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Wednesday, December 11, 2024

Corcept Misses Primary Endpoint in Phase 2 ALS Study

 Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of medications to treat severe endocrinologic, oncologic, metabolic, and neurologic disorders by modulating the effects of the hormone cortisol, today announced results from the DAZALS study, a randomized, double-blind, placebo-controlled, Phase 2 trial evaluating two doses (150 mg and 300 mg) of its proprietary selective cortisol modulator dazucorilant in patients with ALS. Upon completion of the trial, patients were eligible to enter an open-label, long-term extension study, in which they received 300 mg of dazucorilant.

DAZALS did not meet its primary endpoint, which was the change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) in patients who received dazucorilant compared to those who received placebo. Patients who received dazucorilant experienced substantially more gastrointestinal upset at the onset of treatment than those who received placebo. During the 24-week study, no deaths (0/83) were observed in the 300 mg arm, compared to 5 deaths (5/82) in the placebo group (p-value: 0.02). The open-label, long-term extension study will continue and overall survival will be assessed in March 2025 after all patients have had one year pass since the onset of treatment. Dazucorilant has been granted Fast Track Designation by the U.S. Food and Drug Administration.

https://www.businesswire.com/news/home/20241211463748/en

Editas cut to Equal Weight from Overweight by Wells Fargo

 Target to $4 from $7

https://finviz.com/quote.ashx?t=EDIT&p=d

'Simply Robbery': Moscow To Retaliate After US Hands Ukraine $20BN Utilizing Russian Assets

 Russia on Wednesday blasted the US disbursing a $20 billion loan to Ukraine backed by frozen Russian assets as "theft" and "simply robbery" while vowing that retaliation will soon come.

On Tuesday, the Biden administration announced it disbursed the $20 billion loan for Ukraine, to eventually be paid back using interest earned on frozen Russian Central Bank assets, which has been a controversial plan long in preparation.

AFP/Getty Images

Washington said it issued the funds as part of the bigger total $50 billion loan being provided by the Group of Seven (G7) nations.

Russia's foreign ministry on Wednesday further said the move "will not go answered". It warned that it has "sufficient capacity and leverage to retaliate by seizing Western assets under its jurisdiction".

In announcing the major action, US Treasury Secretary Janet Yellen had described the following:

"These funds — paid for by the windfall proceeds earned from Russia’s own immobilized assets — will provide Ukraine a critical infusion of support as it defends its country against an unprovoked war of aggression."

"The $50 billion collectively being provided by the G7 through this initiative will help ensure Ukraine has the resources it needs to sustain emergency services, hospitals, and other foundations of its brave resistance," she added.

This is all part of Biden and NATO allies' efforts to 'Trump proof' future aid and support to Ukraine for years to come. Trump is expected to 'probably' reduce US defense aid to Ukraine. Trump officials have warned that Kiev would see funding greatly reduced or even pulled if it is unwilling to engage Moscow seriously at the negotiating table.

A key rationale of Trump's team in making the case for a necessary and quick winding down of the war is that the West must avoid nuclear confrontation or a WW3 scenario with Russia at all costs.

War-weary populations across Europe and the West are also in favor of peace, all recent polling shows, and Trump has been given a clear mandate by US voters to seek a diplomatic end to the war.

Zelensky has in response said: "What is needed are concrete, strong actions that will force him [Putin] to peace, not persuasion and attempts at appeasement, which he sees as a sign of weakness and uses to his advantage."

https://www.zerohedge.com/geopolitical/simply-robbery-moscow-vows-retaliation-after-us-hands-ukraine-20bn-utilizing-russian

Human beta cell regeneration research spurs hope for cure for diabetes

 Diabetes researchers and bioinformaticians from the Icahn School of Medicine at Mount Sinai have developed a new understanding of how human beta cell regenerative drugs work. These drugs, developed at Mount Sinai, may hold promise for the more than 500 million people in the world with diabetes. The results of this study were published this month in Cell Reports Medicine.

Diabetes develops when cells in the pancreas known as beta cells become unable to produce insulin, a hormone that is essential to regulating blood sugar levels. While great progress has been made toward discovering a durable therapy, none are scalable therapeutic options for millions of diabetics across the globe.

