Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
HER2 is an important prognostic biomarker for 20–30% of breast cancers, which is the most common cancer in women. Overexpression of the HER2 receptor stimulates breast cells to proliferate and differentiate uncontrollably, thereby enhancing the malignancy of breast cancer and resulting in a poor prognosis for affected individuals. Current therapies to suppress the overexpression of HER2 in breast cancer mainly involve treatment with HER2-specific monoclonal antibodies. However, these monoclonal anti-HER2 antibodies have severe side effects in clinical trials, such as diarrhea, abnormal liver function, and drug resistance. Removing HER2 from the plasma membrane or inhibiting the gene expression of HER2 is a promising alternative that could limit the malignancy of HER2-positive cancer cells.
DNA origami is an emerging field of DNA-based nanotechnology and intelligent DNA nanorobots show great promise in working as a drug delivery system in healthcare. Different DNA-based nanorobots have been developed as affordable and facile therapeutic drugs. In particular, many studies reported that a tetrahedral framework nucleic acid (tFNA) could serve as a promising DNA nanocarrier for many antitumor drugs, owing to its high biocompatibility and biosecurity. For example, tFNA was reported to effectively deliver paclitaxel or doxorubicin to cancer cells for reversing drug resistance, small interfering RNAs (siRNAs) have been modified into tFNA for targeted drug delivery. Moreover, the production and storage of tFNA are not complicated, and they can be quickly degraded in lysosomes by cells. Since both free HApt and tFNA can be diverted into lysosomes, so, combining the HApt and tFNA as a novel DNA nanorobot (namely, HApt-tFNA) can be an effective strategy to improve its delivery and therapeutic efficacy in treating HER2-positive breast cancer.
Researchers reported that a DNA framework-based intelligent DNA nanorobot for selective lysosomal degradation of tumor-specific proteins on cancer cells. An anti-HER2 aptamer (HApt) was site-specifically anchored on a tetrahedral framework nucleic acid (tFNA). This DNA nanorobot (HApt-tFNA) could target HER2-positive breast cancer cells and specifically induce the lysosomal degradation of the membrane protein HER2. An injection of the DNA nanorobot into a mouse model revealed that the presence of tFNA enhanced the stability and prolonged the blood circulation time of HApt, and HApt-tFNA could therefore drive HER2 into lysosomal degradation with a higher efficiency. The formation of the HER2-HApt-tFNA complexes resulted in the HER2-mediated endocytosis and digestion in lysosomes, which effectively reduced the amount of HER2 on the cell surfaces. An increased HER2 digestion through HApt-tFNA further induced cell apoptosis and arrested cell growth. Hence, this novel DNA nanorobot sheds new light on targeted protein degradation for precision breast cancer therapy.
It was previously reported that tFNA was degraded by lysosomes and could enhance cell autophagy. Results indicated that free Cy5-HApt and Cy5-HApt-tFNA could enter the lysosomes; thus, tFNA can be regarded as an efficient nanocarrier to transmit HApt into the target organelle. The DNA nanorobot composed of HApt and tFNA showed a higher stability and a more effective performance than free HApt against HER2-positive breast cancer cells. The PI3K/AKT pathway was inhibited when membrane-bound HER2 decreased in SK-BR-3 cells under the action of HApt-tFNA. The research findings suggest that tFNA can enhance the anticancer effects of HApt on SK-BR-3 cells; while HApt-tFNA can bind to HER2 specifically, the compounded HER2-HApt-tFNA complexes can then be transferred and degraded in lysosomes. After these processes, the accumulation of HER2 in the plasma membrane would decrease, which could also influence the downstream PI3K/AKT signaling pathway that is associated with cell growth and death.
However, some limitations need to be noted when interpreting the findings: (i) the cytotoxicity of the nanorobot on HER2-positive cancer cells was weak, and the anticancer effects between conventional monoclonal antibodies and HApt-tFNA was not compared; (ii) the differences in delivery efficiency between tFNA and other nanocarriers need to be confirmed; and (iii) the confirmation of anticancer effects of HApt-tFNA on tumors within animals remains challenging. Despite these limitations, the present study provided novel evidence of the biological effects of tFNA when combined with HApt. Although the stability and the anticancer effects of HApt-tFNA may require further improvement before clinical application, this study initiates a promising step toward the development of nanomedicines with novel and intelligent DNA nanorobots for tumor treatment.
Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Pancreatic cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing.
Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (PDAC) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease.
The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology.
PDAC is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. In the present study to comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, single-cell RNA-seq (scRNA-seq) was employed to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases. The diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, were identified in PDAC.
The researchers found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, it was found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, the findings provided a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.
15th Annual Personalized Medicine Conference at Harvard Medical School – THE PARADIGM EVOLVES, November 13 – 14, 2019 • Harvard Medical School, Boston, MA
The 15th Annual Personalized Medicine Conference at Harvard Medical School will explore the science, business, and policy issues facing personalized medicine as scientists refine their understanding of how groundbreaking molecular diagnostics augmented by artificial intelligence, advanced data analytics, and digital health applications can empower both physicians and patients with information about how an expanded set of biological characteristics — including those found in the proteome and microbiome — may influence their health and their responses to increasingly impactful therapies.
