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Saturday, July 11, 2020

Kymera Therapeutics begins potential $2bn R&D deal with Sanofi

US biotech Kymera Therapeutics has begun a strategic collaboration with Sanofi to develop and market several drugs tackling immune-inflammatory disease, which could be worth up to $2 billion. 
The deal will focus on first-in-class protein degrader therapies targeting a protein known as IRAK4 – short for interleukin-1 receptor-associated kinase 4. 
Kymera is set to receive $150m in cash up front and may receive more than $2 billion if pre-agreed development, regulatory, and sales goals are met, as well as “significant” royalty payments. 
Massachusetts-based Kymera has retained the option to participate in US development and marketing for both programmes.  
This includes the ability to participate equally in the costs, profits and losses after opt-in, and to co-promote partnered products in the US. 
The $150 million gives Sanofi rights to develop its small molecule IRAK4 protein degraders in inflammation and immunology indications, and a second earlier stage undisclosed programme. 
Kymera will advance the IRAK4 programme through phase 1 clinical trials after which Sanofi will assume clinical development and marketing responsibilities. Sanofi will lead all clinical development activities for the second programme. 
Kymera will have the option to participate in the development of both programmes in the US during clinical development. Kymera will retain global rights to its IRAK4 programme in oncology indications. 
IRAK4 is believed to play a key role in multiple immune-inflammatory diseases, including hidradenitis suppurativa, atopic dermatitis and rheumatoid arthritis. 
It is a key protein involved in inflammation mediated by the activation of toll-like receptors (TLRs) and IL-1 receptors (IL-1Rs). 
While TLR and IL-1R signalling via IRAK4 is involved in the normal immune response, aberrant activation of these pathways is the underlying cause of multiple immune-inflammatory conditions. 
Kymera said preclinical data showing an oral daily administration of an IRAK4 degrader can lead to complete knockdown of IRAK4 in skin and immune cells in higher species and is well tolerated. 

Can Covid-19 Trigger The Onset Of Diabetes?

