Biotech week ahead, Aug. 23

 Biotech stocks swayed back and forth before ending the week lower. With earnings news dying down and an empty initial public offerings calendar, it was broader market cues, clinical readouts and regulatory actions that moved stocks during the week.

Virpax Pharmaceuticals, Inc.VRPX 9.7% was among the biggest gainers of the week following a positive regulatory communication regarding its MMS019.

Sesen Bio, Inc. SESN 9.91% extended its losses that were set in motion by an unexpected FDA rejection of its investigational bladder cancer drug Vicineum.

Eli Lilly and Company 

LLY 0.24% and partner Boehringer Ingelheim received Food and Drug Administration approval for Jardiance as a treatment option for a specific type of heart failure. The regulator also granted accelerated approval for GlaxoSmithKline's GSK 0.11% Jemperli for patients with previously treated, mismatch repair-deficient solid cancers. This is the second approval granted to the anti-PD-1 antibody treatment.

Among other key developments of the week was Lilly reorganizing its business with the objective of giving increased focus to its neuroscience business. Johnson & Johnson, Inc. JNJ 0.52% announced the transitioning of CEO Alex Gorsky to the role of executive chairman and the elevation of insider Joaquin Duato as CEO.

Here are the key catalytic events scheduled for the unfolding week.

Conferences

International Society for Experimental Hematology, ISEH, 2021 Virtual Scientific Meeting: Aug. 25-28

PDUFA Dates

The FDA is scheduled to rule on Axsome Therapeutics, Inc.'s AXSM 8.29% dextromethorphan-bupropion (AXS-05) as a treatment option for major depressive disorder. The PDUFA date is set for Sunday, Aug. 22. The prospect of approval coming through by the deadline is bleak, as the company indicated in its Aug. 9 earnings release that the FDA has identified deficiencies in the application.

Cara Therapeutics, Inc. CARA 10.39% and Vifor Pharma await an FDA nod for the new drug application for their Korsuva injection to treat moderate-to-severe pruritus in hemodialysis patients. The decision is due by Monday, Aug. 22.

Clinical Readouts

Aileron Therapeutics, Inc. ALRN 0.99% will present at the ISEH meeting. final data from the completed Phase 1b trial of ALRN-6924 in patients with small-cell lung cancer and initial findings from ongoing healthy volunteer Study of ALRN-6924.

Earnings

Ascendis Pharma A/S ASND 1.15% (Wednesday, after the close)

IPOs

IPO Quiet Period Expiry

• Icosavax, Inc. ICVX 1.5%
• Rallybio Corporation RLYB 1.78%
• Nuvalent, Inc. NUVL 2.35%
• MaxCyte, Inc. MXCT 3.61%
• Omega Therapeutics, Inc. OMGA 1.31%
• Rain Therapeutics Inc. RAIN 1.95%
• RxSight, Inc. RXST 0.67%
• Immuneering Corporation IMRX 0.29%
• IN8bio, Inc. INAB 2.16%
• Tenaya Therapeutics, Inc. TNYA 7.14%
• ABVC BioPharma, Inc. ABVC 6.45%

https://www.benzinga.com/general/biotech/21/08/22598635/the-week-ahead-in-biotech-cara-fda-decision-ascendis-earnings-aileron-data-presentation-and-more

Pandemic upends norms around peer-reviewed studies

 The seemingly insatiable demand for medical information during the pandemic has accelerated the practice of making emerging science more quickly available to scientists, lawmakers and the public.

That’s putting a spotlight on preprint studies — papers that are published before being peer-reviewed — at a time when the world is eager to learn about even the slightest change in the coronavirus.

But while experts welcome the increased accessibility and speed of preprints, their growing popularity also poses challenges since the public is essentially left to digest troves of complicated data and findings mostly on their own, sometimes leading to misinterpretation or misinformation. 

