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Archive for the 'FDA Regulatory Affairs' Category
2022 FDA Drug Approval List, 2022 Biological Approvals and Approved Cellular and Gene Therapy Products
Posted in cell-based therapy, Drug Discovery Chemistry, FDA, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical R&D Informatics, Pharmacodynamics and Pharmacokinetics, Regenerative Biology and Medicine on January 17, 2023| Leave a Comment »
Tal Bahar's post on LinkedIn on 1/17/2023
Novel Drug Approvals for 2022
FDA's Center for Drug Evaluation and Research (CDER)
New Molecular Entities ("NMEs")
Some of these products have never been used in clinical practice. Below is a listing of new molecular entities and new therapeutic biological products that CDER approved in 2022. This listing does not contain vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products, or other products that the Center for Biologics Evaluation and Research approved in 2022.
Others are the same as, or related to, previously approved products, and they will compete with those products in the marketplace. See Drugs@FDA for information about all of CDER's approved drugs and biological products.
Certain drugs are classified as new molecular entities ("NMEs") for purposes of FDA review. Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient drug or as part of a combination product. These products frequently provide important new therapies for patients. Some drugs are characterized as NMEs for administrative purposes, but nonetheless contain active moieties that are closely related to active moieties in products that FDA has previously approved. FDA's classification of a drug as an "NME" for review purposes is distinct from FDA's determination of whether a drug product is a "new chemical entity" or "NCE" within the meaning of the Federal Food, Drug, and Cosmetic Act.
37. NexoBrid
anacaulase-bcdb
12/28/2022 To remove eschar in adults with deep partial thickness or full thickness thermal burns
36. Briumvi
ublituximab-xiiy
12/28/2022 To treat relapsing forms of multiple sclerosis
35. Xenoview
12/23/2022 To evaluate pulmonary function and imaging
34. Lunsumio
12/22/2022 To treat adults with relapsed or refractory follicular lymphoma, a type of non-Hodgkin lymphoma
33. Sunlenca lenacapavir 12/22/2022 To treat adults with HIV whose HIV infections cannot be successfully treated with other available treatments due to resistance, intolerance, or safety considerations
32. Krazati adagrasib 12/12/2022
31. Rezlidhia olutasidenib 12/1/2022
30. Tzield teplizumab-mzwv 11/18/22
To delay the onset of stage 3 type 1 diabetes
29. Elahere
28. Tecvayli teclistamab-cqyv 10/25/2022 To treat relapsed or refractory multiple myeloma among adults who have received at least four specific lines of therapy
27. Imjudo tremelimumab 10/21/2022 To treat unresectable hepatocellular carcinoma
26. Lytgobi futibatinib 9/30/2022
25. Relyvrio sodium phenylbutyrate/taurursodiol 9/29/2022
To treat amyotrophic lateral sclerosis (ALS)
24. Omlonti oomidenepag isopropyl ophthalmic solution 9/22/2022 To reduce elevated intraocular pressure in patients with open‑angle glaucoma or ocular hypertension
23. Elucirem gadopiclenol 9/21/2022 To detect and visualize lesions, together with MRI, with abnormal vascularity in the central nervous system and the body
22. Terlivaz terlipressin 9/14/2022 To improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function
21. Rolvedon eflapegrastim 9/9/2022 To decrease the incidence of infection in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia
20. Sotyktu deucravacitinib 9/9/2022 To treat moderate-to-severe plaque psoriasis
19. Daxxify daxibotulinumtoixnA-lanm 9/7/2022 To treat moderate-to-severe glabellar lines associated with corrugator and/or procerus muscle activity
18. Spevigo spesolimab-sbzo 9/1/2022 To treat generalized pustular psoriasis flares
17. Xenpozyme Olipudase alfa 8/31/2022 To treat Acid Sphingomyelinase Deficiency
16. Amvuttra vutrisiran 6/13/2022
15. Vtama tapinarof 5/23/2022 To treat plaque psoriasis
14. Mounjaro tirzepatide 5/13/2022 To improve blood sugar control in diabetes, in addition to diet and exercise
13. Voquezna vonoprazan, amoxicillin, and clarithromycin 5/3/2022 To treat Helicobacter pylori infection
12. Camzyos mavacamten 4/28/2022 To treat certain classes of obstructive hypertrophic cardiomyopathy
11. Vivjoa oteseconazole 4/26/2022 To reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are not of reproductive potential
10. Pluvicto lutetium (177Lu) vipivotide tetraxetan 3/23/2022 To treat prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer following other therapies
9. Opdualag nivolumab and relatlimab-rmbw 3/18/2022 To treat unresectable or metastatic melanoma
8. Ztalmy ganaxolone 3/18/2022 To treat seizures in cyclin-dependent kinase-like 5 deficiency disorder
7. Vonjo pacritinib 2/28/2022 To treat intermediate or high-risk primary or secondary myelofibrosis in adults with low platelets
6. Pyrukynd mitapivat 2/17/2022 To treat hemolytic anemia in pyruvate kinase deficiency
5. Enjaymo sutimlimab-jome 2/4/2022 To decrease the need for red blood cell transfusion due to hemolysis in cold agglutinin disease
4. Vabysmo faricimab-svoa 1/28/2022 To treat neovascular (wet) aged-related macular degeneration and diabetic macular edema
tebentafusp-tebn 1/25/2022 To treat unresectable or metastatic uveal melanoma
2. Cibinqo abrocitinib 1/14/2022 To treat refractory, moderate-to-severe atopic dermatitis
1. Quviviq daridorexant 1/7/2022 To treat insomnia
https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2022
INNOVATION PREDICTABILITY ACCESS FDA's Center for Drug Evaluation and Research
CDER's Novel Drug Approvals of 2022
First-in-Class Drugs
Drugs for Rare Diseases
Other Novel Drug Approvals
Innovation: Expedited Development and Review Pathways
Breakthrough Therapy
Priority Review
Overall Use of Expedited Development and Review Methods
Predictability: Meeting PDUFA Goals
Access: First Cycle Approvals and First in U.S. Approvals
New Uses of Approved Drugs
Approved Drugs Expanded for New Pediatric Populations
Biosimilar and Interchangeable Biosimilar Approvals
Other CDER Actions
Appendix A: CDER's Novel Approvals of 2022 (in alphabetical order)
Appendix B: Novel Drug Designations
https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022
2022 Biological Approvals
The Center for Biologics Evaluation and Research (CBER) regulates products under a variety of regulatory authorities. See the Development & Approval Process page for a description of what products are approved as Biologics License Applications (BLAs), Premarket Approvals (PMAs), New Drug Applications (NDAs) or 510Ks.
Biologics License Applications and Supplements
New BLAs (except those for blood banking), and BLA supplements that are expected to significantly enhance the public health (e.g., for new/expanded indications, new routes of administration, new dosage formulations and improved safety).
2022 Biological License Application Approvals
2022 Biological License Application Supplement Noteworthy Approvals
2022 Biological New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) Approvals
Other Applications Approved or Cleared by the Center for Biologics Evaluation and Research (CBER)
Medical devices involved in the collection, processing, testing, manufacture and administration of licensed blood, blood components and cellular products.
2022 Biological Device Application Approvals
Development & Approval Process (CBER)
Biologics Products & Establishments
Transfer of Therapeutic Products to the Center for Drug Evaluation and Research
https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/2022-biological-approvals
Approved Cellular and Gene Therapy Products
Below is a list of licensed products from the Office of Tissues and Advanced Therapies (OTAT).
Approved Products
ABECMA (idecabtagene vicleucel)
Celgene Corporation, a Bristol-Myers Squibb Company
ADSTILADRIN
Ferring Pharmaceuticals A/S
ALLOCORD (HPC, Cord Blood)
SSM Cardinal Glennon Children's Medical Center
BREYANZI
Juno Therapeutics, Inc., a Bristol-Myers Squibb Company
CARVYKTI (ciltacabtagene autoleucel)
Janssen Biotech, Inc.
CLEVECORD (HPC Cord Blood)
Cleveland Cord Blood Center
Ducord, HPC Cord Blood
Duke University School of Medicine
GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen)
Organogenesis Incorporated
HEMACORD (HPC, cord blood)
New York Blood Center
HEMGENIX
CSL Behring LLC
HPC, Cord Blood
Clinimmune Labs, University of Colorado Cord Blood Bank
HPC, Cord Blood – MD Anderson Cord Blood Bank
MD Anderson Cord Blood Bank
HPC, Cord Blood – LifeSouth
LifeSouth Community Blood Centers, Inc.
HPC, Cord Blood – Bloodworks
Bloodworks
IMLYGIC (talimogene laherparepvec)
BioVex, Inc., a subsidiary of Amgen Inc.
KYMRIAH (tisagenlecleucel)
LAVIV (Azficel-T)
Fibrocell Technologies
LUXTURNA
Spark Therapeutics, Inc.
MACI (Autologous Cultured Chondrocytes on a Porcine Collagen Membrane)
Vericel Corp.
PROVENGE (sipuleucel-T)
Dendreon Corp.
RETHYMIC
Enzyvant Therapeutics GmbH
SKYSONA (elivaldogene autotemcel)
bluebird bio, Inc.
STRATAGRAFT
Stratatech Corporation
TECARTUS (brexucabtagene autoleucel)
Kite Pharma, Inc.
YESCARTA (axicabtagene ciloleucel)
Kite Pharma, Incorporated
ZYNTEGLO (betibeglogene autotemcel)
ZOLGENSMA (onasemnogene abeparvovec-xioi)
Novartis Gene Therapies, Inc.
What Is Gene Therapy? How Does It Work?
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
2022 forecast: Cell, gene therapy makers push past regulatory, payer hurdles to set up high hopes for next year
By Arlene Weintraub
There are five FDA-approved CAR-T treatments for blood cancers and two gene therapies to treat rare diseases now on the market in the U.S. The late-stage pipeline could produce several more cancer CAR-Ts and gene therapies to treat a range of diseases.