It’s enough that SARS-CoV-2, the virus that causes Covid-19, can cause pneumonia, kidney failure, blood clots, arrhythmias and even heart attacks, but the potential that the virus may also lead to onset of diabetes provides a new set of implications and potential complications for survivors.
A recent report in Nature details the rationale and proposed mechanisms behind the ability of the virus to damage specialized cells in the pancreas that make insulin, otherwise known as beta cells, contained in surrounding specialized cells (islets).
When beta cells are destroyed, and the body is unable to manufacture insulin, a person develops elevated blood sugar, known as hyperglycemia, which effectively switches the body to an alternate pathway for energy using ketones and ketone bodies as a primary source. Using ketones bodies for energy will trigger a dangerous state where the body produces harmful acids, leading to diabetic ketoacidosis (DKA), which can be fatal if left untreated.
What’s clear is that diabetes is already recognized as a key risk factor for developing severe Covid-19, and persons with this condition have a higher risk of death.
But new research is emerging that the virus not only causes a more severe course in diabetics, but may also trigger onset of the condition in a subset of patients. The potential for a crush of patients with new onset diabetes (Type 1) may be a new reality that the medical community is yet to face.
“It’s important to note that not only are new diabetes cases possible but the more common scenario would be the development of diabetes complications in patients who already have diabetes such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemia syndrome (HHS), said Dr. Minisha Sood, an endocrinologist at Lenox Hill Hospital in New York City. “These conditions are characterized by very high blood glucose and dehydration, among other symptoms.”
Clinicians are now seeing previously well people with no history of diabetes who have suddenly developed new onset diabetes after being infected with SARS-CoV-2, along with the dangerous complication, DKA, in which people develop acid in their blood stream, accompanied by rapid breathing, which can lead to shock and death.
“Knowing the symptoms of DKA and HHS is important so one may seek medical care in a timely manner. It’s critical for patients with diabetes to have a plan in place should they contract Covid-19 in terms of having enough medication, glucose testing supplies and access to their doctors and healthcare providers should they develop complications,” added Sood.
If we look back at patients who developed SARS back in 2002-2003, there is a linkage with development of autoimmune conditions such as type 1 diabetes. We also know that many organs which play a role in regulation of blood sugar—the liver, pancreas, kidneys, small intestine and adipose tissue (fat)— have a large number of ACE-2 receptors, the receptor on the surface of cells that the virus attaches to using its “spike protein”. Thats said, the basis for onset of ketosis-prone diabetes following infection with influenza or herpes has been previously reported in the medical literature.
Additional research recently published using miniature lab grown pancreases also suggests that the virus may cause diabetes by injuring the specialized cells, beta cells, that regulate blood sugar.
That said, other researchers have been less convinced about the strength of the connection between Covid-19 and new onset or worsening of diabetes.
“We need to keep an eye on diabetes rates in those with prior COVID-19, and determine if rates go up over and above expected levels,” said Naveed Sattar, a metabolic-disease researcher at the University of Glasgow, UK in the Nature report.
Clearly, more rigorous studies will be necessary to more definitively establish this link.
That said, a new collaborative research endeavor, the CovDiab Registry, was recently established by a group of researchers to study the presentation and spectrum of illness of patients with newly developed diabetes or complications related to existing diabetes.
The Registry will be useful, the researchers believe, in order to determine not only causes, but whether the diabetic state as a result of Covid-19 is permanent. Another goal will also be to look at those who are pre-diabetic and determine whether Covid-19 accelerates the pathway to Type 2 DM.
In fact, a letter published last month in the New England Journal of Medicine and signed by an international group of 17 leading diabetes experts involved in the CoviDiab Registry project, announced the establishment of the Global Registry of new cases of diabetes in patients with COVID-19.
Clinical observations thus far demonstrate a bi-directional relationship between Covid-19 and diabetes. On the one hand, diabetes is associated with increased risk of Covid-19 severity and mortality. Between 20 and 30% of patients who died with Covid-19 have been reported to have diabetes. At the same time, new-onset diabetes and life threatening metabolic complications of pre-existing diabetes such as DKA have also been in people with Covid-19.
“Diabetes is one of the most prevalent chronic diseases and we are now realizing the consequences of the inevitable clash between two pandemics,” said Francesco Rubino, Professor of Metabolic Surgery at King’s College London and co-lead investigator of the CoviDiab Registry project in a press release.” Given the short period of human contact with this new coronavirus, the exact mechanism by which the virus influences glucose metabolism is still unclear and we don’t know whether the acute manifestation of diabetes in these patients represent classic type 1, type 2 or possibly a new form of diabetes.”
One research group at Weill Cornell Medicine in New York City believes that the virus may directly damage the pancreas itself. Using so called “organoids”, miniature artificial lab- grown organs, Shuibing Chen and her team demonstrated that the virus can infect beta cells (which make insulin) a portion of which die. The virus seems to also induce production of cytokines which can trigger what’s believed to be an inflammatory response that can lead to death of beta cells.
We certainly don’t have all the answers just yet. While the organoid study does add some strength to the premise that SARS-CoV-2 may either cause or make existing diabetes worse, this research is still not enough to establish a definitive link, let alone causation.
It’s certainly possible that SARS-CoV-2 could produce a heightened inflammatory state which could inhibit the ability of the pancreas to accurately detect glucose and release insulin, while diminishing the capacity and ability of the liver to sense insulin. The end result could potentially lead to diabetes. That said, severe fatigue and muscle atrophy or breakdown could place people at risk for pre-diabetes into a diabetic state.
Long term studies will be essential to better understand the multiple potential mechanisms involved. Stay tuned!

