Biden finds new ways to spend on bureaucracy 'to prevent and prepare for pandemics'

 The Biden administration on Tuesday unveiled a new national biodefense strategy, aiming to adapt lessons drawn from the rocky response to the Covid-19 pandemic as it prepares the country for future public health emergencies.

The strategy, which has been long anticipated, includes such goals as strengthening public health workforces both in the United States and globally, and establishing international mechanisms to bolster laboratory safety.

The government’s plan outlines policy targets for more than 20 federal agencies to help the country and world try to prevent epidemics, detect them faster, respond when they occur, minimize their impact, and recover, senior administration officials said on a call with reporters Monday as they previewed the strategy. Oversight for the strategy will be at the White House, under the national security advisor.

The strategy also outlines “moonshot” targets that officials said were not possible as of now but could be achieved within a decade with the proper resources. There are 26 families of viruses known to be able to infect people, “many of which we are far less prepared for than coronaviruses,” a senior administration official said on the call. Government and industry scientists, for example, had already been developing coronavirus vaccines when the SARS-CoV-2 virus, which causes Covid-19, emerged in late 2019.

“One of the important things that Covid has taught us is that we need to be able to move much faster to counter pandemic threats, and we also need to be prepared for completely unknown threats,” the official said.

The moonshot targets include being able to test for new pathogens within 12 hours and make rapid tests available within 90 days; develop vaccines within 100 days and manufacture enough for the U.S. population within 130 days and for the high-risk global population within 200 days; and repurpose existing drugs within 90 days and develop new treatments within 180 days.

The administration officials said they were starting to pursue some of these goals with agencies’ baseline funding, but noted that President Biden has asked Congress to allocate $88 billion over five years for pandemic preparedness.

t’s not clear if lawmakers have much of an appetite for additional public health spending. Republicans in Congress have balked at recent requests for funding for the ongoing monkeypox and Covid-19 responses.

The new biodefense strategy envisions recruiting, training, and sustaining a public health workforce — including laboratory technicians, veterinarians, and community health workers — to not only better detect emerging diseases but respond to them. Public health departments in the United States have long warned they’re underfunded and overworked, a dynamic only exacerbated by the pandemic. But administration officials said the goal was not only to build up such a public health army in the United States, but that they were also committed to helping at least 50 countries strengthen their own local capacities.

The administration’s plan also calls for international mechanisms that can help strengthen lab safety and biosecurity practices around the world. The pandemic has led to heated questions about the risks and benefits of research into potentially dangerous viruses amid speculation that the coronavirus could have “leaked” from a virology institute in Wuhan, China, even as recent research has indicated that the outbreak likely started as a result of a spillover from animals.

Still, the administration’s plan is to be ready for all biological threats and epidemics, “whether they’re naturally occurring, deliberate, or accidental,” as one senior official said.

https://www.statnews.com/2022/10/18/white-house-plan-prepare-future-pandemics/

Boston U testing of lab-made version of Covid virus draws government scrutiny

 Research at Boston University that involved testing a lab-made hybrid version of the SARS-CoV-2 virus is garnering heated headlines alleging the scientists involved could have unleashed a new pathogen.

There is no evidence the work, performed under biosecurity level 3 precautions in BU’s National Emerging Infectious Diseases Laboratories, was conducted improperly or unsafely. In fact, it was approved by an internal biosafety review committee and Boston’s Public Health Commission, the university said Monday night.

But it has become apparent that the research team did not clear the work with the National Institute of Allergy and Infectious Diseases, which was one of the funders of the project. The agency indicated it is going to be looking for some answers as to why it first learned of the work through media reports.

Emily Erbelding, director of NIAID’s division of microbiology and infectious diseases, said the BU team’s original grant applications did not specify that the scientists wanted to do this precise work. Nor did the group make clear that it was doing experiments that might involve enhancing a pathogen of pandemic potential in the progress reports it provided to NIAID.

"I think we’re going to have conversations over upcoming days,” Erbelding told STAT in an interview.

Asked if the research team should have informed NIAID of its intention to do the work, Erbelding said: “We wish that they would have, yes.”