RELATED: ASH: Bristol Myers' Breyanzi, Gilead's Yescarta lock horns in race to move CAR-T therapy to earlier lymphoma
One of the biggest races to watch in the cell therapy space will be that between Gilead Sciences' Yescarta and Bristol Myers Squibb's Breyanzi, both of which are gunning to move their CAR-Ts into earlier lines of treatment in large B-cell lymphoma (LBCL). At ASH, both companies rolled out impressive data from their trials in the second-line setting, but Gilead could have the upper hand by virtue of its three-year head start in the market, analysts said. Gilead expects to hear from the FDA on a label expansion in the second-line setting in April.
https://www.fiercepharma.com/pharma/cell-and-gene-therapy-makers-push-past-regulatory-payer-hurdles-to-set-up-high-hopes-for
#TUBiol5227: Biomarkers & Biotargets: Genetic Testing and Bioethics
Posted in and Bioethics, Bio-Ethics, BioBanking, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Biomarkers & Medical Diagnostics, BioSimilars, Biotechnology, BioTechnology - Venture Creation, Cancer and Current Therapeutics, Cancer Genomics, Clinical Diagnostics, Clinical Genomics, Conference Coverage with Social Media, Ethics and Leadership, FDA, FDA Regulatory Affairs, Federal Budget Appropriations, Health Economics and Outcomes Research, Health Law Policy, Healthcare costs and reimbursement, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, interventional oncology, Next Generation Sequencing (NGS), Patent Law in Biotech, Patents, Patient Experience, Personal Health Applications: Tech Innovations serves HealhCare, Personalized and Precision Medicine & Genomic Research, Personalized Medicine Coalition, Precision Cancer Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Voices of Patients and Healthcare Providers, tagged #TUBiol5227, bioethics, biomarkers, Drug development, FDA, healthcare, insurers, legal, Patient, payers, physician-patient, Regulatory on September 28, 2021| Leave a Comment »
The advent of direct to consumer (DTC) genetic testing and the resultant rapid increase in its popularity as well as companies offering such services has created some urgent and unique bioethical challenges surrounding this niche in the marketplace. At first, most DTC companies like 23andMe and Ancestry.com offered non-clinical or non-FDA approved genetic testing as a way for consumers to draw casual inferences from their DNA sequence and existence of known genes that are linked to disease risk, or to get a glimpse of their familial background. However, many issues arose, including legal, privacy, medical, and bioethical issues. Below are some articles which will explain and discuss many of these problems associated with the DTC genetic testing market as well as some alternatives which may exist.
'Direct-to-Consumer (DTC) Genetic Testing Market to hit USD 2.5 Bn by 2024' by Global Market Insights
This post has the following link to the market analysis of the DTC market (https://www.gminsights.com/pressrelease/direct-to-consumer-dtc-genetic-testing-market). Below is the highlights of the report.
As you can see,this market segment appears to want to expand into the nutritional consulting business as well as targeted biomarkers for specific diseases.
Rising incidence of genetic disorders across the globe will augment the market growth
Increasing prevalence of genetic disorders will propel the demand for direct-to-consumer genetic testing and will augment industry growth over the projected timeline. Increasing cases of genetic diseases such as breast cancer, achondroplasia, colorectal cancer and other diseases have elevated the need for cost-effective and efficient genetic testing avenues in the healthcare market.
For instance, according to the World Cancer Research Fund (WCRF), in 2018, over 2 million new cases of cancer were diagnosed across the globe. Also, breast cancer is stated as the second most commonly occurring cancer. Availability of superior quality and advanced direct-to-consumer genetic testing has drastically reduced the mortality rates in people suffering from cancer by providing vigilant surveillance data even before the onset of the disease. Hence, the aforementioned factors will propel the direct-to-consumer genetic testing market overt the forecast timeline.
Get more details on this report – Request Free Sample PDF
Nutrigenomic Testing will provide robust market growth
The nutrigenomic testing segment was valued over USD 220 million market value in 2019 and its market will witness a tremendous growth over 2020-2028. The growth of the market segment is attributed to increasing research activities related to nutritional aspects. Moreover, obesity is another major factor that will boost the demand for direct-to-consumer genetic testing market.
Nutrigenomics testing enables professionals to recommend nutritional guidance and personalized diet to obese people and help them to keep their weight under control while maintaining a healthy lifestyle. Hence, above mentioned factors are anticipated to augment the demand and adoption rate of direct-to-consumer genetic testing through 2028.
Browse key industry insights spread across 161 pages with 126 market data tables & 10 figures & charts from the report, "Direct-To-Consumer Genetic Testing Market Size By Test Type (Carrier Testing, Predictive Testing, Ancestry & Relationship Testing, Nutrigenomics Testing), By Distribution Channel (Online Platforms, Over-the-Counter), By Technology (Targeted Analysis, Single Nucleotide Polymorphism (SNP) Chips, Whole Genome Sequencing (WGS)), Industry Analysis Report, Regional Outlook, Application Potential, Price Trends, Competitive Market Share & Forecast, 2020 – 2028" in detail along with the table of contents:
https://www.gminsights.com/industry-analysis/direct-to-consumer-dtc-genetic-testing-market
Targeted analysis techniques will drive the market growth over the foreseeable future
Based on technology, the DTC genetic testing market is segmented into whole genome sequencing (WGS), targeted analysis, and single nucleotide polymorphism (SNP) chips. The targeted analysis market segment is projected to witness around 12% CAGR over the forecast period. The segmental growth is attributed to the recent advancements in genetic testing methods that has revolutionized the detection and characterization of genetic codes.
Targeted analysis is mainly utilized to determine any defects in genes that are responsible for a disorder or a disease. Also, growing demand for personalized medicine amongst the population suffering from genetic diseases will boost the demand for targeted analysis technology. As the technology is relatively cheaper, it is highly preferred method used in direct-to-consumer genetic testing procedures. These advantages of targeted analysis are expected to enhance the market growth over the foreseeable future.
Over-the-counter segment will experience a notable growth over the forecast period
The over-the-counter distribution channel is projected to witness around 11% CAGR through 2028. The segmental growth is attributed to the ease in purchasing a test kit for the consumers living in rural areas of developing countries. Consumers prefer over-the-counter distribution channel as they are directly examined by regulatory agencies making it safer to use, thereby driving the market growth over the forecast timeline.
Favorable regulations provide lucrative growth opportunities for direct-to-consumer genetic testing
Europe direct-to-consumer genetic testing market held around 26% share in 2019 and was valued at around USD 290 million. The regional growth is due to elevated government spending on healthcare to provide easy access to genetic testing avenues. Furthermore, European regulatory bodies are working on improving the regulations set on the direct-to-consumer genetic testing methods. Hence, the above-mentioned factors will play significant role in the market growth.
Focus of market players on introducing innovative direct-to-consumer genetic testing devices will offer several growth opportunities
Few of the eminent players operating in direct-to-consumer genetic testing market share include Ancestry, Color Genomics, Living DNA, Mapmygenome, Easy DNA, FamilytreeDNA (Gene By Gene), Full Genome Corporation, Helix OpCo LLC, Identigene, Karmagenes, MyHeritage, Pathway genomics, Genesis Healthcare, and 23andMe. These market players have undertaken various business strategies to enhance their financial stability and help them evolve as leading companies in the direct-to-consumer genetic testing industry.
For example, in November 2018, Helix launched a new genetic testing product, DNA discovery kit, that allows customer to delve into their ancestry. This development expanded the firm's product portfolio, thereby propelling industry growth in the market.
The following posts discuss bioethical issues related to genetic testing and personalized medicine from a clinicians and scientisit's perspective
Question: Each of these articles discusses certain bioethical issues although focuses on personalized medicine and treatment. Given your understanding of the robust process involved in validating clinical biomarkers and the current state of the DTC market, how could DTC testing results misinform patients and create mistrust in the physician-patient relationship?
Personalized Medicine, Omics, and Health Disparities in Cancer: Can Personalized Medicine Help Reduce the Disparity Problem?
Diversity and Health Disparity Issues Need to be Addressed for GWAS and Precision Medicine Studies
Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?
The following posts discuss the bioethical concerns of genetic testing from a patient's perspective:
Ethics Behind Genetic Testing in Breast Cancer: A Webinar by Laura Carfang of survivingbreastcancer.org
Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk
23andMe Product can be obtained for Free from a new app called Genes for Good: UMich's Facebook-based Genomics Project
Question: If you are developing a targeted treatment with a companion diagnostic, what bioethical concerns would you address during the drug development process to ensure fair, equitable and ethical treatment of all patients, in trials as well as post market?
Articles on Genetic Testing, Companion Diagnostics and Regulatory Mechanisms
Centers for Medicare & Medicaid Services announced that the federal healthcare program will cover the costs of cancer gene tests that have been approved by the Food and Drug Administration
Real Time Coverage @BIOConvention #BIO2019: Genome Editing and Regulatory Harmonization: Progress and Challenges
New York Times vs. Personalized Medicine? PMC President: Times' Critique of Streamlined Regulatory Approval for Personalized Treatments 'Ignores Promising Implications' of Field
Live Conference Coverage @Medcitynews Converge 2018 Philadelphia: Early Diagnosis Through Predictive Biomarkers, NonInvasive Testing
Protecting Your Biotech IP and Market Strategy: Notes from Life Sciences Collaborative 2015 Meeting
Question: What type of regulatory concerns should one have during the drug development process in regards to use of biomarker testing? From the last article on Protecting Your IP how important is it, as a drug developer, to involve all payers during the drug development process?
Science Policy Forum: Should we trust healthcare explanations from AI predictive systems?
Posted in AI Models in Healthcare, AI-assisted Cardiac MRI, Artificial Intelligence - Breakthroughs in Theories and Technologies, Artificial Intelligence Applications in Health Care, Artificial Intelligence in Health Care - Tools & Innovations, Artificial Intelligence in Medicine - Applications in Therapeutics, Bio-Ethics, BioIT: BioInformatics, Biological Networks, FDA, FDA Regulatory Affairs, Health Economics and Outcomes Research, Health Law Policy, Image Processing/Computing, Machine Learning, Personal Health Applications: Tech Innovations serves HealhCare, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged AAAS, AI medical imaging, AI/ML, Artificial intelligence, explainability, explanatory AI, FDA, healthcare, image-interpretation training, interpretable AI, Machine Learning models, medical decision-making, medical decisionmaking, Medical imaging, Safety on July 31, 2021| Leave a Comment »
Some in industry voice their concerns
Curator: Stephen J. Williams, PhD
Post on AI healthcare and explainable AI
In a Policy Forum article in Science "Beware explanations from AI in health care", Boris Babic, Sara Gerke, Theodoros Evgeniou, and Glenn Cohen discuss the caveats on relying on explainable versus interpretable artificial intelligence (AI) and Machine Learning (ML) algorithms to make complex health decisions. The FDA has already approved some AI/ML algorithms for analysis of medical images for diagnostic purposes. These have been discussed in prior posts on this site, as well as issues arising from multi-center trials. The authors of this perspective article argue that choice of type of algorithm (explainable versus interpretable) algorithms may have far reaching consequences in health care.