80% Hospitalized With Coronavirus Still Had Symptoms Two Months Later

A new study looking at people discharged from hospital after treatment for Covid-19 has found that 4 in 5 of them were still reporting symptoms even 2 months later.
The research published in the Journal of the American Medical Association looked at 143 patients from Italy who had been hospitalized with Covid-19 and survived.
On average, patients were assessed two months after the onset of their first Covid-19 symptom and had spent two weeks in hospital recovering, with 28 patients receiving invasive, or non-invasive ventilation. At the time of the assessment, none of the patients reported fever, or any symptoms of acute Covid-19 but over half reported fatigue and 43% reported shortness of breath. Almost a third of the survivors reported joint pain and 22% had chest pain.
Only 13% of patients were free of any Covid-19-related symptoms after 2 months, whereas over half of people reported three or more symptoms. The study also asked patients a number of questions related to their quality of life, with 44% of patients saying their quality of life was worse than before they were sick.
Covid-19 is often written off by naysayers as a disease which only severely affects older people, but people profiled in this study were between 19-84 years old, with an average age of 57.
Of note, the study only looked at people who had been hospitalized with Covid-19, so the findings may not reflect people who have had less-severe Covid-19, not requiring hospitalization. Additionally, almost three quarters of the patients experienced signs of interstitial pneumonia when in hospital and it is not unusual for people to experience symptoms for several months following severe pneumonia, even if it is not caused by the SARS-CoV2 coronavirus.
However, the new findings add growing evidence that in some people, Covid-19 can cause persistent and long-lasting symptoms, even long after the virus itself can no longer be detected. Many physicians have warned that Covid-19 could cause long-term disability in some people who survive the disease and have called for more research into both the acute and chronic effects of the virus.

NYC restaurants battling rat problems in early reopening stage

As if New York City restaurants don’t have enough to contend with, they’re now battling armies of rats.
Resilient restaurateurs, battling back from the COVID-19 outbreak and lock-down, are worried that outdoor diners just now returning will flee amid the pesky and persistent vermin.
“Last night, a customer had a baby rat running on his shoe and I let you just imagine his reaction,” said Giacomo Romano, the owner of Ciccio, an Italian restaurant in SoHo, to NBC New York.
Ciccio said the filthy conditions of nearby Father Fagan Park, now a gathering spot for skateboarders, was making the rat problem worse.
“There are a lot of new holes in the ground-cover by the plants,” Romano said.
One parkgoer told the station he watched several rats go from one spot to another as he sat on the park bench.
Pasquale Giacobbe, who owns a barbershop nearby, said, “I already don’t have the help from the state, no loans from nobody. At least they can come do something (about the rats), for all the tax we pay.”

With social distancing, schools should be safe to reopen this fall – pediatricians

