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UBC scientists unveil world’s first molecular-level analysis of Omicron spike protein

Researchers at UBC’s faculty of medicine have conducted the world’s first molecular-level structural analysis of the Omicron variant spike protein. The findings were published today in Science.  Credit: UBC Faculty of Medicine Researchers at UBC’s…

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Researchers at UBC’s faculty of medicine have conducted the world’s first molecular-level structural analysis of the Omicron variant spike protein. The findings were published today in Science

Credit: UBC Faculty of Medicine

Researchers at UBC’s faculty of medicine have conducted the world’s first molecular-level structural analysis of the Omicron variant spike protein. The findings were published today in Science

The analysis—done at near atomic resolution using cryo-electron microscopy—reveals how the heavily mutated Omicron variant attaches to and infects human cells. 

“Understanding the molecular structure of the viral spike protein is important as it will allow us to develop more effective treatments against Omicron and related variants in the future,” said lead author Dr. Sriram Subramaniam (he/him), professor in UBC’s department of biochemistry and molecular biology. “By analyzing the mechanisms by which the virus infects human cells, we can develop better treatments that disrupt that process and neutralize the virus.”

The spike protein, which is located on the outside of a coronavirus, enables SARS-CoV-2 to enter human cells. The Omicron variant has an unprecedented 37 mutations on its spike protein—three to five times more than previous variants. 

The structural analysis revealed that several mutations (R493, S496 and R498) create new salt bridges and hydrogen bonds between the spike protein and the human cell receptor known as ACE2. The researchers concluded that these new bonds appear to increase binding affinity—how strongly the virus attaches to human cells—while other mutations (K417N) decrease the strength of this bond.

“Overall, the findings show that Omicron has greater binding affinity than the original virus, with levels more comparable to what we see with the Delta variant,” said Dr. Subramaniam. “It is remarkable that the Omicron variant evolved to retain its ability to bind with human cells despite such extensive mutations.”

The researchers conducted further experiments showing that the Omicron spike protein exhibits increased antibody evasion. In contrast to previous variants, Omicron showed measurable evasion from all six monoclonal antibodies tested, with complete escape from five. The variant also displayed increased evasion of antibodies collected from vaccinated individuals and unvaccinated COVID-19 patients. 

“Notably, Omicron was less evasive of the immunity created by vaccines, compared to immunity from natural infection in unvaccinated patients. This suggests that vaccination remains our best defence,” said Dr. Subramaniam. 
 
Based on the observed increase in binding affinity and antibody evasion, the researchers say that the spike protein mutations are likely contributing factors to the increased transmissibility of the Omicron variant.  

Next, Dr. Subramaniam says his research team will leverage this knowledge to support the development of more effective treatments. 

“An important focus for our team is to better understand the binding of neutralizing antibodies and treatments that will be effective across the entire range of variants, and how those can be used to develop variant-resistant treatments.” 


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Updated: US sees spike in Paxlovid usage as Merck’s molnupiravir and AstraZeneca’s Evusheld are slower off the shelf

New data from HHS show that more than 162,000 courses of Pfizer’s Covid-19 antiviral Paxlovid were administered across the US over the past week, continuing…

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New data from HHS show that more than 162,000 courses of Pfizer’s Covid-19 antiviral Paxlovid were administered across the US over the past week, continuing a streak of increased usage of the pill, and signaling not only rising case numbers but more awareness of how to access it.

In comparison to this week, about 670,000 courses of the Pfizer pill have been administered across the first five months since Paxlovid has been on the US market, averaging about 33,000 courses administered per week in that time.

A Pfizer spokesperson told Endpoints News the company does “not have any concerns nor foresee any supply issues in our ability to support if [usage] rates increase.”

Cumulatively, as of May 24, almost 3.8 million doses of Paxlovid have been made available to states so far by the federal government, and about 2.4 million of those have been ordered by states, with more than 831,000 courses administered.

Signs for such a spike in usage were evident earlier this month, as in a call with reporters senior HHS officials credited the surge in the use of Paxlovid to their outreach, and through the Biden administration’s Test to Treat initiative, which allows for use of Paxlovid with a positive test at participating pharmacies.

“We have seen more than a 315% increase in Paxlovid use over the past four weeks. In the first week of May, nearly 115,000 courses were dispensed,” an official said at the time.

Meanwhile, outside of Paxlovid, few other treatment options are really in wide use.

