Single injection of monoclonal antibody induces SARS-CoV-2 neutralising antibodies exceeding those from infection, vaccination

  

View ORCID ProfileSimone Lanini, Stefano Milleri,  View ORCID ProfileEmanuele Andreano, Sarah Nosari,  View ORCID ProfileIda Paciello,  View ORCID ProfileGiulia Piccini, Alessandra Gentili, Adhuna Phogat,  View ORCID ProfileInesa Hyseni,  View ORCID ProfileMargherita Leonardi,  View ORCID ProfileAlessandro Torelli,  View ORCID ProfileEmanuele Montomoli, Andrea Paolini, Andrea Frosini,  View ORCID ProfileAndrea Antinori,  View ORCID ProfileEmanuele Nicastri,  View ORCID ProfileEnrico Girardi,  View ORCID ProfileMaria Maddalena Plazzi,  View ORCID ProfileGiuseppe Ippolito, Francesco Vaia, Giovanni Della Cioppa,  View ORCID ProfileRino Rappuoli

doi: https://doi.org/10.1101/2021.08.03.21261441

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.08.03.21261441v1.full.pdf

Summary

Background The emerging threat represented by SARS-CoV-2 variants, demands the development of therapies for better clinical management of COVID-19. MAD0004J08 is an extremely potent Fc-engineered monoclonal antibody (mAb) able to neutralise in vitro all current SARS-CoV-2 variants of concern (VoCs). This ongoing study, evaluates safety, pharmacokinetics and SARS-CoV-2 sera neutralization effect of MAD0004J08 when administered as single dose intramuscularly in healthy adults.

Method We conducted a dose escalation study with sequential enrolment of three cohorts, each with an increasing dose level of MAD0004J08 (48mg, 100mg and 400mg). Within each cohort, 10 young healthy adults were randomized with 4:1 ratio to a single intramuscular (i.m.) injection of MAD0004J08 or placebo. The primary endpoint is the proportion of subjects with severe and/or serious treatment emergent adverse events (TEAEs) within 7 days post-treatment. Secondary endpoints reported in this paper are the proportion of subjects with solicited TEAEs up 7 days post dosing, MAD0004J08 serum concentrations and neutralising activity versus the original SARS-COV-2 Wuhan virus at different timepoints post-dosing. As post-hoc analyses, we compared the sera neutralising titres of subjects who received MAD0004J08 with those of people that had received the COVID-19 BNT162b2 mRNA vaccine in the previous sixty days (n=10) and COVID-19 convalescent patients (n=20), and assessed serum neutralisation activity against the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS-CoV-2 variants of concern.

Findings A total of 30 subjects, 10 per cohort, were enrolled and randomized. Data up to 30 days were available and analysed in this report. No severe TEAEs were reported in any of the cohorts in the 7 days post-treatment. MAD0004J08 was detected in the sera of treated subjects within few hours post-administration and reached almost maximal levels on day 8. The geometric mean neutralising titres (GMT) assessed against the original Wuhan virus peaked on day 8 and ranged 226 – 905, 905 – 2,560, and 1,280 – 5,120 for cohort 1, 2 and 3 respectively. The sera neutralising GMT in MAD0004J08 treated subjects in all the three cohorts were found to be 1·5-54·5-fold higher compared to sera from convalescent patients and 1·83– 76·4-fold higher compared to sera from COVID-19 vaccinees. Finally, GMT in MAD0004J08 treated subjects showed high neutralising titres versus the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS-CoV-2 VoCs.

Interpretation A single dose administration of MAD0004J08 via i.m. route is safe and well tolerated and results in a rapid systemic distribution of the MAD0004J08 and sera neutralising titres higher than COVID-19 convalescent and vaccinated subjects. A single dose administration of MAD0004J08 is also sufficient to effectively neutralise major SARS-CoV-2 variants of concern. Based on these results, a Phase 2-3 trial is ongoing to further assess the safety, dosage, and efficacy of MAD0004J08 in asymptomatic or mild-moderate symptomatic COVID-19 patients.

Funding EU Malaria Fund, Ministero dello Sviluppo Economico, Ministero della Salute, Regione Toscana, Toscana Life Sciences Sviluppo and European Research Council.

