NeuroBo: Positive Recommendation from Independent Data Safety Monitoring of Phase 2/3 Covid Trial

 Committee Advises Continuation of Trial Without Modification

NeuroBo Pharmaceuticals, Inc. (Nasdaq: NRBO), a clinical-stage biotechnology company focused on developing and commercializing multimodal disease-modifying therapies for viral, neuropathic and neurodegenerative diseases, today announced that an independent Data Monitoring Committee (DMC) reviewed safety data from 36 patients treated in the Phase 2/3 clinical trial of NeuroBo's lead drug candidate, ANA001, a proprietary oral niclosamide formulation being developed as a potential treatment for COVID-19. Based on those findings, the DMC recommended the continuation of the trial without modification.

The two-part Phase 2/3 multi-center, double blind, placebo-controlled study to assess safety, tolerability, and efficacy of ANA001 is being conducted in the U.S. In both phases of the study, hospitalized patients with moderate to severe COVID-19 (patients not requiring ventilators) receive a seven-day course of ANA001 (niclosamide capsules) in addition to standard-of-care treatment. The Phase 2 part of the trial is expected to enroll 60 patients and the primary objective is to assess safety and tolerability. Secondary objectives include measurements of efficacy (median time to hospital discharge) and pharmacokinetics (PK).

The Phase 3 part of the trial is expected to enroll several hundred patients, with the primary endpoints being median time to hospital discharge, safety and tolerability. Secondary objectives will evaluate clinical improvement and the need and duration for rescue therapy.

https://finance.yahoo.com/news/neurobo-pharmaceuticals-announces-positive-recommendation-120000876.html

US to open Canada, Mexico land borders for vaccinated travelers in Nov.

 The Biden administration is preparing to reopen the U.S.'s land borders with Canada and Mexico to fully vaccinated individuals traveling for nonessential reasons at some point in early November, according to senior administration officials.

An official announcement will be made Wednesday by the Department of Homeland Security that will amend the restrictions, known as Title 19. 

Senior administration officials previewing the announcement said the move to reopen the land borders in early November will align with a previously announced policy to loosen COVID-19 restrictions for fully vaccinated air travelers. Officials said a specific date has yet to be determined.

Unvaccinated travelers will still be prohibited from traveling to the United States for nonessential reasons until the second phase of the policy.

Beginning in early January, any foreign national travelers crossing the land borders must be fully vaccinated, whether coming for essential or nonessential reasons. A senior administration official said the phased approach will provide "ample time" for essential travelers like truckers to get vaccinated.

According to a separate senior official, Customs and Border Protection agents will be in charge of enforcing the vaccine requirement. 

CBP officers will ask about vaccination status at the border, the official said, and then based on the officers' discretion, the official said some people will be sent to a secondary screening and have their documents checked.

Restrictions on cross border travel have been renewed monthly since the beginning of the pandemic in March 2020. The current restrictions, which were extended last month through Oct. 21, have come under heavy criticism from lawmakers and travel industry lobbyists.

The restrictions don't apply to cross-border trade, U.S. citizens and lawful permanent residents, as well as people traveling for medical purposes or to attend school, among others

Currently, fully vaccinated U.S. citizens are allowed into Canada, but Canadians are not allowed to cross into the U.S. by land. Mexico is open to all travelers.

It remains unclear which vaccines the U.S. will recognize, what documentation will be needed, and whether there will be any exemptions allowed. 

The separate senior administration official said the Centers for Disease Control and Prevention is working on guidance for the specific vaccines.  