Artificial intelligence and machine learning (AI/ML) algorithms are increasingly developed in health care for diagnosis and treatment of a variety of medical conditions (1). However, despite the technical prowess of such systems, their adoption has been challenging, and whether and how much they will actually improve health care remains to be seen. A central reason for this is that the effectiveness of AI/ML-based medical devices depends largely on the behavioral characteristics of its users, who, for example, are often vulnerable to well-documented biases or algorithmic aversion (2). Many stakeholders increasingly identify the so-called black-box nature of predictive algorithms as the core source of users' skepticism, lack of trust, and slow uptake (3, 4). As a result, lawmakers have been moving in the direction of requiring the availability of explanations for black-box algorithmic decisions (5). Indeed, a near-consensus is emerging in favor of explainable AI/ML among academics, governments, and civil society groups. Many are drawn to this approach to harness the accuracy benefits of noninterpretable AI/ML such as deep learning or neural nets while also supporting transparency, trust, and adoption. We argue that this consensus, at least as applied to health care, both overstates the benefits and undercounts the drawbacks of requiring black-box algorithms to be explainable.
Source: https://science.sciencemag.org/content/373/6552/284?_ga=2.166262518.995809660.1627762475-1953442883.1627762475
Types of AI/ML Algorithms: Explainable and Interpretable algorithms
Interpretable AI: A typical AI/ML task requires constructing algorithms from vector inputs and generating an output related to an outcome (like diagnosing a cardiac event from an image). Generally the algorithm has to be trained on past data with known parameters. When an algorithm is called interpretable, this means that the algorithm uses a transparent or "white box" function which is easily understandable. Such example might be a linear function to determine relationships where parameters are simple and not complex. Although they may not be as accurate as the more complex explainable AI/ML algorithms, they are open, transparent, and easily understood by the operators.
Explainable AI/ML: This type of algorithm depends upon multiple complex parameters and takes a first round of predictions from a "black box" model then uses a second algorithm from an interpretable function to better approximate outputs of the first model. The first algorithm is trained not with original data but based on predictions resembling multiple iterations of computing. Therefore this method is more accurate or deemed more reliable in prediction however is very complex and is not easily understandable. Many medical devices that use an AI/ML algorithm use this type. An example is deep learning and neural networks.
The purpose of both these methodologies is to deal with problems of opacity, or that AI predictions based from a black box undermines trust in the AI.
For a deeper understanding of these two types of algorithms see here:
https://www.kdnuggets.com/2018/12/machine-learning-explainability-interpretability-ai.html
or https://www.bmc.com/blogs/machine-learning-interpretability-vs-explainability/
(a longer read but great explanation)
From the above blog post of Jonathan Johnson
How interpretability is different from explainability
Why a model might need to be interpretable and/or explainable
Who is working to solve the black box problem—and how
What is interpretability?
Does Chipotle make your stomach hurt? Does loud noise accelerate hearing loss? Are women less aggressive than men? If a machine learning model can create a definition around these relationships, it is interpretable.
All models must start with a hypothesis. Human curiosity propels a being to intuit that one thing relates to another. "Hmm…multiple black people shot by policemen…seemingly out of proportion to other races…something might be systemic?" Explore.
People create internal models to interpret their surroundings. In the field of machine learning, these models can be tested and verified as either accurate or inaccurate representations of the world.
Interpretability means that the cause and effect can be determined.
What is explainability?
ML models are often called black-box models because they allow a pre-set number of empty parameters, or nodes, to be assigned values by the machine learning algorithm. Specifically, the back-propagation step is responsible for updating the weights based on its error function.
To predict when a person might die—the fun gamble one might play when calculating a life insurance premium, and the strange bet a person makes against their own life when purchasing a life insurance package—a model will take in its inputs, and output a percent chance the given person has at living to age 80.
Below is an image of a neural network. The inputs are the yellow; the outputs are the orange. Like a rubric to an overall grade, explainability shows how significant each of the parameters, all the blue nodes, contribute to the final decision.
In this neural network, the hidden layers (the two columns of blue dots) would be the black box.
For example, we have these data inputs:
BMI score
Number of years spent smoking
Career category
If this model had high explainability, we'd be able to say, for instance:
The career category is about 40% important
The number of years spent smoking weighs in at 35% important
The age is 15% important
The BMI score is 10% important
Explainability: important, not always necessary
Explainability becomes significant in the field of machine learning because, often, it is not apparent. Explainability is often unnecessary. A machine learning engineer can build a model without ever having considered the model's explainability. It is an extra step in the building process—like wearing a seat belt while driving a car. It is unnecessary for the car to perform, but offers insurance when things crash.
The benefit a deep neural net offers to engineers is it creates a black box of parameters, like fake additional data points, that allow a model to base its decisions against. These fake data points go unknown to the engineer. The black box, or hidden layers, allow a model to make associations among the given data points to predict better results. For example, if we are deciding how long someone might have to live, and we use career data as an input, it is possible the model sorts the careers into high- and low-risk career options all on its own.
Perhaps we inspect a node and see it relates oil rig workers, underwater welders, and boat cooks to each other. It is possible the neural net makes connections between the lifespan of these individuals and puts a placeholder in the deep net to associate these. If we were to examine the individual nodes in the black box, we could note this clustering interprets water careers to be a high-risk job.
In the previous chart, each one of the lines connecting from the yellow dot to the blue dot can represent a signal, weighing the importance of that node in determining the overall score of the output.
If that signal is high, that node is significant to the model's overall performance.
If that signal is low, the node is insignificant.
With this understanding, we can define explainability as:
Knowledge of what one node represents and how important it is to the model's performance.
So how does choice of these two different algorithms make a difference with respect to health care and medical decision making?
The authors argue:
"Regulators like the FDA should focus on those aspects of the AI/ML system that directly bear on its safety and effectiveness – in particular, how does it perform in the hands of its intended users?"
A suggestion for
Enhanced more involved clinical trials
Provide individuals added flexibility when interacting with a model, for example inputting their own test data
More interaction between user and model generators
Determining in which situations call for interpretable AI versus explainable (for instance predicting which patients will require dialysis after kidney damage)
Other articles on AI/ML in medicine and healthcare on this Open Access Journal include
Applying AI to Improve Interpretation of Medical Imaging
Real Time Coverage @BIOConvention #BIO2019: Machine Learning and Artificial Intelligence #AI: Realizing Precision Medicine One Patient at a Time
LIVE Day Three – World Medical Innovation Forum ARTIFICIAL INTELLIGENCE, Boston, MA USA, Monday, April 10, 2019
Cardiac MRI Imaging Breakthrough: The First AI-assisted Cardiac MRI Scan Solution, HeartVista Receives FDA 510(k) Clearance for One Click™ Cardiac MRI Package
19 of the 49 New Therapeutic Molecular Entities FDA approved in 2020 — as well as a new Cell-based therapy — are Personalized Medicines
Posted in FDA Regulatory Affairs, New Drug Approval, Personalized and Precision Medicine & Genomic Research on March 2, 2021| Leave a Comment »
2020 DRUG APPROVALS
19 of the 49 new therapeutic molecular entities FDA approved in 2020 — as well as a new cell-based therapy — are personalized medicines.
Newly Approved Therapeutic Molecular Entities
1. Ayvakit (avapritinib) — for the treatment of metastatic gastrointestinal stromal tumor (GIST). The decision to use this product is informed by the PDGFRA exon 18 biomarker status in the tumors of patients.
2. Nexletol (bempedoic acid) — for the treatment of adults with familial hypercholesterolemia who require additional lowering of LDL-C. The use of this product can be informed by the FH biomarker (LOLR, APOB, PCSK9) status in patients.
3. Tukysa (tucatinib) — for the treatment of metastatic breast cancer. The decision to use this product is informed by the HER2 biomarker status in the tumors of patients.
4. Pemazyre (pemigatinib) — for the treatment of cholangiocarcinoma. The decision to use this product is informed by the FGFR2 biomarker status in the tumors of patients.
5. Trodelvy (sacituzumab govitecan-hziy) — for the treatment of metastatic triple-negative breast cancer. The decision to use this product is informed by the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) biomarker statuses in the tumors of patients. Personalized Medicine at FDA 7
6. Tabrecta (capmatinib) — for the treatment of non-small cell lung cancer (NSCLC). The decision to use this product is informed by the MET exon 14 biomarker status in the tumors of patients.
7. Retevmo (selpercatinib) — for the treatment of lung and thyroid cancers. The decision to use this product is informed by the RET fusion biomarker status in the tumors of patients.
8. Uplizna (inebilizumab-cdon) — for the treatment of neuromyelitis optica spectrum disorder. The decision to use this product is informed by the AQP4 biomarker status in patients.
9. Rukobia (fostemsavir) — for the treatment of human immunodeficiency virus (HIV) infection in adults with multidrug-resistant HIV-1 infection. The use of this product can be informed by the HIV-1 expression levels in patients.
10. Evrysdi (risdiplam) — for the treatment of spinal muscular atrophy. This product selectively targets the SMN2 biomarker in patients.
11. Olinvyk (oliceridine) — for the management of acute pain. The use of this product can be informed by the CYP2D6 biomarker status in patients.
12. Viltepso (viltolarsen) — for the treatment of Duchenne muscular dystrophy. This product selectively targets, and its use is informed by, the DMD gene exon 53 biomarker in patients.
13. Enspryng (satralizumab-mwge) — for the treatment of neuromyelitis optica spectrum disorder. The decision to use this product is informed by the AQP4 biomarker status in patients.
14. Gavreto (pralsetinib) — for the treatment of non-small cell lung cancer (NSCLC). The decision to use this product is informed by the RET fusion biomarker status in the tumors of patients.
15. Zokinvy (lonafarnib) — for the treatment of progeroid laminopathies. The decision to use this product is informed by the LMN4 and/or ZMPSTE24 biomarker statuses in patients. 8 Personalized Medicine at FDA Methodology: When evaluating new molecular entities, PMC defined personalized medicines as those therapeutic products for which the label includes reference to specific biological markers, often identified by diagnostic tools, that help guide decisions and/or procedures for their use in individual patients.
16. Oxlumo (lumasiran) — for the treatment of hyperoxaluria type 1. This product selectively targets the hydroxy acid oxidase 1 (HAO1) biomarker in patients.
17. Imcivree (setmelanotide) — for the treatment of obesity due to pro-opiomelanocortin (POMC) deficiency. The decision to use this product is informed by the POMC, PCSK1, or LEPR biomarker statuses in patients.
18. Orladeyo (berotralstat) — for the treatment of hereditary angioedema types I and II. The use of this product can be informed by the C1-INH biomarker status in patients.
19. Margenza (margetuximab-cmkb) — for the treatment of breast cancer. The decision to use this product is informed by the human epidermal growth factor receptor 2 (HER2) biomarker status in the tumors of patients. Newly Approved Cell-Based Therapy
20. Tecartus (brexucabtagene autoleucel) — for the treatment of mantle cell lymphoma (MCL). The treatment is a fully integrated CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with refractory MCL.
https://mma.prnewswire.com/media/1436855/PM_at_FDA_The_Scope_Significance_of_Progress_in_2020.pdf?p=pdf
Did FDA Reverse Course on Convalescent Plasma Therapy for COVID-19?