WELCOME RECEPTION – NOVEMBER 13, 2019 – 6:15 P.M.
at the Isabella Stewart Gardner Museum, 25 Evans Way, Boston, MA 02115
Joseph B. Martin Conference Center at Harvard Medical School 77 Avenue Louis Pasteur, Boston, MA 02115
8:55 a.m.
Opening Remarks
SPEAKER | Edward Abrahams, Ph.D., President, Personalized Medicine Coalition
9:00 a.m.
The Era of the ‘Living Drug:’ A Keynote Conversation With Dr. Carl June, Pioneer of CAR T-cell Therapy
During this opening keynote session, the University of Pennsylvania’s Dr. Carl June, the discoverer of the chimeric antigen receptor (CAR) T-cell therapies that are unlocking a new era of personalized cancer care, will join Immatics US Chief Medical Officer Dr. Stephen L. Eck for a wide-ranging conversation about the future of personalized medicine, touching on issues including but not limited to access and affordability, regulation and manufacturing, and T-cell therapies beyond cancer. » Read More
MODERATOR | Stephen L. Eck, M.D., Ph.D., Chief Medical Officer, Immatics US
Carl June, M.D., Richard W. Vague Professor in Immunotherapy, University of Pennsylvania
9:45 a.m.
Transformative Technologies: Previewing the Value Proposition and Outlook for Disruptive Tools Designed to Enable Personalized Medicine
Emerging personalized medicine technologies may help facilitate earlier interventions that eliminate the need for expensive treatment of advanced diseases that have devastating consequences for patients. They can also help target treatments to only those patients who will benefit. But the success of these technologies depends on whether they can be integrated into a health system that has historically focused on treating diseases after symptoms have intensified, usually based on the assumption that every patient taking a given medication will respond to the treatment in a similar way.
During this session, Section 32 Managing Partner Michael J. Pellini, M.D., M.B.A., will moderate a discussion between industry representatives and a payer about the value proposition and outlook for disruptive technologies that are designed to support more informed disease prevention and treatment plans. The conversation will focus on how developments in areas including but not limited to artificial intelligence, data analytics, genomic sequencing, liquid biopsies, and proteomics may impact the prevention, diagnosis, and treatment of diseases including cancer, cardiovascular diseases, and diabetes. » Read More
MODERATOR | Michael J. Pellini, M.D., Managing Partner, Section 32
Nancy Mendelsohn, M.D., Chief Medical Officer, Special Needs Initiative, UnitedHealth Group
Joshua Ofman, M.D., Chief of Corporate Strategy and External Affairs, Grail
Eric Schadt, Ph.D., CEO, Sema4
Roy Smythe, M.D., CEO, SomaLogic
10:30 a.m.
Networking Break
11:15 a.m.
Developing Diagnostics — Opportunities and Challenges in Personalized Medicine: A Two-Part Discussion
Diagnostic test developers are working to make personalized medicine possible by giving physicians tools that help them select the optimal treatment for every patient. Doing so requires that they navigate a complex business and policy landscape while being mindful of the day-to-day needs of payers and health care providers.
In this context, Mark P. Stevenson, Executive Vice President, Chief Operating Officer, Thermo Fisher Scientific, will take 10 minutes to introduce this two-part discussion titled “Developing Diagnostics — Opportunities and Challenges in Personalized Medicine.”
INTRODUCTION | Mark P. Stevenson, Executive Vice President, Chief Operating Officer, Thermo Fisher Scientific
Discussion Part 1
Developing Diagnostics — From Concept to the Clinic: Perspectives on the Landscape for Developing and Integrating Personalized Medicine Diagnostics into Health Systems
To kick off the “Developing Diagnostics” discussion, Moffitt Cancer Center’s DeBartolo Family Personalized Medicine Institute Medical Director Howard McLeod, Pharm.D., will moderate a conversation among leaders from the clinical, diagnostics, IT, and pharmaceutical communities about the landscape for developing and integrating personalized medicine diagnostics into health systems. » Read More
MODERATOR | Howard McLeod, Pharm.D., Medical Director, DeBartolo Family Personalized Medicine Institute at Moffitt Cancer Center
Hakan Sakul, Ph.D., Vice President, Head of Diagnostics, Worldwide R & D and Medical, Pfizer
Kenna R. Mills Shaw, Ph.D., Executive Director, MD Anderson Institute for Personalized Cancer Therapy
Discussion Part 2 Developing Diagnostics — The Role of Research: A Closer Look at Efforts to Encourage the Clinical Adoption of Personalized Medicine Diagnostics by Studying the Clinical and Economic Utility of Genomic Sequencing
During the second portion of the “Developing Diagnostics” session, a health care provider, a health economist, an industry leader, and a payer representative will join moderator and Personalized Medicine Coalition Senior Vice President for Science Policy Daryl Pritchard, Ph.D., to examine the impact of emerging research on the clinical and economic utility of genomic sequencing for patients with diseases including but not limited to cancer and suspected rare diseases.
MODERATOR | Daryl Pritchard, Ph.D., Senior Vice President, Science Policy, Personalized Medicine Coalition
Roy J. Gandolfi, M.D., Medical Director, SelectHealth
Lincoln Nadauld, M.D., Ph.D., Chief, Precision Health, Intermountain Healthcare
Peter J. Neumann, Sc.D., Director, Center for the Evaluation of Value and Risk in Health at the Institute for Clinical Research and Health Policy Studies, Tufts Medical Center
Ammar Qadan, Vice President, Global Head of Market Access, Illumina
12:55 p.m.