The official said the CDC told airlines last week that all vaccines authorized and approved by the Food and Drug Administration as well as by the World Health Organization would meet the requirements for air travel, and while no final decision has been made, the requirements for land crossings would likely align. 

https://thehill.com/policy/healthcare/576472-us-to-ease-covid-restrictions-on-canada-mexico-land-crossings

Support for computational repurposing of bumetanide for APOE4-related Alzheimer’s

 

Alice Taubes, 

Phil Nova, 

[…]

Yadong Huang 

• DOIhttps://doi.org/10.1038/s43587-021-00122-7

• Abstract

  The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analyzing publicly available human brain databases. We then queried these signatures against the Connectivity Map database, which contains transcriptomic perturbations of more than 1,300 drugs, to identify those that best reverse APOE genotype-specific AD signatures. Bumetanide was identified as a top drug for APOE4-related AD. Treatment of APOE4-knock-in mice without or with amyloid β (Aβ) accumulation using bumetanide rescued electrophysiological, pathological or cognitive deficits. Single-nucleus RNA sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in APOE4 induced pluripotent stem cell (iPSC)-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two electronic health record databases, suggesting the effectiveness of bumetanide in preventing AD.

• https://www.nature.com/articles/s43587-021-00122-7

FDA Gives First Greenlight to E-Cig

 The first electronic nicotine delivery system (ENDS) has passed the FDA's premarket approval process, showing reduced harm compared with traditional tobacco products, the agency announced Tuesday.

R.J. Reynolds Vapor Company gained approval for its Vuse Solo device and affiliated tobacco-flavored cartridges while at the same time receiving rejection notices for 10 other applications for flavored products. While FDA refused to specify the rejected products for commercial confidentiality reasons, it said an application for menthol-flavored Vuse Solo products are still under review.

FDA faced a court-ordered deadline last month to respond to vape manufacturers' applications for their products to stay on the market but missed it for Reynolds and the other two top market leaders' applications.

Congress gave the FDA authority in 2009 to oversee such products by "deeming" e-cigarettes and other non-traditional nicotine delivery systems as tobacco products under the agency's oversight and subject to marketing restrictions, which it did in 2016.

Manufacturers were to submit applications with evidence that these ENDS would be "appropriate for the protection of public health," both in terms of youth use and for traditional cigarette cessation overall, so that the FDA could review them by Sept. 9, 2021 under its Premarket Tobacco Product Application (PMTA) pathway.

The newly approved Vuse Solo product had proven in a study that it exposed users to fewer harmful and potentially harmful aerosols than traditional combusted cigarettes and proved to have less toxic aerosols in nonclinical studies as well.

"The manufacturer's data demonstrates its tobacco-flavored products could benefit addicted adult smokers who switch to these products -- either completely or with a significant reduction in cigarette consumption -- by reducing their exposure to harmful chemicals," said Mitch Zeller, JD, director of the FDA's Center for Tobacco Products, in a statement.

One key concern with e-cigarettes has been use among youth, and FDA noted that Vuse was cited by 10% of vaping high school students as their usual brand in the 2021 National Youth Tobacco Survey.

While taking that data "very seriously" when reviewing these products for approval, the FDA cited evidence that youth were less likely to start vaping with tobacco-flavored products and then switch to traditional cigarettes -- health advocates have called fruit, candy, or mint flavors a driver of teen use and addiction.

"These data reinforce the FDA's decision to authorize the tobacco-flavored products because these products are less appealing to youth and authorizing these products may be beneficial for adult combusted cigarette users who completely switch to ENDS or significantly reduce their cigarette consumption," the agency's press release noted.

The agency has said it will review sweet and fruity flavored e-cigarette applications on an individual basis without blanket rules for the industry, as the Wall Street Journal reported.

FDA said it will also continue monitoring marketing and use by young people. If there's evidence that the products cause people, especially youth, to initiate using tobacco, authorization could be withdrawn.

"While today's action permits the tobacco products to be sold in the U.S., it does not mean these products are safe or 'FDA approved,'" the agency cautioned. "All tobacco products are harmful and addictive and those who do not use tobacco products should not start."

https://www.medpagetoday.com/publichealthpolicy/healthpolicy/94993

Fed judge grants religious exemption to NY’s COVID vax mandate pending final ruling

 An upstate New York federal judge granted a preliminary injunction against Gov. Kathy Hochul’s COVID-19 vaccine mandate, barring the state Department of Health from enforcing the requirement on healthcare workers who claim religious exemptions while the case is being decided. 