Preprint studies are not a new phenomenon, but COVID-19 heightened public awareness of them because they provided information much sooner than waiting months or years for publication in a journal — a timeline that is not considered feasible during a pandemic when public health officials need to make decisions to prevent deaths.

“We cannot wait,” Leana Wen, an emergency physician and public health professor at George Washington University, said. “We don't have that kind of time when there is a deadly virus, and months of delays would cost thousands or more lives.”

MedRxiv, one of the biggest sites that publishes preprints, had only been running for about six months by January 2020. That month 217 manuscripts, all unrelated to COVID-19, were posted, compared to in May, when the server had 1,625 preprint studies on the virus published.

“If you wait for the peer review publication, you're far behind in the field,” said Harlan Krumholz, one of medRxiv’s co-founders and a cardiologist at Yale University.

“I can either stick my head in the sand or I can realize this is just a new way of communicating science and clinical research,” he added. 

MedRxiv said it screens the preprints before publishing them to ensure they’re not anonymous, and that they don’t contain any privacy violations, Krumholz said. The company also makes the call on whether it would be “harmful” to release the study before it’s peer reviewed.

While some have speculated that the focus on preprints could allow for unreliable research to be amplified, there’s no data to suggest the studies on COVID-19 are published at a lower rate or withdrawn at a higher rate than other research.

A total of 11,300 pandemic-related preprints were posted to medRxiv between January 2020 and March 2021. At least 38 percent of those studies have since been peer-reviewed and published, with more likely in the coming months. As a point of comparison, 38 percent of nonpandemic-related preprints posted to medRxiv since January 2020 have been peer-reviewed and published in journals.

The database Retraction Watch said there is the same ratio of retractions among studies related to COVID-19 as those on other topics. In total, it has documented 149 retractions on COVID-19, with about one-third being preprints.

Initially, the database did not include withdrawals of preprint studies, according to Ivan Oransky, co-founder of Retraction Watch.

“We quickly realized that that would be leaving out an important part of the picture if we left them out, so we've now started cataloging those,” he said.

Amid the surge of preprints, MIT Press launched Rapid Reviews: COVID-19 to speed up the peer review of COVID-19-related articles.

Still, the larger spotlight on COVID-19 preprints has raised concerns the media and public could misconstrue the results of early studies as finalized science and use it to make personal health decisions.

A study published in Health Communication in January found that about 43 percent of studied news articles on preprints did not indicate the study was preliminary or not yet peer-reviewed.

Scientists say the medical community and the media need to do a better job of communicating to the public the evolving nature of scientific knowledge and the fact that each preprint study does not provide unrefuted solutions. Experts also say the public should consider preprints as just one piece of the puzzle rather than the full picture.

MedRxiv includes a disclaimer on its website emphasizing that preprints are “preliminary” and “have not been certified by peer review.”

“They should not be relied on to guide clinical practice or health-related behavior and should not be reported in news media as established information,” the website says.

“Science is a method, and it's a process of thinking and exploring new ideas and building consensus over time,” Michael Cronce, an assistant editor for Rapid Reviews: COVID-19, said. “And so I think that you're inevitably gonna run into conflicts when you're trying to come to conclusions as quickly as possible with a minimal amount of information.”

Rapid Reviews: COVID-19 is designed to wade through the surge of coronavirus-related preprints, speed up the peer review of valuable studies and work to limit the spread of misleading information.

Prabhjot Singh, an associate clinical professor of medicine at Mount Sinai Health System in New York, said he thinks preprints will remain a major component of the research field following the pandemic, so scientists have to be aware their preprinted studies could be distorted.

“I think you can't put preprints back into the box,” he said. “We need to just be increasingly aware that very fresh, scientific information that's still in the process of science is going to be taken out of context or people will try to make interpretations about it. And part of what we have to do is educate the public about the strengths and limitations of the scientific process."

The scientific community has come a long way in closing the “huge, huge gap of knowledge” on COVID-19, said Michael Mackert, director of the Center for Health Communication at the University of Texas at Austin.