Seated Luncheon
2:00 p.m.
Preparing Policies: A Keynote Address on the Policy Landscape for Personalized Medicine by Dr. Scott Gottlieb, Resident Fellow, American Enterprise Institute
During this keynote address, former U.S. Food and Drug Administration (FDA) commissioner Dr. Scott Gottlieb, who is now serving as Resident Fellow at the American Enterprise Institute, will share his thoughts on the evolving policy landscape for personalized medicine. » Read More
SPEAKER | Scott Gottlieb, M.D., Resident Fellow, American Enterprise Institute
2:45 p.m.
The 15th Annual Leadership in Personalized Medicine Award
After accepting the 15th Annual Leadership in Personalized Medicine Award, Genomic Health Chief Scientific Officer Dr. Steven Shak will share his vision for the future of the field with conference attendees. » Read More
AWARDEE | Steven Shak, M.D., Chief Scientific Officer, Genomic Health
3:15 p.m.
Networking Break
4:00 p.m.
Wellness in the Workplace: Understanding the Opportunities and Challenges Associated With Employer-Sponsored Genetic Testing Programs for Healthy Patients
Reasoning that genetic testing may encourage healthy lifestyles by providing information about an employee’s relative risk of developing various diseases, employers seeking to improve patients’ lives and mitigate downstream health care costs have begun to sponsor genetic testing for healthy employees by partnering with various genetic testing companies, some of which sell the tests directly to consumers.
This session, moderated by Quest Diagnostics Chief Medical Officer Jay G. Wohlgemuth, M.D., who is responsible for overseeing health care benefits for Quest’s employees, will spotlight two employer-sponsored genetic testing partnerships and explore the relevant issues. The panel discussion will focus on the significance of information generated from genetic testing, the differences between various genetic testing business models, and the privacy risks associated with the collection of genetic data.
MODERATOR | Jay G. Wohlgemuth, M.D., Chief Medical Officer, Senior Vice President, Quest Diagnostics
Jane Cheshire Gilbert, C.P.A., Director, Retiree Health Care, Teachers’ Retirement System of Kentucky
Karen E. Knudsen, Ph.D., Executive Vice President, Oncology Services, Jefferson Health; Enterprise Director, Sidney Kimmel Cancer Center at Thomas Jefferson University
Othman Laraki, CEO, Color Genomics (invited)
Scott Megill, President, CEO, Coriell Life Sciences
5:00 p.m.
Overcoming Opioids: Considering the Potential of Personalized Medicine to Address the Opioid Crisis in the US
Emerging technologies present new opportunities to study the genetic, biological, and environmental factors that drive public health crises, with an eye toward developing personalized medicine health care strategies that can mitigate their devastating consequences.
To kick off this session, Dr. Avenel Joseph, Director of Policy and Oversight for the Office of Sen. Edward J. Markey, will define the larger context for the opioid crisis in Massachusetts and the rest of the country before Dr. Alissa M. Resch, Chief Scientific Officer, Coriell Institute for Medical Research, announces findings from Coriell’s ongoing effort to inform interventions that may help prevent opioid addiction by identifying with more precision which patients are most likely to develop dependency on this class of drugs.
INTRODUCTION | Avenel Joseph, Ph.D., Director of Policy and Oversight, Office of Sen. Edward J. Markey (invited)
SPEAKER | Alissa M. Resch, Ph.D., Chief Scientific Officer, Coriell Institute for Medical Research
5:30 p.m.
Closing Remarks
SPEAKER | Edward Abrahams, Ph.D., President, Personalized Medicine Coalition
6:15 p.m.
Welcome Reception at the Isabella Stewart Gardner Museum
PART II
Targeting Treatment
8:00 a.m.
Registration and Continental Breakfast
Joseph B. Martin Conference Center at Harvard Medical School 77 Avenue Louis Pasteur, Boston, MA 02115
8:55 a.m.
Opening Remarks
SPEAKER | Stephen L. Eck, M.D., Ph.D., Chief Medical Officer, Immatics US
9:00 a.m.
Going Global: Learning From Governmental Efforts to Advance Personalized Medicine Around the World
Global leaders are working to accelerate an era of personalized medicine around the world by encouraging innovation, modernizing policies, and reforming health systems to speed the clinical adoption of personalized medicine products and services.
During this panel discussion, four governmental representatives will share their visions for the future of personalized medicine and elaborate on their efforts to accelerate progress in the field.
MODERATOR | Antonio L. Andreu, M.D., Ph.D., Scientific Director, EATRIS (European Infrastructure for Translational Medicine)
Asmaa Ali J. F. Althani, Ph.D., Dean, College of Health Sciences, Qatar University; Chair, Qatar Genome Program Committee; Board Vice Chairperson, Qatar Biobank
Noella Bigirimana, Strategic Advisor, Rwanda Biomedical Center, Ministry of Health, Government of Rwanda
Liisa-Maria Voipio-Pulkki, M.D., Ph.D., Director General, Chief Medical Officer, Ministry of Social Affairs and Health, Finland
Raquel Yotti, M.D., Ph.D., General Director, Instituto de Salud Carlos III (Spain)
10:00 a.m.