For more than 15 years, researchers at the Icahn School of Medicine at Mount Sinai have worked tirelessly to find a solution to cure diabetes by identifying a  that could make human beta cells regenerate.

In 2015, Mount Sinai researchers discovered the first such drug, called harmine. Harmine is a member of a class of drugs called DYRK1A inhibitors. In 2019 and 2020, the researchers reported that DYRK1A inhibitors can synergize with TGF-beta signaling as well as GLP-1 receptor agonist (GLP-1RA) drugs such as semaglutide (e.g., Ozempic) and exenatide (Byetta) to induce more robust levels of human beta cell regeneration. Finally, in July 2024, they showed that harmine alone increases human beta cell mass by 300%, and if a GLP-1RA is added, by 700%.

A key question has been how harmine causes beta cells to regenerate. In the newest study, the research team reports that the new, regenerated beta cells may be coming from an unexpected source: a second pancreatic cell type called alpha cells. Since alpha cells are abundant in people with type 1 and type 2 diabetes, they may be able to serve as a source for new beta cells in both common types of diabetes.

"This is an exciting finding that shows harmine-family drugs may be able to induce lineage conversion in human pancreatic islets," says Esra Karakose, Ph.D., Assistant Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai and corresponding author of the study. "It may mean that people with all forms of diabetes have a large potential 'reservoir' for future , just waiting to be activated by drugs like harmine."

"It has been remarkable and rewarding to watch this multi-group story unfold over the past 15 years," added Andrew F. Stewart, MD, Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute.

He and Peng Wang, Ph.D., Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at the Icahn School of Medicine at Mount Sinai, conceived of and performed the initial high-throughput drug screen that led to the discovery of harmine, described in Nature Medicine in 2015.

"A simple pill, perhaps together with a GLP1RA like semaglutide, is affordable and scalable to the millions of people with ," said Dr. Stewart. The Mount Sinai team is moving these studies to human trials.

More information: Esra Karakose et al, Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors, Cell Reports Medicine (2024). DOI: 10.1016/j.xcrm.2024.101832


https://medicalxpress.com/news/2024-12-human-beta-cell-regeneration-closer.html

New target for diabetic heart disease therapy

 Some patients with diabetes develop a serious condition known as diabetic cardiomyopathy, which proceeds slowly and cannot be directly attributed to hypertension or other cardiovascular disorders. This often under-diagnosed heart function impairment is one of the leading causes of death in diabetic patients and it affects both type 1 and type 2 diabetics. There is no current specific drug treatment or clinical protocol approved to address this disease.

A study published in the journal Pharmacological Research describes a potential target that could spur the design of new therapeutic strategies to specifically treat .

The paper describes the beneficial effects on the disease of activating a protein—the nuclear receptor PPARβ/δ—present in all body cells and especially abundant in organs and tissues with more active metabolism (, heart, liver or adipose tissue).

Manuel Vázquez-Carrera and Xavier Palomer, from the UB's Faculty of Pharmacy and Food Sciences, the UB Institute of Biomedicine (IBUB) and the Sant Joan de Déu Research Institute (IRSJD), led the study as experts from the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Center (CIBERDEM).

Other researchers on this paper are Fátima Crispi, from the UB's Faculty of Medicine and Health Sciences, BCNatal (IRSJD and Hospital Clínic—IDIBAPS) and the Center for Biomedical Research Network on Rare Diseases (CIBERER); Francisco Nistal, from the University of Cantabria and the Marqués de Valdecilla University Hospital and the Center for Biomedical Research Network on Cardiovascular Diseases (CIBERCV), and Walter Wahli, from the University of Lausanne (Switzerland), among other experts.

A protein involved in cardiac pathologies

Alterations in metabolism, inflammation, fibrosis and cardiac cell death by apoptosis are some of the causes for the development of diabetic cardiomyopathy. The study reveals that activation of the PPARβ/δ receptor can help to slow down the processes of inflammation and fibrosis in laboratory animal models and human cardiac cells under hyperglycemic conditions.