The research has been posted online as a preprint, meaning it has not yet been peer-reviewed. The senior author is Mohsan Saeed, from BU’s National Emerging Infectious Diseases Laboratories. STAT reached out to Saeed on Monday but had not received a response by the time this article was published.

In emailed comments, the university later disputed the claims made by some media outlets that the work had created a more dangerous virus.

The email, from Rachel Lapal Cavallario, associate vice president for public relations and social media, said that the work was not, as claimed, gain of function research, a term that refers to manipulation of pathogens to make them more dangerous. “In fact, this research made the virus [replication] less dangerous,” the email stated, adding that other research groups have conducted similar work.

In the paper Saeed and colleagues reported on research they conducted that involved creating a hybrid or chimeric virus — in which the spike protein of an Omicron version of SARS-2 was fused to a virus of the Wuhan strain, the original version that emerged from China in 2020. Omicron viruses first emerged in late 2021 and have since splintered into multiple different sub variants.

The goal of the research was to determine if the mutations in the Omicron spike protein were responsible for this variant’s increased ability to evade the immunity to SARS-2 that humans have built up, and whether the changes led to Omicron’s lower rate of severity.

The testing actually showed, though, that the chimeric virus was more lethal to a type of lab mice than Omicron itself, killing 80% of the mice infected. Importantly, the original Wuhan strain killed 100% of mice it was tested in.

The conclusion of the study is that mutations in the spike protein of the Omicron variant are responsible for the strain’s ability to evade immunity people have built up via vaccination, infections, or both, but they are not responsible for the apparent decrease in severity of the Omicron viruses.

“Consistent with studies published by others, this work shows that it is not the spike protein that drives Omicron pathogenicity, but instead other viral proteins. Determination of those proteins will lead to better diagnostics and disease management strategies,” Saeed said in a comment circulated by the university.

Research that has the potential to make pathogens more dangerous has been a hot-button issue for years. About a decade ago, a high-profile debate over whether it was safe to publish controversial studies done on a dangerous bird flu virus, H5N1, led to a re-writing of the rules around this type of work. Another review of the policy is currently underway, led by the National Science Advisory Board for Biosecurity.

The controversy around research on pathogens of pandemic potential has gained ground since the start of the Covid-19 pandemic, which some scientists and others believe may have been an accidental or deliberate result of research on bat coronaviruses at the Wuhan Institute of Virology in the Chinese city where the pandemic is believed to have begun. (There is a lot of evidence that points to the virus spreading from a wet market in the city, not the Wuhan lab. But proving something didn’t happen three years after the fact is a challenge that may be impossible to meet.)

Under NIAID’s policy, proposals to do federally funded research that could produce so-called enhanced pathogens of pandemic potential should be referred to a committee that would assess the risks and benefits of the work. The policy is known as P3CO framework.

Erbelding said NIAID would probably have convened such a committee in this case, had it known that Saeed’s team planned to develop a chimeric virus.

“What we would have wanted to do is to talk about exactly what they wanted to do in advance, and if it met what the P3CO framework defines as enhanced pathogen of pandemic potential, ePPP, we could have put a package forward for review by the committee that’s convened by HHS, the office of the assistant secretary for preparedness and response. That’s what the framework lays out and that’s what we would have done,” she said.

Erbelding noted, however, that some of the media coverage of the study over-estimates the risk the work may have posed. “That 80% kill rate, that headline doesn’t tell the whole story,” she said. “Because Wuhan” — the original strain — “killed all the mice.”

The fatality rate seen in this strain of mice when they were infected with these viruses raises questions about how good a model they are for what happens when people are infected with SARS-2. The Wuhan strain killed less than 1% of people who were infected.

Virologist Angela Rasmussen, who was not involved in the research, had some sympathy for the BU scientists, saying there is ambiguity in the rules as they are currently written.

“Because so much of the definition of ePPP pertains to ‘reasonable anticipation’ of results in humans (and animal models are not always good proxies of this), it’s very difficult for researchers to say ‘Oh yes, this is ePPP,” Rasmussen wrote in response to questions from STAT.

