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Science Policy Forum: Should we trust healthcare explanations from AI predictive systems?

Some in industry voice their concerns

Curator: Stephen J. Williams, PhD

Post on AI healthcare and explainable AI

   In a Policy Forum article in ScienceBeware 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.

Summary

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

  1.  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.
  2. 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:

  • Age
  • 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

 

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19 of the 49 New Therapeutic Molecular Entities FDA approved in 2020 — as well as a new Cell-based therapy — are Personalized Medicines

Reporter: Aviva Lev-Ari, PhD, RN

 

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.

 

SOURCE

https://mma.prnewswire.com/media/1436855/PM_at_FDA_The_Scope_Significance_of_Progress_in_2020.pdf?p=pdf

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Did FDA Reverse Course on Convalescent Plasma Therapy for COVID-19?

Reporter: Stephen J. Williams, PhD

 

Starting with a timeline of recent announcements by the FDA on convalescent plasma therapy

April 16, 2020

FDA STATEMENT

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-led 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

August 23, 2020

 

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:

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.

Background

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.

Pathways for Use of Investigational COVID-19 Convalescent Plasma

The following pathways are available for administering or studying the use of COVID-19 convalescent plasma:

  1. Clinical Trials

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.

  1. Expanded Access

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 Protocol

  1. 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

August 23, 2020

 

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.

 

August 24, 2020

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

 

 

August 25, 2020

 

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

KEY POINTS

  • 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

https://twitter.com/SteveFDA/status/1298071619236245504?s=20

August 26, 2020

In an interview with Bloomberg’s , 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/

 

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National Public Radio interview with Dr. Anthony Fauci on his optimism on a COVID-19 vaccine by early 2021

Reporter: Stephen J. Williams, PhD

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

  1. universal wearing of masks
  2. distancing properly from each other
  3. 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.

Going back to school

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

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

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Updated listing of COVID-19 vaccine and therapeutic trials from NIH Clinical Trials.gov

Curator: Stephen J. Williams, PhD

 

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)

Study Description

Go to 

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

 

Detailed Description:

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)

Study Description

Go to 

Brief Summary:

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.

 

Detailed Description:

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

Study was withdrawn before participants were enrolled.

 

Therapy for Pneumonia Patients iInfected by 2019 Novel Coronavirus (NCT04293692)

Study Description

Go to 

Brief Summary:

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.

Detailed Description:

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.

Sponsor:

Puren Hospital Affiliated to Wuhan University of Science and Technology

Collaborator:

Wuhan Hamilton Bio-technology Co., Ltd

Study was withdrawn before participants were enrolled.

 

Prognositc Factors in COVID-19 Patients Complicated With Hypertension (NCT04272710)

Study Description

Brief Summary:

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

Detailed Description:

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

Control

hypertension patients without ACEI treatment when suffered with novel coronavirus infection in China

 

Locations

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.)

Read Full Post »

Clinical Trial for the Use of Nitric Oxide to Treat Severe COVID-19 Infection

Reporter and Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED 5/26/2020

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

Affiliations expand

Free PMC article

Abstract

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.

 

UPDATED ON 4/21/2020

A Possible Explanation for the COVID-19 Racial Disparity

— And a possible solution

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.

Last Updated April 21, 2020
SOURCE

 

Previous research found nitric oxide has antiviral properties against coronaviruses.

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.”

SOURCE
Source:
University of Alabama at Birmingham
Media Contacts:
Adam Pope – University of Alabama at Birmingham
Image Source:
The image is credited to University of Alabama at Birmingham.

Other related articles published in this Open Access Online Scientific Journal include the following:

  • 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

Curator: Aviva Lev-Ari, PhD, RN

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

 

BUNDLED BY AMAZON.COM INTO A SIX-VOLUME SERIES FOR $515

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Six Volumes

  1. Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms. On com since 6/21/2013 https://lnkd.in/8DANfq
  2. Cardiovascular Diseases, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation. On com since 11/30/2015 https://lnkd.in/ekbuNZ3
  3. Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics. On com since 11/29/2015 https://lnkd.in/ecp5mrA
  4. Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases. On com since 12/26/2015 https://lnkd.in/dwqM3K3
  5. Cardiovascular Diseases, Volume Five: Pharmacological Agents in Treatment of Cardiovascular Diseases. On com since 12/23/2018 https://lnkd.in/e3r87cQ
  6. Cardiovascular Diseases, Volume Six: Interventional Cardiology for Disease Diagnosis and Cardiac Surgery for Condition Treatment. On com since 12/24/2018 https://lnkd.in/e_CTb4R

  • Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms. On Amazon.com since 6/21/2013

http://www.amazon.com/dp/B00DINFFYC

Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1) by [Margaret Baker PhD, Tilda Barliya PhD, Anamika Sarkar PhD, Ritu Saxena PhD, Stephen J. Williams PhD, Larry Bernstein MD FCAP, Aviva Lev-Ari PhD RN, Aviral Vatsa PhD]

Perspectives on Nitric Oxide in Disease Mechanisms (Biomed e-Books Book 1) Kindle Edition

Table of Contents

Chapter 1:

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

Aviral Vatsa, PhD, MBBS

1.2.2 Nitric Oxide: Role in Cardiovascular Health and Disease

Aviral Vatsa, PhD, MBBS

1.3 Endothelial Blood Cell Interactions: Platelet, Leukocyte and Monocyte

1.3.1 Nitric Oxide: Chemistry and Function

Aviral Vatsa, PhD, MBBS

1.4 Signaling Pathways

1.4.1 Nitric Oxide Signaling Pathways

Aviral Vatsa, PhD, MBBS

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

Larry H. Bernstein, MD, FCAP

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

Aviva Lev-Ari, PhD, RN

 

Chapter 2:

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

Larry H Bernstein, MD, FCAP

2.2.2 Endothelial Function and Cardiovascular Disease

Larry H Bernstein, MD, FCAP

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

Aviva Lev-Ari, PhD, RN

Chapter 3:

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

Aviva Lev-Ari, PhD, RN

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

Aviva Lev-Ari, PhD, RN

3.2.2 Bystolic’s generic Nebivolol – Positive Effect on circulating Endothelial Progenitor Cells Endogenous Augmentation

Aviva Lev-Ari, PhD, RN

3.2.3 Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Aviva Lev-Ari, PhD, RN

3.2.4 Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, RN

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?

Aviva Lev-Ari, PhD, RN

3.4 Hypotension and Shock: Cardiovascular Collapse

3.4.1 Nitric Oxide and Sepsis, Hemodynamic Collapse and the Search for Therapeutic Options

Larry H Bernstein, MD, FCAP

3.4.2 Sepsis, Multi-organ Dysfunction Syndrome, and Septic Shock: A Conundrum of Signaling Pathways Cascading Out of Control

Larry H Bernstein, MD, FCAP

3.5 Hemorrhagic and Thrombo-embolic Events

3.5.1 Nitric Oxide Function in Coagulation

Larry H Bernstein, MD, FCAP

Chapter 4:

Nitric Oxide and Neurodegenerative Diseases

4.1 Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?

Stephen J. Williams, PhD

Chapter 5:

Bone Metabolism

5.1 Nitric Oxide in Bone Metabolism

Aviral Vatsa, PhD, MBBS

Chapter 6:

Nitric Oxide and Systemic Inflammatory Disease

6.1 Nitric Oxide and Immune Responses: Part 1

Aviral Vatsa, PhD, MBBS

6.2 Nitric Oxide and Immune Responses: Part 2

Aviral Vatsa, PhD, MBBS

6.3 Nitric Oxide Production in Systemic Sclerosis

Aviral Vatsa, PhD. MBBS

Chapter 7:

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

Larry H Bernstein, MD, FCAP

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

Aviva Lev-Ari, PhD, RN

Chapter 8:

Nitric Oxide and Kidney Dysfunction

8.1 Part I: The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide

Larry H. Bernstein, MD, FCAP

8.2 Part II: Nitric Oxide and iNOS have Key Roles in Kidney Diseases

Larry H. Bernstein, MD, FCAP

8.3 Part III: The Molecular Biology of Renal Disorders: Nitric Oxide

Larry H. Bernstein, MD, FCAP

8.4 Part IV: New Insights on Nitric Oxide Donors

Larry H. Bernstein, MD, FCAP

8.5 The Essential Role of Nitric Oxide and Therapeutic Nitric Oxide Donor Targets in Renal Pharmacotherapy

Larry H. Bernstein, MD, FCAP

Chapter 9:

Nitric Oxide and Cancer

9.1 Crucial role of Nitric Oxide in Cancer

Ritu Saxena, Ph.D.