“Upon review, plaintiffs have established at this early stage of the litigation that they are likely to succeed on the merits of this constitutional claim,” wrote Utica federal Judge David Hurd Tuesday.

He granted the request in response to a religious-freedom lawsuit filed last month against Hochul, the DOH and Attorney General Letitia James by 17 anonymous healthcare workers — the majority being Catholic — claiming the state’s mandate violated their constitutional rights.

Hurd’s decision extends a temporary restraining order granted shortly after the suit was filed and prohibits employers from citing the state’s mandate to deny exemption requests. It also pauses the DOH’s ability to enforce the rule, or revoke any religious exemptions granted since the mandate took effect on Sept. 27.

New York Gov. Kathy Hochul has said she will fight in court to keep the vaccine mandate in NY.

Hans Pennink

The mandate also permits employers to fire workers if they refused to comply and did not have a valid medical exemption. 

“Plaintiffs have established that [the mandate] conflicts with longstanding federal protections for religious beliefs and that they and others will suffer irreparable harm in the absence of injunctive relief,” he added. 

“These conclusions have nothing to do with how an individual employer should handle an individual employee’s religious objection to a workplace vaccination requirement. But they have everything to do with the proper division of federal and state power.”

Hochul said she will continue to defend the mandate in court.

“My responsibility as Governor is to protect the people of this state, and requiring health care workers to get vaccinated accomplishes that. I stand behind this mandate, and I will fight this decision in court to keep New Yorkers safe,” she responded in a statement.

The healthcare workers argued in their lawsuit that they refused to be inoculated with the available coronavirus vaccines “because they all employ fetal cell lines derived from procured abortion in testing, development or production.”

The filing alleges the plaintiffs have “been threatened with professional discipline, loss of licensure, admitting privileges, reputational harm, and/or the imminent termination of their employment as a result of their refusal to comply.”

The complaint also alleges the mandate violates the US Constitution’s supremacy clause, under which federal law takes precedence over state law, and the equal protection clause of the 14th Amendment, which prohibits official discrimination.

NY has not initially added religious exemptions to its list for a way out of the COVID-19 vaccine mandate.

Lynne Sladky, File/AP
Originally the state considered allowing religious exemptions in addition to the medical exemptions, but that language was removed before the emergency rule was adopted Aug. 26 by the DOH.

“This intentional change in language is the kind of “religious gerrymander” that triggers heightened scrutiny,” wrote Hurd. 

So far, nearly 10,000 healthcare workers in hospitals and nursing homes have claimed a nonmedical exemption, according to data provided by the DOH last week.

That figure includes 7,019 hospital employees — 1.4 percent of around 521,000 employees statewide — and 2,934 nursing home workers — or 2.1 percent of 140,917 total employees statewide.

A smaller number have been approved for medical exemptions including 2,607 hospital workers — or .06 percent total — and 674 nursing home staffers — 0.5 percent.

It’s unclear how many workers statewide have been fired as the result of the mandate, but Northwell Health — the state’s largest hospital and clinical network — canned 1,400 workers last week for refusing to get the shot. 

The system employs roughly 76,000 individuals. 

“With this decision the court rightly recognized that yesterday’s ‘front line heroes’ in dealing with COVID cannot suddenly be treated as disease-carrying villains and kicked to the curb by the command of a state health bureaucracy,” said Christopher Ferrara, special counsel for the Thomas More Society, a Chicago-based conservative law firm representing the plaintiffs. 

People and teachers protest against COVID vaccine mandates outside the Manhattan Federal Court Tuesday, Oct. 12, 2021, in New York.

Eduardo Munoz Alvarez/AP

Several plaintiffs “contracted COVID while treating patients, recovered, and were allowed to return to work with the same protective measures that were good enough for the 18 months that they were the heroes in the battle against the virus,” he added. 

“There is no ‘science’ to show that these same measures are suddenly inadequate – especially when they are allowed for those with medical exemptions.”