“I’d personally reach out for clarification from NIAID when in doubt, but it’s often not obvious when additional guidance is warranted. And because it’s not very transparent, it’s hard to look at other decisions NIAID has made for examples,” she said.

“I’m very tired of people suggesting that virologists and NIAID are reckless or don’t care about biosafety,” said Rasmussen, a coronavirus expert at the University of Saskatchewan’s Vaccine and Infectious Disease Organization. “The problem isn’t that. The problem is that the guidelines and expectations aren’t clear for many experiments and the process isn’t transparent.”

https://www.statnews.com/2022/10/17/boston-university-researchers-testing-of-lab-made-version-of-covid-virus-draws-government-scrutiny/

AstraZeneca, FibroGen's roxadustat holds promise for sickle cell

 A patient with beta thalassemia or sickle cell disease—genetic disorders that affect the blood protein hemoglobin in red blood cells—currently has only two options for treatment. They can medicate the diseases’ many lifelong symptoms, or they can undergo a curative bone marrow transplant. 

Now, new research from St. Jude Children’s Research Hospital in Memphis, Tenneesee, opens the door to another possibility: the use of proline hydroxylase inhibitor roxadustat, a drug developed by Fibrogen and AstraZeneca that’s currently under late-stage investigation for treating anemia in chronic kidney disease, to produce healthy hemoglobin. In the results of a study published Oct. 12 in Nature, the scientists described how they used the drug to reverse cell sickling in red blood cells from patients with sickle cell disease.

To understand how the drugs could benefit sickle cell and beta thalassemia patients, it helps to know a little bit about hemoglobin and how it develops. Hemoglobin’s job is to latch on to oxygen so red blood cells can carry it around the body. Fetal hemoglobin, or HbF, contains two “alpha” subunits and two “gamma” subunits. The gamma subunits are replaced by “beta” subunits soon after birth.

That’s where the trouble starts: In patients who have beta thalassemia or sickle cell disease, there’s a mutation in the gene for the beta subunit. This causes the cell to form a sickle shape in sickle cell patients, while in beta thalassemia, it results in less hemoglobin production overall. In both cases, the patients’ tissues can’t get sufficient oxygen, resulting in a range of life-altering and dangerous symptoms. As a solution, scientists have been exploring ways to induce HbF production in adults.

“We have known for many years that persistent HbF expression after birth can alleviate the symptoms of sickle cell disease and beta thalassemia,” Michael Weiss, M.D., Ph.D., corresponding author and St. Jude Hematology Department chair, said in a press release. “Very high HbF levels can cure these diseases, despite the defective [genes] being present.”

The St. Jude scientists pieced together earlier work by other researchers to hypothesize that one route to boosting HbF might lie in the pathway that helps red blood cells sense and adapt to hypoxia, or low oxygen conditions. Clinical observations had shown that high altitude exposure, heart and lung disease and certain types of anemia—all low-oxygen states—increased red blood cell production. And Nobel Prize-winning studies on cells’ hypoxia detection machinery turned up a good protein to start with: a transcription factor called hypoxia-inducible factor 1, or HIF1, which is upregulated in the absence of oxygen.

Homing in on HIF1, the St. Jude team performed a series of screenings and studies on red blood cells and their precursors from sickle cell patients. Their results of showed that HIF1’s activity regulated hundreds of genes, including some that increased expression of the gamma subunits on hemoglobin—the ones found in HbF. Further experiments found that both hypoxia and inhibition of enzymes by roxadustat prevented HIF1 breakdown, allowing it to accumulate and ultimately increasing HbF levels. This made the drug a worthy candidate for study in patients with sickle cell disease and beta thalassemia, the researchers said.

The team noted that roxadustat could have other benefits, too. Besides activating HbF production, they also stimulate the creation of erythropoietin, a hormone from the kidneys that increases the rate of red blood cell production. This mechanism had made it useful for treating anemia in chronic kidney disease, a condition that also impacts patients with sickle cell disease. 

“Approximately 20% of adult sickle cell disease patients develop kidney failure with related anemia,” Weiss said. “Proline hydroxylase inhibitors might serve a dual purpose in these individuals by stimulating the production of both erythropoietin and HbF.”