Evidence before this study We searched PUBMED, MEDLINE and MedRxiv for clinical trials, meta-analyses and randomized controlled trials evaluating the antibody neutralization titres vs. different SARS-CoV-2 variants of concern obtained from subjects who received monoclonal antibodies for the treatment of COVID-19 using the following search terms: (“COVID-19” OR “SARS-CoV-2”) AND (“monoclonal antibody” OR “neutralising antibody”) AND (“variants” OR “variants of concern”). No relevant studies were identified.

Added value of this study This is the first human study assessing safety, PK and neutralising potential of MAD0004J08, a monoclonal antibody against SARS-CoV-2 wild type Wuhan virus and variants of concern, administered intramuscularly at low dosages (48, 100 and 400 mg). MAD0004J08 showed to be safe and well tolerated in the tested dose range. Anti-spike antibodies were detected in the sera of tested SARS-CoV-2 negative healthy adults few hours post-injection. In addition, the sera obtained from MAD0004J08treated subjects, showed to have high neutralisation titres against the Wuhan virus, the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) variants of concern.

Implications of all the available evidence A potent monoclonal antibody such as MAD0004J08, capable of neutralising multiple variants of concern of SARS-CoV-2 rapidly and long lastingly when given as a single intramuscular injection. The antibody, presently tested in a phase 2-3 efficacy trial, can be a major advancement in the prophylaxis and clinical management of COVID-19, because of its broad spectrum, ease of use in non-hospital settings and economic sustainability.

Competing Interest Statement

Rino Rappuoli is an employee of GSK group of companies. Emanuele Andreano, Ida Paciello and Rino Rappuoli are listed as inventors of full-length human monoclonal antibodies described in Italian patent applications n. 102020000015754 filed on June 30th 2020, 102020000018955 filed on August 3rd 2020 and 102020000029969 filed on 4th of December 2020, and the international patent system number PCT/IB2021/055755 filed on the 28th of June 2021.

Clinical Trial

NCT04932850

Funding Statement

This study was supported by the EU Malaria Fund, inaugurated on the 3rd of June 2020 and initiated by the kENUP Foundation. This publication was supported by the COVID-2020-12371817 project, which has received funding from the Italian Ministry of Health (Ministero della Salute), from the Italian Ministry of Economic (Ministero dello Sviluppo Economico) through the Contratti di Sviluppo funding program, and from Regione Toscana. This work was funded by the European Research Council (ERC) advanced grant agreement number 787552 (vAMRes). This publication was supported by the European Virus Archive goes Global (EVAg) project, which has received funding from the European Union Horizon 2020 research and innovation program under grant agreement No 653316.

https://www.medrxiv.org/content/10.1101/2021.08.03.21261441v1

Licensed drug could reduce SARS-CoV-2 infection by up to 70%: lab study

 A licensed drug normally used to treat abnormal levels of fatty substances in the blood could reduce infection caused by the SARS-CoV-2 virus by up to 70 per cent, reveals a study in the laboratory by an international collaboration of researchers.

The research team, led by the University of Birmingham and Keele University in the UK and the San Raffaele Scientific Institute in Italy, has demonstrated that fenofibrate and its active form (fenofibric acid) can significantly reduce SARS-COV-2 infection in human cells in the laboratory. Importantly, reduction of infection was obtained using concentrations of the drug which are safe and achievable using the standard clinical dose of fenofibrate. Fenofibrate, which is approved for use by most countries in the world including the US Food and Drug Administration (FDA) and the UK's National Institute for Health and Care Excellence (NICE), is an oral drug currently used to treat conditions such as high levels of cholesterol and lipids (fatty substances) in the blood.

The team is now calling for clinical trials to test the drug in hospitalised COVID-19 patients, to be carried out in addition to two clinical trials also currently underway in such patients in research being led by the Hospital of the University of Pennsylvania in the US and Hebrew University of Jerusalem in Israel.

