patients receive today.
+Added: We have four interventional clinical trials underway to evaluate the efficacy of HER2
+Added: targeted therapies in breast cancer patients selected with our CELsignia HER2 Pathway Activity Test.
+Added: second CELsignia test for breast cancer evaluates independent c-Met signaling activity and its involvement with HER family signaling
+Added: in HER2-negative breast cancer tumor cells.
+Added: Our internal studies show that approximately 20%-25% of HER2-negative breast cancer patients
+Added: have abnormal c-Met signaling activity that is co-activated with abnormal HER family signaling.
+Added: These studies suggest that this sub-group
+Added: of HER2-negative breast cancer patients may best respond to treatment with a combination of HER family and c-Met inhibitors.
+Added: one interventional clinical trial underway to evaluate the efficacy of HER2 and c-Met targeted therapies, in previously treated
+Added: metastatic HER2-negative breast cancer patients selected with our CELsignia Multi-Pathway Activity Test, or CELsignia MP Test.
+Added: third CELsignia test for breast cancer evaluates PI3K signaling in HER2-negative breast cancer tumor cells.
+Added: Our internal studies demonstrate
+Added: how measurement of PI3K-involved signaling may provide a more sensitive and specific method of identifying patients most likely to benefit
+Added: from PI3K inhibitors than current genetic tests that measure PI3K mutations.
+Added: We intend to combine these three tests to expand the CELsignia
+Added: With this next generation CELsignia test, we plan to provide an analysis of EGFR/HER1, HER2, HER3, c-MET, and PI3K-node involved
+Added: signaling activity for each patient tumor specimen received.
+Added: addition, we completed development of our first CELsignia test for ovarian cancer in 2020.
+Added: This test identifies a new sub-group of ovarian
+Added: cancer patients with tumors that have abnormal c-Met and HER2 signaling activity.
+Added: These findings suggest that a significant sub-group
+Added: of ovarian cancer patients may respond to treatment with a combination of ErbB and c-Met inhibitors.
+Added: Nearly 14,000 women a year die from
+Added: ovarian cancer, a disease that has less than a 50% five-year survival rate and a limited range of targeted therapy options.
+Added: thus a significant unmet need for additional therapeutic options for ovarian cancer patients.
+Added: As a companion diagnostic, our CELsignia
+Added: test for ovarian cancer will be intended to help pharmaceutical companies obtain new drug indications and expand treatment options for
+Added: this challenging tumor type.
+Added: overall commercialization strategy is to develop diagnostics that expand the patient population eligible for targeted therapies.
+Added: In furtherance
+Added: of this strategy, we have been and will continue to seek collaborations with pharmaceutical companies to field clinical trials to advance
+Added: the clinical development of their targeted therapies with the eventual goal of obtaining FDA approval of a new drug indication.
+Added: Clinical Trials
+Added: are currently collaborating on five Phase II clinical trials to evaluate the efficacy of our collaboration partners’ targeted therapies
+Added: in patients selected with one of our CELsignia tests.
+Added: The goal of these trials is to support the development of five potential new drug
+Added: indications to treat patient groups found responsive by our CELsignia test to their approved targeted therapies.
+Added: These clinical trials
+Added: Clinical Trial to Evaluate Efficacy of Genentech’s HER2 Targeted Therapies.
+Added: We are collaborating with NSABP Foundation, Inc.
+Added: (“NSABP”) and Genentech, Inc.
+Added: (“Genentech”) to evaluate the efficacy and safety of Genentech’s drugs,
+Added: Herceptin (trastuzumab) and Perjeta (pertuzumab), and chemotherapy in breast cancer patients selected with our CELsignia test.
+Added: on NSABP’s updated estimates of patient enrollment rates to reflect the impact of COVID-19, including the recent variants,
+Added: interim results are expected to be available in the first half of 2023 and final results approximately nine months later.
+Added: is to demonstrate that patients who have an abnormal HER2 signaling pathway, as identified by our CELsignia test, respond to treatment
+Added: with a matching targeted therapy.
+Added: Clinical Trial to Evaluate Efficacy of Puma’s HER2 Targeted Therapy.
+Added: We are collaborating with Puma Biotechnology, Inc.
+Added: and West Cancer Center to conduct a Phase II single-arm interventional trial to evaluate the efficacy and safety of Puma’s
+Added: drug, Nerlynx (neratinib), and chemotherapy in breast cancer patients selected with our CELsignia test.
+Added: Based on West Cancer Center’s
+Added: updated estimates of patient enrollment rates to reflect the impact of COVID-19, including the recent variants, interim results are
+Added: expected to be available in the first half of 2023 and final results approximately nine months later.
+Added: The goal of the trial is to
+Added: demonstrate that triple-negative breast cancer patients who have a hyperactive HER2 signaling tumor, as identified by the CELsignia
+Added: test, respond to treatment with Nerlynx, a matching HER2 therapy.
+Added: Clinical Trial to Evaluate Efficacy of Puma’s HER2 Targeted Therapy.
+Added: In December 2020, we announced a clinical trial collaboration
+Added: with Massachusetts General Hospital and Puma, a biopharmaceutical company, to conduct a Phase II clinical trial.
+Added: This open-label
+Added: Phase II trial will evaluate the efficacy and safety of Puma’s drug, Nerlynx (neratinib), and Faslodex (fulvestrant), an AstraZeneca
+Added: drug, in previously treated metastatic EHR-positive (HR+), HER2-negative breast cancer patients selected with our CELsignia HER2
+Added: Pathway Activity Test.
+Added: Based on Massachusetts General Hospital’s estimates of patient enrollment rates, we expect to obtain
+Added: interim results 12-15 months after the protocol is activated and final results 12 to 15 months later.
+Added: The goal of the trial is to
+Added: demonstrate that previously treated HR+, HER2-negative metastatic breast cancer patients who have hyperactive HER2 signaling
+Added: tumors, as identified by the CELsignia test, respond to treatment with Nerlynx in combination with Faslodex, a hormonal therapy that
+Added: targets the estrogen receptor.
+Added: Clinical Trial to Evaluate Efficacy of Puma’s pan-HER Inhibitor and chemotherapy.
+Added: In October 2021, we announced a clinical
+Added: trial collaboration with University of Rochester Wilmot Cancer Center and Puma, to conduct a Phase II clinical trial.
+Added: This open-label
+Added: Phase II trial will evaluate the efficacy and safety of Puma’s drug, Nerlynx (neratinib), and the chemotherapy capecitabine,
+Added: in previously treated metastatic HER2-negative breast cancer patients with brain metastases selected with our CELsignia HER2 Pathway
+Added: Activity Test.
+Added: Based on University of Rochester Wilmot Cancer Center estimates of patient enrollment rates, we expect to obtain interim
+Added: results 12-15 months after the protocol is activated and the final results 12 to 15 months later.
+Added: We expect enrollment to begin in
+Added: the second half of 2022.
+Added: The goal of the trial is to demonstrate that previously treated HER2-negative metastatic breast cancer patients
+Added: with brain metastases who have hyperactive HER2 signaling tumors, as identified by the CELsignia test, respond to treatment with
+Added: Nerlynx in combination with capecitabine.
+Added: Clinical Trial to Evaluate Efficacy of Novartis’s c-Met Inhibitor and Puma’s pan-HER Inhibitor.
+Added: In March 2021, we announced
+Added: a clinical trial collaboration with MD Anderson Cancer Center, Novartis AG, and Puma, to conduct a Phase I/II clinical trial.
+Added: open-label Phase I/II trial will evaluate the efficacy and safety of Novartis’ c-Met inhibitor, Tabrecta (capmatinib), and
+Added: Puma’s pan-HER inhibitor, Nerlynx (neratinib), in previously treated metastatic HER2-negative breast cancer patients selected
+Added: with our CELsignia MP Test.
+Added: Based on MD Anderson’s estimates of patient enrollment rates, we expect to obtain interim results
+Added: 12-15 months after the protocol is activated and final results 12-15 months later.
+Added: The goal of the trial is to demonstrate that previously
+Added: treated HER2-negative metastatic breast cancer patients who have hyperactive HER2 and c-Met signaling tumors, as identified by the
+Added: CELsignia test, respond to treatment with Tabrecta in combination with Nerlynx.
+Added: Diagnostics Industry
+Added: to the Centers for Disease Control and Prevention, cancer was the second-leading cause of death in the United States in 2020, responsible
+Added: for nearly one of every four deaths.
+Added: There are many types of cancer treatment options, including surgery, radiation therapy, chemotherapy,
+Added: immunotherapy, hormone therapy, stem cell transplant, and targeted therapy.
+Added: Targeted therapies are drugs or other substances that block
+Added: the growth and spread of cancer by interfering with specific molecular targets involved in the progression of cancer.
+Added: Targeted therapies
+Added: differ from standard chemotherapy drugs in that they are often cytostatic (block tumor cell proliferation) rather than cytotoxic (kill
+Added: tumor cells).
+Added: According to the National Cancer Institute, there are currently more than 90 approved targeted oncology therapies, some
+Added: of which cost more than $100,000 per treatment course.
+Added: tests to detect single biomarkers are now widely used by pathologists to determine the molecular sub-type of a cancer.
+Added: When a molecular
+Added: biomarker test is used to support the choice of therapy to prescribe, it is often referred to as a “companion diagnostic.”
+Added: Increasing numbers of targeted therapeutics are prescribed based on the results from a companion diagnostic test to detect the presence
+Added: of a molecular biomarker.
Only patients testing positive for the biomarker are eligible to receive the associated therapy.
−Removed: Companion diagnostics are becoming increasingly important to the pharmaceutical industry.
−Removed: The use of companion diagnostics to better match patients to effective treatments positively impacts clinical outcomes and lowers expenditures on drugs that do not benefit patients.
−Removed: Stratifying the eligible patient population to include only likely responders is particularly important when the percentage of likely responders is only a fraction of the total cancer population.
−Removed: In these circumstances, narrowing the eligible patient population is often necessary to meet the clinical endpoint targets required to receive FDA drug approval.
−Removed: Our Market Opportunities
−Removed: Companion Diagnostic Development Opportunities
−Removed: We believe there at least 50 different potential opportunities for our company to collaborate on companion diagnostic programs with pharmaceutical companies.
−Removed: Our ability to develop partnering relationships with these pharmaceutical companies will be predicated on a number of factors, including the size of the patient population our CELsignia test identifies, the remaining patent life of the matching targeted therapy, and the success or failure of clinical trials we have conducted with other pharmaceutical companies.
−Removed: Completing clinical trials requires, among other things, successful enrollment of patients, meeting trial endpoint goals, and completing the trial in a timely manner.
−Removed: The time to complete a clinical trial can vary widely depending on a number of factors, many of which will be specific to any particular clinical trial.
−Removed: We believe the revenue opportunity per companion diagnostic program will be consistent with other development programs pharmaceutical companies support.
−Removed: In addition, the revenue for an individual companion diagnostic program would represent only a small fraction of the potential value that the new drug indication could create for our pharmaceutical company partner.
−Removed: For some drugs, our tests could double the number of patients eligible for a targeted therapy.
−Removed: CELsignia Testing Opportunities
−Removed: We expect to generate recurring companion diagnostic testing revenues once a CELsignia companion diagnostic-linked drug therapy is approved for patient use.
−Removed: On average, we believe that the lifetime value of providing the companion diagnostic test will significantly exceed the revenue generated from the companion diagnostic development program.
−Removed: We expect to offer each CELsignia test to patients at prices ranging from $4,000-$7,000, depending on the number of pathways evaluated.
−Removed: No tests directly comparable to the CELsignia tests are available today to offer reference points for pricing purposes.
−Removed: Pricing for several proprietary complex genomic tests, however, fall within this range and we believe this provides guidance on the amount insurance companies are willing to pay for highly informative tests that guide patient care.
−Removed: CELsignia Technology Background
−Removed: The Role of Cellular Signaling Pathways in Cancer
−Removed: Cancer is a class of exceedingly complex and diverse diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate and destroy normal body tissue and disrupt normal organ function.
−Removed: In normal cells, a series of biochemical activities, known as signal transduction, transmit biochemical signals through an interconnected network of signaling pathways to control cell proliferation and survival.
−Removed: Cancer arises when alterations occur in one or more of these signaling pathways and normal cell processes are disrupted, resulting in uncontrolled cell proliferation.
−Removed: These alterations are driven by a variety of cellular aberrations, including genetic mutations and dysregulated signaling pathway mechanisms.
−Removed: Identifying the alteration driving an individual’s cancer is complicated by the immense complexity of these signal transduction processes and the practically unquantifiable number of pathway variables.
−Removed: As recently as 20 years ago, most cancers were classified and subsequently treated solely on the basis of the anatomical location of the tumor in the body.
−Removed: Chemotherapies that kill rapidly dividing cells were widely used, but they had only limited efficacy for many patients and caused a wide range of dangerous side effects due to lack of discrimination for tumor tissue.
−Removed: As tools to identify molecular mutations became available, scientists began to uncover correlations between certain molecular mutations, cancer tissue type, and a patient’s prognosis.
−Removed: This fostered the development of molecularly targeted therapeutics that were designed to disrupt the specific cellular function of the drug target, typically abnormal signaling pathway activity, associated with the molecular mutation.
−Removed: These targeted therapies greatly improved outcomes for some cancer patients and are a testament to the efficacy of targeted therapies when effectively prescribed.
−Removed: According to information published by the Journal of Clinical Oncology in July 2017, targeted therapies are oftentimes 10 to 20 times more expensive than chemotherapies.
−Removed: In conjunction with the advent of targeted therapies, new molecular diagnostics were developed to help physicians refine the classification of a patient’s cancer into sub-types based on the presence of specific molecular anomalies, such as genetic mutations or over-expressed proteins.
−Removed: Such mutations or over-expressed proteins are commonly referred to as “biomarkers” when they are used to diagnose a disease and evaluate treatment options.
−Removed: For instance, breast cancer diagnostic tests are performed to determine whether two protein biomarkers, human epidermal growth factor receptor 2 (HER2) or estrogen receptors (ER), are overexpressed in the cancer cells.
−Removed: The results of these tests are used to classify the patient’s cancer molecular sub-type and to guide selection of a corresponding targeted drug therapy.
−Removed: The launch and on-going development of many new targeted therapies and the increasing use of companion molecular diagnostics to guide selection of the most appropriate therapy for each patient ushered in the era of so-called “precision medicine” in oncology.
−Removed: Advances in genomic and proteomic techniques and drug discovery enabled researchers to identify new drug targets, new molecular diagnostics, and drugs that would specifically bind to the target.
−Removed: While the increased usage of targeted therapies has improved patient outcomes, there is increasing recognition that the promise of molecularly guided diagnoses and targeted treatment has fallen far short of expectations.
−Removed: This is generally due to the heterogeneous nature of these diseases from patient to patient and the challenge of identifying the specific cellular dysfunction driving a cancer patient’s tumor growth.
−Removed: No matter how sophisticated or detailed, a point-in-time molecular profile can only provide a snapshot of a tumor.
−Removed: As a result, the genetic mutations many current tests identify are often only weakly correlated to the abnormal signaling driving a patient’s cancer.
−Removed: This is because protein and gene profiling provide an incomplete assessment of the biochemical activity promoting cancer tumor growth.
−Removed: In fact, when dysregulated, the activity of signaling pathway networks are, we believe, not possible to assess using current genetic analyses, despite the impressive investments in mapping the human genome and advancements in techniques to identify molecular mutations.
−Removed: The combination of the heterogeneous nature of cancer and the weak correlation of abnormal signaling to many genetic mutations helps explain why the response rates for patients treated with many targeted therapies are often less than 50%, and in some cases as low as 20%.
−Removed: For a patient to respond to a targeted therapy designed to disrupt disease-related signaling activity, two factors must be present:
−Removed: (1) the patient’s diseased cells must have the same signaling pathway dysfunction the drug is designed to inhibit, and (2) the drug affects its targeted pathway as intended.
−Removed: Current state-of-the-art genomic tests use cell fragments, which limits them to evaluating the presence or concentration of a genetic mutation or protein.
−Removed: These tests cannot evaluate either dynamic signaling activity or whether a drug can affect that activity.
−Removed: When a patient’s genomic biomarker status does not represent underlying signaling pathway dysfunction, this can lead to selection of the wrong targeted therapy to treat the patient.
−Removed: Of particular interest to us are those patients with dysregulated signaling who lack a corresponding biomarker;
−Removed: they are not currently eligible to receive any targeted therapy that treats their dysregulated signaling.
−Removed: To measure dynamic cellular activity, living patient tumor cells are required.
−Removed: Until our advancements, efforts to use living patient tumor cells have been limited by the lack of reliable methods to extract and culture cancer cells from patient tumors.
−Removed: These previously limited efforts reflect the emphasis amongst cancer researchers on creating stable cell lines for use to model cell function or to study and screen millions of test compounds in drug discovery programs.
−Removed: Pharmaceutical companies driving the commercial development of cell technologies work primarily with immortalized cells or cell lines genetically modified to express a target or mutation of interest.