In January, the US Conference of Catholic Bishops said, “it can be morally acceptable to receive a vaccine that uses abortion-derived cell lines if there are no other available vaccines comparable in safety and efficacy with no connection to abortion.”

https://nypost.com/2021/10/12/judge-grants-religious-exemption-to-ny-covid-vaccine-mandate/

What we know about mixing and matching Covid vaccines

 Later this week an expert committee that advises the Centers for Disease Control and Prevention will hear about the results of a clinical trial that could influence how Covid vaccines are used in this country at some point in the future. The trial, conducted by the National Institute of Allergy and Infectious Diseases, is a so-called mix-and-match trial, testing the Covid vaccines authorized in the U.S. in combinations with each other.

The goal of the trial was to see whether using a different vaccine as a booster shot improves protection. So does getting a dose of Pfizer vaccine after getting a single dose of Johnson & Johnson’s vaccine trigger production of more antibodies than a second dose of the J&J would? Are the messenger RNA vaccines made by Pfizer and Moderna virtually interchangeable, or does switching even there produce a broader set of immune responses?

This isn’t theoretical. The booster shot most vaccinated Americans are in the process of getting or booking may not be the last needed. Figuring out how to optimize use of the current generation of Covid vaccines is critical, a number of experts have told STAT.

Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy, said we need to realize that many questions remain to be answered about use of these vaccines. We don’t know the optimal dose. We don’t know the most effective interval between doses. We don’t know how many doses we’re going to need and we don’t know whether we would get more durable protection if we mix up the vaccines each person receives, he said.

In terms of how we use Covid vaccines, we’re in the very early days, Osterholm said, adding that now that we have effective vaccines, we need to start figuring out how best to use them. “We have to start adopting a public health mindset for decision making,” he said.

What follows is a primer on what we know about mixing Covid vaccines.

Let’s start with the terminology

If you get a booster jab that is of the same brand as your previous jab or jabs, you are getting a homologous booster. In the United States, most people who have been vaccinated have had homologous vaccine series and homologous boosters.

There may be some exceptions. Earlier in the vaccine rollout, when supplies were scarce, the CDC advised that people could be given a second shot of whatever vaccine was on hand if they were due for their second shot of vaccine and no supplies of the brand they were due to get were available.

If your original series of vaccines or the booster were from different manufacturers, you have what’s called a heterologous vaccine series or a heterologous boost.

A few vaccines are actually designed to capture the benefits of heterologous boosting. For instance, Johnson & Johnson’s Ebola vaccine uses two different types of vaccines — one of which is made using a similar design to the company’s Covid vaccine. Likewise, the Sputnik V vaccine is made up of two doses of similar but not identical vaccines, each made using a different adenovirus that has been modified to carry genetic material from the SARS-CoV-2 virus. In both cases, the goal was to ensure that the immune response the first dose generated didn’t prevent the second shot from taking effect.

Necessity is the mother of invention

As mentioned above, most immunized people in the United States were vaccinated with a homologous series of vaccines. But elsewhere heterologous regimens were used for a couple of different reasons.

In the early days of the vaccine rollout, some countries opted to use heterologous boosts because they didn’t have adequate supply to be able to give people a matching shot when they were due for their second dose. And after the AstraZeneca vaccine was seen to cause serious clotting problems in some people who received it (a problem later seen with the J&J vaccine too), some countries stopped using it or limited its use to older adults, for whom the risk of a clotting event after vaccination appeared to be lower. Younger adults were offered one of the mRNA vaccines as their second dose instead.

Kathryn Edwards, a vaccines researcher at Vanderbilt University, suggested the United States should probably look at whether specific brands of booster doses should be targeted at certain populations — or more specifically, if certain people should be steered away from certain vaccines when it comes time for them to get boosters. With concerns about myocarditis in young males associated with mRNA vaccines and clotting problems reported mainly with younger women who got one of the viral vectored vaccines, such as the J&J, maybe it’s time to think about who gets which type of Covid vaccine, Edwards said.

A natural experiment turns into a border barrier

Countries like the United Kingdom, Canada, France, and Germany that used heterologous vaccine approaches have created a travel conundrum for their citizens.