Innovation in the Era of Personalized Medicine: A Keynote Conversation With Dr. Paul Stoffels, Chief Scientific Officer, Johnson & Johnson
During this fireside chat with CNBC Reporter Meg Tirrell, Johnson & Johnson Chief Scientific Officer Paul Stoffels, M.D., will help frame the second half of the conference program by sharing the pharmaceutical industry’s perspective on the emerging issues in health care, touching on topics including costs, prices, and access.
MODERATOR | Meg Tirrell, Reporter, CNBC
Paul Stoffels, M.D., Vice Chairman, Executive Committee, Chief Scientific Officer, Johnson & Johnson
10:30 a.m.
Networking Break
11:00 a.m.
Prospecting the Pipeline: Exploring the Implications of a Biopharmaceutical Pipeline Dominated by Personalized Treatments
As researchers develop an enhanced understanding of the molecular causes that underpin various diseases, many biopharmaceutical companies have begun to develop therapies that are targeted to patient subgroups and even personalized to individual patients. In oncology, for example, there are reportedly more than 900 personalized “immunotherapy” treatments being tested in the clinic, with more than 1,000 in preclinical development. The challenging scientific questions and systemic implications associated with these new therapies do not always fit neatly into existing regulatory, payment, and care delivery frameworks.
During this session, CNBC Reporter Meg Tirrell will moderate a panel discussion that explores the scientific, regulatory, reimbursement, and other systemic issues associated with future gene editing treatments, gene therapies, immunotherapies, and targeted therapies. The panelists, who include an industry representative, a government payer, a researcher, and an academic leader, will also consider a new approach to immunotherapy for cancer patients in which a unique product is developed for every patient treated.
MODERATOR | Meg Tirrell, Reporter, CNBC
George Poste, Ph.D., D.Sc., Director, Complex Adaptive Systems, Arizona State University
Tamara Syrek Jensen, J.D., Director, Coverage and Analysis Group, U.S. Centers for Medicare and Medicaid Services (invited)
Alex Vadas, Ph.D., Managing Director, Partner, LEK Consulting
12:00 p.m.
Bag Lunch
1:00 p.m.
Harvard Business School Case Study: Dementia Discovery Fund
This interactive case study discussion will explore how and why a group of government agencies, nonprofit organizations, and pharmaceutical companies came together to support the Dementia Discovery Fund, focusing on whether a disease-specific venture that seeks to create meaningful new medicines in part by capitalizing on the evolving science underpinning personalized medicine can successfully balance social and business objectives.
MODERATOR | Richard Hamermesh, D.B.A., Co-Faculty Chair, Harvard Business School Kraft Precision Medicine Accelerator
2:00 p.m.
Toward a Shared Value Proposition in Health Care: Pursuing Value-Based Solutions in Research, Regulation, Reimbursement, and Clinical Adoption
To advance the principles of personalized medicine, the field’s proponents will need to align representatives from multiple sectors of the health system on a shared value proposition that recognizes the importance of addressing the shortcomings of one-size-fits-all medicine.
During this session, M2Gen Executive Chairman William S. Dalton, Ph.D., M.D., will convene a commercial payer, an industry representative, a patient, and a value assessment framework developer to explore research, regulatory, clinical adoption, and especially reimbursement solutions that will, in the interest of patients, advance the principles of personalized medicine.
MODERATOR | William S. Dalton, Ph.D., M.D., Executive Chairman, M2Gen
Bonnie J. Addario, Co-Founder, Chair, GO2 Foundation for Lung Cancer
Sarah K. Emond, M.P.P., Executive Vice President, Chief Operating Officer, Institute for Clinical and Economic Review
Anne-Marie Martin, Ph.D., Senior Vice President, Global Head of Precision Medicine, Novartis Pharmaceuticals Corporation
Michael Sherman, M.D., Chief Medical Officer, Senior Vice President, Harvard Pilgrim Health Care
3:00 p.m.
Closing Remarks
SPEAKER | Edward Abrahams, Ph.D., President, Personalized Medicine Coalition
scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Present day technological advances have facilitated unprecedented opportunities for studying biological systems at single-cell level resolution. For example, single-cell RNA sequencing (scRNA-seq) enables the measurement of transcriptomic information of thousands of individual cells in one experiment. Analyses of such data provide information that was not accessible using bulk sequencing, which can only assess average properties of cell populations. Single-cell measurements, however, can capture the heterogeneity of a population of cells. In particular, single-cell studies allow for the identification of novel cell types, states, and dynamics.
One of the most prominent uses of the scRNA-seq technology is the identification of subpopulations of cells present in a sample and comparing such subpopulations across samples. Such information is crucial for understanding the heterogeneity of cells in a sample and for comparative analysis of samples from different conditions, tissues, and species. A frequently used approach is to cluster every dataset separately, inspect marker genes for each cluster, and compare these clusters in an attempt to determine which cell types were shared between samples. This approach, however, relies on the existence of predefined or clearly identifiable marker genes and their consistent measurement across subpopulations.