But experts are still discovering and researching new data related to the pandemic, including on variants and booster vaccines, which officials continue to use to make decisions.

“I think preprints are gonna have a pretty important role to play throughout this pandemic, just because we have to keep learning new things and course correcting as we go, because there's just a lot we still don't know and can't know,” Mackert said.

https://thehill.com/policy/healthcare/568768-pandemic-upends-norms-around-peer-reviewed-studies

Mask mandates, vaccine proof on the rise, but not everyone is on board

 Masks mandates are on the rise as the Delta variant of COVID-19 continues to spread across the United States — amplifying divisions between supporters of anti-coronavirus protocols and opponents who emphasize personal freedom.

On Thursday at midnight, L.A. County enacted an outdoor mask mandate for large events with over 10,000 attendees, including concerts, festivals, and sporting venues — regardless of vaccination status. This comes after the L.A. County Public Health Department reported nearly 2,500 new COVID-19 cases earlier this week.

Los Angeles, which recently reinstated an indoor mask mandate for most public spaces, has been aggressive in its pandemic approach — with other major cities following suit. Washington, D.C., Chicago, and San Diego have enacted similar indoor masking requirements of their own, while New York City just began requiring vaccination proof for key indoor activities.

On the East Coast, New York City hosted a star-studded outdoor concert on Saturday with Bruce Springsteen, Jennifer Hudson, Paul Simon, and others performing live in Central Park. The free concert required proof of vaccination to attend but, given the fact that it was also outdoors, masks were optional. 

The Big Apple was the first major city to require vaccination proof in order to enter bars, gyms, restaurants, and concerts. Broadway, which is set to reopen next month after over one and a half years of shutdown, will require both proof of vaccination, along with masks. 

Still, questions remain over how city officials plan to enforce the mandate with black-market alternatives springing up online for those unwilling to get a proper vaccination. The more aggressive policies have sharpened the divisions between those willing to comply, and those who are pushing back for a variety of reasons. 

In a new Yahoo Finance Twitter poll, over 31,000 users responded to the question, "Would you avoid going to a restaurant if proof of COVID-19 vaccination is required for entry?"

80.3% of respondents answered "yes," whereas 19.7% responded "no." 

The overwhelming amount of "yes" votes suggests some businesses may see a direct impact to operations as a result of the increased mandates, especially in major cities like NYC, where vaccine proof is already required. Others have pointed out the unintended consequences of such policies that may exclude vaccine-hesitant people of color and the working class.

Meanwhile, states like Texas and Florida, which have large pockets of unvaccinated individuals, have banned mask mandates — a stark contrast compared to New York and California. 

Public school boards have been at the center of the debate, with some defying governor orders by making masks a requirement. In South Florida, officials have made masks mandatory for both students and faculty in the public school system — despite the state's overarching order. 

Fort Lauderdale Mayor Dean Trantalis told Yahoo Finance in a recent interview that, if given the chance, he'd urge Florida Governor Ron Desantis to rethink the mask ban, explaining that "people are willing" to us them.

"If there is an alternative political agenda trying to appeal to some sort of outlier group thinking that's going to advance a person politically I think they're just misguiding what people really want," the mayor continued.

Similarly, the Texas public school system saw a big win on masking last week. According to a public health guidance letter penned by the Texas Education Agency on Thursday, enforcement of Governor Greg Abbott’s mask ban will be dropped temporarily due to ongoing court challenges to the ban. 

So far in Texas, seven counties and 48 school districts have defied the governor by ordering mask mandates, according to The Associated Press.  

https://finance.yahoo.com/news/mask-mandates-proof-of-vaccination-on-the-rise-but-not-everyone-is-on-board-new-yf-poll-data-shows-131145145.html

US Says Kabul Evacuees Don't Need COVID Tests

 Amid the chaos and confusion at the airport, the United States said it had taken at least one step to ease requirements for those seeking to leave: COVID-19 tests.