Merck’s molnupiravir, known commercially as Lagevrio, has struggled to make its way out of the inventory closet, according to the latest numbers posted by HHS.

Only about 20,000 courses of the Merck pill were used in the past week, and only about 13% of the total US inventory of molnupiravir has been used to date. That compares with about 35% of overall usage of Paxlovid courses ordered by states so far, and the bulk of those orders have come within the last several months.

But for AstraZeneca’s preexposure mAb Evusheld, only about 16,000 courses were administered in the past week. About 38% of all Evusheld ordered by states has been administered so far, according to the latest HHS numbers.

For Eli Lilly’s bebtelovimab, which is a monoclonal antibody that’s supposed to be used ahead of molnupiravir if both are on hand, about 100,000 courses in total have been administered of 379,526 courses ordered (542,330 courses available). Bebtelovimab is the follow-on mAb after Lilly’s former combo mAb (850,000+ courses distributed earlier in the pandemic) that lost efficacy against the latest variant.

Meanwhile, HHS has become less and less transparent with its data and information on its distribution of Covid-19 therapeutics.

After the Trump administration, and the beginning of the Biden administration allowed for the public posting of weekly calls between HHS and states on Covid-19 therapeutic distribution, those calls have since been made private and the prior recordings have been deleted from the ASPR website.

In addition, each week’s therapeutic administration numbers have to be tallied independently because HHS now deletes the previous week’s numbers.

Editor’s note: Article updated to add Pfizer comment and note the stats for Lilly’s Covid-19 treatments bebtelovimab too.

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Why are clinical trials struggling with diversity?

In the diverse world we live in, the products we produce, the services we create and the places
The post Why are clinical trials struggling with diversity?…

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In the diverse world we live in, the products we produce, the services we create and the places we work should be as equally representative. In recent years this has seen diversity, equity, and inclusion (DEI) become a big focus for industries to get right.

Within pharma and healthcare, where greater representation has been proven to lead to better health outcomes for all patients and the pharmaceutical companies developing medicines, change is also happening.

Fair and timely access to efficacious medicine is one of the vital tenets of the healthcare industry and is a critical building block of the sector’s environmental, social and governance (ESG) objectives. But historically there are groups that are typically neglected due to the current systems in place. Racial disparities are still commonplace in many clinical trials with white-ethnic groups often overrepresented amongst trial participants.

Factors such as ethnicity, gender, sexual orientation and age can contribute to interindividual differences in treatment responses and risks of adverse events. Inadequate clinical trial representations of all populations can therefore leave underrepresented groups vulnerable due to the lack of subgroup-specific data.

While many pharma companies are actively working on initiatives to improve diversity in clinical trials, we still have a long way to go. The good news is that technology is being harnessed to promote a DEI-conscious agenda within the clinical trial space, making diversity more attainable than it ever has been.

To understand why improving diversity, mitigating bias, and reinforcing inclusion in clinical trials is such a big task, it’s important to understand the challenges currently at play.

Unpacking the status quo

Traditional Randomised Control Trials (RCTs) continue to form the backbone of clinical efficacy and safety data submitted to health authorities for regulatory review. A risk-benefit approach underpins the decision-making process to evaluate human drugs, drug/device combinations and advanced therapy medicinal products for licensing of human medicines.

It is well-established that safety and efficacy data is highly influenced by internal (intrinsic: ethnicity, sex, age, genetic background) and external (extrinsic: climate, education, access to healthcare) factors. The challenge for regulators and pharma companies is that safety and efficacy data from an RCT may not always translate to the real world ‘effectiveness’ of a medicine (how efficacious the drug is in patients once marketed) which is governed by these complex intrinsic and extrinsic factors.

To mitigate against potentially lower drug efficacy or a different drug safety profile in a wider population vs those findings evidenced in RCTs it is important for companies to include ‘patient-orientated’ outcomes (relief of symptoms) alongside traditional endpoints (blood pressure, glucose concentrations). The diversity of clinical trial patients in the context of disease prevalence is key to capturing ‘patient-orientated’ outcomes in populations. For example, with skin conditions, textbooks, studies, and trial photos often present lighter-skinned individuals’ symptoms, which are bound to differ in darker skinned individuals.

The pandemic brought imbalances into sharp focus

The race to produce a vaccine which could protect the world against COVID-19 brought the topic of diversity in clinical trials, or lack of it, into sharp focus.