Although the aligned data can then be clustered to reveal subpopulations and their correspondence, solving the subpopulation-mapping problem by performing global alignment first and clustering second overlooks the original information about subpopulations existing in each experiment. In contrast, an approach addressing this problem directly might represent a more suitable solution. So, keeping this in mind the researchers developed a computational method, single-cell subpopulations comparison (scPopCorn), that allows for comparative analysis of two or more single-cell populations.
The performance of scPopCorn was tested in three distinct settings. First, its potential was demonstrated in identifying and aligning subpopulations from single-cell data from human and mouse pancreatic single-cell data. Next, scPopCorn was applied to the task of aligning biological replicates of mouse kidney single-cell data. scPopCorn achieved the best performance over the previously published tools. Finally, it was applied to compare populations of cells from cancer and healthy brain tissues, revealing the relation of neoplastic cells to neural cells and astrocytes. Consequently, as a result of this integrative approach, scPopCorn provides a powerful tool for comparative analysis of single-cell populations.
This scPopCorn is basically a computational method for the identification of subpopulations of cells present within individual single-cell experiments and mapping of these subpopulations across these experiments. Different from other approaches, scPopCorn performs the tasks of population identification and mapping simultaneously by optimizing a function that combines both objectives. When applied to complex biological data, scPopCorn outperforms previous methods. However, it should be kept in mind that scPopCorn assumes the input single-cell data to consist of separable subpopulations and it is not designed to perform a comparative analysis of single cell trajectories datasets that do not fulfill this constraint.
Several innovations developed in this work contributed to the performance of scPopCorn. First, unifying the above-mentioned tasks into a single problem statement allowed for integrating the signal from different experiments while identifying subpopulations within each experiment. Such an incorporation aids the reduction of biological and experimental noise. The researchers believe that the ideas introduced in scPopCorn not only enabled the design of a highly accurate identification of subpopulations and mapping approach, but can also provide a stepping stone for other tools to interrogate the relationships between single cell experiments.
First Cost-Effectiveness Study of Multi-Gene Panel Sequencing in Advanced Non-Small Cell Lung Cancer Shows Moderate Cost-Effectiveness, Exposes Crucial Practice Gap
WASHINGTON (June 27, 2019) — The results of the first economic modeling study to estimate the cost-effectiveness of “multi-gene panel sequencing” (MGPS) as compared to standard-of-care, single-gene tests for patients with advanced non-small cell lung cancer (aNSCLC) show that the MGPS tests are moderately cost-effective but could deliver more value if patients with test results identifying actionable genetic mutations consistently received genetically guided treatments. The results of the study, which was commissioned by the Personalized Medicine Coalition (PMC), underline the need to align clinical practices with an era of personalized medicine in which physicians can use diagnostic tests to identify specific biological markers that inform targeted prevention and treatment plans.
The study, which was published yesterday in JCO Clinical Cancer Informatics, analyzed the clinical and economic value of using MGPS testing to identify patients with tumors that over-express genetic mutations that could be targeted by available therapies designed to inhibit the function of those genes — a mainstay of modern care for aNSCLC patients. Using data provided by Flatiron Health, researchers examined clinical and cost information associated with the care of 5,688 patients with aNSCLC treated between 2011 – 2016, separating them into cohorts who received MGPS tests that assess at least 30 genetic mutations at once and those who received only “single-marker genetic testing” (SMGT) of less than 30 genes.
Compared to SMGT, the MGPS testing strategy, including downstream treatment and monitoring of disease, incurred costs equal to $148,478 for each year of life that it facilitated, a level suggesting that MGPS is moderately cost-effective compared to commonly cited thresholds in the U.S., which range from $50,000 to $200,000 per life year (LY) gained.
The authors of the study point out, however, that physicians only prescribed a targeted therapy to some of the patients whose MGPS test results revealed actionable mutations. MGPS tests can only improve downstream patient outcomes if actionable results are used to put the patient on a targeted treatment regimen that is more effective than the therapy they would otherwise have been prescribed. It is therefore impossible for the cost of an MGPS test to translate into additional LYs if actionable results do not result in the selection of a targeted treatment regimen.
Although MGPS testing revealed actionable mutations in 30.1 percent of the patients in the study cohort, only 21.4 percent of patients who underwent MGPS testing received a targeted treatment.
The study’s authors calculated that if all MGPS-tested patients with actionable mutations had received a targeted therapy, MGPS testing would deliver measurably better value ($110,000 per LY gained).
“This research underlines the importance of ensuring that clinical practices keep pace with scientific progress in personalized medicine so that we can maximize the benefits of diagnostic tests that can improve patient care and make the health system more efficient by ensuring that safe and effective targeted therapies are prescribed to those patients who will benefit,” said PMC President Edward Abrahams.
The study’s authors include Dr. Lotte Steuten, Vice President and Head of Consulting, The Office of Health Economics, London, U.K., and Affiliate Associate Faculty Member, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center; Dr. Bernardo Goulart, Associate Faculty Member, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center; Dr. Neal Meropol, Vice President, Research Oncology, Flatiron Health; Dr. Daryl Pritchard, Senior Vice President, Science Policy, Personalized Medicine Coalition; and Dr. Scott Ramsey, Director, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center.
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About the Personalized Medicine Coalition:
The Personalized Medicine Coalition, representing innovators, scientists, patients, providers and payers, promotes the understanding and adoption of personalized medicine concepts, services and products to benefit patients and the health system. For more information, please visit www.personalizedmedicinecoalition.org.