Although Afghanistan had been a hotspot for the coronavirus pandemic, the State Department said Thursday that evacuees are not required to get a negative COVID-19 result to travel.

“A blanket humanitarian waiver has been implemented for COVID testing for all persons the U.S. government is relocating from Afghanistan,” the department said.

It referred questions about how the matter would be handled once evacuees arrive in the United States to the Department of Health and Human Services. Medical exams, including coronavirus tests, had been required for evacuees prior to Taliban’s weekend takeover of Kabul, which added extra urgency to efforts to get at-risk Afghans out of the country.

https://www.usnews.com/news/world/articles/2021-08-19/the-latest-biden-to-keep-troops-in-until-us-evacuees-out

The Vaccinated Are Worried and Scientists Don’t Have Answers

 

Anecdotes tell us what the data can’t: Vaccinated people appear to be getting the coronavirus at a surprisingly high rate. But exactly how often isn’t clear, nor is it certain how likely they are to spread the virus to others. And now, there’s growing concern that vaccinated people may be more vulnerable to serious illness than previously thought.

There’s a dearth of scientific studies with concrete answers, leaving public policy makers and corporate executives to formulate plans based on fragmented information. While some are renewing mask mandates or delaying office reopenings, others cite the lack of clarity to justify staying the course. It can all feel like a mess.

“We have to be humble about what we do know and what we don’t know,” said Tom Frieden, a former director of the Centers for Disease Control and Prevention and the head of the nonprofit Resolve to Save Lives. “There are a few things we can say definitively. One is that this is a hard question to address.”

Absent clear public health messaging, vaccinated people are left confused about how to protect themselves. Just how vulnerable they are is a key variable not just for public health officials trying to figure out, say, when booster shots might be needed, but also to inform decisions about whether to roll back reopenings amid a new wave of the virus. On a smaller scale, the unknowns have left music lovers unsure if it’s OK to see a concert and prompted a fresh round of hang-wringing among parents pondering what school is going to look like. 

In lieu of answers, what has emerged is a host of case studies providing somewhat different pictures of breakthrough infections. Variables including when the surveys were conducted, whether the delta variant was present, how much of the population was vaccinated and even what the weather was like at the time make it hard to compare results and suss out patterns. It’s difficult to know which data might ultimately carry more heft.

“It’s quite clear that we have more breakthroughs now,” said Monica Gandhi, an infectious disease expert at the University of California, San Francisco. “We all know someone who has had one. But we don’t have great clinical data.”

One of the best known outbreaks among vaccinated people occurred in the small beach town of Provincetown, Massachusetts, as thousands of vaccinated and unvaccinated alike gathered on dance floors and at house parties over the Fourth of July weekend to celebrate the holiday -- and what seemed like a turning point in the pandemic. About three-fourths of the 469 infections were among vaccinated people. 

Authors of a CDC case study said this might mean that they were just as likely to transmit Covid-19 as the unvaccinated. Even so, they cautioned, as more people are vaccinated, it’s natural that they would also account for a larger share of Covid-19 infections and this one study was not sufficient to draw any conclusions. The incident prompted the CDC to reverse a recommendation it had issued just a few weeks earlier and once again urge the vaccinated to mask up in certain settings.

Still, the particular details of that cluster of cases may have made that outbreak especially bad, according to Gandhi.

“The rate of mild symptomatic outbreaks in this population was higher because of a lot of indoor activity (including intimacy), rain that weekend, not much outside time and mixture of people with different vaccination status,” she said in an email.

A newly released, far larger CDC case study of infections in New York state, meanwhile, found that the number of breakthrough infections has steadily ticked up since May, accounting for almost 4% of cases by mid-July. Those researchers cautioned that factors such as easing public health restrictions and the rise of the highly contagious delta variant might impact the results. 