Posted in Antibody Responses Predict Antigen Exposure, Biomarkers & Medical Diagnostics, Biomarkers: Inflammation, COVID-19, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Economic Impact of Coronavirus Pandemic, FDA, FDA Regulatory Affairs, Human Antibody Response, Human Circulating Antibody Repertoire, Immune Engineering, Immune-Mediation (independent immunopathology: lung and reticuloendothelial system), Infectious Disease Immunodiagnostics, Pharmacovigilance, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, SARS-COV2 Hijacking the Complement and Coagulation Systems, Serology tests for coronavirus antibodies, Synthetic Immunology: Hacking Immune Cells, Treatment Protocols for COVID-19, Viral diseases, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged #COVID-19, convalescent plasma, FDA, passive immunity, SARS-CoV-2 on August 26, 2020| Leave a Comment »
Reporter: Stephen J. Williams, PhD
Starting with a timeline of recent announcements by the FDA on convalescent plasma therapy
Coronavirus (COVID-19) Update: FDA Encourages Recovered Patients to Donate Plasma for Development of Blood-Related Therapies
As part of the all-of-America approach to fighting the COVID-19 pandemic, the U.S. Food and Drug Administration has been working with partners across the U.S. government, academia and industry to expedite the development and availability of critical medical products to treat this novel virus. Today, we are providing an update on one potential treatment called convalescent plasma and encouraging those who have recovered from COVID-19 to donate plasma to help others fight this disease.
Convalescent plasma is an antibody-rich product made from blood donated by people who have recovered from the disease caused by the virus. Prior experience with respiratory viruses and limited data that have emerged from China suggest that convalescent plasma has the potential to lessen the severity or shorten the length of illness caused by COVID-19. It is important that we evaluate this potential therapy in the context of clinical trials, through expanded access, as well as facilitate emergency access for individual patients, as appropriate.
The response to the agency's recently announced national efforts to facilitate the development of and access to convalescent plasma has been tremendous. More than 1,040 sites and 950 physician investigators nationwide have signed on to participate in the Mayo Clinic-ledExternal Link Disclaimer expanded access protocol. A number of clinical trials are also taking place to evaluate the safety and efficacy of convalescent plasma and the FDA has granted numerous single patient emergency investigational new drug (eIND) applications as well.
Source: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-encourages-recovered-patients-donate-plasma-development-blood
Recommendations for Investigational COVID-19 Convalescent Plasma
FDA issues guidelines on clinical trials and obtaining emergency enrollment concerning convalescent plasma
FDA has issued guidance to provide recommendations to health care providers and investigators on the administration and study of investigational convalescent plasma collected from individuals who have recovered from COVID-19 (COVID-19 convalescent plasma) during the public health emergency.
The guidance provides recommendations on the following:
pathways for use of investigational COVID-19 convalescent plasma
collection of COVID-19 convalescent plasma, including donor eligibility and donor qualifications
labeling, and
Because COVID-19 convalescent plasma has not yet been approved for use by FDA, it is regulated as an investigational product. A health care provider must participate in one of the pathways described below. FDA does not collect COVID-19 convalescent plasma or provide COVID-19 convalescent plasma. Health care providers or acute care facilities should instead obtain COVID-19 convalescent plasma from an FDA-registered blood establishment.
Excerpts from the guidance document are provided below.
The Food and Drug Administration (FDA or Agency) plays a critical role in protecting the United States (U.S.) from threats including emerging infectious diseases, such as the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support response efforts to this pandemic.
One investigational treatment being explored for COVID-19 is the use of convalescent plasma collected from individuals who have recovered from COVID-19. Convalescent plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 (the virus that causes COVID-19) is being studied for administration to patients with COVID-19. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2003 SARS-CoV-1 epidemic, the 2009-2010 H1N1 influenza virus pandemic, and the 2012 MERS-CoV epidemic.
Although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19. Therefore, it is important to study the safety and efficacy of COVID-19 convalescent plasma in clinical trials.
The following pathways are available for administering or studying the use of COVID-19 convalescent plasma:
Investigators wishing to study the use of convalescent plasma in a clinical trial should submit requests to FDA for investigational use under the traditional IND regulatory pathway (21 CFR Part 312). CBER's Office of Blood Research and Review is committed to engaging with sponsors and reviewing such requests expeditiously. During the COVID-19 pandemic, INDs may be submitted via email to CBERDCC_eMailSub@fda.hhs.gov.
An IND application for expanded access is an alternative for use of COVID-19 convalescent plasma for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials (21 CFR 312.305). FDA has worked with multiple federal partners and academia to open an expanded access protocol to facilitate access to COVID-19 convalescent plasma across the nation. Access to this investigational product may be available through participation of acute care facilities in an investigational expanded access protocol under an IND that is already in place.
Currently, the following protocol is in place: National Expanded Access Treatment ProtocolExternal Link Disclaimer
Single Patient Emergency IND
Although participation in clinical trials or an expanded access program are ways for patients to obtain access to convalescent plasma, for various reasons these may not be readily available to all patients in potential need. Therefore, given the public health emergency that the COVID-19 pandemic presents, and while clinical trials are being conducted and a national expanded access protocol is available, FDA also is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patient's physician requesting a single patient emergency IND (eIND) for the individual patient under 21 CFR 312.310. This process allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization, if the applicable regulatory criteria are met. Note, in such case, a licensed physician seeking to administer COVID-19 convalescent plasma to an individual patient must request the eIND (see 21 CFR 312.310(b)).
To Obtain a Single Patient Emergency IND
The requesting physician may contact FDA by completing Form FDA 3926 (https://www.fda.gov/media/98616/download) and submitting the form by email to CBER_eIND_Covid-19@FDA.HHS.gov.
FACT SHEET FOR PATIENTS AND PARENTS/CAREGIVERS EMERGENCY USE AUTHORIZATION (EUA) OF COVID-19 CONVALESCENT PLASMA FOR TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS
FDA issues fact sheet for patients on donating plasma
FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment, Another Achievement in Administration's Fight Against Pandemic
Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients as part of the agency's ongoing efforts to fight COVID-19. Based on scientific evidence available, the FDA concluded, as outlined in its decision memorandum, this product may be effective in treating COVID-19 and that the known and potential benefits of the product outweigh the known and potential risks of the product.
Today's action follows the FDA's extensive review of the science and data generated over the past several months stemming from efforts to facilitate emergency access to convalescent plasma for patients as clinical trials to definitively demonstrate safety and efficacy remain ongoing.
The EUA authorizes the distribution of COVID-19 convalescent plasma in the U.S. and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19.
Alex Azar, Health and Human Services Secretary:
"The FDA's emergency authorization for convalescent plasma is a milestone achievement in President Trump's efforts to save lives from COVID-19," said Secretary Azar. "The Trump Administration recognized the potential of convalescent plasma early on. Months ago, the FDA, BARDA, and private partners began work on making this product available across the country while continuing to evaluate data through clinical trials. Our work on convalescent plasma has delivered broader access to the product than is available in any other country and reached more than 70,000 American patients so far. We are deeply grateful to Americans who have already donated and encourage individuals who have recovered from COVID-19 to consider donating convalescent plasma."
Stephen M. Hahn, M.D., FDA Commissioner:
"I am committed to releasing safe and potentially helpful treatments for COVID-19 as quickly as possible in order to save lives. We're encouraged by the early promising data that we've seen about convalescent plasma. The data from studies conducted this year shows that plasma from patients who've recovered from COVID-19 has the potential to help treat those who are suffering from the effects of getting this terrible virus," said Dr. Hahn. "At the same time, we will continue to work with researchers to continue randomized clinical trials to study the safety and effectiveness of convalescent plasma in treating patients infected with the novel coronavirus."
Scientific Evidence on Convalescent Plasma
Based on an evaluation of the EUA criteria and the totality of the available scientific evidence, the FDA's Center for Biologics Evaluation and Research determined that the statutory criteria for issuing an EUA criteria were met.
The FDA determined that it is reasonable to believe that COVID-19 convalescent plasma may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients. The agency also determined that the known and potential benefits of the product, when used to treat COVID-19, outweigh the known and potential risks of the product and that that there are no adequate, approved, and available alternative treatments.
Donate COVID-19 Plasma
FDA posts video and blog about how to donate plasms if you had been infected with COVID
https://youtu.be/PlX15rWdBbY
Please go to https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma
to read more from FDA
CLINICAL MEMORANDUM From: , OBRR/DBCD/CRS To: , OBRR Through: , OBRR/DBCD , OBRR/DBCD , OBRR/DBCD/CRS Re: EUA 26382: Emergency Use Authorization (EUA) Request (original request 8/12/20; amended request 8/23/20) Product: COVID-19 Convalescent Plasma Items reviewed: EUA request Fact Sheet for Health Care Providers Fact Sheet for Recipients Sponsor: Robert Kadlec, M.D. Assistant Secretary for Preparedness and Response (ASPR) Office of Assistant Secretary for Preparedness and Response (ASPR) U.S. Department of Health and Human Services (HHS) EXECUTIVE SUMMARY COVID-19 Convalescent Plasma (CCP), an unapproved biological product, is proposed for use under an Emergency Use Authorization (EUA) under section 564 of the Federal Food, Drug, and Cosmetic Act (the Act),(21 USC 360bbb-3) as a passive immune therapy for the treatment of hospitalized patients with COVID-19, a serious or life-threatening disease. There currently is no adequate, approved, and available alternative to CCP for treating COVID-19. The sponsor has pointed to four lines of evidence to support that CCP may be effective in the treatment of hospitalized patients with COVID-19: 1) History of convalescent plasma for respiratory coronaviruses; 2) Evidence of preclinical safety and efficacy in animal models; 3) Published studies of the safety and efficacy of CCP; and 4) Data on safety and efficacy from the National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic. Considering the totality of the scientific evidence presented in the EUA, I conclude that current data for the use of CCP in adult hospitalized patients with COVID-19 supports the conclusion that CCP meets the "may be effective" criterion for issuance of an EUA from section 564(c)(2)(A) of the Act. It is reasonable to conclude that the known and potential benefits of CCP outweigh the known and potential risks of CCP for the proposed EUA. Current data suggest the largest clinical benefit is associated with high-titer units of CCP administered early course of the disease.
Source: https://www.fda.gov/media/141480/download
And Today August 26, 2020
A letter, from Senator Warren, to Commissioner Hahn from Senate Committee asking for documentation for any communication between FDA and White House
August 25, 2020 Dr. Stephen M. Hahn, M.D. Commissioner of Food and Drugs U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 Dear Commissioner Hahn: We write regarding the U.S. Food and Drug Administration's (FDA) troubling decision earlier this week to issue an Emergency Use Authorization (EUA) for convalescent plasma as a treatment for coronavirus disease 2019 (COVID-19).1 Reports suggests that the FDA granted the EUA amid intense political pressure from President Trump and other Administration officials, despite limited evidence of convalescent plasma's effectiveness as a COVID-19 treatment.2 To help us better understand whether the issuance of the blood plasma EUA was motivated by politics, we request copies of any and all communications between FDA and White House officials regarding the blood plasma EUA.