−Removed: These cell lines consist of established cell cultures that proliferate indefinitely and very uniformly.
−Removed: They are used primarily because they provide a highly uniform response when tested with millions of small molecules in the search for potential new drugs, and because techniques to culture these cells are well known, their properties well understood, and other experimental results using them are available for comparison purposes.
−Removed: Conversely, live patient tumor cells are difficult to obtain, are only available in small quantities, and according to several articles published in leading cancer journals between 2017-2019 , the percentage of tumors that yield proliferative cells with conventional culturing methods has until now been well below 50%.
−Removed: For these reasons, researchers prefer paraffin-fixed tissue or cell lines over living tumor cells when studying disease processes or screening drug candidates.
−Removed: This lack of compelling rationale for pharmaceutical companies and academic institutions to work with live tumor cells for research purposes left the field of live tumor cell research in a relatively immature state.
−Removed: Our CELsignia Platform
−Removed: We have made significant investments in research and development to build the first commercially-ready cancer diagnostic platform that we are aware of that measures the signaling pathway activity in a patient’s living tumor cells.
−Removed: To measure dynamic cellular activity, we internally developed two distinct but complementary technologies, which now comprise our CELsignia platform:
−Removed: our proprietary cell microenvironment;
−Removed: our method to quantify dynamic patient cell signaling dysfunction.
−Removed: We utilize our CELsignia platform to create CELsignia tests that measure specific signaling pathway activity in various tumor types.
−Removed: Cell microenvironment.
−Removed: Previous research has shown that cancer cells extracted from a patient’s tumor share the molecular features of the primary cancers from which they were derived and could provide an ex vivo (outside the patient) model of a patient’s tumor.
+Added: diagnostics are becoming increasingly important to the pharmaceutical industry.
+Added: The use of companion diagnostics to better match patients
+Added: to effective treatments positively impacts clinical outcomes and lowers expenditures on drugs that do not benefit patients.
+Added: the eligible patient population to include only likely responders is particularly important when the percentage of likely responders
+Added: is only a fraction of the total cancer population.
+Added: In these circumstances, narrowing the eligible patient population is often necessary
+Added: to meet the clinical endpoint targets required to receive FDA drug approval.
+Added: Testing Opportunities
+Added: expect to generate recurring companion diagnostic testing revenues once a CELsignia companion diagnostic-linked drug therapy is approved
+Added: for patient use.
+Added: On average, we believe that the lifetime value of providing the companion diagnostic test will significantly exceed
+Added: the revenue generated from the companion diagnostic development program.
+Added: We expect to offer each CELsignia test to patients at prices
+Added: ranging from $4,000–$7,000, depending on the number of pathways evaluated.
+Added: No tests directly comparable to the CELsignia tests
+Added: are available today to offer reference points for pricing purposes.
+Added: Pricing for several proprietary complex genomic tests, however, fall
+Added: within this range and we believe this provides guidance on the amount insurance companies are willing to pay for highly informative tests
+Added: that guide patient care.
+Added: CELsignia Platform
+Added: have made significant investments in research and development of our CELsignia platform.
+Added: To measure dynamic cellular activity, we internally
+Added: developed two distinct but complementary technologies, which now comprise our CELsignia platform:
+Added: proprietary cell microenvironment;
+Added: method to quantify dynamic patient cell signaling dysfunction.
+Added: utilize our CELsignia platform to create CELsignia tests that measure specific signaling pathway activity in various tumor types.
+Added: microenvironment .
+Added: Previous research has shown that cancer cells extracted from a patient’s tumor share the molecular features
+Added: of the primary cancers from which they were derived and could provide an ex vivo (outside the patient) model of a patient’s
The technology around tumor cell extraction from individual patients and culturing techniques, however, has largely remained undeveloped.
−Removed: For instance, we are not aware of any competing diagnostic tests that use live patient tumor cells to measure dynamic cell signaling activity.
−Removed: Studies on the topic have historically highlighted the challenges of deriving a viable patient tumor cell sample from an individual patient tumor specimen.
−Removed: We have developed a cell microenvironment to extract and expand viable tumor cells from fresh human tumor tissue, which meets the three critical clinical parameters a patient-derived tumor cell sample would need to satisfy in order to meet the regulatory and clinical requirements for a diagnostic test measuring signaling activity:
−Removed: The patient cell sample tested must reflect the starting tumor’s composition.
−Removed: If samples do not reflect the original tumor’s composition, test results derived from that sample may not be representative of the patient’s tumor.
−Removed: The sample must be available for testing in less than 21 days.
−Removed: Clinicians generally require test results in cases of complex diseases such as cancer within two to three weeks so they can begin treatment of their patient as soon as the initial symptoms are evaluated or a preliminary diagnosis is made.
−Removed: At least 90% of the tumor specimens obtained from a patient must yield testable samples.
−Removed: Clinicians will only order tests that require a patient specimen when they are highly likely to receive a test result.
−Removed: Dynamic patient cell signaling quantification.
−Removed: The second component of our CELsignia platform involves methods to quantify specific dynamic signal transduction events in patient derived tumor cells.
−Removed: The complexity of signal transduction processes is immense, and the permutations of the pathway variables are practically unquantifiable.
+Added: For instance, we are not aware of any competing diagnostic tests that use live patient tumor cells to measure dynamic cell signaling
+Added: Studies on the topic have historically highlighted the challenges of deriving a viable patient tumor cell sample from an individual
+Added: patient tumor specimen.
+Added: have developed a cell microenvironment to extract and expand viable tumor cells from fresh human tumor tissue, which meets the three
+Added: critical clinical parameters a patient-derived tumor cell sample would need to satisfy in order to meet the regulatory and clinical requirements
+Added: for a diagnostic test measuring signaling activity:
+Added: patient cell sample tested must reflect the starting tumor’s composition.
+Added: If samples do not reflect the original tumor’s
+Added: composition, test results derived from that sample may not be representative of the patient’s tumor.
+Added: sample must be available for testing in less than 21 days.
+Added: Clinicians generally require test results in cases of complex diseases
+Added: such as cancer within two to three weeks so they can begin treatment of their patient as soon as the initial symptoms are evaluated
+Added: or a preliminary diagnosis is made.
+Added: least 90% of the tumor specimens obtained from a patient must yield testable samples.
+Added: Clinicians will only order tests that require
+Added: a patient specimen when they are highly likely to receive a test result.
+Added: patient cell signaling quantification .
+Added: The second component of our CELsignia platform involves methods to quantify specific dynamic
+Added: signal transduction events in patient derived tumor cells.
+Added: The complexity of signal transduction processes is immense, and the permutations
+Added: of the pathway variables are practically unquantifiable.
Current analytical methods to assess these variables use cell fragments.
−Removed: Point-in-time measurements are limited to assessment of the compositional status (e.g., mutation), concentration level (e.g., protein amount), or activation status (e.g., phosphorylation) of a finite number of signaling pathway components.
−Removed: A key insight underlying our technology was our observation that, no matter how sophisticated or detailed, a point-in-time molecular profile would only provide a snapshot.
−Removed: These methods could not provide a complete, dynamic assessment of the signaling activity driving a patient’s cancer.
−Removed: These point-in-time molecular analyses would, in many cases, only provide a weak correlation to the presence of the signaling pathway dysfunction driving a patient’s cancer.
−Removed: Instead, we concluded that a complete diagnosis of cancer and an assessment of a patient’s response to treating their disease requires measurement of the underlying activity of signaling pathways in live patient tumor cells.
−Removed: To measure live real-time dynamic cell signaling activity, we utilize an impedance biosensor instrument.
−Removed: An impedance biosensor is an analytical platform that converts changes in cellular activity to a measurable electrical signal.
−Removed: When cells are stimulated and change their function, the accompanying changes alter the electrical signal that is measured.
−Removed: The output value is quantified over time and used to determine a Signaling Function Score.
−Removed: To determine the activity of a specific signaling pathway, an activating agent specific to a pathway receptor is used to turn on the pathway and a corresponding inhibitory agent specific to the pathway receptor is used to turn signaling off.
−Removed: When signaling pathways are stimulated in this manner, a change in the electrical signal occurs and Signaling Function Score recorded.
−Removed: By relying on the principle of detecting signaling pathway activity, we believe we can develop tests for a range of disease types and targeted therapies that affect various cellular pathways.
−Removed: We believe our pioneering efforts have substantially advanced the technology of culturing primary tumor cells and analyzing cell signaling activity to guide therapy selection.
−Removed: We have three issued U.S.
−Removed: patents, five issued international patents, five pending U.S.
−Removed: patent applications, 23 pending non-U.S.
−Removed: patent applications, and one pending international PCT patent application, as well as significant proprietary know-how and trade secrets for the various cell sample preparation and cellular analysis methods we have developed.
−Removed: New Product Development
−Removed: We are leveraging our CELsignia technology to discover new cancer sub-types that a genomic test cannot detect.
−Removed: These new sub-types are characterized by the hyperactive signaling pathway our test identifies.
−Removed: These sub-types cannot be detected by genomic tests because they lack a corresponding molecular biomarker to identify it.
−Removed: We will translate our discoveries into companion diagnostic tests.
−Removed: We have already discovered several new breast cancer sub-types:
−Removed: HER2-negative breast cancers that are ER-positive or ER-negative with either (i) abnormal HER2 signaling, (ii) abnormal HER-family signaling coincident with abnormal c-Met signaling, and (iii) abnormal PI3K signaling.
−Removed: We are currently conducting research to identify additional cancer sub-types in five solid tumor types.
−Removed: Our research studies to date have identified eight potentially new lung, ovarian, kidney, and bladder cancer sub-types that involve dysregulated oncogenic signaling pathways.
−Removed: Multiple dysregulated pathways were active in each of these tumor types.
−Removed: These studies confirm that the CELsignia platform can be a cancer sub-type discovery engine and that we can create a multi-pathway test to identify the specific driver in a patient’s tumor.
−Removed: We expect to eventually expand the tumor types we evaluate to include colon, head and neck, leukemia, esophageal, and gastric cancers.
−Removed: We will seek to identify individual signaling pathways that may be driving at least 5% to 10% of the total cancers in each tissue area.
−Removed: Once we have characterized the prevalence of the different sub-types of signaling dysfunction in each tumor type and validated the tests for the different pathways, our plan will be to launch a corresponding CELsignia test.
−Removed: Eventually, each CELsignia test will analyze multiple pathways in a patient’s tumor to identify the specific pathway dysfunction driving a patient’s cancer.
−Removed: Testing multiple pathways will thus provide a system view of the patient’s cancer using dynamic functional analysis.
−Removed: We believe this will result in more accurate diagnosis of a patient compared to molecular diagnostics that are using next generation sequencing to assess the status of multiple static biomarkers.
−Removed: Clinical Trial Approach
−Removed: A major component of our development and commercial activities is providing clinical data from interventional clinical trials using our CELsignia tests.
−Removed: The goal of our clinical trial strategy is to demonstrate that patients found by a CELsignia test to have abnormal pathway signaling will respond favorably to a matching targeted therapy.
−Removed: Once our first trial demonstrates that our CELsignia test identifies patients responsive to targeted therapies, we expect pharmaceutical companies to partner with us to fund trials to evaluate new potential indications for their drugs with patients identified by one of our CELsignia tests.
−Removed: The trials will be designed to confirm that patients with abnormal pathway signaling obtain a superior clinical response to a therapy targeting that pathway than to the standard-of-care therapy they currently receive.
−Removed: For trials involving patients not currently eligible for a cancer drug that targets a certain pathway, we would first obtain a tissue specimen from each subject and perform the CELsignia test to identify subjects who have abnormal signaling.
−Removed: These patients would then be randomly assigned to either an arm that receives the current standard-of-care therapy or one that includes the current standard-of-care therapy plus the targeted therapy.
−Removed: All patients would be monitored until their disease progresses or until the end of the treatment regimen.
−Removed: CELsignia Multi-Pathway Activity Test
−Removed: Our CELsignia MP Test is a qualitative LDT that measures HER2, c-Met, and PI3K signaling activity in breast and ovarian tumor cells obtained from patients previously diagnosed with cancer to determine whether or not the patients have one of the following cancer sub-types:
−Removed: Abnormal HER2 signaling driven cancer
−Removed: Abnormal c-Met and HER2 signaling driven cancer
−Removed: Abnormal PI3K-involved signaling driven cancer
−Removed: Abnormal HER2 Signaling Driven Cancer
−Removed: Approximately 15% of breast cancer patients are diagnosed with HER2+ breast cancer when their tumor cells are found to have overexpressed or amplified levels of HER2.
−Removed: These patients are treated with anti-HER2 targeted therapies in combination with chemotherapies.
−Removed: Results from a number of clinical trial results for HER2 drugs reveal that only about 40% of HER2-positive patients respond to them.
−Removed: In addition, findings from several clinical trials have shown that a sub-set of HER2-negative patients benefit from therapies that target HER2.
−Removed: These results highlight the relatively weak correlation between HER2 receptor or gene amplification status and drug response.
−Removed: Despite the widely recognized role that a dysregulated HER2-related signaling network plays in promoting breast cancer, only tests measuring a single reactant, HER2 protein, are performed in the clinic to diagnose it;
−Removed: we believe no diagnostic tests are available today that measure HER2 signaling activity within a patient’s breast tumor epithelial cells.
−Removed: This focus on measuring HER2 expression-levels reflects the widely-held view that measuring a patient’s HER2 status is sufficient to diagnose HER2-driven breast cancers.
−Removed: When only HER2 expression is measured, though, patients classified as HER2-negative but whose tumor cells have abnormal HER2 signaling are diagnosed as not having HER2-driven breast cancer, when, in fact, they do.
−Removed: Since current genomic methods cannot identify HER2-negative breast cancer patients who have the HER2-driven cancer, a new method was required.
−Removed: Such a method would need to analyze the HER2-signaling pathways (MAPK and PI3K) associated with HER2 cancers in a patient’s tumor cells.
−Removed: Our CELsignia MP Test identifies patients whose HER2 status as determined by conventional techniques does not represent the correct diagnosis of their breast cancer at a functional level.
−Removed: For the sub-group of HER2-negative breast cancer patients diagnosed with abnormal HER2-signaling, it would be intended that they receive treatment with HER2 therapies.
−Removed: Abnormal c-Met Signaling coincident with Abnormal HER2 signaling
−Removed: Signaling through c-Met is necessary for normal cell development.
−Removed: Numerous studies have established the significant role of the c-Met pathway in tumor growth and metastasis.
−Removed: Crosstalk between c-Met and HER family receptors is also suspected of playing a role in tumor progression and resistance to HER targeted therapies.
−Removed: Numerous clinical trials have evaluated dual inhibition of c-Met and HER pathways in a variety of tumor types, but they have produced mostly negative results.
−Removed: Since subjects enrolled in these trials were primarily ones with c-Met protein overexpression or gene amplification, other biological factors, such as c-Met and HER signaling activity, are likely more important to measure when identifying patients eligible for c-Met therapies.
−Removed: Our recent studies found that a subset of HER2-negative breast cancer patients have abnormal c-Met signaling coincident with abnormal HER2 signaling.
−Removed: The c-Met expression level of each patient studied was normal.
−Removed: Strong evidence was found that c-Met and HER2 signaling is co-involved and may explain why a c-Met tyrosine kinase inhibitor is not an effective antagonist when c-Met is hyperactive for this patient sub-set.
−Removed: Additionally, evidence was found that simultaneous inhibition of EGFR/HER1, HER2, and HER3 signaling, in addition to inhibition of c-Met signaling, was necessary to inhibit HER2 and c-Met signaling activity most effectively.
−Removed: For the sub-group of HER2-negative breast cancer patients and ovarian cancer patients diagnosed with abnormal c-Met and HER2-signaling, it would be intended that they receive treatment with a combination of pan-HER and c-Met inhibitors.
−Removed: Abnormal PI3K Signaling Tumors
−Removed: The PI3K signaling pathway is a key regulator of normal cellular processes involved in cell growth, proliferation, metabolism, motility, survival, and apoptosis.
−Removed: Aberrant activation of the PI3K pathway promotes the survival and proliferation of tumor cells in many human cancers.
−Removed: In breast cancer, only patients with certain PI3K mutations are eligible for treatment with a PI3K inhibitor.
−Removed: However, recent clinical trial results suggest that factors other than PIK3CA sequence variance status may be important to measure when identifying patients eligible for PI3K inhibitors.
−Removed: In one Phase III clinical trial, the net increase in the objective response rate of PI3KCA-mutated late stage breast cancer patients who received alpelisib, a PIK3CA inhibitor, and fulvestrant versus those who received fulvestrant alone was less than 20%.
−Removed: Our studies found hyperactive PI3K involved signaling in a sub-set of HER2-negative breast cancer patients.
−Removed: Strong evidence was found that pan-PI3K inhibitors, rather than inhibitors targeting PI3K-α, may provide the most effective attenuation of dysregulated signaling involving the PI3K-node.