Vaccines approved for public use require comprehensive RCTs to establish their safety and efficacy. The demographics of vaccine trial participants should reflect the vulnerable groups to whom infection with the disease presents the greatest risk of harm and mortality. However, this did not happen to the extent it could have during trials for the COVID-19 vaccine.

Research has shown a disproportionately higher rate of COVID-19 infection and mortality among the elderly and minority ethnic groups who are more likely to be negatively impacted by social and economic deprivation linked to pre-existing health conditions. In the UK, during the first wave of the COVID-19 pandemic, ethnic minority groups (except for women in “Chinese” or “White Other” categories) had higher rates of death post-exposure compared with the “White British” population.

These issues are not confined to the UK; in the US, some minority groups including Black, Latino, Pacific Islander and Indigenous peoples have been shown to have twice the COVID mortality rate of Caucasian people.

Despite policies, guidelines, and regulations to promote the diversification of clinical trial groups by the European Medicines Agency (EMA) and FDA, the inclusion of key demographic populations within clinical research continues to be less than proportionate to their representation in society.

Why are certain ethnic groups underrepresented?

Redressing the imbalance in trial participation is not a simple task. Throughout the pandemic, the issue of vaccine hesitancy was compounded by ethnic disparities. This is underpinned by historical mistrust in healthcare organisations, governments, and clinical research, which is still prevalent in some communities.

Factors influencing trust vary between ethnic groups. Reported experiences of discrimination, perceived structural inequalities impacting the access to and quality of healthcare, and concerns of trial under-representation are likely to influence trust issues, of which the latter is within the remit of companies to acknowledge and address with appropriate measures to effect change. Without diverse participation in clinical research there is a lack of breadth in safety and efficacy data. Certain groups of individuals may then not trust that the medicines have been produced with them in mind and may be highly sceptical of the resulting evidence base and prescribing label of medicines.

In the second half of this article, we’ll look at how technology is being used to make clinical trials more diverse and consider some of the lessons learned during the COVID-19 pandemic.

About the authors

Tanya Chambers is an ex-MHRA (Medicine and Healthcare Regulatory Agency) Senior Assessor with over 15 years’ experience principally evaluating preclinical data packages (small molecules and biologics) accompanying clinical trial applications, EU & UK marketing authorization applications (MRP/DCP/Centralised submissions) and variations across all therapeutic areas. Most recently, Tanya led the preclinical rolling review for COVID anti-viral applications resulting in national roll-out, and was product lead for the review of a vast array of development programmes via UK innovative licensing pathways: iLAP and EAMs. In addition, Tanya has working knowledge of the collaborative review of promising oncology treatments alongside Australia (TGA), Canada (Health Canada), UK (MHRA), Singapore (HSA), Switzerland (Swissmedic) and Brazil (ANVISA): ‘Project ORBIS’.

Liam Johnstone has six years of toxicology experience working across regulators in the UK, developing expertise in medicine, consumer product and agrochemical safety whilst working at the MHRA, OPSS and HSE, respectively. As a Non-Clinical Assessor at MHRA he assessed non-clinical data packages for new and generic medicines. He has provided scientific advice to companies both nationally and as part of the Scientific Advice Working Party (SAWP) on the suitability of non-clinical data packages and study plans, as well as generating guidance for the European Medicines Agency (EMA)

 

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Lactation Lab receives FDA Breakthrough Device designation for breast-milk-testing device that allows mothers to test for key nutritional elements in their milk

Los Angeles, May 25, 2022 –Lactation Lab, which offers the most scientifically advanced breast milk testing available, has announced today that the…

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Los Angeles, May 25, 2022 –Lactation Lab, which offers the most scientifically advanced breast milk testing available, has announced today that the U.S. Food and Drug Administration (FDA), has granted the company Breakthrough Device designation for its latest device Emily’s Care Nourish Test System that tests and provides a nutritional analysis of breast milk. 

Credit: Dr. Stephanie Canale

Los Angeles, May 25, 2022 –Lactation Lab, which offers the most scientifically advanced breast milk testing available, has announced today that the U.S. Food and Drug Administration (FDA), has granted the company Breakthrough Device designation for its latest device Emily’s Care Nourish Test System that tests and provides a nutritional analysis of breast milk. 

This first-of-its-kind breast-milk (point of care)-test allows mothers to test for key macronutrients (fat, protein, carbohydrates and adjust their nutritional intake accordingly. The test was developed for use in the NICU, hospital clinics, milk banks and home use. 