Source: https://www.warren.senate.gov/imo/media/doc/2020.08.25%20Letter%20to%20FDA%20re%20Blood%20Plasma%20EUA.pdf
…….. which may have been a response to this article
FDA chief walks back comments on effectiveness of coronavirus plasma treatment
From CNBC: https://www.cnbc.com/2020/08/25/fda-chief-walks-back-comments-on-effectiveness-of-coronavirus-plasma-treatment.html
PUBLISHED TUE, AUG 25 202010:45 AM EDTUPDATED TUE, AUG 25 20204:12 PM EDT
Berkeley Lovelace Jr.@BERKELEYJR
Will Feuer@WILLFOIA
The authorization will allow health-care providers in the U.S. to use the plasma to treat hospitalized patients with Covid-19.
The FDA's emergency use authorization came a day after President Trump accused the agency of delaying enrollment in clinical trials for vaccines or therapeutics.
The criticism from Trump and action from the FDA led some scientists to believe the authorization, which came on the eve of the GOP national convention, was politically motivated.
FDA Commissioner Dr. Stephen Hahn is walking back comments on the benefits of convalescent plasma, saying he could have done a better job of explaining the data on its effectiveness against the coronavirus after authorizing it for emergency use over the weekend.
Commisioners responses over Twitter
https://twitter.com/SteveFDA/status/1298071603675373569?s=20
In an interview with Bloomberg's Drew Armstrong, FDA Commissioner Hahn reiterates that his decision was based on hard evidence and scientific fact, not political pressure. The whole interview is at the link below:
https://www.bloomberg.com/news/articles/2020-08-25/fda-s-hahn-vows-to-stick-to-the-science-amid-vaccine-pressure?sref=yLCixKPR
Some key points:
Dr. Hahn corrected his initial statement about 35% of people would be cured by convalescent plasma. In the interview he stated:
I was trying to do what I do with patients, because patients often understand things in absolute terms versus relative terms. And I should've been more careful, there's no question about it. What I was trying to get to is that if you look at a hundred patients who receive high titre, and a hundred patients who received low titre, the difference between those two particular subset of patients who had these specific criteria was a 35% reduction in mortality. So I frankly did not do a good job of explaining that.
FDA colleagues had frank discussion after the statement was made. He is not asking for other people in HHS to retract their statements, only is concerned that FDA has correct information for physicians and patients
Hahn is worried that people will not enroll due to chance they may be given placebo
He gave no opinion when asked if FDA should be an independent agency
For more articles on COVID19 please go to our Coronavirus Portal at
https://pharmaceuticalintelligence.com/coronavirus-portal/
National Public Radio interview with Dr. Anthony Fauci on his optimism on a COVID-19 vaccine by early 2021
Posted in Biomarkers: Inflammation, Coronavirus Gene Expression, Drug Development Process, Economic Impact of Coronavirus Pandemic, FDA, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Inflammatory Pathophysiology, number of asymptomatic infections, Pharmaceutical Discovery, Population genetics, SARS-CoV-2, Systemic Inflammatory Response Related Disorders, Treatment Protocols for COVID-19, Vaccinology, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged #COVID-19, Anthony Fauci, Coronavirus Vaccines, interview with scientific leaders, National Public Radio, neutralizing antibody, NPR, pharmaceutical development, SARS-CoV-2, vaccine development on July 19, 2020| Leave a Comment »
Below I am giving a link to an important interview by NPR's Judy Woodruff with Dr. Anthony Fauci on his thoughts regarding the recent spikes in cases, the potential for a COVID-19 vaccine by next year, and promising therapeutics in the pipeline. The interview link is given below however I will summarize a few of the highlights of the interview.
Some notes on the interview
Judy Woodruff began her report with some up to date news regarding the recent spike and that Miami Florida has just ordered the additional use of facemasks. She asked Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAD), about if the measures currently in use are enough to bring this spike down. Dr. Fauci said that we need to reboot our efforts, mainly because people are not doing three things which could have prevented this spike mainly
universal wearing of masks
distancing properly from each other
close the bars and pubs (see Wisconsin bars packed after ruling)
It hasn't been a uniform personal effort
Dr. Fauci on testing
We have to use the tests we have out there efficiently and effectively And we have to get them out to the right people who can do the proper identification, isolation, and do proper contract tracing and need to test more widely in a surveillance way to get a feel of the extent and penetrance of this community spread. there needs to be support and money for these testing labs
We have a problem and we need to admit and own it but we need to do the things we know are effective to turn this thing around.
On Vaccines
"May be later this year"
His response to Merck's CEO Ken Frazer who said officials are giving false hop if they say 'end of year' but Dr. Fauci disagrees. He says a year end goal is not outlandish.
What we have been doing is putting certain things in line with each other in an unprecedented way.
Dr. Fauci went on to say that, in the past yes, it took a long time, even years to develop a vaccine but now they have been able to go from sequence of virus to a vaccine development program in days, which is unheard of. Sixty two days later we have gone into phase 1 trials. the speed at which this is occurring is so much faster. He says that generally it would take a couple of years to get a neutralizing antibody but we are already there. Another candidate will be undergoing phase 3 trials by end of this month (July 2020).
He is "cautiously optimistic" that we will have one or more vaccines to give to patients by end of year because given the amount of cases it will be able to get a handle on safety and efficacy by late fall.
Now he says the game changer is that the government is working with companies to ramp up the production of doses of the candidate vaccines so when we find which one works we will have ample doses on hand. He is worried about the anti vaccine movement derailing vaccine testing and vaccinations but says if we keep on informing the public we can combat this.
Dr. Fauci is concerned for the safety of the vulnerable in schools, including students and staff. He wants the US to get down to a reasonable baseline of cases but in the US that baseline after the first wave was still significantly higher than in most countries, where the baseline was more like tens of cases not hundreds of cases.
For more information on COVID-19 Please go to our Coronavirus Portal at
Updated listing of COVID-19 vaccine and therapeutic trials from NIH Clinical Trials.gov
Posted in Biomarkers: Inflammation, Clinical Diagnostics, Clinical Genomics, COVID-19, COVID-19: Pandemic Surgery Guidance, Drug Development Process, Economic Impact of Coronavirus Pandemic, FDA, FDA Regulatory Affairs, Immune-Mediation (independent immunopathology: lung and reticuloendothelial system), Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, number of asymptomatic infections, Pharmaceutical Drug Discovery, SAR-Cov-2 a vasculotropic (blood vessels) RNA Virus, SARS-CoV-2, Seasonality & Environmental Factors in Resurgence, Treatment Protocols for COVID-19, Viral diseases, tagged #COVID-19, Clinical trial, coronavirus, COVID-19, National Institutes of Health (NIH) 's Common Fund, SARS-CoV-2 on April 16, 2020| Leave a Comment »
The following file contains an updated list (search on 4/15/2020) of COVID-19 related clinical trials from https://clinicaltrials.gov/
The Excel file can be uploaded here: Current Covid-19 Trials
Each sheet in the workbook is separated by current COVID-19 vaccine trials, currents COVID-19 trials with the IL6R (interleukin 6 receptor) antagonist tocilizumab, and all COVID related trials. The Excel spreadsheet also contains links to more information about the trials.
As of April 15, 2020 the number of listed trials are as follows:
clinicaltrials.gov search terms Number of results Number of completed trials Number of trials currently recruiting
COVID-19 or SARS-CoV-2 410 5 completed
5 withdrawn 192
1st row terms + vaccine 28 0 15
1st row terms + tocilizumab 16 0 10
1st row terms + hydroxychloroquine 61 1 22
A few highlights of the COVID related trials on clinicaltrials.gov
Withdrawn trials
Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 (NCT04287686)
Brief Summary:
This is an open label, randomized, controlled, pilot clinical study in patients with COVID-19, to obtain preliminary biologic, physiologic, and clinical data in patients with COVID-19 treated with rhACE2 or control patients, to help determine whether a subsequent Phase 2B trial is warranted.
Condition or disease Intervention/treatment Phase
COVID-19 Drug: Recombinant human angiotensin-converting enzyme 2 (rhACE2) Not Applicable
This is a small pilot study investigating whether there is any efficacy signal that warrants a larger Phase 2B trial, or any harm that suggests that such a trial should not be done. It is not expected to produce statistically significant results in the major endpoints. The investigators will examine all of the biologic, physiological, and clinical data to determine whether a Phase 2B trial is warranted.
Primary efficacy analysis will be carried only on patients receiving at least 4 doses of active drug. Safety analysis will be carried out on all patients receiving at least one dose of active drug.
It is planned to enroll more than or equal to 24 subjects with COVID-19. It is expected to have at least 12 evaluable patients in each group.
Experimental group: 0.4 mg/kg rhACE2 IV BID and standard of care Control group: standard of care
Intervention duration: up to 7 days of therapy
No planned interim analysis.
Study was withdrawn before participants were enrolled.
Washed Microbiota Transplantation for Patients With 2019-nCoV Infection (NCT04251767)
Gut dysbiosis co-exists in patients with coronavirus pneumonia. Some of these patients would develop secondary bacterial infections and antibiotic-associated diarrhea (AAD). The recent study on using washed microbiota transplantation (WMT) as rescue therapy in critically ill patients with AAD demonstrated the important clinical benefits and safety of WMT. This clinical trial aims to evaluate the outcome of WMT combining with standard therapy for patients with 2019-novel coronavirus pneumonia, especially for those patients with dysbiosis-related conditions.
An ongoing outbreak of 2019 novel coronavirus was reported in Wuhan, China. 2019-nCoV has caused a cluster of pneumonia cases, and posed continuing epidemic threat to China and even global health. Unfortunately, there is currently no specific effective treatment for the viral infection and the related serious complications. It is in urgent need to find a new specific effective treatment for the 2019-nCoV infection. According to Declaration of Helsinki and International Ethical Guidelines for Health-related Research Involving Humans, the desperately ill patients with 2019-nCov infection during disease outbreaks have a moral right to try unvalidated medical interventions (UMIs) and that it is therefore unethical to restrict access to UMIs to the clinical trial context.