The role of the patient has evolved dramatically over the past decade. Not only are patients increasingly more involved in their healthcare decision making, they are also passionate advocates who work tirelessly to advance drug development research and development and secure a public policy environment that is patient-centric. Join a discussion with patient advocates as they discuss their journeys to diagnosis and their viewpoints on our healthcare system. They will share their perspectives on what it means to be a patient and how they are advocating in their own unique ways to achieve a common goal: bringing new treatments to patients.
Christopher Anselmo: affected by MS but did not understand why he should be involved in a study at the time or share your story but he saw others who benefited from both of these and now is fervent patient advocate. Each patient is worth their weight in gold as needed for other patient support. The why needs to be asked of oneself before go out to other patients or into new trials. Might not see through to end if don’t have that discussion of why doing this.
Eve Bukowski: she had stomach aches, went to hospital, and diagnosed with constipation, but had stage III colon cancer. She was campaigning for Hillary Clinton but then started to campaign for her life. She wound up having multiple therapies and even many I/O trials. Fighting cancer is a mental challenge. She has been fighting for eleven years but has an amazing strength and will.
Emily Kramer: cystic fibrosis patient. Advocates for research as she has a mutant allele (nonsense mut) that is not targeted by the current new therapy against known mutants of CFTR. So started Emily’s Entourage for this orphan of an orphan disease. Funded $4 million in grants and helped develop a new startup and get early seed funding. Noticed that the infrastructure to get these drugs to market was broken and also is investing to shore up these breaks in drug pipeline infrastructure for orphan diseases. For progressive diseases she would like drug developers to shift the timelines or speed with which they get to take a chance and try that new possibility. As a patient advocacy org, they want to partner every step of the way with biotech/pharma, they understand co’s and stakeholders can only do so much but let’s break out of convention.
Julie: many patient advocacy groups go person to person and make a support network.
PEER-REVIEWED MEDICAL JOURNAL PUBLISHES LANDMARK STUDY ON EFFICACY AND SAFETY OF FDgard® (COLM-SST), DEMONSTRATING RAPID REDUCTION OF FUNCTIONAL DYSPEPSIA (FD OR RECURRING, MEAL-TRIGGERED INDIGESTION) SYMPTOMS WITHIN 24 HOURS
FDgard® (COLM-SST), a solid-state microsphere formulation of caraway oil and
l-Menthol, taken daily and proactively 30-60 minutes before meals, showed
statistically significant, rapid reduction of Functional Dyspepsia (FD)
symptoms within 24 hours and, additionally, relief of severe FD symptoms.
FDREST™ clinical trial with FDgard
represents an important medical advance, as no previous trials have shown rapid
relief of FD symptoms. There are no approved products for this highly prevalent
condition.
In FDREST, patients
received greater and more durable benefits with the addition of FDgard taken
daily and proactively to their typical medical regimen.
FDREST is the first
clinical trial in FD to use patented, Site
Specific Targeting (SST®) technology to deliver the FDgard
formulation to the upper belly (duodenum), the primary site of disturbance in
FD.
FDgard represents an
effective, safe and well-tolerated option to address the unmet medical needs of
millions of adults with FD.
Reporter: Gail S. Thornton
Boca Raton Fl., – (April 30, 2019) – IM HealthScience today announced that Clinical and Translational Gastroenterology (CTG), a peer-reviewed medical journal, has published the U.S. results of a landmark, double-blind, placebo-controlled study, FDREST™ (Functional Dyspepsia Reduction Evaluation and Safety Trial), which showed statistically significant, rapid reduction of Functional Dyspepsia (FD or recurring, meal-triggered indigestion) symptoms within 24 hours and, additionally, relief of severe FD symptoms.
The
FDREST study demonstrated that patients who took COLM-SST (FDgard®) on a daily
and proactive basis, 30 to 60 minutes before meals, along with commonly used
off-label FD medications versus patients who took placebo along with commonly
used off-label FD medications, experienced a statistically significant, rapid
reduction of FD symptoms within 24 hours across the FD study population.
This
study had a higher hurdle than previous studies on a similar combination of
ingredients. Firstly, concomitant medications for FD symptoms were allowed in
order to assess FDgard in a real-world setting. Second, only a subgroup of
patients in FDREST was categorized into the high-symptom burden, while they
constituted the entire groups in previous studies. Among this subgroup of
patients with the high-symptom burden, FDgard showed efficacy at 24 hours. In
spite of the polypharmacy and use of rescue medications for FD, after 48 hours
of first dose, FDgard helped further improve symptoms at 4 weeks, especially in
those high-symptom burden patients. In all cases, FDgard was safe and well-tolerated.
The
study results of FDREST were first presented at Digestive Disease Week (DDW),
the largest gathering of gastroenterologists, in May 2017.
Study Commentary
Commenting on the study, lead author William Chey, M.D., FACG, Director in the Division of Gastroenterology, Michigan Medicine Gastroenterology Clinic, Ann Arbor, said, “This landmark study was designed to answer a very important scientific question about the effectiveness, safety, and tolerability of a novel and innovative formulation of caraway oil and l-Menthol designed as solid state, enteric coated microspheres for targeted duodenal release for FD. In patients taking their usual medications for FD, FDgard was found to be effective, safe and well tolerated in rapidly reducing symptoms and in relieving severe symptoms.” Chey continued, “The positive finding at 24 hours is clinically important as symptoms are often triggered by a meal and patients are looking for rapid relief of those symptoms.”