A number of countries — the United States among them — do not consider people who received two different brands of vaccines fully vaccinated, even if the person’s home country does. This means someone who got an mRNA vaccine as a second dose after receiving an AstraZeneca shot as a priming dose is not deemed fully vaccinated and is not eligible to travel to the U.S. or other countries with the same rule.

Canada has roughly 4 million people who were vaccinated on a heterologous schedule. The U.S. and its northern neighbor share the world’s longest border and in pre-Covid times, travel across it was brisk. Now many Canadians are in limbo, unsure if or when they will be allowed to cross into the U.S.

Figuring out how to deal with a range of vaccines used in a variety of ways around the world is going to be a challenge that the Biden administration and other governments will have to grapple with as international travel increases.

All combos may not be created equal

Is it possible that any combination of vaccine types or brands will work as well — or better — than if the shots were all of a single brand? That’s not yet clear, but it’s possible — even likely — that the combinations and the order in which the vaccines are given will matter.

“A followed by B may not be the same as B followed by A,” explained Bruce Gellin, chief of global public health strategy for the Rockefeller Foundation’s pandemic prevention institute.

A number of small studies done in Europe have shown that following up AstraZeneca’s adenovirus-vectored vaccine with a Pfizer or a Moderna mRNA booster elicits a greater immune response than what is seen from two doses of the AstraZeneca alone. But an ongoing research effort at Britain’s University of Oxford comparing Covid vaccine combinations called the Com-CoV trials suggests that the inverse may not be true.

Scientists conducting the original Com-CoV trial gave volunteers two doses apiece of either AstraZeneca or Pfizer, comparing the antibody levels those regimens elicited to AstraZeneca followed by Pfizer or Pfizer followed by AstraZeneca. Pfizer after AstraZeneca generated higher antibody levels than two doses of AstraZeneca alone; but AstraZeneca after Pfizer was not better than two doses of Pfizer.

“The priming event is really important,” said Barney Graham, who was deputy director of the National Institutes of Health’s Vaccine Research Center until the end of August and who played a critical role in the design of the Moderna and other vaccine prototypes.

Graham explained that the kind of immune response one gets from Covid vaccines is determined by the first dose. “And so it kind of locks you into a repertoire and a pattern of antibody, T-cell balances that carry on through subsequent boosters,” he said.

Much remains to be learned about how to effectively mix Covid vaccines — and it will take time to answer these questions, Graham said. “Those are the kind of things that happen over a 12-year development program. We didn’t do that this time.”

Mixed vaccines carry a punch

In general, Covid vaccines are what’s known as reactogenic; they can carry a wallop. Fevers, sore arms, fatigue, and malaise — a lot of people report feeling kind of crappy in the hours or even day or two after getting a Covid shot.

Complaints about reactogenicity were even greater among people who got mixed vaccine brands, the Com-CoV trial reported. So, potentially more post-vaccination side effects, but nothing unmanageable. “It is reassuring that all reactogenicity symptoms were short lived,” the Com-CoV researchers said in a short study published in late May in The Lancet.

The challenge ahead

If evidence continues to amass suggesting that mixing vaccine brands would be of benefit, how do those data get translated into public policy? That won’t be easy, experts warn.

Typically, regulators like the Food and Drug Administration act on requests from companies. They review data provided by a manufacturer and decide yes, this vaccine or drug can be given to these people or no, it should not be.

But when you are talking about a plan that involves combining products from two different companies, things become much more complex. None of these companies have asked to have a rival’s vaccine used as a booster for their Covid shot — and they’re not likely to.

“Normally the manufacturer puts in an application to do something,” said Glen Nowak, director of the Center for Health and Risk Communication at Grady College of Journalism and Mass Communication. “Who then has that responsibility to bring forward a recommendation to mix and match? I think it’s a very good question.”

The CDC could address the issue, said Norman Baylor, president and CEO of Biologics Consulting and a former head of the FDA’s Office of Vaccines. Its advisory panel, ACIP, could evaluate the data and, if it supports using heterologous boosts, recommend that this is the way the vaccines could be used. Such advice could take the form of what is known as preferential recommendations — effectively not saying that vaccine B must be used after vaccine A, but noting it would be advisable to do so.