There is a vital link between the intestinal tract and respiratory tract, which was exemplified by intestinal complications during respiratory disease and vice versa. Some of these patients can develop secondary bacterial infections and antibiotic-associated diarrhea (AAD). The recent study on using washed microbiota transplantation (WMT) as rescue therapy in critically ill patients with AAD demonstrated the important clinical benefits and safety of WMT. Additionally, the recent animal study provided direct evidence supporting that antibiotics could decrease gut microbiota and the lung stromal interferon signature and facilitate early influenza virus replication in lung epithelia. Importantly, the above antibiotics caused negative effects can be reversed by fecal microbiota transplantation (FMT) which suggested that FMT might be able to induce a significant improvement in the respiratory virus infection. Another evidence is that the microbiota could confer protection against certain virus infection such as influenza virus and respiratory syncytial virus by priming the immune response to viral evasion. The above results suggested that FMT might be a new therapeutic option for the treatment of virus-related pneumonia. The methodology of FMT recently was coined as WMT, which is dependent on the automatic facilities and washing process in a laboratory room. Patients underwent WMT with the decreased rate of adverse events and unchanged clinical efficacy in ulcerative colitis and Crohn's disease. This clinical trial aims to evaluate the outcome of WMT combining with standard therapy for patients with novel coronavirus pneumonia, especially for those patients with dysbiosis-related conditions.
Responsible Party: Faming Zhang, Director of Medical Center for Digestive Diseases, The Second Hospital of Nanjing Medical University
Identifier NCT04251767 History of Changes
Therapy for Pneumonia Patients iInfected by 2019 Novel Coronavirus (NCT04293692)
The 2019 novel coronavirus pneumonia outbroken in Wuhan, China, which spread quickly to 26 countries worldwide and presented a serious threat to public health. It is mainly characterized by fever, dry cough, shortness of breath and breathing difficulties. Some patients may develop into rapid and deadly respiratory system injury with overwhelming inflammation in the lung. Currently, there is no effective treatment in clinical practice. The present clinical trial is to explore the safety and efficacy of Human Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) therapy for novel coronavirus pneumonia patients.
Since late December 2019, human pneumonia cases infected by a novel coronavirus (2019-nCoV) were firstly identified in Wuhan, China. As the virus is contagious and of great epidemic, more and more cases have found in other areas of China and abroad. Up to February 24, a total of 77, 779 confirmed cases were reported in China. At present, there is no effective treatment for patients identified with novel coronavirus pneumonia. Therefore, it's urgent to explore more active therapeutic methods to cure the patients.
Recently, some clinical researches about the 2019 novel coronavirus pneumonia published in The Lancet and The New England Journal of Medicine suggested that massive inflammatory cell infiltration and inflammatory cytokines secretion were found in patients' lungs, alveolar epithelial cells and capillary endothelial cells were damaged, causing acute lung injury. It seems that the key to cure the pneumonia is to inhibit the inflammatory response, resulting to reduce the damage of alveolar epithelial cells and endothelial cells and repair the function of the lung.
Mesenchymal stem cells (MSCs) are widely used in basic research and clinical application. They are proved to migrate to damaged tissues, exert anti-inflammatory and immunoregulatory functions, promote the regeneration of damaged tissues and inhibit tissue fibrosis. Studies have shown that MSCs can significantly reduce acute lung injury in mice caused by H9N2 and H5N1 viruses by reducing the levels of proinflammatory cytokines and the recruitment of inflammatory cells into the lungs. Compared with MSCs from other sources, human umbilical cord-derived MSCs (UC-MSCs) have been widely applied to various diseases due to their convenient collection, no ethical controversy, low immunogenicity, and rapid proliferation rate. In our recent research, we confirmed that UC-MSCs can significantly reduce inflammatory cell infiltration and inflammatory factors expression in lung tissue, and significantly protect lung tissue from endotoxin (LPS) -induced acute lung injury in mice.
The purpose of this clinical study is to investigate safety and efficiency of UC-MSCs in treating pneumonia patients infected by 2019-nCoV. The investigators planned to recruit 48 patients aged from 18 to 75 years old and had no severe underlying diseases. In the cell treatment group, 24 patients received 0.5*10E6 UC-MSCs /kg body weight intravenously treatment 4 times every other day besides conventional treatment. In the control group, other 24 patients received conventional treatment plus 4 times of placebo intravenously. The lung CT, blood biochemical examination, lymphocyte subsets, inflammatory factors, 28-days mortality, etc will be evaluated within 24h and 1, 2, 4, 8 weeks after UC-MSCs treatment.
Puren Hospital Affiliated to Wuhan University of Science and Technology
Collaborator:
Wuhan Hamilton Bio-technology Co., Ltd
Prognositc Factors in COVID-19 Patients Complicated With Hypertension (NCT04272710)
There are currently no clinical studies reporting clinical characteristics difference between the hypertension patients with and without ACEI treatment when suffered with novel coronavirus infection in China
At present, the outbreak of the new coronavirus (2019-nCoV) infection in Wuhan and Hubei provinces has attracted great attention from the medical community across the country. Both 2019-nCoV and SARS viruses are coronaviruses, and they have a large homology.
Published laboratory studies have suggested that SARS virus infection and its lung injury are related to angiotensin-converting enzyme 2 (ACE2) in lung tissue. And ACE and ACE2 in the renin-angiotensin system (RAS) are vital central links to maintain hemodynamic stability and normal heart and kidney function in vivo.
A large amount of evidence-based medical evidence shows that ACE inhibitors are the basic therapeutic drugs for maintaining hypertension, reducing the risk of cardiovascular, cerebrovascular, and renal adverse events, improving quality of life, and prolonging life in patients with hypertension. Recent experimental studies suggest that treatment with ACE inhibitors can significantly reduce pulmonary inflammation and cytokine release caused by coronavirus infection.
ACEI treatment
hypertension patients with ACEI treatment when suffered with novel coronavirus infection in China
hypertension patients without ACEI treatment when suffered with novel coronavirus infection in China
The First Affiliated Hospital of Chongqing Medical University Chongqing, China
Sponsors and Collaborators Chongqing Medical University
Responsible PI: Dongying Zhang, Associate Professor, Chongqing Medical University
Withdrawn (Similar projects have been registered, and it needs to be withdrawn.)
Clinical Trial for the Use of Nitric Oxide to Treat Severe COVID-19 Infection
Posted in COVID-19, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Nitric Oxide in Health and Disease, Population Health Management, Population Health Management, Genetics & Pharmaceutical, SARS-CoV-2, Virus Infective Acute Respiratory Syndrome: SARS-CoV on April 14, 2020| Leave a Comment »
. 2009 Dec 5;395(1):1-9.
doi: 10.1016/j.virol.2009.09.007. Epub 2009 Oct 1.
Dual Effect of Nitric Oxide on SARS-CoV Replication: Viral RNA Production and Palmitoylation of the S Protein Are Affected
Sara Akerström1, Vithiagaran Gunalan, Choong Tat Keng, Yee-Joo Tan, Ali Mirazimi
Affiliations expand
DOI: 10.1016/j.virol.2009.09.007
Free PMC article
Nitric oxide is an important molecule playing a key role in a broad range of biological process such as neurotransmission, vasodilatation and immune responses. While the anti-microbiological properties of nitric oxide-derived reactive nitrogen intermediates (RNI) such as peroxynitrite, are known, the mechanism of these effects are as yet poorly studied. Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) belongs to the family Coronaviridae, was first identified during 2002-2003. Mortality in SARS patients ranges from between 6 to 55%. We have previously shown that nitric oxide inhibits the replication cycle of SARS-CoV in vitro by an unknown mechanism. In this study, we have further investigated the mechanism of the inhibition process of nitric oxide against SARS-CoV. We found that peroxynitrite, an intermediate product of nitric oxide in solution formed by the reaction of NO with superoxide, has no effect on the replication cycle of SARS-CoV, suggesting that the inhibition is either directly effected by NO or a derivative other than peroxynitrite. Most interestingly, we found that NO inhibits the replication of SARS-CoV by two distinct mechanisms.
Firstly, NO or its derivatives cause a reduction in the palmitoylation of nascently expressed spike (S) protein which affects the fusion between the S protein and its cognate receptor, angiotensin converting enzyme 2.
Secondly, NO or its derivatives cause a reduction in viral RNA production in the early steps of viral replication, and this could possibly be due to an effect on one or both of the cysteine proteases encoded in Orf1a of SARS-CoV.
A Possible Explanation for the COVID-19 Racial Disparity
— And a possible solution
by Jason Kidde MS, MPAS, PA-C April 18, 2020
While the pathophysiology of hypertension is complex and multifaceted, there are notable racial differences. In the context of COVID-19, the most suspicious difference is a comparative deficiency of L-arginine and subsequently nitric oxide (NO). In this lies a potential explanation for the COVID-19 race disparity
NO is a gas synthesized by our cells and has multiple roles, but perhaps is best known for vascular dilation. In short, NO facilitates relaxation of vascular smooth muscle allowing vessel dilation and increased blood flow.
This on its own has potential implications in acute respiratory distress syndrome (ARDS), a condition that results from severe COVID-19 infection. By improving blood flow across the entire lung, this theoretically results in improved gas exchange and oxygenation of the blood. In fact, there is research that inhaled NO improved oxygenation and other clinical outcomes in SARS-1 patients, and current research in COVID-19 coronavirus (SARS-CoV-2) supports this previously demonstrated efficacy.
Additionally, abnormal blood clotting is an increasingly recognized complication of this disease, both systemically and within the pulmonary circulation. In fact, one of the greatest predictors of death is a serum blood test that indicates elevated clotting activity. Most recently, some physicians have suggested that small clots within the lungs are central to pathogenesis and have administered clot busting drugs known as thrombolytics which abruptly improve oxygenation, albeit transiently, as the medication effect weans and the predisposition to clot formation persists. NO inhibits clot formation, and deficiency may contribute to a prothrombotic state. In fact, it has been shown that inhaled NO decreases the propensity of clotting in ARDS.
However, perhaps the most convincing role of nitric oxide in this disease is its antiviral properties. SARS-CoV-2 infects cells by attaching to a receptor on the lining of the airways called angiotensin-converting enzyme 2 (ACE2). This is the same mechanism by which SAR-1 infects cells. NO specifically alters a surface protein on SARS-1, known as the spike protein, such that it cannot attach to the ACE2 receptor. This results in blocking viral entry into the cell as well as the subsequent replication of the virus. Since SARS-CoV-2 shares the same mechanism of cell entry, we can relatively confidently assume that NO would have a similar effect regarding this novel virus.
Knowing that NO deficiency is common in African Americans and that this population is disproportionately dying from an infection that can be blocked by this gas, augmenting NO seems like a reasonable therapeutic target. While NO is being used as an inhaled gas via mechanical ventilation, this is only suitable for someone ill enough to require mechanical ventilation.
A better way to increase nitric oxide in the minimally ill or even uninfected is to augment the body's ability to create it. There are many pharmacologic ways to do this; however, potentially the most effective, cheapest, and lowest risk is to supplement with the precursor amino-acids L-arginine and L-citrulline. We already know these nutritional supplements result in this very effect and that there seems to be a more potent effect of supplementation on NO production in L-arginine-deficient African Americans.