The
study authors also cited the importance of utilizing the microsphere-based
site-specific targeting of FDgard (caraway oil and l-Menthol, the active
ingredient in peppermint oil) to the duodenum. They wrote, “This site
(duodenum) was targeted primarily due to mounting evidence that gastroduodenal
mucosal integrity and low-grade inflammation play a role in FD. Furthermore,
studies have shown that caraway oil and peppermint oil act on the duodenum to
induce smooth muscle relaxation, and that l-Menthol has anti-inflammatory
effects.” This may help normalize motility effects.
About FDREST™
FDREST™ (Functional Dyspepsia Reduction and Evaluation Safety Trial) was a multi-centered, post-marketing, parallel group,
U.S-based study conducted at seven university-based or gastroenterology
research-based centers (study period July 1, 2015, to September 14, 2016). The
study was designed to compare the efficacy, safety and tolerability of FDgard
plus commonly used, off-label medications for FD vs. a control group of placebo
plus commonly used, off-label medications prescribed for FD.
Ninety-five patients were enrolled
(mean age = 43.4 years; 75.8 percent women). At 24 hours, the active arm
reported a statistically significant reduction in Postprandial Distress Syndrome
(PDS) symptoms (P = 0.039), and a
nonsignificant trend toward benefit of Epigastric Pain Syndrome (EPS) symptoms
(P = 0.074). In patients with more
severe symptoms, approximately three-quarters showed substantial global
improvement (i.e., clinical global impressions) after 4 weeks of treatment vs.
half in the control arm. These differences were statistically significant for
patients with EPS symptoms (epigastric pain or discomfort and burning) (P = 0.046), and trending toward
significance for patients with PDS symptoms (early satiety, abdominal
heaviness, pressure and fullness) (P
= 0.091). There were no statistically significant differences between groups
for Global Overall Symptom scores for the overall population at 2 and 4 weeks.
Dr. Chey said, “The results of this
high-quality study highlight an advance in the management of FD, as current
off-label medications such as PPIs, H2RAs and antidepressants offer only a
modest level of therapeutic gain over placebo and may be associated with
adverse events, especially with continued use. FDgard addresses a significant
unmet medical need for a product to help manage symptoms in the 1 in 6 adults
suffering from this common disorder.”
About Functional
Dyspepsia (FD)
Functional
dyspepsia is a very common disorder affecting 11 percent – 29.2 percent of the
world’s population1, making it comparable in prevalence to IBS. However,
unlike IBS, there is no FDA approved product to treat FD. Sufferers are often
treated off-label with prescribed proton pump inhibitors (PPIs), histamine
type-2 receptor antagonists (H2RAs), antidepressants, and prokinetics. While
offering relief to a portion of FD patients, some of these have been associated
with adverse events. Functional dyspepsia can have a negative effect on
workplace attendance and productivity, with associated costs estimated in
excess of $18 billion annually.2
In
FD, which is typically recurring, meal-triggered indigestion with no known
organic cause, the normal digestive processes are disrupted along with
digestion and absorption of food nutrients. FD is accompanied by symptoms such
as epigastric pain or discomfort, epigastric burning, postprandial fullness,
inability to finish a normal sized meal, heaviness, pressure, bloating in the
upper abdomen, nausea, and belching. When doctors diagnose FD, they often
identify patients as those who have these symptoms for at least three months,
with symptom onset six months previously.
About FDgard®
FDgard® is a
nonprescription medical food designed to address the unmet medical need for
products to help manage Functional Dyspepsia (FD or recurring, meal-triggered
indigestion) and its accompanying symptoms. FDgard capsules contain
caraway oil and l-Menthol, the primary component in peppermint oil, for the
dietary management of FD. These two main ingredients are specially formulated
to be available in a solid state. With
patented Site Specific Targeting (SST®) technology pioneered by IM
HealthScience, FDgard capsules release individually triple-coated, solid-state
microspheres of caraway oil and l-Menthol quickly and reliably where they are
needed most in FD — the duodenum or upper belly. The l-Menthol helps with
smooth muscle relaxation and provides analgesic and anti-inflammatory
activities.3–5 Caraway oil helps mitigate the effect of gastric acid on
the stomach wall and also helps to normalize gallbladder function and may help
to normalize motility in the small intestine (primarily the duodenum) and in
the stomach.6,7 In addition to caraway oil and l-Menthol, FDgard also
provides fiber and amino acids (from gelatin protein). These ingredients have
additional positive effects on the gut wall and thus help toward normalizing
digestion and absorption.
Caraway
oil and peppermint oil have a history of working in FD. In multiple clinical
studies, the combination of caraway oil and peppermint oil has been shown to
manage FD and its accompanying symptoms, such as reducing the intensity of
epigastric pain, pain frequency, dyspeptic discomfort, and the intensity of
sensations of pressure, abdominal heaviness and fullness significantly better
than control.8,9 Cisapride, no longer an FDA-approved pro-motility drug
after its removal from the market in 2000 due to cardiovascular side effects,
was shown to have efficacy similar to a caraway oil/peppermint oil formulation10.