−Removed: Our studies also found that the signaling activity involving PI3K-α is likely more important to measure than the mutational status of PI3K-α when selecting patients for treatment with a PI3K-α inhibitor like alpelisib.
−Removed: Interventional Clinical Trials in Process using a CELsignia Test to Select Patients for Treatment
−Removed: FACT-1 Clinical Trial to Evaluate Efficacy of Genentech’s HER2 Targeted Therapies
−Removed: In July 2018, we activated the first site in a clinical trial with NSABP to evaluate the efficacy and safety of Genentech’s drugs, Herceptin (trastuzumab) and Perjeta (pertuzumab), and chemotherapy in breast cancer patients selected with our CELsignia test.
−Removed: NSABP serves as the sponsor and principal investigator of the trial and is responsible for, among other things, setting up clinical sites, enrolling patients, and managing clinical data.
−Removed: NSABP contracted separately with Genentech to provide Herceptin and Perjeta for the study at no cost.
−Removed: We are performing the CELsignia HER2 Pathway Activity Test to select patients for the trial and are providing the funding for the trial’s patient-related costs.
−Removed: Completing this trial will require, among other things, successful enrollment of patients, meeting trial endpoint goals, and completing the trial in a timely manner.
−Removed: As of February 2021, there were 27 activated sites participating in the FACT-1 trial.
−Removed: The enrollment rate of patients has fallen short of the expectations NSABP originally provided.
−Removed: Based on NSABP’s updated estimates of patient enrollment rates to reflect the impact of COVID-19, we expect to obtain interim results in the fourth quarter of 2021 or first quarter of 2022 and final results approximately nine months later.
−Removed: NSABP is one of the country’s premier clinical research cooperatives.
−Removed: Its members include many of the country’s leading medical centers and their investigators are amongst the most respected in the breast cancer field.
−Removed: Genentech is one of the largest biopharmaceutical companies in the world and was the first company to launch a HER2 targeted therapy;
−Removed: their anti-HER2 targeted therapies have more than 50% market share.
−Removed: We submitted an Investigational Device Exemption, or IDE, application to the FDA to obtain approval to use our CELsignia HER2 Pathway Activity Test in a clinical trial setting.
−Removed: The IDE submission included validation test protocols and study reports, manufacturing process summaries, and relevant publications.
−Removed: The FDA approved our IDE in early 2017.
−Removed: The goal is to demonstrate that patients who have an abnormal HER2 signaling pathway, as identified by our CELsignia test, respond to treatment with a matching targeted therapy.
−Removed: A synopsis of the trial protocol is provided below.
−Removed: FACT-1 Clinical Trial Synopsis
−Removed: Primary Objective
−Removed: To evaluate the efficacy of neoadjuvant HER2 drug treatment in early-stage HER2-negative breast cancer patients with abnormal HER2 signaling
−Removed: Sites/Sponsor
−Removed: In v estigational Arm
−Removed: Multi-center in collaboration with NSABP and Genentech
−Removed: 54 HER2-negative early-stage breast cancer (26 ER+/28ER-)
−Removed: Pathological complete response (ypT0/Tis ypN0)
−Removed: AC-T + Trastuzumab + Pertuzumab
−Removed: FACT-2 Clinical Trial to Evaluate Efficacy of Puma’s HER2 Targeted Therapy
−Removed: In July 2019, we activated a clinical trial with Puma and West Cancer Center to conduct a Phase II single-arm interventional trial to evaluate the efficacy and safety of Puma’s drug, Nerlynx (neratinib), and chemotherapy in breast cancer patients selected with our CELsignia test.
−Removed: West Cancer Center serves as the sponsor and principal investigator of the trial and is responsible for enrolling patients and managing clinical data.
−Removed: Puma supplies Nerlynx, its pan-HER inhibitor currently approved by the FDA for extended adjuvant treatment of early-stage HER2-positive breast cancer.
−Removed: We provide the CELsignia HER2 Pathway Activity Test to select triple-negative breast cancer patients who have hyperactive HER2-driven signaling pathways for the trial and will initially fund the patient-related trial costs.
−Removed: Based on West Cancer Center estimates to reflect the impact of COVID-19, we expect interim results from this trial in the fourth quarter of 2021 or first quarter of 2022 and final results approximately nine months later.
−Removed: We submitted an IDE application to the FDA to use our CELsignia HER2 Pathway Activity Test for this clinical trial and received approval in mid-2018.
−Removed: The goal of the trial is to demonstrate that triple-negative breast cancer patients who have a hyperactive HER2 signaling tumor, as identified by the CELsignia test, respond to treatment with Nerlynx, a matching HER2 therapy.
−Removed: We believe there is significant clinical interest in finding new diagnostic tests and targeted therapies for triple-negative breast cancer patients because fewer drug treatment options are available to them relative to other breast cancer sub-types.
−Removed: A synopsis of the trial protocol is provided below.
−Removed: FACT-2 Clinical Trial Synopsis
−Removed: Primary Objective
−Removed: To evaluate the efficacy of neoadjuvant HER2 drug treatment in early-stage triple-negative breast cancer patients with abnormal HER2 signaling
−Removed: Sites/Sponsor
−Removed: In v estigational Arm
−Removed: Multi-center in collaboration with West Cancer Center and Puma
−Removed: 27 early-stage triple-negative breast cancer with abnormal HER2 signaling
−Removed: Pathological complete response (ypT0/Tis ypN0)
−Removed: Neratinib then Paclitaxel + Carboplatin + Neratinib
−Removed: FACT-3 Clinical Trial to Evaluate Efficacy of Pfizer’s pan-HER and c-Met Targeted Therapies
−Removed: In January 2021, we announced a clinical trial collaboration with Sarah Cannon Research Institute, a global leader in cancer research, and Pfizer Inc., a global biopharmaceutical company, to conduct a Phase II clinical trial.
−Removed: This open-label Phase II trial will evaluate the efficacy and safety of two Pfizer targeted therapies, Vizimpro (dacomitinib), a pan-HER inhibitor, and Xalkori (crizotinib), a c-Met inhibitor, in previously treated metastatic HER2-negative breast cancer patients selected with our CELsignia Multi-Pathway Activity Test.
−Removed: Under the agreement, Sarah Cannon will serve as the sponsor and principal investigator of the trial and will be responsible for enrolling patients and managing clinical data.
−Removed: Pfizer will supply Vizimpro and Xalkori, targeted therapies currently approved by the FDA to treat metastatic non-small cell lung cancer.
−Removed: We will provide our CELsignia Multi-Pathway Activity Test to select HER2- metastatic breast cancer patients who have hyperactive HER2 and c-Met signaling pathways for the trial and will fund the patient-related trial costs.
−Removed: Based on the Sarah Cannon Research Institute’s estimates of patient enrollment rates, we expect to obtain interim results 12 to 15 months after the protocol is activated and final results 12-15 months later.
−Removed: We expect enrollment to begin in the second quarter of 2021.
−Removed: The Sarah Cannon Research Institute is one of the world’s leading clinical research organizations and has participated in clinical trials for a majority of approved cancer therapies over the last decade.
−Removed: Pfizer is one of the largest biopharmaceutical companies in the world and offers a number of targeted therapies for cancer patients.
−Removed: The goal of the trial is to demonstrate that previously treated HER2-negative metastatic breast cancer patients who have hyperactive HER2 and c-Met signaling tumors, as identified by the CELsignia test, respond to treatment with Vizimpro in combination with Xalkori.
−Removed: We believe there is significant clinical interest in finding new diagnostic tests and targeted therapies for metastatic HER2-negative breast cancer patients whose disease progressed on prior therapies.
−Removed: The anti-tumor effect of blockading EGFR/HER1, HER2, HER3 and c-Met pathways when the HER2 and c-Met pathways are hyperactive has been demonstrated in animal models.
−Removed: A synopsis of the trial protocol is provided below.
−Removed: FACT-3 Clinical Trial Synopsis
−Removed: Primary Objective
−Removed: To assess the efficacy of combined Vizimpro plus Xalkori in previously treated HER2-negative metastatic breast cancer subjects with hyperactive HER2 and c-Met signaling tumors
−Removed: Sites/Sponsor
−Removed: In v estigational Arm
−Removed: Multi-center in collaboration with Sarah Cannon Research Institute and Pfizer
−Removed: 23 late-stage HER2-negative breast cancer with abnormal HER2/c-Met signaling
−Removed: Objective response using RECIST 1.1 criteria
−Removed: Vizimpro and Xalkori
−Removed: FACT-4 Clinical Trial to Evaluate Efficacy of Puma’s HER2 Targeted Therapy
−Removed: In December 2020, we announced a clinical trial collaboration with Massachusetts General Hospital and Puma Biotechnology, a biopharmaceutical company, to conduct a Phase II clinical trial.
−Removed: This open-label Phase II trial will evaluate the efficacy and safety of Puma’s drug, Nerlynx (neratinib), and Faslodex (fulvestrant), an AstraZeneca drug, in previously treated metastatic HR-positive (HR+), HER2-negative breast cancer patients selected with our CELsignia HER2 Pathway Activity Test.
−Removed: Under the agreement, Massachusetts General Hospital will serve as the sponsor and the principal investigator of this study, while the UCLA Jonsson Comprehensive Cancer Center and the Vanderbilt-Ingram Cancer Center will serve as co-sponsors.
−Removed: Each of these institutions is amongst the United States’ 51 NCI-Designated Comprehensive Cancer Centers tasked with developing new approaches to diagnosing and treating cancer.
−Removed: Puma will supply Nerlynx, its HER2 inhibitor currently approved by the FDA for early and late-stage HER2-positive breast cancer.
−Removed: We will provide our CELsignia HER2 Pathway Activity Test to select HR+, HER2-negative metastatic breast cancer patients who have hyperactive HER2-driven signaling pathways for the trial and will fund the patient-related trial costs.
−Removed: Based on Massachusetts General Hospital’s estimates of patient enrollment rates, we expect to obtain interim results 12 to 15 months after the protocol is activated and final results 12 to 15 months later.
−Removed: We expect enrollment to begin in the second quarter of 2021.
−Removed: The goal of the trial is to demonstrate that previously treated HR+, HER2-negative metastatic breast cancer patients who have hyperactive HER2 signaling tumors, as identified by the CELsignia test, respond to treatment with Nerlynx in combination with Faslodex, a hormonal therapy that targets the estrogen receptor.
−Removed: We believe there is significant clinical interest in finding new diagnostic tests and targeted therapies for metastatic HR+, HER2-negative breast cancer patients whose disease progressed on prior therapies.
−Removed: Of particular interest are new therapeutic combinations that can overcome resistance to anti-estrogen therapies like Faslodex.
−Removed: The blockade of estrogen receptor and HER2 pathways when the HER2 pathway is hyperactive using a combination of Neratinib and Faslodex has been demonstrated in animal models.
−Removed: A synopsis of the trial protocol is provided below.
−Removed: FACT-4 Clinical Trial Synopsis
−Removed: Primary Objective
−Removed: To assess the efficacy of combining Nerlynx plus Faslodex in previously treated metastatic HR-positive, HER2-negative patients with hyperactive HER2 signaling tumors
−Removed: Sites/Sponsor
−Removed: In v estigational Arm
−Removed: Multi-center in collaboration with Mass General and Puma
−Removed: 23 late-stage HR+/HER2-negative breast cancer with abnormal HER2 signaling
−Removed: Objective response using RECIST 1.1 criteria
−Removed: Nerlynx and Faslodex
+Added: Point-in-time
+Added: measurements are limited to assessment of the compositional status (e.g., mutation), concentration level (e.g., protein amount), or activation
+Added: status (e.g., phosphorylation) of a finite number of signaling pathway components.
+Added: A key insight underlying our technology was our observation
+Added: that, no matter how sophisticated or detailed, a point-in-time molecular profile would only provide a snapshot.
+Added: These methods could not
+Added: provide a complete, dynamic assessment of the signaling activity driving a patient’s cancer.
+Added: These point-in-time molecular analyses
+Added: would, in many cases, only provide a weak correlation to the presence of the signaling pathway dysfunction driving a patient’s
+Added: Instead, we concluded that a complete diagnosis of cancer and an assessment of a patient’s response to treating their disease
+Added: requires measurement of the underlying activity of signaling pathways in live patient tumor cells.
+Added: measure live real-time dynamic cell signaling activity, we utilize an impedance biosensor instrument.
+Added: An impedance biosensor is an analytical
+Added: platform that converts changes in cellular activity to a measurable electrical signal.
+Added: When cells are stimulated and change their function,
+Added: the accompanying changes alter the electrical signal that is measured.
+Added: The output value is quantified over time and used to determine
+Added: a Signaling Function Score.
+Added: To determine the activity of a specific signaling pathway, an activating agent specific to a pathway receptor
+Added: is used to turn on the pathway and a corresponding inhibitory agent specific to the pathway receptor is used to turn signaling off.
+Added: signaling pathways are stimulated in this manner, a change in the electrical signal occurs and Signaling Function Score recorded.
+Added: relying on the principle of detecting signaling pathway activity, we believe we can develop tests for a range of disease types and targeted
+Added: therapies that affect various cellular pathways.
+Added: Multi-Pathway Activity Test
+Added: CELsignia MP Test is a qualitative LDT that measures HER2, c-Met, and PI3K signaling activity in breast and ovarian tumor cells obtained
+Added: from patients previously diagnosed with cancer to determine whether or not the patients have one of the following cancer sub-types:
+Added: HER2 signaling driven cancer
+Added: c-Met and HER2 signaling driven cancer
+Added: PI3K-involved signaling driven cancer
Commercialization Strategy
−Removed: Our commercial activities will target three complementary groups at various phases of the development of our CELsignia tests.
−Removed: Pharmaceutical companies.
−Removed: For each CELsignia test we develop to diagnose a new cancer sub-type, we will identify the matching targeted therapies, either currently approved or in the investigational phase, and the manufacturer of those therapies.
−Removed: We will initiate discussions and seek to reach development agreements with each of these pharmaceutical companies when we have verified the prevalence of the cancer sub-type and completed successful animal studies.
−Removed: Medical and surgical oncologists.
−Removed: We will initially target key opinion leaders (KOLs) in each cancer type once we have completed the analytical validation of a CELsignia test.
−Removed: This will allow us to build awareness and credibility for the CELsignia test as we are generating clinical validation data.
−Removed: When a new drug indication is received that requires use of a CELsignia companion diagnostic to identify eligible patients, we will coordinate the pharmaceutical company’s go-to-market activities with our own.
−Removed: This coordination will allow us to significantly leverage the pharmaceutical company’s sales, marketing, and reimbursement activities, unlike traditional molecular diagnostic companies.
−Removed: When a new drug indication is received that requires use of a CELsignia companion diagnostic to identify eligible patients, we expect to coordinate the pharmaceutical company’s reimbursement activities with our own.
−Removed: Our CELsignia tests are LDT’s and subject to regulation under CLIA.
+Added: commercial activities will target three complementary groups at various phases of the development of our CELsignia tests.
+Added: Pharmaceutical
+Added: For each CELsignia test we develop to diagnose a new cancer sub-type, we intend to identify the matching targeted
+Added: therapies, either currently approved or in the investigational phase, and the manufacturer of those therapies.
+Added: We intend to initiate
+Added: discussions and seek to reach development agreements with each of these pharmaceutical companies when we have verified the prevalence
+Added: of the cancer sub-type and completed successful animal studies.
+Added: and surgical oncologists.
+Added: We plan to initially target key opinion leaders (KOLs) in each cancer type once we have completed the
+Added: analytical validation of a CELsignia test.
+Added: This will allow us to build awareness and credibility for the CELsignia test as we are
+Added: generating clinical validation data.
+Added: When a new drug indication is received that requires use of a CELsignia companion diagnostic
+Added: to identify eligible patients, we will coordinate the pharmaceutical company’s go-to-market activities with our own.
+Added: This coordination
+Added: will allow us to significantly leverage the pharmaceutical company’s sales, marketing, and reimbursement activities, unlike
+Added: traditional molecular diagnostic companies.
+Added: When a new drug indication is received that requires use of a CELsignia companion diagnostic to identify eligible patients, we
+Added: expect to coordinate the pharmaceutical company’s reimbursement activities with our own.
+Added: CELsignia tests are laboratory developed tests, or LDTs, and subject to regulation under the Clinical Laboratory Improvement Amendments,
We completed the analytical validation of our first CELsignia test and received CLIA certification in 2016.
−Removed: Our current focus is to field clinical trials with leading cancer centers in collaboration with pharmaceutical companies to demonstrate that cancer patients diagnosed with an abnormal signaling pathway by a CELsignia test respond efficaciously to treatment with a matching targeted therapy.
−Removed: Once favorable efficacy data is available, we expect to generate revenues from CELsignia tests performed in conjunction with the clinical trials a pharmaceutical company will field during the registrational phase of our partners’ drug approval process.