SARS-CoV-2, the virus that causes COVID-19, infects the host through an interaction between the Spike protein on the surface of the virus and the ACE2 receptor protein on host cells. In this study, responding to the global COVID-19 pandemic, the team tested a panel of already licensed drugs -- including fenofibrate -- to identify candidates that disrupt ACE2 and Spike interactions. Having identified fenofibrate as a candidate, they then tested the efficacy of the drug in reducing infection in cells in the laboratory using the original strains of the SARS-CoV-2 virus isolated in 2020. They found fenofibrate reduced infection by up to 70%. Additional unpublished data also indicates that fenofibrate is equally effective against the newer variants of SARS-CoV-2 including the alpha and beta variants and research is ongoing into its efficacy in the delta variant.

Corresponding author Dr Farhat Khanim, of the University of Birmingham in the UK, explained: "The development of new more infectious SARS-CoV-2 variants has resulted in a rapid expansion in infection rates and deaths in several countries around the world, especially the UK, US and Europe. Whilst vaccine programmes will hopefully reduce infection rates and virus spread in the longer term, there is still an urgent need to expand our arsenal of drugs to treat SARS-CoV-2-positive patients."

Co-corresponding author Dr Alan Richardson, of Keele University in the UK, added: "Whilst in some countries vaccination programmes are progressing at speed, vaccine uptake rates are variable and for most low middle income countries, significant proportions of the population are unlikely to be vaccinated until 2022. Furthermore, whilst vaccination has been shown to reduce infection rates and severity of disease, we are as yet unsure of the strength and duration of the response. Therapies are still urgently needed to manage COVID-19 patients who develop symptoms or require hospitalisation."

Co-author Dr Elisa Vicenzi, of the San Raffaele Scientific Institute in Milan, Italy, said: "Our data indicates that fenofibrate may have the potential to reduce the severity of COVID-19 symptoms and also virus spread. Given that fenofibrate is an oral drug which is very cheap and available worldwide, together with its extensive history of clinical use and its good safety profile, our data has global implications -- especially in low-middle income countries and in those individuals for whom vaccines are not recommended or suitable such as children, those with hyper-immune disorders and those using immune-suppressants."

First author Dr Scott Davies, also of the University of Birmingham, concluded: "We now urgently need further clinical studies to establish whether fenofibrate is a potential therapeutic agent to treat SARS-CoV-2 infection."

The research, published today (Aug 6) in Frontiers in Pharmacology, was also carried out in collaboration with the University of Copenhagen in Denmark and the University of Liverpool in the UK.

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Story Source:

Materials provided by University of Birmingham. Note: Content may be edited for style and length.

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Journal Reference:

1. Scott P. Davies, Courtney J. Mycroft-West, Isabel Pagani, Harriet J. Hill, Yen-Hsi Chen, Richard Karlsson, Ieva Bagdonaite, Scott E. Guimond, Zania Stamataki, Marcelo Andrade De Lima, Jeremy E. Turnbull, Zhang Yang, Elisa Vicenzi, Mark A. Skidmore, Farhat L. Khanim, Alan Richardson. The Hyperlipidaemic Drug Fenofibrate Significantly Reduces Infection by SARS-CoV-2 in Cell Culture Models. Frontiers in Pharmacology, 2021; 12 DOI: 10.3389/fphar.2021.660490

https://www.sciencedaily.com/releases/2021/08/210806104405.htm

Potential COVID-19 medication found among tapeworm drugs

 A group of medications long prescribed to treat tapeworm has inspired a compound that shows two-pronged effectiveness against COVID-19 in laboratory studies, according to a new publication appearing online in the journal ACS Infectious Disease.

The compound, part of a class of molecules called salicylanilides, was designed in the laboratory of Professor Kim Janda, PhD, the Ely R. Callaway, Jr. Professor of Chemistry and director of the Worm Institute for Research and Medicine at Scripps Research, in La Jolla, CA.

"It has been known for 10 or 15 years that salicylanilides work against certain viruses," Janda says. "However, they tend to be gut-restricted and can have toxicity issues."

Janda's compound overcomes both issues, in mouse and cell-based tests, acting as both an antiviral and an anti-inflammatory drug-like compound, with properties that auger well for its use in pill form.

Salicylanilides were first discovered in Germany in the 1950s and used to address worm infections in cattle. Versions including the drug niclosamide are used in animals and humans today to treat tapeworm. They have also been studied for anti-cancer and antimicrobial properties.