Complete
and final results from a real-world, observational study of 600 patients who
took FDgard, called FDACT™ (Functional Dyspepsia Adherence and Compliance Trial), were selected after peer
review and presented by William D. Chey, M.D., FACG, at the World Congress of
Gastroenterology at ACG 2017 in Orlando, Florida. The data showed there was a
consistently high level of patient satisfaction and rapid improvement of FD
symptoms with the product. A majority of patients (95 percent) reported major
or moderate improvement in their overall FD symptoms, while many patients (86.4
percent) indicated experiencing relief from symptoms within 2 hours after
taking FDgard. The findings from FDACT
substantiate the data reported in FDREST.
The usual adult dose of
FDgard is 2 capsules, as needed, up to two times a day, not to exceed six
capsules per day. Many physicians are now recommending taking FDgard daily and
proactively 30-60 minutes before a meal, as this enables the supportive effect
of FDgard to start as early as possible. While FDgard does not require a
prescription and is available in retail outlets and online, it is a medical
food that should be used under medical supervision.
About IM HealthScience®
IM
HealthScience® (IMH) is the innovator of IBgard®and
FDgard®for the dietary management of Irritable Bowel Syndrome
(IBS) and Functional Dyspepsia (FD or recurring, meal-triggered indigestion),
respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic
fibers, to its product line via an acquisition. The sister subsidiary of IMH,
Physician’s Seal®, also provides REMfresh®,
a
well-known continuous release and absorption melatonin
(CRA-melatonin™) supplement for sleep.
IMH is a privately held company based in Boca
Raton, Florida. It was founded in 2010 by a team of highly experienced
pharmaceutical research and development and management executives. The company
is dedicated to developing products to address overall health and wellness,
especially in digestive health conditions with a high unmet medical need. The
IM HealthScience advantage comes from developing products based on its
patented, targeted-delivery technologies called Site Specific Targeting (SST).
For more information, visit www.imhealthscience.com to learn about
the company, or www.IBgard.com,
1. Mahadeva S, Goh KL. Epidemiology of
functional dyspepsia. A global perspective. World J Gastroenterol. 2006.
doi:10.3748/wjg.v12.i17.2661.
2. Lacy BE, Weiser KT, Kennedy AT, Crowell
MD, Talley NJ. Functional dyspepsia: the economic impact to patients. Aliment
Pharmacol Ther. 2013;38(May):170-177. doi:10.1111/apt.12355.
3. Amato A, Liotta R, Mulè F. Effects of
menthol on circular smooth muscle of human colon: Analysis of the mechanism of
action. Eur J Pharmacol. 2014. doi:10.1016/j.ejphar.2014.07.018.
4. Liu B, Fan L, Balakrishna S, Sui A, Moris
JB, Jordt S-E. TRPM8 is the Principal Mediator of Menthol-induced Analgesia of
Acute and Inflammatory Pain. Pain. 2013;154(10):2169-2177.
doi:10.1016/j.pain.2013.06.043.TRPM8.
5. Juergens U, Stober M, Vetter H. The
anti-inflammatory activity of L-menthol compared to mint oil in human monocytes
in vitro: a novel perspective for its therapeutic use in inflammatory diseases.
Eur J Med Res. 1998;3(12):539-545.
6. Alhaider A, Al-Mofleh I, Mossa J,
Al-Sohaibani M, Rafatullah S, Qureshi S. Effect of Carum carvi on
experimentally induced gastric mucosal damage in Wistar albino rats. Int J
Pharmacol. 2006;2(3):309-315.
7. Micklefield G, Jung O, Greving I, May B.
Effects of intraduodenal application of peppermint oil (WS 1340) and caraway
oil (WS 1520) on gastroduodenal motility in healthy volunteers. Phyther Res.
2003;17:135-140. doi:10.1002/ptr.1089.
8. May B, Köhler S, Schneider B. Efficacy
and tolerability of a fixed combination of peppermint oil and caraway oil in
patients suffering from functional dyspepsia. Aliment Pharmacol Ther.
2000;14:1671-1677. doi:10.1046/j.1365-2036.2000.00873.x.
9. Rich G, Shah A, Koloski N, et al. A
randomized placebo-controlled trial on the effects of Menthacarin, a
proprietary peppermint- and caraway-oil-preparation, on symptoms and quality of
life in patients with functional dyspepsia. Neurogastroenterol Motil.
2017;29(May):e13132. doi:10.1111/nmo.13132.
10. Madisch A, Heydenreich C, Wieland V,
Hufnagel R, Hotz J. Treatment of Functional Dyspepsia with a Fixed Peppermint
Oil and Caraway Oil Combination Preparation as Compared to Cisapride – A
multicenter, reference-controlled double-blind equivalence study. Arzneimittelforsch
Drug Res. 1999;49(II):925-932.
This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. This information should not be used for diagnosing a health problem or disease. While medical foods do not require prior approval by the FDA for marketing, they must comply with regulations. It should not be assumed that medical foods are alternatives for FDA-approved drugs. Only doctors can definitively diagnose functional dyspepsia. Use under medical supervision. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.fdgard.com. Individual results may vary.
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