Summary

Nitric oxide and its role in vascular biology

 

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Injectable inclisiran (siRNA) as 3rd anti-PCSK9 behind mAbs Repatha and Praluent

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 4/27/2021

Combining AstraZeneca’s ‘good’ cholesterol booster with PCSK9 inhibition shows promise in heart disease

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.

SOURCE

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.”

SOURCE

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

Read Full Post »

Transthyretin amyloid cardiomyopathy (ATTR-CM): U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ for this Rare and Fatal Disease

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 6/30/2021

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

June 26, 2021
DOI: 10.1056/NEJMoa2107454

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.)

SOURCE

https://www.nejm.org/doi/full/10.1056/NEJMoa2107454

UPDATED on 11/22/2019

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.

SOURCE

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
EDT

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.

SOURCE

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

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eProceedings for BIO 2019 International Convention, June 3-6, 2019 Philadelphia Convention Center; Philadelphia PA, Real Time Coverage by Stephen J. Williams, PhD @StephenJWillia2

 

CONFERENCE OVERVIEW

Real Time Coverage of BIO 2019 International Convention, June 3-6, 2019 Philadelphia Convention Center; Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/05/31/real-time-coverage-of-bio-international-convention-june-3-6-2019-philadelphia-convention-center-philadelphia-pa/

 

LECTURES & PANELS

Real Time Coverage @BIOConvention #BIO2019: Machine Learning and Artificial Intelligence: Realizing Precision Medicine One Patient at a Time, 6/5/2019, Philadelphia PA

Reporter: Stephen J Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/05/real-time-coverage-bioconvention-bio2019-machine-learning-and-artificial-intelligence-realizing-precision-medicine-one-patient-at-a-time/

 

Real Time Coverage @BIOConvention #BIO2019: Genome Editing and Regulatory Harmonization: Progress and Challenges, 6/5/2019. Philadelphia PA

Reporter: Stephen J Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/05/real-time-coverage-bioconvention-bio2019-genome-editing-and-regulatory-harmonization-progress-and-challenges/

 

Real Time Coverage @BIOConvention #BIO2019: Precision Medicine Beyond Oncology June 5, 2019, Philadelphia PA

Reporter: Stephen J Williams PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/05/real-time-coverage-bioconvention-bio2019-precision-medicine-beyond-oncology-june-5-philadelphia-pa/

 

Real Time @BIOConvention #BIO2019:#Bitcoin Your Data! From Trusted Pharma Silos to Trustless Community-Owned Blockchain-Based Precision Medicine Data Trials, 6/5/2019, Philadelphia PA

Reporter: Stephen J Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/05/real-time-bioconvention-bio2019bitcoin-your-data-from-trusted-pharma-silos-to-trustless-community-owned-blockchain-based-precision-medicine-data-trials/

 

Real Time Coverage @BIOConvention #BIO2019: Keynote Address Jamie Dimon CEO @jpmorgan June 5, 2019, Philadelphia, PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/05/real-time-coverage-bioconvention-bio2019-keynote-address-jamie-dimon-ceo-jpmorgan-june-5-philadelphia/

 

Real Time Coverage @BIOConvention #BIO2019: Chat with @FDA Commissioner, & Challenges in Biotech & Gene Therapy June 4, 2019, Philadelphia, PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/04/real-time-coverage-bioconvention-bio2019-chat-with-fda-commissioner-challenges-in-biotech-gene-therapy-june-4-philadelphia/

 

Falling in Love with Science: Championing Science for Everyone, Everywhere June 4 2019, Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/04/real-time-coverage-bioconvention-bio2019-falling-in-love-with-science-championing-science-for-everyone-everywhere/

 

Real Time Coverage @BIOConvention #BIO2019: June 4 Morning Sessions; Global Biotech Investment & Public-Private Partnerships, 6/4/2019, Philadelphia PA

Reporter: Stephen J Williams PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/04/real-time-coverage-bioconvention-bio2019-june-4-morning-sessions-global-biotech-investment-public-private-partnerships/

 

Real Time Coverage @BIOConvention #BIO2019: Understanding the Voices of Patients: Unique Perspectives on Healthcare; June 4, 2019, 11:00 AM, Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/04/real-time-coverage-bioconvention-bio2019-understanding-the-voices-of-patients-unique-perspectives-on-healthcare-june-4/

 