The modified salicylanilide compound that Janda created was one of about 60 that he built years ago for another project. When the SARS-CoV-2 virus became a global pandemic in early 2020, knowing that they may have antiviral properties, he started screening his old collection, first in cells with collaborators from Sorrento Therapeutics and The University of Texas Medical Branch, and later, after seeing promising results, working with Scripps Research immunologist John Teijaro, PhD, who conducted rodent studies.

One compound stood out. Dubbed simply "No. 11," it differs from the commercial tapeworm medicines in key ways, including its ability to pass beyond the gut and be absorbed into the bloodstream -- and without the worrisome toxicity.

"Niclosamide is basically digestive-track restricted, and that makes sense, because that's where parasites reside," Janda says. "For that reason, simple drug repurposing for a COVID treatment would be counterintuitive, as you want something that is readily bioavailable, yet does not possess the systemic toxicity that niclosamide has."

About 80 percent of salicylanilide 11 passed into the bloodstream, compared to about 10 percent of the antiparasitic drug niclosamide, which has recently entered clinical trials as a COVID-19 treatment, Janda says.

The experiments showed that of the many modified salicylanilides he had built in his laboratory, No. 11 affected pandemic coronavirus infections in two ways. First, it interfered with how the virus deposited its genetic material into infected cells, a process called endocytosis. Endocytosis requires the virus to form a lipid-based packet around viral genes. The packet enters the infected cell and dissolves, so the infected cell's protein-building machinery can read it and churn out new viral copies. No. 11 appears to prevent the packet's dissolution.

"The compound's antiviral mechanism is the key," Janda says. "It blocks the viral material from getting out of the endosome, and it just gets degraded. This process does not allow new viral particles to be made as readily."

Importantly, because it acts inside cells rather than on viral spikes, questions about whether it would work in new variants like Delta and Lambda aren't a concern, he adds.

"This mechanism is not dependent on the virus spike protein, so these new variants coming up aren't going to relegate us to finding new molecules as is the case with vaccines or antibodies," Janda says.

In addition, No. 11 helped quiet potentially toxic inflammation in the research animals, Janda says, which could be important for treating acute respiratory distress associated with life-threatening COVID infections. It reduced levels of interleukin 6, a signaling protein which is a key contributor of inflammation typically found in advanced stages of COVID-19.

Better medications against COVID-19 are urgently needed, as highly infectious new variants drive renewed surges of illness and death globally. But Janda says salicylanilide No. 11 was created long before the pandemic.

After fighting an unpleasant bacterial infection called Clostridioides difficile about 10 years ago,he saw a clear need for better treatment options. Multi-drug-resistant strains of C. difficile have become a major cause of drug-resistant diarrheal disease outbreaks in health care institutions globally, and among people using antibiotics. As director of the Worm Institute, which focused on parasitic infections, Janda was very familiar with salicylanilides, and knew of their antimicrobial properties. His laboratory created a "library" of modified salicylanilides several of which showed strong efficacy against C. difficile, and the collection was subsequently licensed by pharmaceutical firm Sorrento Therapeutics. Among them was salicylanilide 11.

"Salicylanilide 11 actually was placed on the back burner in my laboratory against C. difficile because it's not as gut-restricted as we would like it to be," Janda says. "But salicylanilide 11 has got a lot of really positive things going for it as a potential therapeutic for COVID."

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Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Steven Blake, Namir Shaabani, Lisa M. Eubanks, Junki Maruyama, John T. Manning, Nathan Beutler, Slobodan Paessler, Henry Ji, John R. Teijaro, Kim D. Janda. Salicylanilides Reduce SARS-CoV-2 Replication and Suppress Induction of Inflammatory Cytokines in a Rodent Model. ACS Infectious Diseases, 2021; DOI: 10.1021/acsinfecdis.1c00253

https://www.sciencedaily.com/releases/2021/08/210806171924.htm

CMS axes hospital price transparency mandate from 2022 inpatient pay rule

 

• In a win for providers, CMS dropped a requirement that would have forced hospitals to disclose their contract terms with Medicare Advantage plans from its final inpatient pay rule for 2022 released Monday.
• The rule bumps payment for inpatient services by 2.5%, which will result in hospitals getting $2.3 billion more than this year, CMS said. The agency expects Medicare disproportionate share hospital payments and uncompensated costs to drop by $1.4 billion in 2022 compared to this year, while long-term care hospitals will get a 1.1% payment bump, or a gain of $42 million.
• Medicare will also continue shelling out add-on payments for COVID-19 treatments and therapies through the end of the fiscal year when the public health emergency ends, in a bid to reduce hospital stays and deaths, CMS said in a statement on the rule.