−Removed: We also expect that the agreements we enter into with the pharmaceutical companies partnering with us on these registrational trials will include milestone payments at initiation and completion of trials and perhaps at various other negotiated points during the trials.
−Removed: We expect to generate revenue from the sale of CELsignia tests ordered by physicians upon the approval of our pharmaceutical company’s matching drug, as a companion diagnostic.
−Removed: A key requirement for success of these partnerships will be clinical trial results that demonstrate the advantages of using a CELsignia test as a companion diagnostic.
−Removed: We intend to position our unique and highly differentiated tests as practice changing advancements in patient care.
−Removed: To inform key stakeholders of the value of our solution in order to drive adoption and reimbursement, we expect to employ the following diverse commercialization strategies over time:
−Removed: leverage our pharmaceutical partnership and their go-to-market initiatives for the drug with which our companion diagnostic is partnered;
−Removed: collaborate with oncology thought leaders, KOLs, and leading institutions on clinical research, publications, and product development;
−Removed: build an experienced, oncology-focused sales force in the United States and international distribution channels that are supported by dedicated company personnel;
−Removed: integrate into the everyday practice of clinicians through our medical affairs and client services efforts;
−Removed: publish important medical and scientific data in peer-reviewed journals and present at major industry conferences, conduct clinical trials;
−Removed: work with patient advocacy groups, leading cancer philanthropic organizations, and medical societies to drive awareness of CELsignia tests and the importance of incorporating functional cellular analysis into cancer treatment.
−Removed: Through these efforts, we will seek to promote our CELsignia test’s unique capabilities throughout the oncology community-from patients, to the physicians treating them, to the third-party payors for these treatments and to biopharmaceutical companies developing new treatments-all with the goal of facilitating better-informed treatment decisions for the greatest number of patients.
−Removed: A CELsignia test would be launched upon the approval of a pharmaceutical company’s matching drug as a companion diagnostic.
−Removed: We would expect physicians, typically a medical or surgical oncologist, to order our tests in conjunction with the roll-out of the pharmaceutical company’s matching drug.
−Removed: The physician will prescribe a CELsignia test and coordinate provision of a patient specimen from a biopsy or surgical procedure.
−Removed: The fresh tissue would then be shipped overnight directly to our laboratory where we would use our proprietary methods to extract diseased cell samples from the patient’s tissue and perform the CELsignia tests ordered.
−Removed: Test results would typically be available in 10 to 14 days after receipt of the patient specimen.
−Removed: For each patient sample analyzed, a Signaling Function Score would be calculated quantitatively and converted into a final qualitative result:
+Added: Our current focus
+Added: is to field clinical trials with leading cancer centers in collaboration with pharmaceutical companies to demonstrate that cancer patients
+Added: diagnosed with an abnormal signaling pathway by a CELsignia test respond efficaciously to treatment with a matching targeted therapy.
+Added: Once favorable efficacy data is available, we expect to generate revenues from CELsignia tests performed in conjunction with the clinical
+Added: trials a pharmaceutical company will field during the registrational phase of our partners’ drug approval process.
+Added: We also expect
+Added: that the agreements we enter into with the pharmaceutical companies partnering with us on these registrational trials will include milestone
+Added: payments at initiation and completion of trials and perhaps at various other negotiated points during the trials.
+Added: We expect to generate
+Added: revenue from the sale of CELsignia tests ordered by physicians upon the approval of our pharmaceutical company’s matching drug,
+Added: as a companion diagnostic.
+Added: A key requirement for success of these partnerships will be clinical trial results that demonstrate the advantages
+Added: of using a CELsignia test as a companion diagnostic.
+Added: intend to position our unique and highly differentiated tests as practice changing advancements in patient care.
+Added: To inform key stakeholders
+Added: of the value of our solution in order to drive adoption and reimbursement, we expect to employ the following diverse commercialization
+Added: strategies over time:
+Added: our pharmaceutical partnership and their go-to-market initiatives for the drug with which our companion diagnostic is partnered;
+Added: with oncology thought leaders, KOLs, and leading institutions on clinical research, publications, and product development;
+Added: an experienced, oncology-focused sales force in the United States and international distribution channels that are supported by dedicated
+Added: company personnel;
+Added: into the everyday practice of clinicians through our medical affairs and client services efforts;
+Added: important medical and scientific data in peer-reviewed journals and present at major industry conferences, conduct clinical trials;
+Added: with patient advocacy groups, leading cancer philanthropic organizations, and medical societies to drive awareness of CELsignia tests
+Added: and the importance of incorporating functional cellular analysis into cancer treatment.
+Added: these efforts, we will seek to promote our CELsignia test’s unique capabilities throughout the oncology community—from patients,
+Added: to the physicians treating them, to the third-party payors for these treatments and to biopharmaceutical companies developing new treatments—all
+Added: with the goal of facilitating better-informed treatment decisions for the greatest number of patients.
+Added: CELsignia test would be launched upon the approval of a pharmaceutical company’s matching drug as a companion diagnostic.
+Added: expect physicians, typically a medical or surgical oncologist, to order our tests in conjunction with the roll-out of the pharmaceutical
+Added: company’s matching drug.
+Added: The physician will prescribe a CELsignia test and coordinate provision of a patient specimen from a biopsy
+Added: or surgical procedure.
+Added: The fresh tissue would then be shipped overnight directly to our laboratory where we would use our proprietary
+Added: methods to extract diseased cell samples from the patient’s tissue and perform the CELsignia tests ordered.
+Added: Test results would
+Added: typically be available in 10 to 14 days after receipt of the patient specimen.
+Added: For each patient sample analyzed, a Signaling Function
+Added: Score would be calculated quantitatively and converted into a final qualitative result:
abnormal or normal.
−Removed: For patients found to have an abnormal signaling pathway, clinicians would use the results of the CELsignia test as a guide to select a targeted drug that inhibits the abnormal signaling activity identified.
−Removed: United States
−Removed: For our first tests, we will target the estimated 4,300 medical oncologists working in hospitals and cancer centers in the United States.
−Removed: We expect to hire domestic sales professionals with typically over 10 years of experience in clinical oncology sales working at leading biopharmaceutical or specialty reference laboratory companies.
−Removed: In general, we intend to focus our initial sales efforts on building relationships with KOLs and researchers at leading academic research institutions to demonstrate the scientific credibility of our CELsignia tests.
−Removed: We also plan to build relationships in community oncology practice settings through leading physician networks and community hospitals and community-based cancer centers.
−Removed: We will also attend national and regional clinical meetings focused on cancer treatment for our anti-cancer tests.
−Removed: We believe the unique and important nature of the results our CELsignia tests provide, and their positioning as a companion diagnostic, will drive many medical oncologists to independently seek out our tests once they become aware of them.
−Removed: We believe this may allow us to achieve our market penetration goals with a sales force and marketing expenses significantly less costly than has been experienced by molecular diagnostic companies.
−Removed: International
−Removed: We believe we can serve the international market from our laboratory in Minnesota.
−Removed: We expect to establish an international presence using local distributors that sell to physicians and coordinate shipment of specimens to the United States.
−Removed: To serve international markets, we would expect to add dedicated regional managers located outside the United States to oversee our relationships at the local level.
−Removed: Pricing and Reimbursement
−Removed: The principal groups that we expect to pay us in the future for our CELsignia tests include:
−Removed: commercial third-party payors;
−Removed: government payors, including Medicare and state Medicaid plans;
−Removed: biopharmaceutical customers;
−Removed: hospitals, cancer centers, and other institutions;
−Removed: Adequate reimbursement will be an important factor in achieving broad clinical adoption of our CELsignia tests.
−Removed: At the same time, we believe broad clinical adoption will help drive favorable reimbursement decisions.
−Removed: To achieve broad reimbursement coverage with commercial third-party payors and government payors, including Medicare and Medicaid, we plan to demonstrate the economic and clinical value of our CELsignia tests to payors by employing a multi-pronged strategy:
−Removed: Set a high bar for analytical validation.
−Removed: We expect to present data on the characterization of new cancer sub-types by CELsignia tests at conferences and will seek to publish the results in peer-reviewed journals.
−Removed: Meet the evidence standards necessary to be consistent with leading clinical guidelines.
−Removed: We believe inclusion in leading clinical practice guidelines plays a critical role in payers’ coverage decisions.
−Removed: We plan to conduct clinical validation and clinical utility studies that are consistent with the requirements of the widely recognized National Comprehensive Cancer Network clinical practice guidelines.
−Removed: Execute an internal managed care policy and claims adjudication function as part of our core business operations.
−Removed: We plan to make obtaining adequate and widespread reimbursement a critical component of our business operations.
−Removed: We expect to hire a team of in-house claims processing and reimbursement specialists who will work with patients and payers to navigate the claims process and obtain maximum reimbursement.
−Removed: Cultivate a network of KOLs.
−Removed: KOLs are able to influence clinical practice by publishing research and determining whether new tests should be integrated into practice guidelines.
−Removed: We expect to collaborate with KOLs early in the development process to ensure our clinical studies are designed and executed in a way that clearly demonstrates the benefits of our tests to physicians and payers.
−Removed: Compile a growing library of peer-reviewed studies that demonstrate the test is effective.
−Removed: We will seek to publish peer-reviewed articles and review papers to help support our efforts to obtain widespread adoption and reimbursement of our CELsignia tests.
−Removed: In each disease area we pursue, we intend to conduct studies in order to develop similar supporting literature.
−Removed: Reduce expenditures.
−Removed: We intend to build economic models to measure the financial benefits of using our CELsignia test in guiding patient treatment and minimizing the use of drugs that will not likely have a positive impact.
−Removed: We plan to use the data we gather through the use of these models as we meet with commercial third-party payors and government payors.
−Removed: Exploit efforts by commercial third-party and government payors to contain healthcare costs.
−Removed: A major cost reduction opportunity is to reduce expenditures for drug courses that provide no patient benefit.
−Removed: Our technology will enable physicians to prescribe therapies that have significantly higher response rates than has been the case with targeted therapies to date.
−Removed: Since this will lower the drug cost per responsive patient, we believe widespread use of our CELsignia tests is consistent with payors goals of delivering health care more cost effectively.
−Removed: Our Competition
−Removed: At present, we are not aware of any other companies that offer diagnostic tests that use a patient’s live tumor cells to identify the signaling pathway driving a patient’s cancer.
−Removed: There are several companies focused on developing genomic or proteomic analyses of a patient’s diseased cells.
−Removed: Initial efforts identified protein targets or genetic mutations, oftentimes referred to as “biomarkers,” that are associated with a disease process to enable development of drugs more closely tailored to specific patient populations.
−Removed: As tools for human genome analysis have become less expensive, a number of companies have also recently launched more complex genomic test panels and gene expression signatures tests.
−Removed: These tests rely on a static measurement of molecular properties and mathematical analysis to identify statistically significant correlations between the selected molecular properties and a clinical condition or outcome of populations of patients with the “same” disease.
−Removed: These genetic tests often have limited predictive success because they only identify some, but not all, of, the molecular and cellular conditions required for a drug therapy to function in a patient.
−Removed: They may identify the presence of the genes associated with a disease, but they cannot determine how the gene products function in the context of a particular individual.
−Removed: Providers of genomic or proteomic tests include diagnostic kit manufacturers, hospitals, and independent laboratories.
−Removed: We do not plan to develop tests where a molecular biomarker can identify drug responsive patients, so our current tests will not compete directly against the tests provided by these other companies.
−Removed: The table below provides a summary of the points of differentiation between our signaling function analysis approach and the molecular approaches used by our potential competitors.
−Removed: Current Molecular Methods vs.
−Removed: Our Pathway Activity Analysis Platform
−Removed: Type of Cell Sample Used:
−Removed: Tumor cell fragments
−Removed: (fixed, lysed, DNA)
−Removed: Live tumor cells
−Removed: Type of Analysis Performed
−Removed: Single point-in-time mutation(s) status or protein amount, or activation status
−Removed: Quantify signaling pathway activity over 24-hour period
−Removed: Relationship to disease driver
−Removed: Disease driver evaluated
−Removed: Only a single or small set of components of the cell are evaluated
−Removed: The activity of the entire signaling pathway is assessed
−Removed: Drug function evaluated
−Removed: Cannot assess drug function with cell fragments
−Removed: Drug’s effect on signaling pathway activity in patient’s cells quantified
−Removed: Foundation Medicine, Caris Life Sciences, NeoGenomics, LabCorp, Quest, Nanostring, Paradigm, Biocept, Exosome Diagnostics, Guardant Health, Roche Diagnostics, Qiagen, Myriad, Genomic Health
−Removed: We are not aware of any available tests directly comparable to the CELsignia tests.
−Removed: We expect to offer each CELsignia test to patients at list prices ranging from $4,000 to $7,000, depending on the number of pathways evaluated.
−Removed: List prices for several proprietary complex genomic tests fall within this range, and we believe this provides guidance as to the pricing of highly informative tests that guide cancer patient care.
−Removed: Intellectual Property
−Removed: We believe one of our core competitive advantages is the strength of our intellectual property portfolio.
−Removed: We developed our CELsignia technology internally.
−Removed: We are seeking both U.S.
−Removed: patents to protect our inventions.
−Removed: We have three issued U.S.
+Added: For patients found to have
+Added: an abnormal signaling pathway, clinicians would use the results of the CELsignia test as a guide to select a targeted drug that inhibits
+Added: the abnormal signaling activity identified.
+Added: and Reimbursement
+Added: principal groups that we expect to pay us in the future for our CELsignia tests include:
+Added: third-party payors;
+Added: payors, including Medicare and state Medicaid plans;
+Added: biopharmaceutical
+Added: cancer centers, and other institutions;
+Added: reimbursement will be an important factor in achieving broad clinical adoption of our CELsignia tests.
+Added: At the same time, we believe broad
+Added: clinical adoption will help drive favorable reimbursement decisions.
+Added: To achieve broad reimbursement coverage with commercial third-party
+Added: payors and government payors, including Medicare and Medicaid, we plan to demonstrate the economic and clinical value of our CELsignia
+Added: tests to payors by employing a multi-pronged strategy:
+Added: a high bar for analytical validation.
+Added: We expect to present data on the characterization of new cancer sub-types by CELsignia
+Added: tests at conferences and will seek to publish the results in peer-reviewed journals.
+Added: the evidence standards necessary to be consistent with leading clinical guidelines.
+Added: We believe inclusion in leading clinical
+Added: practice guidelines plays a critical role in payers’ coverage decisions.
+Added: We plan to conduct clinical validation and clinical
+Added: utility studies that are consistent with the requirements of the widely recognized National Comprehensive Cancer Network clinical
+Added: practice guidelines.
+Added: an internal managed care policy and claims adjudication function as part of our core business operations.
+Added: We plan to make obtaining
+Added: adequate and widespread reimbursement a critical component of our business operations.
+Added: We expect to hire a team of in-house claims
+Added: processing and reimbursement specialists who will work with patients and payors to navigate the claims process and obtain maximum
+Added: reimbursement.
+Added: a network of KOLs.
+Added: KOLs are able to influence clinical practice by publishing research and determining whether new tests should
+Added: be integrated into practice guidelines.
+Added: We expect to collaborate with KOLs early in the development process to ensure our clinical
+Added: studies are designed and executed in a way that clearly demonstrates the benefits of our tests to physicians and payers.
+Added: a growing library of peer-reviewed studies that demonstrate the test is effective.
+Added: We will seek to publish peer-reviewed articles
+Added: and review papers to help support our efforts to obtain widespread adoption and reimbursement of our CELsignia tests.
+Added: In each disease
+Added: area we pursue, we intend to conduct studies in order to develop similar supporting literature.
+Added: expenditures.
+Added: We intend to build economic models to measure the financial benefits of using our CELsignia test in guiding patient
+Added: treatment and minimizing the use of drugs that will not likely have a positive impact.
+Added: We plan to use the data we gather through
+Added: the use of these models as we meet with commercial third-party payors and government payors.
+Added: efforts by commercial third-party and government payors to contain healthcare costs.
+Added: A major cost reduction opportunity is to
+Added: reduce expenditures for drug courses that provide no patient benefit.
+Added: Our technology will enable physicians to prescribe therapies
+Added: that have significantly higher response rates than has been the case with targeted therapies to date.
+Added: Since this will lower the drug
+Added: cost per responsive patient, we believe widespread use of our CELsignia tests is consistent with payors goals of delivering health
+Added: care more cost effectively.
+Added: present, we are not aware of any other companies that offer diagnostic tests that use a patient’s live tumor cells to identify
+Added: the signaling pathway driving a patient’s cancer.
+Added: There are several companies focused on developing genomic or proteomic analyses
+Added: of a patient’s diseased cells.
+Added: Initial efforts identified protein targets or genetic mutations, oftentimes referred to as “biomarkers,”
+Added: that are associated with a disease process to enable development of drugs more closely tailored to specific patient populations.
+Added: tools for human genome analysis have become less expensive, a number of companies have also recently launched more complex genomic test
+Added: panels and gene expression signatures tests.