As they prepare to work with clinical researchers to see whether the drugs have therapeutic potential, the scientists have more to explore. They hope to figure out the mechanism by which HIF1 induces expression of the gene for the gamma subunit in HbF as well as to figure out how it regulates red blood cell formation and function in other ways.

https://www.fiercebiotech.com/research/hypoxia-boosts-fetal-hemoglobin-red-blood-cells

After M&A sprint, newly unveiled Actylis aims to be 'much more than just a distributor'

 After a busy stretch at the bargaining table, chemical supplier Aceto unveiled a new way of working in January, folding a half-dozen acquisitions into its new hybrid production and distribution model. Now, more than two years after starting its manufacturing metamorphosis, Aceto’s efforts have given way to a new company altogether.

Borne out of Aceto and 10 other businesses—comprising eight specialty manufacturers and three sourcing companies—Actylis debuted this fall with ambitions to become a “global specialty ingredients manufacturing and sourcing powerhouse,” the fledgling company said in a recent release.

Aceto has been in the sourcing and supply game for more than 70 years, but the company decided to embark on a transformation shortly after the arrival of its current CEO Gilles Cottier in 2019, the chief executive said in a recent interview with Fierce Pharma. Now having met its goal to become “much more than just a distributor,” Aceto has fallen in line with the other companies behind Actylis. Cottier is now CEO of the newly branded Actylis.

Wedding production, distribution and R&D capabilities, Actylis is angling to carve out a spot as one of the world’s top manufacturers and sourcing experts for raw materials and performance ingredients. Aside from its significant stake in the pharmaceutical industry, Actylis also runs in nutritional, agricultural and specialty chemicals markets.

On the biopharma manufacturing front, the global enterprise consists of industry players like A&C and A&C Bio Buffer as well as Cascade Chemistry, which makes drug ingredients, regulatory starting materials and advanced intermediates. With Cascade added to the fold, the company said back in January it had gained the ability to support its clients throughout the drug development process. The move also boosted its access to North American manufacturing capacity.

At present, Actylis’s workforce stands more than 850 strong, spanning 10 different countries across three continents. The company’s procurement teams are based out of sites across North America, Europe and Asia. The company notes it has a significant presence in India.

That global presence is another strength of Actylis’, the company’s senior vice president of marketing and operations, Edward Roullard, said during the interview. It’s not just about meeting customers close to home, either, but giving them options, Roullard explained.

While “the noise around onshoring has gotten louder,” the lesson so far is that bringing manufacturing home is no easy task, Roullard added.

“It is going to shift,” Roullard said, explaining that “you are going to see more demand [for local production and supply], but it’s not something that is just implemented in six months.”

https://www.fiercepharma.com/manufacturing/after-acetos-ma-sprint-manufacturing-actylis-aims-be-much-more-just-distributor-ceo

Roche recalls new eye therapy Susvimo on leakage fears, aims for market return 'within a year or so'

 Just as doctors were starting to cozy up to Roche and Genentech’s new eye drug delivery therapy, the companies are pulling the product from U.S. shelves.

Roche has launched a voluntary recall of Susvimo—an implant approved for wet age-related macular degeneration (AMD) that dispenses a special formulation of ranibizumab—thanks to manufacturing problems with the device. The problem relates to the septum, or the seal on the port delivery device that keeps medicine from leaking out once it’s been injected, Roche Pharmaceuticals CEO Bill Anderson explained on a Tuesday investor call.

“[T]hat seal could fail after repeat dosing,” he said.

“And so we decided, because it didn't meet our performance standards, and [because] we want to make sure that we have high reliability, we decided to voluntarily stop distribution of the port delivery system,” he added.

While new patients looking to switch to Roche’s option—which boasts less frequent dosing versus Regeneron rival Eylea and even Roche and Genentech’s own Vabysmo—are out of luck for the time being, patients who already have Susvimo will “continue to receive their refills,” Anderson said.

In the meantime, Roche and Genentech “want to make some corrections to the manufacturing process that we hope can assure greater reliability,” the Roche pharmaceutical chief said.