Yet another CDC case study, in Colorado, found that the breakthrough infection rate in one county, Mesa, was significantly higher than the rest of the state, at 7% versus about 5%. The report suggested it was perhaps because the delta variant was circulating more widely there, but also noted the ages of patients in Mesa and the lower vaccination rate may have played a role.

Research out of Israel seems to back the idea that protection from severe disease wanes in the months after inoculation, and more recently, that breakthrough cases may eventually lead to an uptick in hospitalizations. The information is preliminary and severe breakthrough cases are still rare, but it bolsters the case that some people will need booster shots in coming months.

Case studies and data from some states in the U.S. have similarly shown an increase in breakthrough cases over time. But with the delta variant also on the rise, it’s difficult to tell whether waning immunity to any type of coronavirus infection is to blame, or if the vaccinations are particularly ineffective against the delta variant. It could be both, of course. Changing behavior among vaccinated people could be a factor, too, as they return to social gatherings and travel and dining indoors.

All that said, some facts are well established at this point. Vaccinated people infected with the virus are much less likely to need to go to the hospital, much less likely to need intubation and much less likely to die from the illness. There’s no doubt that vaccines provide significant protection. But a large proportion of the nation -- almost 30% of U.S. adults -- have not been vaccinated, a fact that has conspired with the highly contagious delta variant to push the country into a new wave of outbreaks. 

“The big picture here is that the vaccines are working and the reason for the spike in the U.S. is we have too little vaccine uptake,” Frieden said. 

To a certain extent, breakthrough cases of any virus are expected. In clinical trials, no Covid vaccine was 100% effective -- even the best vaccines never are. The more the virus is in circulation, the greater the risk of breakthrough cases. It’s also common for some aspects of viral immunity to naturally wane over time.

For the time being, there are simply more questions than answers. Are breakthrough infections ticking up because of the delta variant, waning immunity or a return to normal life? Are vaccinated people more vulnerable to severe illness than previously thought? Just how common are breakthrough infections? It’s anyone’s guess.

“It is generally the case that we have to make public health decisions based on imperfect data,” Frieden said. “But there is just a lot we don’t know.”

https://www.bloomberg.com/news/articles/2021-08-21/science-can-t-keep-up-with-virus-creating-worry-for-vaccinated

COVID vaccines protect against Delta, but their effectiveness wanes

 The Pfizer–BioNTech and Oxford–AstraZeneca COVID-19 vaccines are effective against the highly infectious Delta variant of SARS-CoV-2 — but their protection drops away over time, a study of infections in the United Kingdom has concluded.

Researchers at the University of Oxford, UK, and the country’s Office for National Statistics analysed a vast data set comprising the results of 2,580,021 PCR tests to check for SARS-CoV-2 from 384,543 UK adults between 1 December 2020 and 16 May 2021 — when the Alpha variant was dominant — and 811,624 test results from 358,983 people between 17 May and 1 August 2021, when the Delta variant was more prevalent.

The results, published in a preprint on 19 August1, suggest that both vaccines are effective against Delta after two doses, but that the protection they offer wanes with time. The vaccine made by Pfizer in New York City and BioNTech in Mainz, Germany, was 92% effective at keeping people from developing a high viral load — a high concentration of the virus in their test samples — 14 days after the second dose. But the vaccine’s effectiveness fell to 90%, 85% and 78% after 30, 60 and 90 days, respectively.

The vaccine developed by Oxford and the pharmaceutical company AstraZeneca in Cambridge, UK, was 69% effective against a high viral load 14 days after the second dose, falling to 61% by 90 days.

The drop in effectiveness shouldn’t be cause for alarm, says Sarah Walker, a medical statistician at the University of Oxford who led the study. For “both of these vaccines, two doses are still doing really well against Delta”, she says.

The study shows that vaccinated people who become infected with the Delta variant carry high peak levels of virus. When the Alpha variant was dominant in the United Kingdom, vaccinated people who became infected had much lower peak viral loads.