The Medicare Hospital Inpatient Prospective Payment System and Long-Term Care Hospital Prospective Payment System sets payment rates for inpatient stays. The new final rule outlining the payment systems for 2022 is meant to build on Biden administration priorities to close health equity gaps and expand access to diagnostics and therapies during the pandemic and beyond, CMS said.

In shaping the rule, regulators used data from the 2019 fiscal year, before the pandemic, to approximate inpatient hospital utilization for 2022, when hopefully the worst of COVID-19 is in the rear view.

The 2.5% pay bump for acute hospitals is lower than the 2.8% proposed in the initial draft of the rule released in April — and lower than the 2.9% pay bump for the 2021 fiscal year — but "largely within the range of market expectations," Credit Suisse analyst A.J. Rice said in a note.

Hospitals will receive about $7.2 billion in uncompensated care payments for the 2022 fiscal year, a decrease of about $1.1 billion from 2021.

Though rates may be slightly below what was initially proposed, the rule gives major wins for providers in the price transparency arenas. CMS finalized its proposal to repeal a requirement that hospitals include the median payer-specific negotiated charge with their MA plans on their Medicare cost reports, a step trade groups like the American Hospital Association strongly supported earlier this year.

The requirement would have resulted in about 64,000 hours of administrative burden, CMS said. However, the agency noted nixing the requirement doesn't dilute its commitment to price transparency, even as research shows a majority of hospitals aren't complying with a Trump-era rule on disclosing some negotiated rates.

Under the final rule, hospitals and long-term care facilities will have to report COVID-19 vaccination rates for their employees to CMS, which could affect their payments for 2023 and beyond, CMS said. Providers will also have to share more data with public health agencies to facilitate outbreak and threat management, and smoother case and lab reporting, in a bid to streamline emergency response in the future.

CMS also added a maternal morbidity measurement to its inpatient quality reporting program, under which hospitals have to report whether they participate in efforts to better perinatal health, including safety practices. The goal is to encourage hospitals to standardize protocols addressing obstetric emergencies and complications during pregnancy and childbirth, which disproportionately affect minority populations, CMS said.

The agency also sought comment on a number of proposals to force reporting of health disparities based on demographic factors, including race and ethnicity. One potential idea was to create a health equity score measure modeled after one used to rate MA plans.

However, CMS said it was still digesting stakeholder comments — it received more than 6,500 on the proposed rule overall — around ways to improve health equity, and would weave those into future rulemaking.

The Biden administration also didn't finalize proposed changes to organ acquisition payments or graduate medical education slots.

CMS did enact an imputed floor wage index required by the American Rescue Plan passed in March this year. Under the policy, which is designed to tweak payments based on varying labor costs in urban versus rural areas, New Jersey, Rhode Island, Delaware, Connecticut and Washington, D.C. should see slight increases in their wage indices.

And CMS approved 19 new technologies for add-on payments, including nine technologies under the alternative pathway for new medical devices part of the Food and Drug Administration's breakthrough devices program, and two approved under the FDA's pathway for infectious disease products. CMS will also continue add-on payments for all 23 technologies currently receiving add-on payments.

The agency estimates Medicare spending on new technology add-on payments will be $1.5 billion in 2022, nearly a 77% hike over 2021 spending.

https://www.healthcaredive.com/news/cms-axes-hospital-price-transparency-mandate-from-2022-inpatient-payment-ru/604351/

5 must-watch panels at an unprecedented HIMSS21

 HIMSS21 kicks off Monday in Las Vegas as the first major healthcare conference to be in person since the COVID-19 pandemic lockdowns early last year. Its sponsoring group, the Healthcare Information and Management Systems Society (HIMSS), canceled its 2020 conference days before it was scheduled to begin in March due to COVID-19 concerns — concerns that now dog this year's event, as the highly infectious delta variant contributes to rising cases across the U.S.