Therefore, a reasonable action is to expedite clinical trials to further investigate this theory. At a minimum, we need to start a conversation to improve our understanding of the role of nitric oxide deficiency as a risk factor for disease severity. It is my strong belief that augmenting NO via L-arginine and L-citrulline not only has potential for treatment and reducing progression to severe illness, but given the safety profile, it may be most valuable as a preventative measure.
It could save many lives at a minimal cost.
Jason Kidde, MS, MPAS, is a physician assistant at University of Utah Health in Salt Lake City.
https://www.medpagetoday.com/infectiousdisease/covid19/86023?xid=nl_mpt_SRCardiology_2020-04-21&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_042120&utm_term=NL_Spec_Cardiology_Update_Active
Previous research found nitric oxide has antiviral properties against coronaviruses.
FeaturedNeuroscience
ummary: A new clinical trial is enrolling patients with severe COVID-19 symptoms to assess the effect of nitric oxide in treating the virus. Previous research found nitric oxide has antiviral properties against coronaviruses. The effect was tested and demonstrated during the SARS outbreak in the early 2000s.
Source: University of Alabama at Birmingham
The University of Alabama at Birmingham has been selected to begin enrolling patients in an international study assessing the use of inhaled nitric oxide (iNO) to improve outcomes for COVID-19 patients with severely damaged lungs.
iNO has been used for the treatment of failing lungs, but it was also found to have antiviral properties against coronaviruses
"In humans, nitric oxide is generated within the blood vessels and regulates blood pressure, and prevents formation of clots and also destroys potential toxins," Arora said.
The UAB team says this pandemic has led to an extraordinary unifying response by the medical community, including ICU physicians, nurses, respiratory therapists, clinical trial specialists, reviewers and medical administrators, allowing for faster than normal approvals for potentially lifesaving research studies.
"The fact that we are able to get this trial started quickly was due to collaborations across specialties and fields of expertise at UAB with the common goal of providing the highest quality of scientifically proven care for our COVID-19 patients," Arora said. "We are all trying to fight this together, and I hope, with our resilience, we shall overcome these difficult times."
Adam Pope – University of Alabama at Birmingham
The image is credited to University of Alabama at Birmingham.
https://neurosciencenews.com/coronavirus-nitric-oxide-16134/
Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use of iNO in the Institutional Market, Therapy Demand and Cost of Care vs. Existing Supply Solutions
https://pharmaceuticalintelligence.com/2013/06/03/clinical-indications-for-use-of-inhaled-nitric-oxide-ino-in-the-adult-patient-market-clinical-outcomes-after-use-therapy-demand-and-cost-of-care/
Series A: e-Books on Cardiovascular Diseases
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Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1) Kindle Edition
by Margaret Baker PhD(Author), Tilda Barliya PhD(Author), Anamika Sarkar PhD(Author), Ritu Saxena PhD(Author), Stephen J. Williams PhD(Author), Larry Bernstein MD FCAP(Editor), Aviva Lev-Ari PhD RN(Editor), Aviral Vatsa PhD(Editor) Format: Kindle Edition
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Book 1 of 6 in Series A: Cardiovascular Diseases
Nitric Oxide Basic Research
1.1 Discovery of Nitric Oxide
1.1.1 Discovery of Nitric Oxide and its Role in Vascular Biology
Aviral Vatsa, PhD, MBBS
1.1.2 Nitric Oxide: The Nobel Prize in Physiology or Medicine
Aviva Lev-Ari, PhD, RN
1.2 Nitric Oxide Synthase(s)
1.2.1 Nitric Oxide: A Short Historic Perspective
1.2.2 Nitric Oxide: Role in Cardiovascular Health and Disease
1.3 Endothelial Blood Cell Interactions: Platelet, Leukocyte and Monocyte
1.3.1 Nitric Oxide: Chemistry and Function
1.4 Signaling Pathways
1.4.1 Nitric Oxide Signaling Pathways
1.4.2 Nitric Oxide has a Ubiquitous Role in the Regulation of Glycolysis – with a Concomitant Influence on Mitochondrial Function
Larry H. Bernstein, MD, FCAP
1.5 Oxidative Stress
1.5.1 Mitochondrial Damage and Repair under Oxidative Stress
1.6 Oxygen and Nitrogen Reactive Species
1.6.1 Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium
Larry H Bernstein, MD, FCAP
1.6.2 Prostacyclin and Nitric Oxide: Adventures in vascular biology – a tale of two mediators
Nitric Oxide and Circulatory Diseases
2.1 Endothelial Dysruption and Denudation
2.1.1 Blood-vessels-generating Stem Cells Discovered
Ritu Saxena, PhD
2.1.2 Differential Distribution of Nitric Oxide – A 3-D Mathematical Model
Anamika Sarkar, PhD
2.1.3 Nitric Oxide Nutritional Remedies for Hypertension and Atherosclerosis. It's 12AM: Do you know where your electrons are?
Meg Baker, PhD
2.2 Endothelin and ET Receptors
2.2.1 Statins' Nonlipid Effects on Vascular Endothelium through eNOS Activation
2.2.2 Endothelial Function and Cardiovascular Disease
2.2.3 Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation: Observations on Intellectual Property Development for an Unrecognized Future Fast Acting Therapy for Patients at High Risk for Macrovascular Events
Therapeutic Cardiovascular Targets
3.1 Nitric oxide and therapeutic Targets
3.1.1 Cardiovascular Disease (CVD) and the Role of Agent Alternatives in Endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production
3.1.2 Telling NO to Cardiac Risk
Stephen W Williams, PhD
3.1.3 Nitric Oxide and its Impact on Cardiothoracic Surgery
Tilda Barliya PhD
3.2 Therapeutic opportunities for Endothelial Progenitor Cells
3.2.1 Inhibition of ET-1, ETA and ETA-ETB, Induction of Nitric Oxide production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): eEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography
3.2.2 Bystolic's generic Nebivolol – Positive Effect on circulating Endothelial Progenitor Cells Endogenous Augmentation
3.2.3 Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral
3.2.4 Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs
3.3 Hypertension, Congestive Heart Failure and Endothelin Biomarker
3.3.1 Clinical Trials Results for Endothelin System: Pathophysiological Role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Markers of Disease Severity or Genetic Determination?
3.4 Hypotension and Shock: Cardiovascular Collapse
3.4.1 Nitric Oxide and Sepsis, Hemodynamic Collapse and the Search for Therapeutic Options
3.4.2 Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control
3.5 Hemorrhagic and Thrombo-embolic Events
3.5.1 Nitric Oxide Function in Coagulation
Nitric Oxide and Neurodegenerative Diseases
4.1 Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?
Stephen J. Williams, PhD
Bone Metabolism
5.1 Nitric Oxide in Bone Metabolism
Nitric Oxide and Systemic Inflammatory Disease
6.1 Nitric Oxide and Immune Responses: Part 1
6.3 Nitric Oxide Production in Systemic Sclerosis
Aviral Vatsa, PhD. MBBS
Nitric Oxide: Lung and Alveolar Gas Exchange
7.1 'Lung on a Chip'
Ritu Saxena, Ph.D.
7.2 Low Bioavailability of Nitric Oxide due to Misbalance in Cell Free Hemoglobin in Sickle Cell Disease – A Computational Model
Anamika Sarkar, Ph.D.
7.3 The Rationale and Use of Inhaled Nitric Oxide in Pulmonary Artery Hypertension and Right Sided Heart Failure
7.4 Transposon-mediated Gene Therapy improves Pulmonary Hemodynamics and attenuates Right Ventricular Hypertrophy: eNOS gene therapy reduces Pulmonary vascular remodeling and Arterial wall hyperplasia
Nitric Oxide and Kidney Dysfunction
8.1 Part I: The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide
8.2 Part II: Nitric Oxide and iNOS have Key Roles in Kidney Diseases
8.3 Part III: The Molecular Biology of Renal Disorders: Nitric Oxide
8.4 Part IV: New Insights on Nitric Oxide Donors
8.5 The Essential Role of Nitric Oxide and Therapeutic Nitric Oxide Donor Targets in Renal Pharmacotherapy
Nitric Oxide and Cancer
9.1 Crucial role of Nitric Oxide in Cancer
Nitric oxide and its role in vascular biology
Injectable inclisiran (siRNA) as 3rd anti-PCSK9 behind mAbs Repatha and Praluent
Posted in Atherogenic Processes & Pathology, Drug Delivery Platform Technology, Exosomes: Natural Carriers for siRNA Delivery, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Gene Therapy & Gene Editing Development, Genome Biology, Genomics Pharmacy, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease on November 18, 2019| Leave a Comment »
Combining AstraZeneca's 'good' cholesterol booster with PCSK9 inhibition shows promise in heart disease
by Angus Liu |
The drug, dubbed MEDI5884, is designed to neutralize a circulating enzyme called endothelial lipase. The protein regulates HDL in the blood by breaking down lipids called phospholipids. Previous studies have found increased endothelial lipase levels in people with obesity and coronary artery disease.
In monkeys, blocking endothelial lipase with MEDI5884 increased plasma HDL-C in a dose-dependent manner, the AZ team reported in a study published in Science Translational Medicine. At the highest dose tested, researchers recorded a roughly twofold increase in HDL-C within two weeks. The effect lasted throughout the two-month study.
RELATED: Regeneron's Evkeeza, carrying big price tag, wins FDA approval in ultra-rare cholesterol disease
The AZ team also tested the drug in a small group of healthy volunteers in a phase 1 study. The treatment increased HDL-C—though to a lesser extent than it had in the monkeys—without causing any major side effects, the researchers said. The drug also increased the size and number of HDL particles.
Oddly, the researchers also observed a concurrent increase in bad cholesterol in both monkeys and humans. So they decided to combine MEDI5884 with an anti-PCSK9 antibody drug. The FDA has approved two PCSK9 inhibitors to lower LDL-C and reduce CV risks: Sanofi and Regeneron's Praluent and Amgen's Repatha.
In monkeys pretreated with a PCSK9 inhibitor, MEDI5884 raised HDL-C to a similar degree while the magnitude of the increase in LDL-C was reduced, according to the team.
PCSK9 drugs once carried megablockbuster potential thanks to their strong LDL-lowering effects, but neither Praluent nor Repatha has lived up to expectations. Payer pressure and an ongoing price war haven't helped either player in the market.