Could that happen? Possibly. But if it does happen, it will likely affect the way Covid vaccines are used in the future — in people who haven’t yet started to be vaccinated, or if and when people in the country need a fourth dose of Covid vaccine. Because by the time there are enough data to move forward with this type of policy, most Americans who are currently due for a booster jab will likely have had one.

https://www.statnews.com/2021/10/12/a-primer-on-what-we-know-about-mixing-and-matching-covid-vaccines/

FDA scientists neutral on Moderna Covid-19 vaccine booster ahead of key meeting

 Food and Drug Administration scientists did not take a clear position as to whether the agency should authorize booster doses of the Moderna Covid-19 vaccine in documents released Tuesday.

Posted ahead of a two-day meeting convened by the FDA on booster shots of both the Moderna and Johnson & Johnson vaccines, the documents laid out the case for authorizing Moderna’s proposed booster — a half dose of the existing vaccine — but also noted that data so far make it unclear that the third dose is needed.

“Some real world effectiveness studies have suggested declining efficacy of Moderna COVID-19 Vaccine over time against symptomatic infection or against the Delta variant, while others have not,” FDA scientists wrote in a briefing document. However, they wrote, current data suggest that Covid vaccines that are available in the U.S. still protect against severe Covid-19 disease and death.

At the meeting, an expert panel will discuss and vote on both companies’ booster plans. Such recommendations are used by the FDA to help make decisions, but are not binding.

The meeting appears unlikely to be a repeat of the similar panel held last month to decide whether to authorize booster shots of the Covid-19 vaccine developed by Pfizer and BioNTech. At that time, the advisory committee said that it was uncomfortable recommending boosters for anyone over 16, as the companies had suggested, in part because of the lack of evidence they were necessary and because of the potential risk of myocarditis and pericarditis, heart inflammation that, though rare, may be a result of the vaccine, particularly in younger men.

But the panel is now being asked to recommend the same authorization for Moderna’s booster as it had for Pfizer’s, and the two vaccines are similar. Pfizer’s booster is authorized for individuals 65 years of age and older; those 18 and older at high risk of severe Covid-19; and those whose frequent institutional or occupational exposure puts them at high risk of serious complications of Covid-19. This last group could include health care workers but also grocery store clerks and prison guards.

Still, discussions of the risk of myocarditis could prove important. The FDA’s documents note that most cases of the condition got better on their own, and that it seems to occur mostly in younger men. In analyses of insurance claims data conducted by the FDA, the number of cases in men aged 18 to 25 years ranged from 72.4 per 1 million vaccinated to 283.7 per million. “It is currently not known if there will be an increased risk of myocarditis/pericarditis or other adverse reactions after a booster dose of the Moderna COVID-19 Vaccine,” the FDA researchers wrote.

The committee is also set to take up the matter of whether observational data clearly show the efficacy of the vaccine waning. Panelists could question the use of half the standard vaccine dose (50 micrograms instead of 100) for the booster. In documents submitted to the FDA, Moderna said that both doses resulted in 66-fold increases in antibody levels, but that the lower dose seemed less likely to result in common side effects.

The FDA has not made available its briefing document on the Johnson & Johnson vaccine. In the company’s documents, J&J argued that a second dose of its one-dose vaccine has been shown to increase antibody titers when given either two months after the first dose or six months after the first dose. The two-month regimen was shown to prevent severe Covid-19 in a large clinical trial, but the six-month regimen may provide a bigger boost in antibody titers.

One of the most interesting topics for the meeting comes at the end of day two: the discussion of a National Institutes of Health study that examines what happens when people get a booster dose of a different vaccine than the one they originally received. Allowing such mix-and-match boosters could make it much simpler to give people the shots in the future. It would also open the Covid-19 vaccine market up to many more players, instead of giving Pfizer and Moderna an effective lock on the market.

https://www.statnews.com/2021/10/12/fda-scientists-moderna-covid-vaccine-booster/