HIMSS is offering a corresponding digital event for executives wary of onsite attendance. And for attendees on the ground, masks and proof of vaccination are required on the the HIMSS21 campus and in all public spaces, following updated Centers for Disease Control and Prevention guidance.

But the situation in Las Vegas is worsening, as Clark County sees a surge in cases. As of late July, Clark County was averaging almost 800 new cases a day, up from a low of about 100 reached late May.

And there's early evidence despite the popularity of the annual event, the pandemic has weighed on attendance. According to HIMSS, roughly 18,000 people have registered for the conference so far. That's compared to 43,000 registrants at 2019's event.

But whether attending in-person or via computer screen, HIMSS21 will still be chock full of big names, breaking news and interesting panels. Here are five can't-miss sessions from this year's highly out-of-the-ordinary event.

1. Preserving the Health of a Population — Early Lessons from a Global Pandemic

   Hal Wolf, president and CEO of HIMSS, kicks things of in this Monday keynote where he'll be moderating a slew of public health experts, including the top officials from the World Health Organization and India's Ministry of Health and Family Welfare, in a conversation about keeping populations safe in a worldwide health emergency.

   Insights from this conversation are especially important now, as the delta strain drives rising cases globally despite over a year of efforts to tamp down on the pandemic. Pervasive challenges, including vaccine hesitancy, a shortage of shots in many nations and COVID-19 fatigue, among others, all threaten ongoing efforts by many groups — some represented in this panel — to get the virus under control.

   The panel, which will focus on critical areas of concern across population health, and what stakeholders can do to address them, will take place Monday at 5 p.m. in Venetian's Palazzo Ballroom.

2. Healthcare Cybersecurity Resilience in the Face of Adversity

   Cyberattacks have been ramping up in all industries globally, but bad actors seem to recently be targeting healthcare in droves. According to one report from CI Security, breach reports were up almost 36% in the second half of 2020 compared to the first half, while the number of patient records that were breached increased more than 180%.

   Without targeted investments in cybersecurity, the situation could only worsen, experts say. The increasing seriousness of attacks could even soon threaten the bottom line of some organizations, and — in a worst case scenario — affect the quality of patient care.

   This panel, led by Admiral Mike Rodgers, former National Security Agency director under President Barack Obama, will cover the major cybersecurity challenges facing payers and providers today, and go over strategies so they can ensure risks and exposures to incidents like ransomware are kept to a minimum.

   Speakers at the keynote, which takes place Tuesday morning at 8:30 a.m. in the Venetian's Palazzo Ballroom, also include Michael Coates, former chief information security officer of Twitter; Katie Moussouris, founder and CEO of Luta Security; Christopher Ross, chief information officer of Mayo Clinic; and Alex Stamos, former chief security officer of Facebook.

3. Answering the Call: The Importance of Interoperability Across the Spectrum in the Age of COVID-19 and Beyond

   National Coordinator for Health IT Micky Tripathi will be joining HIMSS virtually this year for this conversation, taking place Tuesday at 11:30 am in Venetian, Veronese 2501.

   Tripathi, who was named head of the Office of the National Coordinator in January, will give an overview of ONC's focus areas in a conversation with Daniel Jernigan, the acting public health science and surveillance deputy director at the CDC.

   Tripathi is expected to touch on ONC's ongoing public health data modernization efforts, along with progress on other action items like improving health equity, a key prong of the Biden administration's healthcare agenda; and fostering interoperability. Despite HHS implementing major provisions in two sweeping interoperability regulations finalized early last year, before COVID-19 hit the U.S., numerous question marks still hang over the policies, including an appropriate punishment for providers found blocking the free flow of information between disparate systems.

   Tripathi has previously promised further action on codifying disincentives for bad actors before the end of the year, and this panel could provide hints on where the agency's head is at in that process, and what else ONC is doing to build on its data-sharing push.