+Added: These tests rely on a static measurement of molecular properties and mathematical analysis
+Added: to identify statistically significant correlations between the selected molecular properties and a clinical condition or outcome of populations
+Added: of patients with the “same” disease.
+Added: genetic tests often have limited predictive success because they only identify some, but not all, of, the molecular and cellular conditions
+Added: required for a drug therapy to function in a patient.
+Added: They may identify the presence of the genes associated with a disease, but they
+Added: cannot determine how the gene products function in the context of a particular individual.
+Added: of genomic or proteomic tests include diagnostic kit manufacturers, hospitals, and independent laboratories.
+Added: We do not plan to develop
+Added: tests where a molecular biomarker can identify drug responsive patients, so our current tests will not compete directly against the tests
+Added: provided by these other companies.
+Added: competitors that have molecular method-based tests include, but are not limited to, Foundation Medicine, Caris Life Sciences, NeoGenomics,
+Added: LabCorp, Quest, Nanostring, Paradigm, Biocept, Exosome Diagnostics, Guardant Health, Roche Diagnostics, Qiagen, Myriad, and Genomic Health.
+Added: Principal Suppliers for CELsignia
+Added: purchase commercially available reagents and instruments from a variety of suppliers.
+Added: Our principal reagent suppliers include Bio-Techne
+Added: Corporation, Selleck Chemicals, Sigma-Aldrich, and VWR International.
+Added: Our principal instrument suppliers include Agilent Technologies,
+Added: Integra Biosciences, Invitrogen, and Thermo Fisher Scientific.
+Added: These items are purchased on a purchase order basis pursuant to the applicable
+Added: supplier’s standard terms and conditions.
+Added: The items purchased from these suppliers are standard products sold widely to the biotechnology
+Added: All items purchased are typically available within several days after an order is placed.
+Added: success depends in part on our ability to obtain and maintain proprietary protection for our product candidates, manufacturing and process
+Added: discoveries and other know-how, to operate without infringing the proprietary rights of others, and to prevent others from infringing
+Added: our proprietary rights.
+Added: We plan to protect our proprietary positions using a variety of methods, which include protecting current U.S.
+Added: and foreign patents related to proprietary technology, inventions and improvements and prosecuting additional U.S.
+Added: and foreign patents
+Added: that we determine are important to the development and implementation of our business.
+Added: For example, we, our licensors, or our collaborators
+Added: currently have, or are pursuing, patents covering the composition of matter for our drug product candidates and we plan to generally
+Added: pursue patent protection covering methods-of-use for one or more clinical programs.
+Added: We also rely on trade secrets, trademarks, know-how,
+Added: continuing technological innovation and potential in-licensing opportunities to develop and maintain our proprietary position.
+Added: entered into the Gedatolisib License Agreement with Pfizer in April 2021, pursuant to which we acquired exclusive worldwide rights under
+Added: Pfizer patents and know-how to develop, manufacture and commercialize gedatolisib.
+Added: We have exclusive licenses under the Gedatolisib License
+Added: Agreement to patent rights in the U.S.
+Added: and numerous foreign jurisdictions relating to gedatolisib.
+Added: The patent rights in-licensed under
+Added: the Gedatolisib License Agreement include 11 granted patents in the U.S.
+Added: and more than 290 patents granted in foreign jurisdictions including
+Added: Australia, Canada, China, France, Germany, Spain, United Kingdom and Japan.
+Added: patent covering gedatolisib as a composition of matter
+Added: has a statutory expiration date in December 2029 and a U.S.
+Added: composition of matter patent that covers the lactic acid form of gedatolisib
+Added: that is currently in clinical development expires in December 2035, in each case, not including patent term adjustment or any patent
+Added: term extension, and relevant foreign counterparts.
+Added: respect to CELsignia, we have three issued U.S.
patents, five issued international patents, five pending U.S.
−Removed: patent applications, 23 pending non-U.S.
+Added: patent applications, 23
+Added: pending non-U.S.
patent applications, and one pending PCT patent application, as well as numerous corresponding non-U.S.
−Removed: patent applications covering our diagnostic approach using cell signaling analysis in living patient cells to guide treatment of patients with targeted therapies.
+Added: patent applications
+Added: covering our diagnostic approach using cell signaling analysis in living patient cells to guide treatment of patients with targeted therapies.
The earliest expiration date of patents is 2033.
−Removed: In addition, we have developed significant proprietary know-how and trade secrets for the various cell sample preparation and cellular analysis methods we have developed.
−Removed: We understand we must develop and maintain protection on the proprietary aspects of our technologies in order to remain competitive.
−Removed: We rely on a combination of patents, copyrights, trademarks, trade secret and other intellectual property laws and confidentiality, material transfer agreements, invention assignment agreements and other contracts to protect our intellectual property rights.
−Removed: We plan to develop names for new products and apply for trademarks and as appropriate secure trademark protection for them, including domain name registration, in relevant jurisdictions.
−Removed: We also have developed a number of proprietary methods, materials, processes, and techniques related to the preparation of patient samples and performance of the CELsignia test that we believe are most effectively protected as trade secrets rather than as patented subject matter.
−Removed: Principal Suppliers
−Removed: We purchase commercially available reagents and instruments from a variety of suppliers.
−Removed: Our principal reagent suppliers include Bio-Techne Corporation, Selleck Chemicals, Sigma-Aldrich, and VWR International.
−Removed: Our principal instrument suppliers include Agilent Technologies, Integra Biosciences, Invitrogen, and Thermo Fisher Scientific.
−Removed: These items are purchased on a purchase order basis pursuant to the applicable supplier’s standard terms and conditions.
−Removed: The items purchased from these suppliers are standard products sold widely to the biotechnology industry.
−Removed: All items purchased are typically available within several days after an order is placed.
−Removed: Government Regulation
−Removed: The Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.
−Removed: Department of Health and Human Services, regulates all clinical laboratory testing (except research) performed on humans in the United States through CLIA.
−Removed: All clinical laboratories that perform clinical lab services on human specimens for the purpose of providing information on the diagnosis, prevention or treatment of disease must receive CLIA certification.
+Added: In addition, we have developed significant proprietary know-how and trade secrets for
+Added: the various cell sample preparation and cellular analysis methods we have developed.
+Added: addition to patents, we rely on trade secrets and know-how to develop and maintain our competitive position.
+Added: We typically rely on trade
+Added: secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
+Added: protect trade secrets and know-how by establishing confidentiality agreements and invention assignment agreements with our employees,
+Added: consultants, scientific advisors, contractors and partners.
+Added: These agreements generally provide that all confidential information developed
+Added: or made known during the course of an individual or entity’s relationship with us must be kept confidential during and after the
+Added: relationship.
+Added: These agreements also generally provide that all inventions resulting from work performed for us or relating to our business
+Added: and conceived or completed during the period of employment or assignment, as applicable, shall be our exclusive property.
+Added: we take other appropriate precautions, such as physical and technological security measures, to guard against misappropriation of our
+Added: proprietary information by third parties.
+Added: of Gedatolisib and Other Drug Products in the United States
+Added: authorities in the U.S.
+Added: at the federal, state and local level and in other countries and jurisdictions, including the EU, extensively
+Added: regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage,
+Added: record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug
+Added: products, such as gedatolisib.
+Added: Generally, before a new drug can be marketed, considerable data demonstrating its quality, safety and
+Added: efficacy must be obtained, organized into a format specific for each regulatory authority and submitted for review and approved by the
+Added: regulatory authority.
+Added: of FDA Approval Process
+Added: the U.S., pharmaceutical products are subject to extensive regulation by the FDA.
+Added: The Federal Food, Drug, and Cosmetic Act, or the FDC
+Added: Act, and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture,
+Added: storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling,
+Added: and import and export of pharmaceutical products.
+Added: Failure to comply with applicable U.S.
+Added: requirements may subject a company to a variety
+Added: of administrative or judicial sanctions, such as FDA refusal to approve pending New Drug Applications, or NDAs, warning or untitled letters,
+Added: product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties and
+Added: criminal prosecution.
+Added: Pharmaceutical
+Added: product development for a new product or certain changes to an approved product in the U.S.
+Added: typically involves preclinical laboratory
+Added: and animal tests, the submission to the FDA of an investigational new drug applicable, or IND, which must become effective before clinical
+Added: testing may commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each
+Added: indication for which FDA approval is sought.
+Added: Satisfaction of FDA pre-market approval requirements typically takes many years and the
+Added: actual time required may vary substantially based upon the type, complexity and novelty of the product or disease.
+Added: tests include laboratory evaluation of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics
+Added: and potential safety and efficacy of the product.
+Added: The conduct of the preclinical tests must comply with federal regulations and requirements,
+Added: including good laboratory practices.
+Added: The results of preclinical testing are submitted to the FDA as part of an IND along with other information,
+Added: including information about product chemistry, manufacturing and controls and a proposed clinical trial protocol.
+Added: Long term preclinical
+Added: tests, such as animal tests of reproductive toxicity and carcinogenicity, may continue after the IND is submitted.
+Added: A 30-day waiting period
+Added: after the submission of each IND is required prior to the commencement of clinical testing in humans.
+Added: If the FDA has neither commented
+Added: on nor questioned the IND within this 30-day period, the clinical trial proposed in the IND may begin.
+Added: clinical stage of development involves the administration of the investigational product to healthy volunteers or disease-affected patients
+Added: under the supervision of qualified investigators, generally physicians not employed by, or under control of, the trial sponsor, in accordance
+Added: with Good Clinical Practices, or GCPs, which include the requirement that all research subjects provide their informed consent for their
+Added: participation in any clinical trial.
+Added: Clinical trials are conducted under protocols detailing, among other things, the objectives of the
+Added: clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and
+Added: assess efficacy.
+Added: Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of an investigational
+Added: new drug applicable, or IND.
+Added: Furthermore, each clinical trial must be reviewed and approved by an Institutional Review Board, or IRB,
+Added: for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical
+Added: trials are minimized and are reasonable in relation to anticipated benefits.
+Added: The IRB also approves the informed consent form that must
+Added: be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.
+Added: also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.
+Added: about most clinical trials must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.
+Added: related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the clinical trial
+Added: is made public as part of the registration of the clinical trial.
+Added: Sponsors are also obligated to discuss the results of their clinical
+Added: trials after completion.
+Added: Disclosure of the results of these trials can be delayed in some cases for up to two years after the date of
+Added: completion of the trial.
+Added: Competitors may use this publicly available information to gain knowledge regarding the progress of development
+Added: Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:
+Added: 1 clinical trials generally involve a small number of healthy volunteers or disease-affected patients who are initially exposed to
+Added: a single dose and then multiple doses of the product candidate.
+Added: The primary purpose of these clinical trials is to assess the metabolism,
+Added: pharmacologic action, side effect tolerability and safety of the drug.
+Added: 2 clinical trials involve studies in disease-affected patients to determine the dose required to produce the desired benefits.
+Added: the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, possible adverse effects and safety
+Added: risks are identified, and a preliminary evaluation of efficacy is conducted.
+Added: 3 clinical trials generally involve a larger number of patients at multiple sites and are designed to provide the data necessary
+Added: to demonstrate the effectiveness of the product for its intended use, its safety in use and to establish the overall benefit/risk
+Added: relationship of the product and provide an adequate basis for product approval.
+Added: These trials may include comparisons with placebo
+Added: and/or other comparator treatments.
+Added: The duration of treatment is often extended to mimic the actual use of a product during marketing.
+Added: registrational trial is a clinical trial that adequately meets regulatory agency requirements for the evaluation of a drug candidate’s
+Added: efficacy and safety such that it can be used to justify the approval of the drug.
+Added: Generally, registrational trials are Phase 3 trials
+Added: but may be Phase 2 trials if the trial design provides a reliable assessment of clinical benefit, particularly in situations where there
+Added: is an unmet medical need.
+Added: Post-approval
+Added: trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.
+Added: These trials are used to
+Added: gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow
+Added: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of a Biologics License
+Added: Application, or BLA.
+Added: reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse
+Added: events occur.
+Added: The FDA or the sponsor may suspend or terminate a clinical trial at any time, or the FDA may impose other sanctions on
+Added: various grounds, including a finding that the research patients are being exposed to an unacceptable health risk.
+Added: Similarly, an IRB can
+Added: suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with
+Added: the requirements of the IRB or if the drug has been associated with unexpected serious harm to patients.
+Added: There are also requirements
+Added: related to registration and reporting of certain clinical trials and completed clinical trial results to public registries.
+Added: completion of the required clinical testing, an NDA is prepared and submitted to the FDA.
+Added: FDA approval of the NDA is required before
+Added: marketing of the product may begin in the U.S.
+Added: The NDA must include the results of all preclinical, clinical and other testing and a
+Added: compilation of data relating to the product’s pharmacology, chemistry, manufacture and controls.
+Added: The cost of preparing and submitting
+Added: an NDA is substantial.
+Added: The submission of most NDAs is additionally subject to a substantial application user fee, currently $2,875,842
+Added: for Fiscal Year 2021, and the manufacturer and/or sponsor under an approved NDA are also subject to annual program fees for eligible
+Added: products, which are currently $336,432 for Fiscal Year 2021.
+Added: FDA has 60 days from its receipt of an NDA to determine whether the application will be accepted for filing based on the agency’s
+Added: threshold determination that it is sufficiently complete to permit substantive review.
+Added: Once the submission is accepted for filing, the
+Added: FDA begins an in-depth review.
+Added: The FDA has agreed to certain performance goals in the review of new drug applications.
+Added: Most such applications
+Added: for standard review drug products are reviewed within ten to twelve months;
+Added: most applications for priority review drugs are reviewed
+Added: in six to eight months.
+Added: Priority review can be applied to drugs that the FDA determines offer major advances in treatment or provide
+Added: a treatment where no adequate therapy exists.
+Added: The review process for both standard and priority review may be extended by FDA for three
+Added: additional months to consider certain late-submitted information, or information intended to clarify information already provided in
+Added: the submission.
+Added: FDA may also refer applications for novel drug products, or drug products that present difficult questions of safety or efficacy, to
+Added: an advisory committee—typically a panel that includes clinicians and other experts—for review, evaluation and a recommendation
+Added: as to whether the application should be approved.
+Added: The FDA is not bound by the recommendation of an advisory committee, but it generally
+Added: follows such recommendations.
+Added: Before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance
+Added: Additionally, the FDA will inspect the facility or the facilities at which the drug is manufactured.
+Added: FDA will not approve the
+Added: product unless compliance with cGMP is satisfactory and the NDA contains data that provide substantial evidence that the drug is safe
+Added: and effective in the indication studied.
+Added: the FDA evaluates the NDA and the manufacturing facilities, it issues either an approval letter or a complete response letter.
+Added: response letter generally outlines the deficiencies in the submission and may require substantial additional testing, or information,
+Added: in order for the FDA to reconsider the application.
+Added: If, or when, those deficiencies have been addressed to the FDA’s satisfaction
+Added: in a resubmission of the NDA, the FDA will issue an approval letter.
+Added: FDA has committed to reviewing such resubmissions in two or six
+Added: months depending on the type of information included.
+Added: approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.
+Added: As a condition
+Added: of NDA approval, the FDA may require a risk evaluation and mitigation strategy, or REMS, to help ensure that the benefits of the drug
+Added: outweigh the potential risks.
+Added: REMS can include medication guides, communication plans for healthcare professionals and elements to assure
+Added: safe use, or ETASU.
+Added: ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing
+Added: only under certain circumstances, special monitoring and the use of patient registries.
+Added: The requirement for a REMS can materially affect
+Added: the potential market and profitability of the drug.
+Added: Moreover, product approval may require substantial post-approval testing and surveillance
+Added: to monitor the drug’s safety or efficacy.
+Added: Once granted, product approvals may be withdrawn if compliance with regulatory standards
+Added: is not maintained or problems are identified following initial marketing.
+Added: to some of the conditions established in an approved application, including changes in indications, labeling or manufacturing processes
+Added: or facilities, require submission and FDA approval of a new NDA or NDA supplement before the change can be implemented.
+Added: An NDA supplement
+Added: for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures
+Added: and actions in reviewing NDA supplements as it does in reviewing NDAs.
+Added: NDA approval of a new chemical entity, or NCE, which is a drug that contains no active moiety that has been approved by FDA in any other
+Added: NDA, that drug receives five years of marketing exclusivity during which FDA cannot receive any Abbreviated New Drug Application, or
+Added: ANDA, seeking approval of a generic version of that drug.
+Added: Certain changes to a drug, such as the addition of a new indication to the
+Added: package insert, are associated with a three-year period of exclusivity during which FDA cannot approve an ANDA for a generic drug that
+Added: includes the change.
+Added: An ANDA may be submitted one year before NCE exclusivity expires if a Paragraph IV certification is filed.
+Added: is no listed patent in the Orange Book, there may not be a Paragraph IV certification, and, thus, no ANDA may be filed before the expiration
+Added: of the exclusivity period.
+Added: Term Extension
+Added: NDA approval, owners of relevant drug patents may apply for up to a five-year patent extension for one patent.