The AZ team suggested combining endothelial lipase inhibition with a PCSK9 blockade could enhance the efficacy of each component. "[I]t is intriguing to consider dual inhibition of EL and PCSK9 and the potential for synergy that may arise from combined action of the two complementary mechanisms, both targeting different aspects of [reverse cholesterol transport]," the scientists wrote in the study.
https://www.fiercebiotech.com/research/combination-astrazeneca-s-booster-good-cholesterol-and-pcsk9-inhibition-shows-promise-for?mkt_tok=Mjk0LU1RRi0wNTYAAAF8sqquETWOW6kv9ecI1ikHVxrB3MWy4NubkNVJKoZOj4sPNcjIYQiDqfMjH6GAiU0bTgxkNFh_lPioA6TvQOFf_kjQSRvue6JVXWUKGDW1qltaaE4&mrkid=993697
Next stop, filing for approval. The Medicines Company has said it plans to submit inclisiran for FDA review by the end of 2019 and EMA review in the first quarter of 2020. If the drug's approved it'll be the third anti-PCSK9 behind mAbs Repatha and Praluent, and could try to compete on price to gain market share.
The company's been very careful not to disclose its pricing plans for inclisiran, said ORION-10 principal investigator Dr. Scott Wright, professor and cardiologist at the Mayo Clinic. But, Wright said, The Medicines Co. and other companies he advises on clinical trial design "have learned the lesson from the sponsors of the monoclonal antibodies [against PCSK9], they're not going to come in and price a drug that's out of proportion to what the market will bear."
Because the anti-PCSK9 mAbs were initially priced beyond what patients and insurers were willing to pay, "now most of the physicians that I meet have a resistance to using them just because they're fearful about the pre-approval process" with insurers, said Wright. "They're much easier to get approved and paid for today than they've ever been, but that message is not out in the medical community yet."
From: "STAT: AHA in 30 Seconds" <newsletter@statnews.com>
Reply-To: "STAT: AHA in 30 Seconds" <newsletter@statnews.com>
Date: Monday, November 18, 2019 at 2:59 PM
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Subject: Interim look at Amarin data, an inclisiran update, & Philly's giant heart
Transthyretin amyloid cardiomyopathy (ATTR-CM): U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ for this Rare and Fatal Disease
Posted in Cardiomyopathy, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Pharmacotherapy of Cardiovascular Disease, Transthyretin amyloid cardiomyopathy (ATTR-CM) on October 29, 2019| Leave a Comment »
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
DOI: 10.1056/NEJMoa2107454
Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.
After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study.
Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram.
In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.)
Trialists Attack $225K Heart Drug Price Tag
Cardiologists who helped run the pivotal study of Pfizer's heart drug tafamidis (Vyndaqel/Vyndamax) are criticizing the drug's $225,000 annual price tag, Bloomberg reports.
Mathew Maurer, MD, of Columbia University, and three other doctors involved in the trial started speaking out after seeing patients' financial struggles after the drug's market launch earlier this year.
For example: John Rufenacht, a 73-year-old interior designer in Kansas City, Missouri, has Medicare but his out-of-pocket cost was $6,000 for a 90-day supply of the drug, which treats cardiac transthyretin amyloidosis. Rufenacht doesn't qualify for Pfizer's patient assistance programs, most of which direct patients to charities to help them pay.
Maurer aired his complaints in front of colleagues at the Heart Failure Society of America meeting in September, and at the American Heart Association meeting earlier this week, where he and colleagues reported a cost-effectiveness study on the drug, showing it's only cost-effective with a more than 90% price reduction — a cost of $16,563 a year.
Pfizer says its price is appropriate, given the small number of patients in the U.S. with the condition who will receive it — some 100,000 to 150,000, the company estimates. But Maurer and critics say that's likely an underestimate. Diagnosis requires an invasive heart biopsy; there was little incentive to do that when no approved treatment was available.
The company promised to cut the price if more patients start taking the drug.
https://www.medpagetoday.com/publichealthpolicy/ethics/83459?xid=nl_badpractice_2019-11-22&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=BadPractice_112219&utm_term=NL_Gen_Int_Bad_Practice%20-%20Active
Click here to learn more about Pfizer's Rare Disease portfolio and how we empower patients, engage communities in our clinical development programs, and support programs that heighten disease awareness.
U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ FOR USE IN PATIENTS WITH TRANSTHYRETIN AMYLOID CARDIOMYOPATHY, A RARE AND FATAL DISEASE
— First and only medicines approved for patients with either wild-type or hereditary transthyretin amyloid cardiomyopathy —
Monday, May 6, 2019 – 6:45am
NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) announced today that the U.S. Food and Drug Administration (FDA) has approved both VYNDAQEL® (tafamidis meglumine) and VYNDAMAX™ (tafamidis) for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. VYNDAQEL and VYNDAMAX are two oral formulations of the first-in-class transthyretin stabilizer tafamidis, and the first and only medicines approved by the FDA to treat ATTR-CM.
Transthyretin amyloid cardiomyopathy is a rare, life-threatening disease characterized by the buildup of abnormal deposits of misfolded protein called amyloid in the heart and is defined by restrictive cardiomyopathy and progressive heart failure. Previously, there were no medicines approved to treat ATTR-CM; the only available options included symptom management, and, in rare cases, heart (or heart and liver) transplant. It is estimated that the prevalence of ATTR-CM is approximately 100,000 people in the U.S. and only one to two percent of those patients are diagnosed today.
"The approvals of VYNDAQEL and VYNDAMAX are a testament to the significant research and development investment in our innovative cardiovascular outcomes trial, ATTR-ACT. We are proud to bring these medicines to ATTR-CM patients who are in dire need of treatment," said Brenda Cooperstone, MD, Senior Vice President and Chief Development Officer, Rare Disease, Pfizer Global Product Development. "VYNDAQEL and VYNDAMAX reduce cardiovascular mortality and the frequency of cardiovascular-related hospital stays in patients with wild-type or hereditary forms of this rare disease, giving them a chance for more time with their loved ones."
"Pfizer's purpose is to deliver breakthrough medicines that change patients' lives. The approvals of VYNDAQEL and VYNDAMAX deliver on this promise for patients with ATTR-CM," said Paul Levesque, Global President, Rare Disease. "This milestone is a gamechanger for patients, who until today had no approved medicines for this rare, debilitating and fatal disease. We will continue to focus efforts on working with the physician community to increase awareness and ultimately detection and diagnosis of this disease."
The recommended dosage is either VYNDAQEL 80 mg orally once-daily, taken as four 20 mg capsules, or VYNDAMAX 61 mg orally once-daily, taken as a single capsule. VYNDAMAX was developed for patient convenience; VYNDAQEL and VYNDAMAX are not substitutable on a per milligram basis.
"ATTR-CM is not only fatal, but also significantly underdiagnosed, with some patients cycling through multiple doctors and a myriad of tests over a period of years while the disease progresses," said Isabelle Lousada, Founder and CEO, Amyloidosis Research Consortium. "ATTR-CM is a rare disease for which more education and awareness is needed. The approval of these medicines represents an important advance for patients; however, it is equally important that we work as a community to recognize the critical importance of early diagnosis."
The FDA approval was based on data from the pivotal Phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), the first global, double-blind, randomized, placebo-controlled clinical study to investigate a pharmacological therapy for the treatment of this disease. In ATTR-ACT, VYNDAQEL significantly reduced the hierarchical combination of all-cause mortality and frequency of cardiovascular-related hospitalizations compared to placebo over a 30-month period (p=0.0006). Additionally, individual components of the primary analysis demonstrated a relative reduction in the risk of all-cause mortality and frequency of cardiovascular-related hospitalization of 30% (p=0.026) and 32% (p<0.0001), respectively, with VYNDAQEL versus placebo. Approximately 80% of total deaths were cardiovascular-related in both treatment groups. VYNDAQEL also had significant and consistent treatment effects compared to placebo on functional capacity and health status first observed at six months and continuing through 30 months. Specifically, VYNDAQEL reduced the decline in performance on the six-minute walk test (p<0.0001) and reduced the decline in health status as measured by the Kansas City Cardiomyopathy Questionnaire – Overall Summary score (p<0.0001). VYNDAQEL was well tolerated in this study, with an observed safety profile comparable to placebo. The frequency of adverse events in patients treated with VYNDAQEL was similar to placebo, and similar proportions of VYNDAQEL-treated patients and placebo-treated patients discontinued the study drug because of an adverse event.
Pfizer is committed to helping eligible ATTR-CM patients who have been prescribed VYNDAQEL or VYNDAMAX gain appropriate access. Pfizer supports patients by helping them understand their insurance coverage requirements and can connect eligible patients with financial assistance resources which may be available including the Pfizer Patient Assistance Program.*
About ATTR-CM
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and fatal condition that is caused by destabilization of a transport protein called transthyretin, which is composed of four identical sub units (a tetramer). When unstable transthyretin tetramers dissociate, they result in misfolded proteins that aggregate into amyloid fibrils and deposit in the heart, causing the heart muscle to become stiff, eventually resulting in heart failure. There are two sub-types of ATTR-CM: hereditary, also known as variant, which is caused by a mutation in the transthyretin gene and can occur in people as early as their 50s and 60s; or with no mutation and associated with aging, known as the wild-type form, which is thought to be more common and usually affects men after age 60. Often ATTR-CM is diagnosed only after symptoms have become severe. Once diagnosed, the median life expectancy in patients with ATTR-CM, dependent on sub-type, is approximately two to 3.5 years.
About VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis)
VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis) are oral transthyretin stabilizers that selectively bind to transthyretin, stabilizing the tetramer of the transthyretin transport protein and slowing the formation of amyloid that causes ATTR-CM.
VYNDAMAX 61 mg is a once-daily oral capsule developed for patient convenience. VYNDAQEL and VYNDAMAX are not substitutable on a per milligram basis.
VYNDAQEL was granted Orphan Drug Designation for ATTR-CM in both the EU and U.S. in 2012 and in Japan in 2018. In June 2017 and May 2018, respectively, the FDA granted VYNDAQEL Fast Track and Breakthrough Therapy designations for ATTR-CM. In November 2018, the FDA granted Priority Review for the new drug application (NDA) for VYNDAQEL.
In March 2019, the Ministry of Labor Health and Welfare in Japan approved VYNDAQEL, under SAKIGAKE designation, for patients with wild-type and variant forms of ATTR-CM. Regulatory submissions for the use of VYNDAQEL in patients with ATTR-CM have been submitted to the European Medicines Agency (EMA) and are under review.
VYNDAQEL was first approved in 2011 in the EU for the treatment of transthyretin amyloid polyneuropathy (ATTR-PN), in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. ATTR-PN is a neurodegenerative form of amyloidosis that leads to sensory loss, pain and weakness in the lower limbs and impairment of the autonomic nervous system, Currently, it is approved for ATTR-PN in 40 countries, including Japan, countries in Europe, Brazil, Mexico, Argentina, Israel, Russia, and South Korea. VYNDAQEL and VYNDAMAX are not approved for the treatment of ATTR-PN in the U.S.
https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_vyndaqel_and_vyndamax_for_use_in_patients_with_transthyretin_amyloid_cardiomyopathy_a_rare_and_fatal_disease