4. Health Equity: Taking Center Stage

   ​The Biden administration isn't the only stakeholder laser-focused on health equity. Research has shown that disparities in healthcare access and outcomes have been a perennial problem in the industry for decades, but those inequities have been thrown into stark relief by the COVID-19 pandemic over the past 18 months. And the topic is a major trendline at this year's HIMSS conference, popping up in numerous panels throughout the event.

   This session features executives working to advance health equity across the healthcare ecosystem, including Ronald Copeland, SVP and chief equity, inclusion and diversity officer at integrated system Kaiser Permanente; Denise Fair, chief public health officer of the Detroit Health Department; and Ivor Horn, the director of health equity and product inclusion at Google.

   Panelists plan to dive into the historical, social, epidemiological and demographic context underlying health disparities in the U.S. and illustrate how the pandemic has both exacerbated and challenged the status quo. They'll also address how stakeholders can use data and technology to combat disparities, improving health outcomes for underserved populations, according to HIMSS.

   The conversation kicks off Tuesday at 1 p.m. and takes place in Venetian, Veronese 2501.

5. How has COVID-19 permanently changed healthcare?

   COVID-19 has thrown traditional care models into disarray, and many think those changes will persist in some shape or another after the pandemic is well in the rearview, including higher utilization of virtual care models, more care delivery outside of traditional acute settings and higher patient engagement in their health.

   But what status quo disruptions will become part of the healthcare landscape in the long-term, and what fresh changes could still be ahead?

   At this Wednesday event beginning at 10 a.m. at Venetian, Veronese 2501, panelists will address how novel approaches to care models and technology put in place during the pandemic have resulted in new capabilities to respond more quickly to patient needs and bridge information gaps to better support providers and public health groups.

   The panel includes many high-profile speakers, including Amy Abernathy, former acting commissioner and acting chief information officer of the Food and Drug Administration; Danny Lee, the chief medical informatics officer of Johns Hopkins Community Physicians; Andrew Mellin, chief medical information officer of Surescripts; and Keith Shah, vice president of Optum.

6. https://www.healthcaredive.com/news/5-must-watch-panels-at-an-unprecedented-himss21/604399/

Biotech Investors: Mark Your Calendar For August PDUFA Dates

 The month of July was disappointing from the perspective of Food and Drug Administration decisions, as the agency handed down mostly negative verdicts.

Provention Bio, Inc. (NASDAQ:PRVB), Incyte Corporation (NASDAQ:INCY) and Iterum Therapeutics plc (NASDAQ:ITRM) were among the companies, which faced outright rejections.

ChemoCentryx, Inc. (NASDAQ:CCXI), however, was asked to wait for three more months, as the FDA extended the review period for avacopan as a treatment option for anti-neutrophil cytoplasmic autoantibody-associated vasculitis. The stock reacted positively on a relief rally. Pfizer Inc. (NYSE:PFE) said the FDA notified that the PDUFA dates for abrocitinib in atopic dermatitis and label expansion for Xeljanz in active ankylosing spondylitis were unlikely to be met.

Among the fortunate ones were Merck & Co., Inc. (NYSE:MRK), which received approval for V114, an investigational 15-valent pneumococcal conjugate vaccine, and also for Keytruda-chemo combo in first-line breast cancer setting.

Albireo Pharma, Inc. (NASDAQ:ALBO) obtained the nod for odevixibat for treating pruritus in patients with progressive familial intrahepatic cholestasis, a rare inherited progressive liver disease.

Four new molecular entities were approved during the month, taking the total for thus far in the year to 31.

Here are the key PDUFA dates for the month of August:

Can Eton Score FDA Win For Seizure Drug?

• Company: Eton Pharmaceuticals, Inc.(NASDAQ:ETON)
• Type of Application: NDA
• Candidate: topiramate oral solution
• Indication: seizures
• Date: Aug. 6

Topiramate is one of Eton's three neurology-focused oral liquid product candidates that have been submitted to the FDA.

Eton is seeking approval of topiramate oral solution as a treatment option for three indications – as a monotherapy for partial-onset or primary general tonic-clonic seizures in patients two years age and older, an adjunctive treatment of partial-onset seizures, including seizures associated with Lennox-Gastaut syndrome in patients two years of age and older, and as preventative treatment of migraine in patients 12 years of age and older.