The implications of this aren’t clear, Walker says. “Most of our tests are monthly; we can’t really say very much at all about how long people are infectious for and particularly whether that’s different with Delta,” she says. “Anyone who thinks that if they get infected having been vaccinated, they can’t transmit — that isn’t likely to be true.”

The data also suggest that the time between doses of vaccine doesn’t affect vaccine effectiveness, and that people who have previously tested positive for COVID-19 as well as receiving two vaccine doses have the best protection against future infection.

The analysis focused on the 18–64 age group and didn’t look at hospitalizations or fatalities, points out Dvir Aran, a biomedical data scientist at Technion — Israel Institute of Technology in Haifa. “This study is about infection, not severe disease,” he says. The results back up observations from Israel, which vaccinated its population very early in the pandemic, he says. “We are seeing high levels of breakthrough [infections] in the population that was vaccinated early, and on the other hand, we are seeing robust protection in those vaccinated recently — especially in 12–15-year-olds.”

The results raise questions about whether it could be more effective to have doses of different vaccines, rather than multiple doses of the same one, especially if a third, booster dose is to be considered. Georg Behrens, an immunologist at Hanover Medical School in Germany, says that mixing vaccines could increase their effectiveness. The immune system reacts differently to different types of vaccine — and this could be exploited to trigger a better overall response. “Using a vector-based one first and then something that has no vector, but the same antigen, absolutely makes sense,” says Behrens.

doi: https://doi.org/10.1038/d41586-021-02261-8

https://www.nature.com/articles/d41586-021-02261-8

Phase I Trial of Multi-Peptide COVID-19 Vaccine to Induce SARS-CoV-2 T-Cell Immunity

 

Juliane Walz, Jonas Heitmann, Tatjana Bilich, Claudia Tandler, Annika Nelde, Yacine Maringer, Maddalena Marconato, Julia Reusch, Simon Jäger, Monika Denk, Marion Richter, Leonard Anton, Lisa Weber, Malte Roerden, Jens Bauer, Jonas Rieth, Marcel Wacker, Sebastian Hörber, Andreas Peter, Christoph Meisner, Imma Fischer, Markus Löffler, Reinhild Klein, Hans-Georg Rammensee, Helmut Salih

DOI: 10.21203/rs.3.rs-820910/v1

PDF: https://www.researchsquare.com/article/rs-820910/v1.pdf?c=1629489587000

T-cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS15 emulsified in MontanideTM ISA51 VG, aiming to induce superior SARS-CoV-2 T-cell immunity to combat COVID-19. We conducted a Phase I open-label trial, including 36 participants aged 18 to 80 years, who received one single subcutaneous CoVAC-1 vaccination. The primary endpoint was safety analyzed until day 56. Immunogenicity in terms of CoVac-1-induced T-cell response was analyzed as main secondary endpoint until day 28. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study subjects, while systemic reactogenicity was absent or mild. SARS-CoV-2-specific T-cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T-helper 1 CD4+ and CD8+ T cells. CoVac-1-induced interferon-γ T-cell responses by far surpassed those detected in COVID-19 convalescents and were unaffected by current SARS-CoV-2 variants of concern (VOC). Together, CoVac-1 showed a favorable safety profile and induced broad, potent, and VOC-independent T-cell responses, supporting the presently ongoing evaluation in a Phase II trial for patients with B-cell/antibody deficiency.

Funded by the Ministry of Science, Research and the Arts Baden-Württemberg, Germany; ClinicalTrials.gov number, NCT04546841.

Yes there is potential Competing Interest. T.B., A.N.,H.-G.R., and J.S.W. are listed as inventors on a patent related to the SARS-CoV-2 T cell epitopes included in CoVac-1. H.-G.R. is listed as inventor on a patent related to the adjuvant XS15 included in CoVac-1.

https://www.researchsquare.com/article/rs-820910/v1