+Added: The allowable patent term
+Added: extension is calculated as half of the drug’s testing phase—the time between IND and NDA submission—and all of the
+Added: review phase—the time between NDA submission and approval up to a maximum of five years.
+Added: The time can be shortened if FDA determines
+Added: that the applicant did not pursue approval with due diligence.
+Added: The total patent term after the extension may not exceed 14 years from
+Added: patents that might expire during the application phase, the patent owner may request an interim patent extension.
+Added: An interim patent extension
+Added: increases the patent term by one year and may be renewed up to four times.
+Added: For each interim patent extension granted, the post-approval
+Added: patent extension is reduced by one year.
+Added: The director of the U.S.
+Added: Patent and Trademark Office must determine that approval of the drug
+Added: covered by the patent for which a patent extension is being sought is likely.
+Added: Interim patent extensions are not available for a drug
+Added: for which an NDA has not been submitted.
+Added: Track Designation and Accelerated Approval
+Added: FDA is required to facilitate the development, and expedite the review, of drugs that are intended for the treatment of a serious or
+Added: life-threatening disease or condition for which there is no effective treatment, and which demonstrate the potential to address unmet
+Added: medical needs for the condition.
+Added: Under the Fast Track program, the sponsor of a new drug candidate may request that the FDA designate
+Added: the drug candidate for a specific indication as a Fast Track drug concurrent with, or after, the filing of the IND for the drug candidate.
+Added: The FDA must determine if the drug candidate qualifies for Fast Track Designation within 60 days of receipt of the sponsor’s request.
+Added: the Fast Track program and the FDA’s accelerated approval regulations, the FDA may approve a drug for a serious or life-threatening
+Added: illness that provides meaningful therapeutic benefit to patients over existing treatments based upon a surrogate endpoint that is reasonably
+Added: likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality,
+Added: that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account
+Added: the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.
+Added: clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for
+Added: a direct measurement of how a patient feels, functions or survives.
+Added: Surrogate endpoints can often be measured more easily or more rapidly
+Added: than clinical endpoints.
+Added: A drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including
+Added: the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.
+Added: Failure to conduct required
+Added: post-approval studies, or confirm a clinical benefit during post-marketing studies, will allow the FDA to withdraw the drug from the
+Added: market on an expedited basis.
+Added: All promotional materials for product candidates approved under accelerated regulations are subject to
+Added: prior review by the FDA.
+Added: addition to other benefits such as the ability to use surrogate endpoints and engage in more frequent interactions with the FDA, the
+Added: FDA may initiate review of sections of a Fast Track drug’s NDA before the application is complete.
+Added: This rolling review is available
+Added: if the applicant provides, and the FDA approves, a schedule for the submission of the remaining information and the applicant pays applicable
+Added: However, the FDA’s time period goal for reviewing an application does not begin until the last section of the NDA is
+Added: Additionally, the Fast Track Designation may be withdrawn by the FDA if the FDA believes that the designation is no longer
+Added: supported by data emerging in the clinical trial process.
+Added: Therapy Designation
+Added: Therapy Designation by the FDA provides more extensive development consultation opportunities with FDA senior staff, allows for the rolling
+Added: review of the drug’s application for approval and indicates that the product could be eligible for priority review if supported
+Added: by clinical data at the time of application submission for drugs that are intended to treat a serious or life-threatening disease or
+Added: condition where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies
+Added: on one or more clinically significant endpoints.
+Added: Under the breakthrough therapy program, the sponsor of a new drug candidate may request
+Added: that the FDA designate the drug candidate for a specific indication as a breakthrough therapy concurrent with, or after, the filing of
+Added: the IND for the drug candidate.
+Added: The FDA must determine if the drug candidate qualifies for Breakthrough Therapy Designation within 60
+Added: days of receipt of the sponsor’s request.
+Added: of Clinical Trial Information
+Added: of clinical trials of FDA regulated products, including drugs, are required to register and disclose certain clinical trial information.
+Added: Information related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the
+Added: clinical trial is then made public as part of the registration.
+Added: Sponsors are also obligated to discuss the results of their clinical
+Added: trials after completion.
+Added: Disclosure of the results of these trials can be delayed in certain circumstances for up to two years after
+Added: the date of completion of the trial.
+Added: Competitors may use this publicly available information to gain knowledge regarding the progress
+Added: of development programs.
+Added: of Gedatolisib and Other Drug Products in the European Union
+Added: the EU, our product candidates also may be subject to extensive regulatory requirements.
+Added: As in the U.S., medicinal products can be marketed
+Added: only if a marketing authorization from the competent regulatory agencies has been obtained.
+Added: Similar to the U.S., the various phases of
+Added: preclinical and clinical research in the EU are subject to significant regulatory controls.
+Added: Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP, and the related national implementing provisions of the individual
+Added: EU Member States govern the system for the approval of clinical trials in the EU.
+Added: Under this system, an applicant must obtain prior approval
+Added: from the competent national authority of the EU Member States in which the clinical trial is to be conducted.
+Added: Furthermore, the applicant
+Added: may only start a clinical trial at a specific trial site after the competent ethics committee has issued a favorable opinion.
+Added: trial application must be accompanied by, among other documents, an IMPD, or the Common Technical Document, with supporting information
+Added: prescribed by Directive 2001/20/EC, Directive 2005/28/EC, where relevant the implementing national provisions of the individual EU Member
+Added: States and further detailed in applicable guidance documents.
+Added: All suspected unexpected serious adverse reactions to the investigated
+Added: drug that occur during the clinical trial have to be reported to the competent national authority and the Ethics Committee of the Member
+Added: State where they occurred.
+Added: April 2014, the new Clinical Trials Regulation, (EU) No 536/2014 was adopted.
+Added: Currently, the regulation is anticipated not to come into
+Added: effect before December 2021.
+Added: The Clinical Trials Regulation will be directly applicable in all the EU Member States, repealing the current
+Added: Clinical Trials Directive 2001/20/EC.
+Added: Conduct of all clinical trials performed in the EU will continue to be bound by currently applicable
+Added: provisions until the new Clinical Trials Regulation becomes applicable.
+Added: The extent to which ongoing clinical trials will be governed
+Added: by the Clinical Trials Regulation will depend on when the Clinical Trials Regulation becomes applicable and on the duration of the individual
+Added: clinical trial.
+Added: If a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation becomes
+Added: applicable the Clinical Trials Regulation will at that time begin to apply to the clinical trial.
+Added: new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU.
+Added: The main characteristics of
+Added: the regulation include:
+Added: a streamlined application procedure via a single-entry point, the “EU portal”;
+Added: a single set of documents
+Added: to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;
+Added: and a harmonized
+Added: procedure for the assessment of applications for clinical trials, which is divided in two parts.
+Added: Part I is assessed by the competent
+Added: authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned).
+Added: Part II is assessed separately by each Member State concerned.
+Added: Strict deadlines have been established for the assessment of clinical
+Added: trial applications.
+Added: The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national
+Added: law of the concerned EU Member State.
+Added: However, overall related timelines will be defined by the Clinical Trials Regulation.
+Added: obtain a marketing authorization of a drug in the EU, we may submit Marketing Authorization Applications, or MAA, either under the so-called
+Added: centralized or national authorization procedures.
+Added: centralized procedure provides for the grant of a single marketing authorization following a favorable opinion by the European Medicines
+Added: Agency, or EMA, that is valid in all EU Member States, as well as Iceland, Liechtenstein and Norway.
+Added: The centralized procedure is compulsory
+Added: for medicines produced by specified biotechnological processes, products designated as orphan medicinal products, advanced therapy medicines
+Added: (such as gene-therapy, somatic cell-therapy or tissue-engineered medicines) and products with a new active substance indicated for the
+Added: treatment of specified diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders or autoimmune diseases and other immune
+Added: dysfunctions and viral diseases.
+Added: The centralized procedure is optional for products that represent a significant therapeutic, scientific
+Added: or technical innovation, or whose authorization would be in the interest of public health.
+Added: Under the centralized procedure the maximum
+Added: timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is
+Added: to be provided by the applicant in response to questions asked by the Committee of Medicinal Products for Human Use, or the CHMP.
+Added: assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest,
+Added: particularly from the point of view of therapeutic innovation.
+Added: The timeframe for the evaluation of an MAA under the accelerated assessment
+Added: procedure is of 150 days, excluding stop-clocks.
+Added: Authorization Procedures
+Added: are also two other possible routes to authorize medicinal products in several EU countries, which are available for investigational medicinal
+Added: products that fall outside the scope of the centralized procedure:
+Added: Decentralized
+Added: Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of
+Added: medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized
+Added: recognition procedure.
+Added: In the mutual recognition procedure, a medicine is first authorized in one EU Member State, in accordance
+Added: with the national procedures of that country.
+Added: Following this, further marketing authorizations can be sought from other EU countries
+Added: in a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization.
+Added: the above described procedures, before granting an MAA, the EMA or the competent authorities of the Member States of the European Economic
+Added: Area, or EEA, make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality,
+Added: safety and efficacy.
+Added: Regulatory Exclusivity
+Added: the EU, new products authorized for marketing (i.e., reference products) qualify for eight years of data exclusivity and an additional
+Added: two years of market exclusivity upon marketing authorization.
+Added: The data exclusivity period prevents generic applicants from relying on
+Added: the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic marketing authorization
+Added: in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.
+Added: The market exclusivity
+Added: period prevents a successful generic applicant from commercializing its product in the EU until ten years have elapsed from the initial
+Added: authorization of the reference product in the EU.
+Added: The ten-year market exclusivity period can be extended to a maximum of eleven years
+Added: if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new
+Added: therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical
+Added: benefit in comparison with existing therapies.
+Added: Approval-Related Regulations – Rest of the World
+Added: other countries outside of the EU and the U.S., such as countries in Eastern Europe, Latin America or Asia, the requirements governing
+Added: the conduct of clinical trials, product licensing, pricing and reimbursement vary from jurisdiction to jurisdiction.
+Added: Additionally, the
+Added: clinical trials must be conducted in accordance with cGCP requirements and the applicable regulatory requirements and the ethical principles
+Added: that have their origin in the Declaration of Helsinki.
+Added: If we fail to comply with applicable foreign regulatory requirements, we may be
+Added: subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating
+Added: restrictions and criminal prosecution.
+Added: of CELsignia Tests
+Added: and CMS for Diagnostic
+Added: Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.
+Added: Department of Health and Human Services, regulates all
+Added: clinical laboratory testing (except research) performed on humans in the United States through CLIA.
+Added: All clinical laboratories that perform
+Added: clinical lab services on human specimens for the purpose of providing information on the diagnosis, prevention or treatment of disease
+Added: must receive CLIA certification.
This covers approximately 175,000 laboratories as of 2017.
−Removed: Laboratories must obtain CLIA certification and demonstrate compliance with CLIA requirements as confirmed by an inspection by CMS.
+Added: Laboratories must obtain CLIA certification
+Added: and demonstrate compliance with CLIA requirements as confirmed by an inspection by CMS.
We received our CLIA certification in 2016.
−Removed: We also had our laboratory certified by the College of American Pathologies, or CAP, in 2016, an organization recognized by CMS as a third-party reviewer of clinical laboratories.
−Removed: Several states, including, among others, New York and California, require licensure of out-of-state labs that receive specimens from the state and compliance with the state’s individual laboratory regulations.
−Removed: If our laboratory is out of compliance with CLIA requirements, we may be subject to sanctions such as suspension, limitation or revocation of our CLIA certificate, as well as directed plan of correction, state on-site monitoring, civil money penalties, civil injunctive suit or criminal penalties.
−Removed: We must maintain CLIA compliance and certification to be eligible to bill for services provided to Medicare and Medicaid beneficiaries.
−Removed: If we were to be found out of compliance with CLIA program requirements and subjected to sanction, our business could be harmed.
−Removed: Failure to comply with state licensure laws, if applicable, could subject us to additional sanctions imposed by state licensing authorities.
−Removed: FDA approval or clearance is not currently required for CELsignia tests offered as a stand-alone LDT test.
−Removed: If we are partnered with a drug company to launch a CELsignia test as a companion diagnostic for a new drug indication, we would be required to obtain premarket approval, or PMA, in conjunction with the pharmaceutical company seeking a new drug approval for the matching therapy.
−Removed: Historically, the FDA has exercised enforcement discretion with respect to tests performed solely in a central laboratory, like the CELsignia tests or LDTs.
−Removed: The FDA has not required laboratories that furnish only LDTs to comply with the agency’s requirements for medical devices (e.g., establishment registration, device listing, quality systems regulations, premarket clearance or premarket approval, and post-market controls).
−Removed: Although the FDA proposed regulations that would apply to LDTs, the FDA recently decided that, at present, those regulations are not moving forward towards approval and implementation.
−Removed: In mid-2014, the FDA published a draft Guidance Document describing a proposed approach for a regulatory framework for LDTs that would have resulted in most of the high-value LDT tests marketed today eventually being required to obtain 510(k) clearances or PMAs.
−Removed: If implemented, this regulatory framework would require most hospital clinical labs to abandon a number of tests they perform or to pursue regulatory clearances or approvals to perform them.
−Removed: These proposals met significant resistance from Congress, the hospital industry, and independent clinical laboratories.
−Removed: The FDA indicated in late 2016 that it does not intend to finalize the draft Guidance Document at this time.
+Added: also had our laboratory certified by the College of American Pathologies, or CAP, in 2016, an organization recognized by CMS as a third-party
+Added: reviewer of clinical laboratories.
+Added: Several states, including, among others, New York and California, require licensure of out-of-state
+Added: labs that receive specimens from the state and compliance with the state’s individual laboratory regulations.
+Added: our laboratory is out of compliance with CLIA requirements, we may be subject to sanctions such as suspension, limitation or revocation
+Added: of our CLIA certificate, as well as directed plan of correction, state on-site monitoring, civil money penalties, civil injunctive suit
+Added: or criminal penalties.
+Added: We must maintain CLIA compliance and certification to be eligible to bill for services provided to Medicare and
+Added: Medicaid beneficiaries.
+Added: If we were to be found out of compliance with CLIA program requirements and subjected to sanction, our business
+Added: could be harmed.
+Added: Failure to comply with state licensure laws, if applicable, could subject us to additional sanctions imposed by state
+Added: licensing authorities.
+Added: for Diagnostics
+Added: approval or clearance is not currently required for CELsignia tests offered as a stand-alone LDT test.
+Added: If we are partnered with a drug
+Added: company to launch a CELsignia test as a companion diagnostic for a new drug indication, we would be required to obtain premarket approval,
+Added: or PMA, in conjunction with the pharmaceutical company seeking a new drug approval for the matching therapy.
+Added: Historically, the FDA has
+Added: exercised enforcement discretion with respect to tests performed solely in a central laboratory, like the CELsignia tests or LDTs.
+Added: FDA has not required laboratories that furnish only LDTs to comply with the agency’s requirements for medical devices (e.g., establishment
+Added: registration, device listing, quality systems regulations, premarket clearance or premarket approval, and post-market controls).
+Added: the FDA proposed regulations that would apply to LDTs, the FDA decided that, at present, those regulations are not moving forward towards
+Added: approval and implementation.
+Added: In mid-2014, the FDA published a draft Guidance Document describing a proposed approach for a regulatory
+Added: framework for LDTs that would have resulted in most of the high-value LDT tests marketed today eventually being required to obtain 510(k)
+Added: clearances or PMAs.
+Added: If implemented, this regulatory framework would require most hospital clinical labs to abandon a number of tests
+Added: they perform or to pursue regulatory clearances or approvals to perform them.
+Added: These proposals met significant resistance from Congress,
+Added: the hospital industry, and independent clinical laboratories.
+Added: The FDA indicated in late 2016 that it does not intend to finalize the
+Added: draft Guidance Document at this time.
However, the FDA continues to discuss potential regulatory approaches to LDTs.
−Removed: HIPAA and HITECH
−Removed: Under the administrative simplification provisions of the Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health (“HITECH Act”), the U.S.
−Removed: Department of Health and Human Services, or HHS, issued regulations that establish uniform standards governing the conduct of certain electronic healthcare transactions and protecting the privacy and security of protected health information used or disclosed by healthcare providers and other covered entities.
−Removed: HIPAA includes the following primary sets of regulations:
−Removed: privacy regulations, security regulations, and standards for electronic transactions, which establish standards for certain healthcare transactions.
−Removed: The privacy and security regulations were extensively amended in 2013 to incorporate new requirements from the HITECH Act.
−Removed: The privacy regulations cover the use and disclosure of protected health information by healthcare providers and other covered entities.
−Removed: They also set forth certain rights that an individual has with respect to his or her protected health information, including, but not limited to, the right to access or amend certain records containing protected health information, or to request restrictions on the use or disclosure of protected health information.
−Removed: The security regulations establish requirements for safeguarding the confidentiality, integrity, and availability of protected health information that is electronically transmitted or electronically stored.