Roche hopes to put Susvimo back on the market “as soon as possible," he added. In terms of a more concrete timeline, it may take several months to sort out the production glitch, which could allow Roche and Genentech to return with their device to market "within a year or so."

The companies are already in the process of conducting the Susvimo pull with the FDA, Genentech said in an emailed statement. The pause on new implantations extends to ongoing global clinical trials, too, the company added.

The company uncovered the defect while testing its commercial supply by repeatedly puncturing Susvimo implants with a needle. Certain devices failed to “perform to our standards,” Genentech said.

There is no medical need to remove the implant if patients already have it. The recall does not extend to the ranibizumab vial or refill needle, Genentech said.

Roche and Genentech have been angling to accentuate Susvimo’s convenience edge over its AMD opponents. Patients can undergo surgery to get the Susvimo implant installed and refilled with Lucentis just twice a year, versus six to 12 injections for Eylea or three to 12 injections of Vabysmo.

Susvimo had been gaining traction with eye doctors, to be sure, but it still faces an intense fight against Regeneron and Bayer’s entrenched blockbuster Eylea. While “the large majority” of 76 ophthalmologists polled acknowledged Susvimo’s “superior duration of response” when compared to Eylea, respondents “overwhelmingly rate Eylea as safer overall and more accessible," according to a recent report from Spherix analysts.

https://www.fiercepharma.com/manufacturing/roche-recalls-susvimo-implant-lucentis-leakage-fears-return-market-expected-within

Promising Use of Bioremediation to Break Down Forever Chemicals

 Early results show that using bioremediation to break down “forever chemicals” is working at an airport around Madison, Wisconsin. At the Dane County Regional Airport, scientists are introducing microbes into the groundwater to reduce the presence of PFAS in the water. Per- and polyfluoroalkyl substances (PFAS) are manmade chemicals that break down very slowly, if at all, in the natural environment. They have been used in food-packaging, cleaning products, paints, fire-fighting foams implemented at airports, and stain and water resistant fabrics, carpeting, and clothing. Studies have correlated adverse health effects to the presence of PFAS in groundwater and soil.

Bioremediation is the process of using living organisms such as fungi and plants and microorganisms such as bacteria to break down pollutants in the environment. Typically, when addressing groundwater remediation, microorganisms are introduced into the water source and provided nutrients. With the added nutrients, scientists are able to stimulate the growth rate of the bacteria and increase their metabolisms to eat the contaminant faster. The bacteria is able to either remove the contaminant completely or break it down into harmless inorganic constituents. One of the most prevalent uses of bioremediation is in the cleanup of oil spills, and was employed extensively for the Exxon Valdez and Deep Water Horizon spills.

Bioremediation is significantly cheaper than alternative methods of remediation such as incineration, solidification, oxidation or land filling. By relying on naturally occurring microorganisms, plants and fungi, the underlying remediation processes are both continuous and renewable. Recent successes with PFAS bioremediation in situ have resulted in cleaning up the environment without the need to move huge amounts of water or soil for treatment. Due to the natural metabolic action of bioremediation, it may take longer than other methods of remediation. However, data from the Dane County Regional Airport revealed a 97% reduction of PFAS in the first nine months.

https://www.jdsupra.com/legalnews/promising-use-of-bioremediation-to-7416352/

'Too Good to be True'? Ultrasound Safely Treats Kidney Stones

 Treatment with transcutaneous, focused ultrasound safely led to the repositioning and rupture of a majority of stones in the urethra when tested in 29 people at two US centers in the first human feasibility study of the technology.

The results "support the efficacy and safety of using ultrasonic propulsion and burst wave lithotripsy [BWL] to reposition and break ureteral stones, potentially relieving pain and facilitating passage in awake patients," write M. Kennedy Hall, MD, an emergency medicine physician at the University of Washington School of Medicine in Seattle, and co-authors in a report published in the November 2022 issue of The Journal of Urology.

"This is the first human trial in awake subjects" of this method for nonsurgically facilitating ureteral stone clearance, and the results of limited patient discomfort and stone motion in 66% of treated patients seem "almost too good to be true," comments Karen L. Stern, MD, a urologist at the Mayo Clinic in Phoenix, Arizona, in an accompanying editorial.