Kids should be able to safely return to reopened schools this fall, resuming their studies with little risk that they will contribute to the COVID-19 pandemic, some infectious disease experts argue.
The so far indicates that do not tend to spread the novel coronavirus between themselves, nor do they appear to regularly infect adults, a new editorial in the journal Pediatrics claims.
“Generally, the younger you are, then the less likely you are to transmit to other children or adults,” said editorial co-author Dr. William Raszka Jr. He’s a pediatric infectious disease specialist with the University of Vermont’s Larner College of Medicine, in Burlington.
“With precautions, schools should reopen,” Raszka said.
The upcoming year became a political football this week, with President Donald Trump threatening to cut federal funding for schools that do not fully reopen in the fall.
But the drive to reopen schools is supported by mounting epidemiological evidence that kids don’t appear to play a major role in the spread of COVID-19, said Dr. Amesh Adalja, a senior scholar with the Johns Hopkins Center for Health Security, in Baltimore.
“We have seen schools open in places like Denmark and Finland without a problem, and day care centers have been open for essential workers throughout the pandemic,” Adalja said. “It will be important for schools to develop a plan for dealing with cases and allowing for social distancing, but we are causing harm to a whole generation of students who are not able to be educated adequately.”
Not all medical experts share this view, however.
States that have COVID-19 infection rates under control might be able to reopen schools, but other places in the midst of a coronavirus infection surge should think twice, said Dr. Matthew Heinz, a hospital physician and internist in Tucson, Ariz.
“Certainly not for my state, if the numbers continue the way they are,” Heinz said of reopening schools in Arizona. “We are in a fulminating virus-on-the-rampage situation. I can’t see where this would be safe. I would caution the leadership in the states that are hardest hit to take appropriate steps to delay reopening.”
Raszka’s editorial in the July 10 issue of Pediatrics accompanied a new study of families in Switzerland that found that adults most often transmit the coronavirus to children.
Only about 8% of the time did children appear to pass COVID-19 to older family members, the researchers found. Most of the time, adults infected kids.
“This contributes to the bulk of evidence that children are infected by adults, but not the other way around,” said senior researcher Dr. Arnaud L’Huillier, a pediatric infectious disease specialist with Geneva University Hospitals in Switzerland. “Reopening schools does not seem to be a public health issue when compared to reopening restaurants, bars and shops.”
Raszka, an associate editor of Pediatrics, also cited other pediatric evidence that’s surfaced during the pandemic:
  • A Chinese study found that nearly all children diagnosed with COVID-19 had contracted the coronavirus from an infected adult.
  • A French boy with COVID-19 exposed more than 80 classmates at three schools to the disease, but none became infected.
  • In New South Wales, nine students and nine staff exposed a total of 735 students and 128 staff across 15 different schools. Only two infections resulted, and one was an adult who transmitted the coronavirus to a child.
“What we’ve seen so far in examinations of household contacts and the experience across the world in schools is that young children very infrequently transmit the virus to other children and to adults, which really supports the idea that particularly young children can re-enter the school system,” Raszka said.
“I keep thinking, let me get this straight—we allow adults into bars to drink without a mask and congregate together for hours on end, but we don’t send kids to school,” Raszka added. “It’s just mind-boggling to me.”
No one knows why children don’t seem to spread COVID-19, he said, particularly given their active role in spreading influenza and other germs.
“With influenza, children are well-known spreaders of the disease,” Raszka said. “That’s been one of the major surprises, that children do not spread or transmit coronavirus as efficiently. It’s sort of mysterious why younger children seem to be much less frequently infected and generally speaking have much less severe disease, and why they don’t transmit as often.”
Schools should still use social distancing if they reopen
It might be that kids with COVID-19 don’t cough as much because they don’t become as sick as adults, or that they don’t have the same sort of extended conversations with each other as adults do, Raszka said.
Despite the evidence, Raszka said schools should still take steps to reduce transmission risk by encouraging social distancing, requiring that students wear masks, and eliminating activities that require large groups of children to congregate in enclosed spaces.
Schools should space desks out as far as they can, have students all face the same direction, and even require classes to eat lunch in the room where they’re taught, he suggested.
“Having 150 kids together having lunch in one small room would potentially encourage transmission,” Raszka said. “Even though we think it’s pretty unlikely, that’s just something we can do to minimize the risk of transmission.”
Trump has criticized school reopening guidelines released by the U.S. Centers for Disease Control and Prevention that call for these sorts of protective measures, but CDC officials have said they will not revise their guidelines and instead will craft additional guidance documents for school officials.
Heinz said he’s concerned that U.S. school districts simply won’t be able to afford to enact the measures urged by the CDC and experts like Raszka.
“Historically, we do not fund our schools adequately by any stretch of the imagination. Where is the budget for the various protections and protocols?” Heinz said. “There’s not money there for anything, in some cases basic supplies for the students, much less a viral pandemic management budget.”
The American Academy of Pediatrics has gone on record supporting reopening, urging school districts in a recent report to do everything they can to bring students back to classrooms.
“Children get much more than an education at school,” AAP president Dr. Sally Goza said during a meeting at the White House on Tuesday, the Washington Post reported. “Being away from peers, teachers and school services has lasting effects for children. Although this will not be easy, pediatricians strongly advocate that we start with the goal of having students physically present at school this fall.”

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