−Removed: The HITECH Act, among other things, made many of HIPAA’s privacy and security standards applicable to business associates of covered entities, and established certain protected health information security breach notification requirements.
−Removed: A covered entity must notify affected individual(s) and HHS when there is a breach of unsecured protected health information.
−Removed: HIPAA also governs patient access to laboratory test reports.
−Removed: Effective October 6, 2014, individuals (or their personal representatives, as applicable), have the right to access test reports directly from clinical laboratories and to direct that copies of those test reports be transmitted to persons or entities designated by the individual.
−Removed: These laws impose significant fines and other penalties for improper use or disclosure of protected health information.
−Removed: Additionally, to the extent that we submit electronic healthcare claims and payment transactions that do not comply with the electronic data transmission standards established under HIPAA and the HITECH Act, payments to us may be delayed or denied.
−Removed: In addition to the federal privacy regulations, there are a number of state laws regarding the privacy and security of health information and personal data that are applicable to our operations.
−Removed: The HIPAA privacy and security regulations establish a uniform federal “floor” that covered entities and business associates must meet and do not supersede state laws that are more stringent or provide individuals with greater rights with respect to the privacy or security of, and access to, their records containing protected health information.
−Removed: The compliance requirements of these various state laws, including additional breach reporting requirements, and the penalties for violation vary widely and new privacy and security laws in this area are evolving.
−Removed: We believe that we have taken the steps required for us to comply with health information privacy and security statutes and regulations in all jurisdictions, both state and federal.
−Removed: However, we may not be able to maintain compliance in all jurisdictions where we do business.
−Removed: Failure to maintain compliance, or changes in state or federal laws regarding privacy or security, could result in civil and/or criminal penalties and could have a material adverse effect on our business.
−Removed: Federal, State and Foreign Fraud and Abuse Laws
−Removed: In the United States, there are various fraud and abuse laws with which we must comply and we are potentially subject to regulation by various federal, state and local authorities, including CMS, other divisions of HHS (e.g., the Office of Inspector General), the U.S.
−Removed: Department of Justice, and individual U.S.
−Removed: Attorney offices within the Department of Justice, and state and local governments.
−Removed: We also may be subject to foreign fraud and abuse laws in connection with our international business activities.
−Removed: In the United States, the federal Anti-Kickback Statute prohibits, among other things, knowingly and willfully offering, paying, soliciting or receiving remuneration to induce, or in return for patient referrals for, or purchasing, leasing, ordering, recommending or arranging for the purchase, lease or order of, any healthcare item or service reimbursable under a governmental payor program.
−Removed: Courts have stated that a financial arrangement may violate the Anti-Kickback Statute if any one purpose of the arrangement is to encourage patient referrals or other federal healthcare program business, regardless of whether there are other legitimate purposes for the arrangement.
−Removed: The definition of “remuneration” has been broadly interpreted to include anything of value, including gifts, discounts, credit arrangements, payments of cash, consulting fees, waivers of co-payments, ownership interests, and providing anything at less than its fair market value.
−Removed: Recognizing that the Anti-Kickback Statute is broad and may technically prohibit many innocuous or beneficial arrangements within the healthcare industry, HHS issued a series of regulatory “safe harbors.” These safe harbor regulations set forth certain provisions, which, if met, will assure healthcare providers and other parties that they will not be prosecuted under the federal Anti-Kickback Statute.
−Removed: Although full compliance with these provisions protects against prosecution under the federal Anti-Kickback Statute, the failure of a transaction or arrangement to fit within a specific safe harbor does not necessarily mean that the transaction or arrangement is illegal or that prosecution under the federal Anti-Kickback Statute will be pursued.
−Removed: Many states also have anti-kickback statutes, some of which may apply to items or services reimbursed by any third-party payor, including commercial insurers.
−Removed: In addition, federal false claims laws, including the federal civil False Claims Act, prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.
−Removed: As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S.
−Removed: Recently, several pharmaceutical and other healthcare companies have been prosecuted under these laws for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product.
−Removed: Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of the product for unapproved, and thus generally non-reimbursable, uses.
−Removed: The civil monetary penalties statute imposes penalties against any person or entity who, among other things, is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.
−Removed: HIPAA created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.
−Removed: In addition, various states have enacted false claim laws analogous to the federal False Claims Act, although many of these state laws apply where a claim is submitted to any third-party payor and not merely a governmental payor program.
−Removed: If our operations are found to be in violation of any of the federal or state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to significant penalties, including without limitation, civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.
−Removed: In Europe, various countries have adopted anti-bribery laws providing for severe consequences, in the form of criminal penalties and/or significant fines, for individuals and/or companies committing a bribery offence.
−Removed: Violations of these anti-bribery laws, or allegations of such violations, could have a negative impact on our business, results of operations and reputation.
−Removed: For instance, in the United Kingdom, under the Bribery Act 2010, which went into effect in July 2011, a bribery occurs when a person offers, gives or promises to give a financial or other advantage to induce or reward another individual to improperly perform certain functions or activities, including any function of a public nature.
−Removed: Bribery of foreign public officials also falls within the scope of the Bribery Act 2010.
−Removed: Under the new regime, an individual found in violation of the Bribery Act 2010 faces imprisonment of up to 10 years.
−Removed: In addition, the individual can be subject to an unlimited fine, as can commercial organizations for failure to prevent bribery.
−Removed: Federal and State Physician Self-Referral Prohibitions
−Removed: Under a federal law directed at “self-referral,” commonly known as the “Stark Law,” there are prohibitions, with certain exceptions, on referrals for certain designated health services, including laboratory services, that are covered by the Medicare and Medicaid programs by physicians who personally, or through a family member, have an investment or ownership interest in, or a compensation arrangement with, an entity performing the tests.
−Removed: The prohibition also extends to payment for any testing referred in violation of the Stark Law.
−Removed: A person who engages in a scheme to circumvent the Stark Law’s referral prohibition may be fined up to $100,000 for each such arrangement or scheme.
−Removed: In addition, any person who presents or causes to be presented a claim to the Medicare or Medicaid programs in violation of the Stark Law is subject to civil monetary penalties of up to $15,000 per bill submission, an assessment of up to three times the amount claimed and possible exclusion from participation in federal governmental payor programs.
−Removed: Bills submitted in violation of the Stark Law may not be paid by Medicare or Medicaid, and any person collecting any amounts with respect to any such prohibited bill is obligated to refund such amounts.
+Added: and Reimbursement of our Product Candidates
+Added: uncertainty exists as to the coverage and reimbursement status of any products we sell or may sell.
+Added: Sales of any of our products will
+Added: depend, in part, on the extent to which the costs of the products will be covered by third-party payors, including government health
+Added: programs such as Medicare and Medicaid, commercial health insurers, managed care organizations or pharmaceutical companies.
+Added: for determining whether a third-party payor will provide coverage for a test sometimes is separate from the process for setting the price
+Added: of a drug product or for establishing the reimbursement rate that a payor will pay for the drug product.
+Added: Third-party payors may limit
+Added: coverage to specific testing products on an approved list, which might not include all of the tests available for a particular indication.
+Added: order to obtain coverage and reimbursement for any product, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate
+Added: the medical necessity and cost-effectiveness of the test.
+Added: Whether or not we conduct such studies, our products may not be considered
+Added: medically necessary or cost-effective.
+Added: A third-party payor’s decision to provide coverage for a test does not imply that an adequate
+Added: reimbursement rate will be approved.
+Added: Further, one payor’s determination to provide coverage for a product does not assure that
+Added: other payors will also provide coverage, and adequate reimbursement, for the product.
+Added: Third-party reimbursement may not be sufficient
+Added: to enable us to maintain price levels high enough to realize an appropriate return on our investment in product development.
+Added: containment of healthcare costs has become a priority of federal, state and foreign governments, and the prices of tests and drugs have
+Added: been a focus in this effort.
+Added: Third-party payors are increasingly challenging the prices charged for medical products and services, examining
+Added: the medical necessity and reviewing the cost-effectiveness of testing products, drug products and medical services and questioning safety
+Added: and efficacy.
+Added: If these third-party payors do not consider our products to be cost-effective compared to other available products or
+Added: treatments, they may not cover our products or, if they do, the level of payment may not be sufficient to allow us to sell our products
+Added: government, state legislatures and foreign governments have shown significant interest in implementing cost-containment
+Added: programs to limit the growth of government-paid healthcare costs, including price controls and restrictions on reimbursement.
+Added: of such controls and measures, and tightening of restrictive policies in jurisdictions with existing controls and measures, could limit
+Added: payments for our testing products or drugs that require use of our testing products and could adversely affect our net revenue and results.
+Added: and reimbursement schemes vary widely from country to country.
+Added: Some countries may require the completion of additional studies that compare
+Added: the cost-effectiveness of a particular test to currently available tests.
+Added: The downward pressure on healthcare costs in general, particularly
+Added: prescription drugs and testing products, has become intense.
+Added: As a result, increasingly high barriers are being erected to the entry of
+Added: new products.
+Added: In addition, in some countries, cross-border imports from low-priced markets exert competitive pressure that may reduce
+Added: pricing within a country.
+Added: Any country that has price controls or reimbursement limitations for testing products may not allow favorable
+Added: reimbursement and pricing arrangements for any of our products.
+Added: policies, third-party reimbursement rates and pricing regulation may change at any time.
+Added: Healthcare Laws
+Added: Manufacturing,
+Added: sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in
+Added: in addition to the FDA, including CMS, the HHS Office of Inspector General and HHS Office for Civil Rights, other divisions
+Added: of the HHS and the Department of Justice.
+Added: providers, physicians, and third-party payors will play a primary role in the recommendation and prescription of any products for which
+Added: we obtain marketing approval.
+Added: Our current and future arrangements with third-party payors, healthcare providers and physicians may expose
+Added: us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements
+Added: and relationships through which we market, sell and distribute our drug and diagnostic products.
+Added: In the U.S., these laws include, without
+Added: limitation, state and federal anti-kickback, false claims, physician transparency, and patient data privacy and security laws and regulations,
+Added: including but not limited to those described below.
+Added: federal Anti-Kickback Statute, or AKS, prohibits, among other things, any person or entity from knowingly and willfully offering,
+Added: paying, soliciting, receiving or providing any remuneration, directly or indirectly, overtly or covertly, to induce or in return for
+Added: purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any good, facility, item or service reimbursable,
+Added: in whole or in part, under Medicare, Medicaid or other federal healthcare programs.
+Added: The term “remuneration” has been broadly
+Added: interpreted to include anything of value.
+Added: The AKS has been interpreted to apply to arrangements between pharmaceutical and medical device
+Added: manufacturers on the one hand and prescribers, purchasers, formulary managers and beneficiaries on the other hand.
+Added: Although there are
+Added: a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe
+Added: harbors are drawn narrowly.
+Added: Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe
+Added: harbor does not make the conduct per se illegal under the AKS.
+Added: Instead, the legality of the arrangement will be evaluated on a case-by-case
+Added: basis based on a cumulative review of all its facts and circumstances.
+Added: Several courts have interpreted the statute’s intent requirement
+Added: to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business,
+Added: the statute has been violated.
+Added: In addition, a person or entity does not need to have actual knowledge of the statute or specific intent
+Added: to violate it in order to have committed a violation.
+Added: Moreover, a claim including items or services resulting from a violation of the
+Added: AKS constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.
+Added: On November 20, 2020, the Office of Inspector
+Added: General, or OIG finalized further modifications to the AKS.
+Added: Under the final rule, OIG added safe harbor protections under the AKS for
+Added: certain coordinated care and value-based arrangements among clinicians, providers, and others.
+Added: The final rule (with some exceptions)
+Added: became effective January 19, 2021.
+Added: We continue to evaluate what effect, if any, this rule will have on our business.
+Added: addition, under a federal law directed at “self-referral,” commonly known as the “Stark Law,” there are prohibitions,
+Added: with certain exceptions, on referrals for certain designated health services, including laboratory services, that are covered by the
+Added: Medicare and Medicaid programs by physicians who personally, or through a family member, have an investment or ownership interest in,
+Added: or a compensation arrangement with, an entity performing the tests.
+Added: The prohibition also extends to payment for any testing referred
+Added: in violation of the Stark Law.
+Added: A person who engages in a scheme to circumvent the Stark Law’s referral prohibition may be fined
+Added: up to $100,000 for each such arrangement or scheme.
+Added: In addition, any person who presents or causes to be presented a claim to the Medicare
+Added: or Medicaid programs in violation of the Stark Law is subject to civil monetary penalties of up to $15,000 per bill submission, an assessment
+Added: of up to three times the amount claimed and possible exclusion from participation in federal governmental payor programs.
+Added: Bills submitted
+Added: in violation of the Stark Law may not be paid by Medicare or Medicaid, and any person collecting any amounts with respect to any such
+Added: prohibited bill is obligated to refund such amounts.
Many states have comparable laws that are not limited to Medicare and Medicaid referrals.
−Removed: Other Regulatory Requirements
−Removed: Our operations use small amounts of hazardous materials in research and development and generate regulated medical waste in the normal course of performing our CELsignia tests.
+Added: we could be held liable under the federal False Claims Act, which imposes civil penalties, including through civil whistleblower or qui
+Added: tam actions, against individuals or entities (including manufacturers) for, among other things, knowingly presenting, or causing to be
+Added: presented to federal programs (including Medicare and Medicaid) claims for items or services that are false or fraudulent, claims for
+Added: items or services not provided as claimed, or claims for medically unnecessary items or services.
+Added: This could apply even if we are not
+Added: submitting claims directly to payors as would be the case with drug products.
+Added: The government may deem manufacturers of such products
+Added: to have “caused” the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information
+Added: to customers or promoting a product off-label.
+Added: Several biopharmaceutical, medical device and other healthcare companies have been prosecuted
+Added: under federal false claims and civil monetary penalty laws for, among other things, allegedly providing free product to customers with
+Added: the expectation that the customers would bill federal programs for the product.
+Added: Other companies have been prosecuted for causing false
+Added: claims to be submitted because of the companies’ marketing of products for unapproved (e.g., or off-label), and thus non-covered,
+Added: In addition, the civil monetary penalties statute imposes penalties against any person who is determined to have presented or caused
+Added: to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided
+Added: as claimed or is false or fraudulent.
+Added: future marketing and activities relating to the reporting of wholesaler or estimated retail prices for our products, if approved, the
+Added: reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state and third-party reimbursement
+Added: for our products, and the sale and marketing of our product candidates, are subject to scrutiny under these laws.
+Added: federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created additional federal criminal statutes that prohibit,
+Added: among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false
+Added: or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare
+Added: benefit program, including private third-party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program,
+Added: willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing or covering
+Added: up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for
+Added: healthcare benefits, items or services.
+Added: Similar to the AKS, a person or entity does not need to have actual knowledge of the statute
+Added: or specific intent to violate it in order to have committed a violation.
+Added: addition, there has been a recent trend of increased federal and state regulation of payments made to physicians and certain other healthcare
+Added: The Affordable Care Act, or the ACA, imposed, among other things, new annual reporting requirements through the Physician
+Added: Payments Sunshine Act for covered manufacturers for certain payments and “transfers of value” provided to physicians (defined
+Added: to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment
+Added: interests held by physicians and their immediate family members.
+Added: Effective January 1, 2022, these reporting obligations will extend to
+Added: include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.
+Added: Failure to submit
+Added: timely, accurately and completely the required information for all payments, transfers of value and ownership or investment interests
+Added: may result in civil monetary penalties.
+Added: Covered manufacturers must submit reports by the 90 th day of each subsequent calendar
+Added: year and the reported information is publicly made available on a searchable website.
+Added: may also be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.
+Added: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their respective implementing
+Added: regulations, including the Final HIPAA Omnibus Rule published on January 25, 2013, impose specified requirements relating to the privacy,
+Added: security and transmission of individually identifiable health information held by covered entities and their business associates.
+Added: other things, HITECH made HIPAA’s security standards directly applicable to “business associates,” defined as independent
+Added: contractors or agents of covered entities that create, receive, maintain or transmit protected health information in connection with
+Added: providing a service for or on behalf of a covered entity, although it is unclear that we would be considered a “business associate”
+Added: in the normal course of our business.
+Added: HITECH also increased the civil and criminal penalties that may be imposed against covered entities,
+Added: business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions
+Added: in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.
+Added: In addition, state laws govern the privacy and security of health information in certain circumstances, many of which differ from each
+Added: other in significant ways and may not have the same requirements, thus complicating compliance efforts.
+Added: See “European Data Collection”
+Added: below for a discussion of data privacy and security enactments of the EU.
+Added: example, California’s Consumer Privacy Act, or CCPA, went into effect in January 2020, and the California Attorney General has
+Added: since promulgated final regulations.
+Added: The law provides broad rights to California consumers with respect to the collection and use of
+Added: their personal information and imposes data protection obligations on certain businesses.
+Added: While the CCPA does not apply to protected
+Added: health information that is subject to HIPAA or personal information collected, used or disclosed in research, as defined by federal law,
+Added: the CCPA may still affect our business activities.