However, Stern notes two study limitations. First, to correctly target the focused ultrasound clinicians first need to visualize a stone with ultrasound. However, "most urologists are not experienced in ultrasound," a limitation that could mean the treatment may be more likely performed by emergency physicians or radiologists in the future.

Second, the study had no control patients, and Stern cautions that the clinical significance of BWL cannot be definitively assessed without a randomized trial that directly compares the new method with either spontaneous stone passage or medical expulsion therapy.

"The authors showed a distal urethral stone passage [rate] of 81%, but those stones passed within days, not minutes, of the procedure, and that rate is not too far off published data on spontaneous passage," Stern notes in her editorial.

Despite these caveats, Stern calls the potential for BWL "immense."

Ultrasound for 10 Minutes or Less

The study enrolled adults who presented to the University of Washington emergency department or endo-urology clinic with a proximal or distal ureteral stone. Twenty-nine awake, unanesthetized patients in whom clinicians had an unobstructed view of a stone in the focal zone received ultrasound treatment performed by trained personnel.

Treatment involved ultrasound bursts of up to 3 seconds for stone propulsion and 30 seconds at a time for BWL. Total ultrasound exposure could not exceed 10 minutes, and no patient underwent more than one treatment. Sixteen patients received treatment for propulsion only, and 13 received both propulsion and BWL treatments.

The primary outcome was stone motion, which occurred in 19 of the 29 patients (66%). A prespecified secondary outcome was passage of the stone in the 26 patients with distal stones. Among the 21 patients with at least 14 days of follow-up, passage occurred in 18 (86%) after an average of 3.9 days following treatment. The researchers also confirmed stone fragmentation in five of the 13 patients (38%) who received BWL treatment.

The researchers infer that ultrasound treatment facilitated stone passage by stone propulsion, fragmentation, and peristalsis.

In an interview in 2021 with Medscape Medical News, Mathew D. Sorensen, MD, a study co-investigator, likened the effect of ultrasound on the stones to a leaf blower on garden debris.

"Essentially, we use the acoustic energy of ultrasound, which gets focused on the stone and creates movement, like a blower," said Sorensen, a urologist at the University of Washington School of Medicine. "A push of energy lasts a second or two, sort of a sweeping movement to try to get fragments to move out of what's usually the bottom of the kidney, toward the exit. Because the energy moves in one way, away from the probe, it's sort of like playing pool," he explained.

All 29 treated patients in the current study tolerated the procedure, and none experienced unanticipated events. No patients needed to visit the emergency department or an intervention because of the treatment, and there were no observed ureter injuries.

Pain Scores Dropped Significantly; Procedure Is "Nearly Painless"

Assessment of pain scores by each patient before and after treatment showed overall significant decreases in both mean and median scores, with 10 patients reporting decreased pain and two reporting increased pain.

When discomfort occurred during the procedure it was described by patients as either similar to a pinprick or as a referred sensation to pass urine and the stone. These effects occurred during 18 of 820 (2%) total propulsive bursts of ultrasound administered.

"It's nearly painless, and you can do it while the patient is awake, and without sedation, which is critical," said Hall in a statement from the University of Washington School of Medicine. He envisions eventually performing the procedure in a clinic or emergency department setting.

All three patients with a proximal stone and three patients with a distal stone who did not pass their stone after treatment underwent surgical stone removal.

The researchers acknowledge that a lack of a control group was a study limitation. They cite a historical, spontaneous stone passage rate of 54% included in a 2016 guideline from the American Urological Association and based on a meta-analysis of 27 studies with 1205 total patients.

The study was funded by the US National Aeronautics and Space Administration, which is interested in having a technology available to treat ureteral stones that may develop during prolonged space travel.

The study received no commercial funding. Four of the study's 23 authors, including Sorensen, are consultants to and hold equity in SonoMotion, a company that has licensed the tested technology from the University of Washington for commercial development. The report did not identify a specific manufacturer of the ultrasound equipment used for treatment.

J Urol 2022;208:1075-1082. Full text

https://www.medscape.com/viewarticle/982608