Real Time Coverage @BIOConvention #BIO2019: Keynote: Siddhartha Mukherjee, Oncologist and Pulitzer Author; June 4 2019, 9AM, Philadelphia PA

Reporter: Stephen J. Williams, PhD. @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/04/real-time-coverage-bioconvention-bio2019-keynote-siddhartha-mukherjee-oncologist-and-pulitzer-author-june-4-9am-philadelphia-pa/

 

Real Time Coverage @BIOConvention #BIO2019:  Issues of Risk and Reproduceability in Translational and Academic Collaboration; 2:30-4:00 June 3, 2019, Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/03/real-time-coverage-bioconvention-bio2019-issues-of-risk-and-reproduceability-in-translational-and-academic-collaboration-230-400-june-3-philadelphia-pareal-time-coverage-bioconvention-bi/

 

Real Time Coverage @BIOConvention #BIO2019: What’s Next: The Landscape of Innovation in 2019 and Beyond. 3-4 PM June 3, 2019, Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/03/real-time-coverage-bioconvention-bio2019-whats-next-the-landscape-of-innovation-in-2019-and-beyond-3-4-pm-june-3-philadelphia-pa/

 

Real Time Coverage @BIOConvention #BIO2019: After Trump’s Drug Pricing Blueprint: What Happens Next? A View from Washington; June 3, 2019 1:00 PM, Philadelphia PA

Reporter: Stephen J. Williams, PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/03/real-time-coverage-bioconvention-bio2019-after-trumps-drug-pricing-blueprint-what-happens-next-a-view-from-washington-june-3-2019-100-pm-philadelphia-pa/

 

Real Time Coverage @BIOConvention #BIO2019: International Cancer Clusters Showcase June 3, 2019, Philadelphia PA

Reporter: Stephen J. Williams PhD @StephenJWillia2

https://pharmaceuticalintelligence.com/2019/06/03/real-time-coverage-bioconvention-bio2019-international-cancer-clusters-showcase-june-3-philadelphia-pa/

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Real Time Coverage @BIOConvention #BIO2019: Genome Editing and Regulatory Harmonization: Progress and Challenges

Reporter: Stephen J Williams, PhD @StephenJWillia2

 

Genome editing offers the potential of new and effective treatments for genetic diseases. As companies work to develop these treatments, regulators are focused on ensuring that any such products meet applicable safety and efficacy requirements. This panel will discuss how European Union and United States regulators are approaching therapeutic use of genome editing, issues in harmonization between these two – and other – jurisdictions, challenges faced by industry as regulatory positions evolve, and steps that organizations and companies can take to facilitate approval and continued efforts at harmonization.

 

CBER:  because of the nature of these gene therapies, which are mainly orphan, there is expedited review.  Since they started this division in 2015, they have received over 1500 applications.

Spark: Most of the issues were issues with the primary disease not the gene therapy so they had to make new endpoint tests so had talks with FDA before they entered phase III.   There has been great collaboration with FDA,  now they partnered with Novartis to get approval outside US.  You should be willing to partner with EU pharmas to expedite the regulatory process outside US.  In China the process is new and Brazil is behind on their gene therapy guidance.  However there is the new issue of repeat testing of your manufacturing process, as manufacturing of gene therapies had been small scale before. However he notes that problems with expedited review is tough because you don’t have alot of time to get data together.  They were lucky that they had already done a randomized trial.

Sidley Austin:  EU regulatory you make application with advance therapy you don’t have a national option, the regulation body assesses a committee to see if has applicability. Then it goes to a safety committee.  EU has been quicker to approve these advance therapies. Twenty five percent of their applications are gene therapies.  Companies having issues with manufacturing.  There can be issues when the final application is formalized after discussions as problems may arise between discussions, preliminary applications, and final applications.

Sarepta: They have a robust gene therapy program.  Their lead is a therapy for DMD (Duchenne’s Muscular Dystrophy) where affected males die by 25. Japan and EU have different regulatory applications and although they are similar and data can be transferred there is more paperwork required by EU.  The US uses an IND for application. Global feedback is very challenging, they have had multiple meetings around the world and takes a long time preparing a briefing package….. putting a strain on the small biotechs.  No company wants to be either just EU centric or US centric they just want to get out to market as fast as possible.

 

Please follow LIVE on TWITTER using the following @ handles and # hashtags:

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@pharma_BI

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# Hashtags

#BIO2019 (official meeting hashtag)

 

 

 

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