+Added: Moreover, on November 3, 2020, California voters passed the California Privacy Rights
+Added: Act, or CPRA, under a ballot initiative.
+Added: The CPRA amends the existing CCPA to include new consumer rights and additional data protection
+Added: The new data protection requirements under the CPRA apply to information collected on or after January 1, 2022.
+Added: promulgation of final regulations, the California State Attorney General has commenced enforcement actions against CCPA violators.
+Added: uncertainty surrounding the implementation of CCPA and the amendments under the CPRA exemplifies the vulnerability of our business to
+Added: the evolving regulatory environment related to personal data and protected health information.
+Added: The California law further expands the
+Added: need for privacy and process enhancements and commitment of resources in support of compliance.
+Added: Moreover, more than ten states have proposed
+Added: bills in the last year with provisions similar to the CCPA and CPRA.
+Added: It is likely that other states will pass laws similar to the CCPA
+Added: and the CPRA in the near future and a federal data protection law may also be on the horizon.
+Added: state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, may apply to sales or marketing
+Added: arrangements and claims involving healthcare items or services.
+Added: Such laws are generally broad and are enforced by various state agencies
+Added: and private actions.
+Added: Also, many states have similar fraud and abuse statutes or regulations that may be broader in scope and may apply
+Added: regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs.
+Added: Some state laws require pharmaceutical
+Added: companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant federal government compliance
+Added: guidance, and require drug manufacturers to report information related to payments and other transfers of value to physicians and other
+Added: healthcare providers, marketing expenditures or drug pricing.
+Added: order to sell products, we must also comply with state laws, including those that require the registration of manufacturers and wholesale
+Added: distributors of drug and biological products.
+Added: These include, in certain states, manufacturers and distributors who ship products into
+Added: the state even if such manufacturers or distributors have no place of business within the state.
+Added: Some states also impose requirements
+Added: on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require
+Added: manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.
+Added: Several states have enacted legislation requiring pharmaceutical and biotechnology companies to establish marketing compliance programs,
+Added: file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities,
+Added: and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician
+Added: prescribing data to pharmaceutical and biotechnology companies for use in sales and marketing, and to prohibit certain other sales and
+Added: marketing practices.
+Added: All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.
+Added: scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform,
+Added: especially in light of the lack of applicable precedent and regulations.
+Added: Federal and state enforcement bodies have recently increased
+Added: their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions,
+Added: convictions and settlements in the healthcare industry.
+Added: It is possible that governmental authorities will conclude that our business
+Added: practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare
+Added: laws and regulations.
+Added: If our operations are found to be in violation of any of these laws or any other governmental regulations that
+Added: may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, contractual
+Added: damages, reputational harm, diminished profits and future earnings, imprisonment, exclusion of drugs from government funded healthcare
+Added: programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations, as well as additional reporting obligations
+Added: and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with
+Added: these laws, any of which could adversely affect our ability to operate our business and our financial results.
+Added: If any of the physicians
+Added: or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they
+Added: may be subject to significant criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.
+Added: Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government
+Added: authorities, can be time- and resource consuming and can divert a company’s attention from the business.
+Added: Data Collection
+Added: collection and use of personal health data in or arising from the EU are governed by the provisions of the Data Protection Directive,
+Added: and the General Data Protection Regulation, or GDPR.
+Added: This directive imposes several requirements relating to the consent of the individuals
+Added: to whom the personal data relates, the information provided to the individuals, notification of data processing obligations to the competent
+Added: national data protection authorities and the security and confidentiality of the personal data.
+Added: The Data Protection Directive and GDPR
+Added: also impose strict rules on the transfer of personal data out of the EU, to the U.S.
+Added: Failure to comply with the requirements of the Data
+Added: Protection Directive, the GDPR and the related national data protection laws of the EU Member States may result in fines and other administrative
+Added: The GDPR introduces new data protection requirements in the EU and substantial fines for breaches of the data protection rules.
+Added: The GDPR regulations may impose additional responsibility and liability in relation to personal data that we process, including in respect
+Added: of clinical trials, and we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules.
+Added: This may be onerous and adversely affect our business, financial condition, results of operations and prospects.
+Added: and Future Legislation
+Added: and other jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare
+Added: system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect
+Added: our ability to profitably sell any product candidates.
+Added: We expect that current laws, as well as other healthcare reform measures that
+Added: may be adopted in the future, may result in more rigorous coverage criteria and additional downward pressure on the price that we, or
+Added: any collaborators, may receive.
+Added: ACA, for example, revised the methodology by which rebates owed by manufacturers for covered outpatient drugs are calculated under the
+Added: Medicaid Drug Rebate Program, extended the Medicaid Drug Rebate Program to utilization of covered drugs dispensed to individuals enrolled
+Added: in Medicaid managed care organizations and subjected manufacturers to new annual fees for certain branded prescription drugs.
+Added: price of our test may be included in the reimbursement rates for certain drugs, this could significantly impact our pricing.
+Added: favorable coverage and reimbursement status is attained for one or more products, less favorable coverage policies and reimbursement
+Added: rates may be implemented in the future.
+Added: its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA,
+Added: and we expect there will be additional challenges and amendments to the ACA in the future.
+Added: For example, various portions of the ACA are
+Added: currently undergoing legal and constitutional challenges in the U.S.
+Added: Supreme Court, and the Trump Administration issued various Executive
+Added: Orders which eliminated cost sharing subsidies and various provisions that would impose a fiscal burden on states or a cost, fee, tax,
+Added: penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.
+Added: Additionally, Congress has introduced several pieces of legislation aimed at significantly revising or repealing the ACA.
+Added: 2018, the CMS published a final rule permitting further collections and payments to and from certain ACA qualified health plans and health
+Added: insurance issuers under the ACA risk adjustment program in response to the outcome of the federal district court litigation regarding
+Added: the method CMS uses to determine this risk adjustment.
+Added: Since then, the ACA risk adjustment program payment parameters have been updated
+Added: It is unclear whether the ACA will be overturned, repealed, replaced, or further amended.
+Added: We cannot predict what affect further
+Added: changes to the ACA would have on our business, especially given the new Biden Administration.
+Added: Additionally,
+Added: other federal health reform measures have been proposed and adopted in the U.S.
+Added: since the ACA was enacted:
+Added: Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.
+Added: A Joint Select Committee on
+Added: Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021,
+Added: was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.
+Added: These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect
+Added: in April 2013 and, due to subsequent legislative amendments to the statute, including the BBA, will remain in effect through 2027,
+Added: unless additional Congressional action is taken.
+Added: However, pursuant to the Coronavirus Aid, Relief and Economic Security Act, or CARES
+Added: Act, and subsequent legislation, these Medicare sequester reductions are suspended from May 1, 2020 through March 31, 2021 due to
+Added: the COVID-19 pandemic.
+Added: Proposed legislation, if passed, would extend this suspension until the end of the pandemic.
+Added: American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, and increased the statute
+Added: of limitations period for the government to recover overpayments to providers from three to five years.
+Added: there has been heightened governmental scrutiny over the manner in which companies set prices for their products, which have resulted
+Added: in several recent Congressional inquiries and proposed and enacted bills designed to, among other things, bring more transparency to
+Added: product pricing, review the relationship between pricing and patient programs, and reform government program reimbursement methodologies
+Added: for products.
+Added: In addition, the U.S.
+Added: government, state legislatures, and foreign governments have shown significant interest in implementing
+Added: cost containment programs, including price-controls, restrictions on reimbursement and requirements for substitution of generic products
+Added: for branded prescription drugs to limit the growth of government paid healthcare costs.
+Added: states in the U.S.
+Added: have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing,
+Added: including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure
+Added: and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
+Added: the Biden administration have each indicated that it will continue to seek new legislative and/or administrative measures to control
+Added: Individual states in the U.S.
+Added: have also been increasingly passing legislation and implementing regulations designed to control
+Added: pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain
+Added: product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other
+Added: countries and bulk purchasing.
+Added: Regulatory Requirements
+Added: operations use small amounts of hazardous materials in research and development and generate regulated medical waste in the normal course
+Added: of performing our CELsignia tests.
This subjects us to a variety of federal, state and local environmental and safety laws and regulations.
−Removed: Some of the regulations under the current regulatory structure provide for strict liability, holding a party potentially liable without regard to fault or negligence.
−Removed: We could be held liable for damages and fines as a result of our, or others’, business operations should contamination of the environment or individual exposure to hazardous substances occur.
−Removed: We cannot predict how changes in laws or development of new regulations will affect our business operations or the cost of compliance.
−Removed: New Legislation and Regulations
−Removed: From time to time, legislation is drafted, introduced and passed in Congress that could significantly change the statutory provisions governing the testing, approval, manufacturing and marketing of products that are or will be regulated by the FDA or CMS.
−Removed: In addition to new legislation, FDA and CMS regulations and policies are often revised or interpreted by the agencies in ways that may significantly affect our business and our products.
−Removed: It is impossible to predict whether further legislative changes will be enacted or FDA or CMS regulations, guidance, policies or interpretations will be changed, or what the impact of such changes, if any, may be.
−Removed: The 2020 presidential election and the resulting change in administration make it even more difficult to predict if and how federal regulations may change and/or federal agencies might alter their positions.
−Removed: Pharmaceutical Coverage, Pricing and Reimbursement
−Removed: Significant uncertainty exists as to the coverage and reimbursement status of any products we sell.
−Removed: Sales of any of our products will depend, in part, on the extent to which the costs of the products will be covered by third-party payors, including government health programs such as Medicare and Medicaid, commercial health insurers, managed care organizations or pharmaceutical companies.
−Removed: The process for determining whether a third-party payor will provide coverage for a test sometimes is separate from the process for setting the price of a drug product or for establishing the reimbursement rate that a payor will pay for the drug product.
−Removed: Third-party payors may limit coverage to specific testing products on an approved list, which might not include all of the tests available for a particular indication.
−Removed: In order to obtain coverage and reimbursement for any product, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the test.
−Removed: Whether or not we conduct such studies, our products may not be considered medically necessary or cost-effective.
−Removed: A third-party payor’s decision to provide coverage for a test does not imply that an adequate reimbursement rate will be approved.
−Removed: Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage, and adequate reimbursement, for the product.
−Removed: Third-party reimbursement may not be sufficient to enable us to maintain price levels high enough to realize an appropriate return on our investment in product development.
−Removed: The containment of healthcare costs has become a priority of federal, state and foreign governments, and the prices of tests and drugs have been a focus in this effort.
−Removed: Third-party payors are increasingly challenging the prices charged for medical products and services, examining the medical necessity and reviewing the cost-effectiveness of testing products, drug products and medical services and questioning safety and efficacy.
−Removed: If these third-party payors do not consider our products to be cost-effective compared to other available tests, they may not cover our products or, if they do, the level of payment may not be sufficient to allow us to sell our products at a profit.
−Removed: government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls and restrictions on reimbursement.
−Removed: Adoption of such controls and measures, and tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for our testing products or drugs that require use of our testing products and could adversely affect our net revenue and results.
−Removed: Pricing and reimbursement schemes vary widely from country to country.
−Removed: Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular test to currently available tests.
−Removed: The downward pressure on healthcare costs in general, particularly prescription drugs and testing products, has become intense.
−Removed: As a result, increasingly high barriers are being erected to the entry of new products.
−Removed: In addition, in some countries, cross-border imports from low-priced markets exert competitive pressure that may reduce pricing within a country.
−Removed: Any country that has price controls or reimbursement limitations for testing products may not allow favorable reimbursement and pricing arrangements for any of our products.
−Removed: Coverage policies, third-party reimbursement rates and test pricing regulation may change at any time.
−Removed: In particular, in the United States, the Affordable Care Act contains provisions that have the potential to substantially change healthcare delivery and financing, including impacting the profitability of testing and drugs.
−Removed: For example, the Affordable Care Act revised the methodology by which rebates owed by manufacturers for covered outpatient drugs are calculated under the Medicaid Drug Rebate Program, extended the Medicaid Drug Rebate Program to utilization of covered drugs dispensed to individuals enrolled in Medicaid managed care organizations and subjected manufacturers to new annual fees for certain branded prescription drugs.
−Removed: As the price of our test may be included in the reimbursement rates for certain drugs, this could significantly impact our pricing.
−Removed: Even if favorable coverage and reimbursement status is attained for one or more products, less favorable coverage policies and reimbursement rates may be implemented in the future.
−Removed: Corporate History
−Removed: We were organized as a Minnesota limited liability company in 2011 and commenced operations in 2012.
−Removed: On September 15, 2017, we converted from a Minnesota limited liability company into a Delaware corporation and changed our name from Celcuity LLC to Celcuity Inc.
−Removed: Employees and Labor Relations
−Removed: As of December 31, 2020, we had 30 full-time employees, most of which were engaged in research and development activities.
−Removed: None of our employees are currently represented by a labor union or covered by a collective bargaining agreement and we believe that our relations with our employees are good.
−Removed: During 2020, our voluntary turnover rate was less than 4%.
−Removed: Our human capital resources objectives include identifying, recruiting, retaining, and incentivizing our existing and new employees.
−Removed: We maintain an equity incentive plan, the principal purposes of which are to attract, retain and reward personnel through the granting of stock-based compensation awards, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.
+Added: Some of the regulations under the current regulatory structure provide for strict liability, holding a party potentially liable without
+Added: regard to fault or negligence.
+Added: We could be held liable for damages and fines as a result of our, or others’, business operations
+Added: should contamination of the environment or individual exposure to hazardous substances occur.
+Added: We cannot predict how changes in laws or
+Added: development of new regulations will affect our business operations or the cost of compliance.
+Added: of COVID-19 on our Business
+Added: help protect the health and safety of our employees, suppliers and collaborators, we took proactive, aggressive action from the earliest
+Added: signs of the outbreak.
+Added: We enacted rigorous safety measures in our laboratory and administrative offices, including implementing social
+Added: distancing protocols, allowing working from home for those employees that do not need to be physically present in a lab to perform their
+Added: work, suspending travel, implementing temperature checks at the entrances to our facilities, extensively and frequently disinfecting
+Added: our workspaces and providing masks to those employees who must be physically present.
+Added: We expect to continue with these measures until
+Added: the COVID-19 pandemic is better contained and we may take further actions as government authorities require or recommend or as we determine
+Added: to be in the best interests of our employees, suppliers, and collaborators.
+Added: Trials and Collaborations
+Added: a result of the COVID-19 pandemic, governmental authorities have implemented and are continuing to implement numerous and constantly
+Added: evolving measures to try to contain the virus, such as travel bans and restrictions, limits on gatherings, quarantines, shelter-in-place
+Added: orders, and business shutdowns.
+Added: As we continue to advance our clinical trial collaborations, we are in close contact with our current
+Added: clinical sponsors, and principal investigators, as well as prospective pharmaceutical company and clinical collaborators, to assess the
+Added: ongoing impact of COVID-19 on our trial enrollment timelines and collaboration discussions.
+Added: In light of the COVID-19 pandemic, the focus
+Added: of healthcare providers and hospitals on fighting the virus, and consistent with the FDA’s updated industry guidance for conducting
+Added: clinical trials issued on March 18, 2020, we are experiencing delays in the enrollment of patients in our ongoing clinical trials.
+Added: now expect interim results from the FACT-1 and FACT-2 trials to be delayed until the first half of 2023 and final results approximately
+Added: nine months later.
+Added: As the impact of COVID-19 on our industry becomes clearer, we may need to reassess the timing of our anticipated clinical
+Added: Prospective clinical trial collaborations with pharmaceutical companies and sponsors may also be delayed but the impact on
+Added: the timing of finalizing agreements is not yet known.
+Added: and Development
+Added: our facility currently remains operational, the evolving measures to try to contain the virus have impacted and may further impact our
+Added: workforce and operations, as well as those of our vendors and suppliers.
+Added: Although there is uncertainty related to the anticipated impact
+Added: of the recent COVID-19 outbreak on our future results, we believe our existing balance of cash and cash equivalents will be sufficient
+Added: to meet our cash needs arising in the ordinary course of business for at least the next twelve months.
+Added: We continue to monitor the rapidly
+Added: evolving situation and guidance from federal, state and local public health authorities and may take additional actions based on their
+Added: recommendations.
+Added: In these circumstances, there may be developments outside our control requiring us to adjust our operating plan.
+Added: were organized as a Minnesota limited liability company in 2011 and commenced operations in 2012.
+Added: On September 15, 2017, we converted
+Added: from a Minnesota limited liability company into a Delaware corporation and changed our name from Celcuity LLC to Celcuity Inc.
+Added: and Labor Relations
+Added: of December 31, 2021, we had 39 full-time employees, most of which were engaged in research and development activities.
+Added: our employees are currently represented by a labor union or covered by a collective bargaining agreement and we believe that our relations
+Added: with our employees are good.
+Added: During 2021, our voluntary turnover rate was approximately 10%.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.