In recent months, Eton has had mixed fortune with respect to regulatory approvals. In late May, the FDA handed down a complete response letter for its NDA for dehydrated alcohol injection for the treatment of methanol poisoning. The regulatory agency, however, cleared the company's Rezipres, or ephedrine hydrochloride injection, for the treatment of hypotension occurring in the setting of anesthesia.

Jazz Hopes For Expanding the Label of Sleep Disorder Drug

• Company: Jazz Pharmaceuticals plc (NASDAQ:JAZZ)
• Type of Application: supplemental NDA
• Candidate: Xywav (JZP-258)
• Indication:
• Date: Aug. 12

Xywav is calcium, magnesium, potassium and sodium oxybates oral solution. It was first approved in July 2020 for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy.

The company is now seeking to expand the label of Xywav to include idiopathic hypersomnia in adults as the second inducation. The regulatory application was accepted for priority review on April 12.

Sesen Bio Seeks Approval For Bladder Cancer Drug

• Company: Sesen Bio, Inc. (NASDAQ:SESN)
• Type of Application: biologic license application
• Candidate: vicinium
• Indication: Bladder cancer
• Date: Aug. 18

Vicineum is a locally administered fusion protein. It's Sesen Bio's lead product candidate that is being investigated for the treatment of high-risk, BCG-unresponsive non-muscle invasive bladder cancer.

The FDA accepted the application for priority review on Feb. 16.

Sesen Bio sees peak revenue of $1 billion to $3 billion globally, with $400 million to $900 million coming from the U.S.

Canaccord Genuity analyst John Newman said Vicineum displays an overall better safety and clinical profile compared to Keytruda, which should lead to FDA approval.

Sanofi Looks to Get Its Pompe Disease Treatment Past The Finish Line After 3-Month Delay

• Company: Sanofi (NASDAQ:SNY)
• Type of Application: BLA
• Candidate: avalglucosidase alfa
• Indication: Pompe disease
• Date: Aug. 18

Avalglucosidase alfa, an enzyme replacement therapy, is being evaluated for the treatment of patients with Pompe disease, a rare degenerative muscle disorder that can impact an individual's ability to move and breathe. It affects an estimated 3,500 people in the U.S. and can manifest at any age from infancy to late adulthood.

The original PDUFA date of May 18 was extended by three months.

Axsome Awaits Approval For Its Potentially First Commercial Product

• Company: Axsome Therapeutics, Inc. (NASDAQ:AXSM)
• Type of Application: NDA
• Candidate: Dextromethorphan-bupropion (AXS-05)
• Indication: major depressive disorder
• Date: Aug. 22

AXS-05, chemically dextromethorphan-bupropion, is an oral investigational drug with multimodal activity under development for the treatment of major depressive disorder and other central nervous system disorders.

The FDA accepted the NDA for priority review on April 26. If approved, Axsome expects to commercially launch the drug in the fourth quarter.

‘Go or no-go' For Cara's Korsuva?

• Company: Cara Therapeutics, Inc. (NASDAQ:CARA) and Vifor Pharma
• Type of Application: Pruritus In hemodialysis Patients
• Candidate: Korsuva injection
• Indication: NDA
• Date: Aug. 23

Cara and partner Vifor Pharma announced FDA acceptance of the NDA for Korsuva on March 8. Korsuva, or difelikefalin, solution for injection is being investigated for the treatment of moderate-to-severe pruritus in hemodialysis patients.

Cara is entitled to 50:50 share of U.S. profit in Fresenius clinics and 60:40 share in non-Fresenius clinics, Needham analyst Joseph Stringer said in a note. Approval in the U.S. will pave the way for a $50 million equity investment and up to $240 million in U.S. sales milestones, he added.

Can Merck-Eisai's Combo Therapy Cross The FDA Hurdle?

• Company: Merck & Eisai Co., Ltd. (OTC:ESALY)
• Type of Application: sBLA and sNDA
• Candidate: Keytruda and Lenvima
• Indication: kidney cancer
• Date: Aug. 25 and 26

The FDA accepted and granted priority review for the applications seeking approvals for the combination of Merck's Keytruda and Eisai's Lenvima for the first-line treatment of patients with advanced renal cell carcinoma.

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