“The FDA Breakthrough Device designation for Emily’s Care Test System is a critical step in serving the most vulnerable infant population,” says Dr. Stephanie Canale, CEO of Lactation Lab. “Research in the past five years demonstrates how important key nutrients are for babies in the first five weeks of life. Nutrition is the only modifiable factor for preterm babies, and our Emily’s Care device provides potentially life-saving data, especially for those at risk of life-threatening conditions.”

The FDA Breakthrough Device designation will expedite regulatory review of Emily’s Care to provide patients and health care providers with quicker access. The designation is only awarded to breakthrough technologies that have the potential to provide effective treatment and diagnosis for life-threatening or irreversible debilitating diseases or conditions.

Founded in 2017 by CEO Dr. Stephanie Canale, Lactation Lab’s proprietary tests were developed by a team of practicing physicians, Ph.D. chemists and toxicologists. The startup company is housed at the Magnify Incubator at the California NanoSystems Institute at UCLA, which provides access to one of the most advanced research labs in the world. 

Lactation Lab is pioneering academic research in breast milk composition, also publishing findings in several prominent scientific journals, including Breastfeeding Medicine and Clinical Lactation.

Canale, a physician formerly at UCLA whose practice largely consisted of new mothers and babies, started Lactation Lab to provide parents with scientific and evidence-based insights, resources, and guidance. As a mom with an infant diagnosed with “failure to thrive,” also known as growth faltering. Canale wondered why there was no way to know what was in her own breast milk. 

“The time is now to empower moms with the kind of information and peace of mind I needed during my own breastfeeding journey. During the Covid-19 pandemic, amid the anxiety of leaving the home and going to doctor’s visits, we decided to bring Emily’s Care directly to mothers and take the guesswork out of breastfeeding,” said Canale. 

Lactation Lab’s breast-milk-test surpasses the creamatocrit breast milk test first developed in 1978. This rudimentary test is still widely used in hospitals, NICUs and support centers. Lactation Lab’s Emily’s aims to replace the existing test with Emily’s Care, which provides more accurate data than infra-red human milk analyzers. The company also just launched Emily’s Care infant supplement, which is the first infant supplement to receive Clean Label Project Certification and will support breastfeeding babies.

“We would like to continue advancements in women’s health to remove the current stigma around postpartum care and breastfeeding,” said Canale. “The data supports objective, evidence-based decision-making not only for hospitals and NICUs, but also for mothers at home. These are revolutionary steps to improve the standard of care surrounding breast milk for mom and baby.” 

Currently in the seed round of funding. Those interested in investing in Lactation Lab may reach out to scanale@lactationlab.com. To learn more, visit lactationlab.com and join the conversation @lactationlab.

About Lactation Lab

Founded by CEO Stephanie Canale, a doctor and mother of two, Lactation Lab is a first-of-its-kind breast-milk-testing kit. Lactation Lab analyzes your breast milk for basic nutritional content like calories and protein, as well as vitamins, fatty acids, and environmental toxins. Results are delivered in a user-friendly report that reads like a food label. Lactation Lab explains how results affect children, offers suggestions for enhancing the quality of milk, and offers personal consultation. Other products include mastitis screening test strips and the company will soon be launching a Clean Label certified infant supplement. Learn more at www.lactationlab.com.

About the FDA Breakthrough Device Program

The FDA Breakthrough Device program enables expedited regulatory assessment of novel technologies with the potential to provide more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. The goal of the Breakthrough Devices Program is to provide patients and health care providers with timely access to these medical devices by speeding up their development, assessment, and review, while preserving the statutory standards for premarket approval, 510(k) clearance, and De Novo marketing authorization, consistent with the Agency’s mission to protect and promote public health.

About Magnify Incubator at the California NanoSystems Institute at UCLA 

Centrally located at UCLA’s Court of Sciences, Magnify strives to enhance the vibrant culture of entrepreneurship at UCLA and the broader Los Angeles region. Magnify was built with one goal in mind: to help startups succeed by vastly accelerating their access to facilities while increasing their capital efficiency and market opportunities.

Related Links

www.lactationlab.com
magnify.cnsi.ucla.edu

Learn more about Lactation Lab from CEO Dr. Stephanie Canale
https://www.youtube.com/watch?v=3t4Q1OX05lg


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