The PPARβ/δ factor is the most abundant member of the peroxisome proliferator-activated receptor (PPAR) family in the heart. However, Vázquez-Carrera notes that "the energy reservoir it contains is barely sufficient to maintain cardiac function for more than 10 seconds, a constant supply of energy obtained through the oxidation of fatty acids (70%) and, to a lesser extent, other substrates such as glucose or lactate, supplied through the blood."

"Most of these pathologies are associated with a decrease in the transcriptional activity of PPARβ/δ and, in fact, it has been suggested that its activation could be useful to treat them. A reduction in the activity of this protein is also implicated in the development of several cardiac disorders," says Vázquez-Carrera. "It also plays an important role in the regulation of inflammation and tissue remodeling," he adds.

Inflammation, fibrosis and diabetic cardiomyopathy

In diabetes or obesity, insulin resistance in the myocardium causes the heart to derive energy almost exclusively from mitochondrial oxidation of fatty acids. This causes lipid accumulation in the myocardium and leads to lipotoxicity, which results in the heart muscle demanding more oxygen.

Diabetic hyperglycemia and lipotoxicity trigger cardiac inflammation and fibrosis through the activation of proinflammatory and profibrotic transcription factors (NF-қB and AP-1). Once activated, these factors drive the process of cardiac remodeling, which increases myocardial stiffness and impairs cardiac relaxation (diastole) after contraction (systole).

The activation of NF-қB and AP-1, together with mitogen-activated protein kinase (MAPK) activity, induces cardiomyocyte cell death, which also contributes to contractile dysfunction in diabetic cardiomyopathy. Professor Palomer points out that "together, all these processes lead to extracellular cardiac remodeling, contractile dysfunction, left ventricular hypertrophy and dilated cardiomyopathy, ultimately leading to heart failure."

How does the PPARβ/δ protein act

To date, it was known that activation of PPARβ/δ in the heart could prevent metabolic dysregulation during diabetes and obesity. This would help prevent heart failure, the inability of the heart to pump blood efficiently to all organs and tissues in the body.

The study reveals that the beneficial effect of the PPARβ/δ protein in diabetic cardiomyopathy is explained by its ability to inhibit the MAPK pathway, according to the results obtained in cultured human cardiac cells.

Oxidative stress, hyperglycaemia and lipotoxicity were also known to accelerate cardiomyocyte inflammation, fibrosis and apoptosis in diabetic cardiomyopathy through the activation of mitogen-activated protein kinases (MAPKs), which also affects tissue remodeling after myocardial infarction.

Vázquez-Carrera points out that "it is not surprising, therefore, that the inhibition of these MAPKs can prevent inflammation and fibrosis not only in the heart, but also in other organs and tissues such as the liver, lung, kidney or even skeletal muscle, in various pathological conditions."

Searching for new treatments

In August 2024, the US Food and Drug Administration (FDA) approved the use of a new selective PPARβ/δ agonist known as seladelpar to treat primary biliary cholangitis, a rare, chronic disease that affects the bile ducts and can cause severe liver damage. As of February, the application for marketing authorization in the European Union is under review.

"In this global health scenario, it might be thought that pharmaceutical companies could be increasingly interested in the research and development of such drugs for the treatment of diabetic cardiomyopathy," the researchers conclude.

More information: Adel Rostami et al, PPARβ/δ prevents inflammation and fibrosis during diabetic cardiomyopathy, Pharmacological Research (2024). DOI: 10.1016/j.phrs.2024.107515


https://medicalxpress.com/news/2024-12-diabetic-heart-disease-therapy.html

San Diego Sheriff 'Will Not' Comply With New 'Super Sanctuary' Protections For Illegals

 The San Diego County Sheriff's office is refusing to comply with the County Board of Supervisors' vote to turn the county into a "super" sanctuary by preventing local law enforcement from complying with federal immigration enforcement efforts.

San Diego County Sheriff Kelly Martinez

With the return of Trump to the White House, the board on Tuesday approved the measure in a 3-1 vote, prohibiting the use of its resources to help ICE, and limiting the use of its jails, county buildings and personnel in assisting federal immigration enforcement agents.

"San Diego County has always been a place where communities are valued, not divided and as a County Supervisor, I'm committed to leading a local government that promotes unity, equity, and justice for all, while upholding the law," said County Chairwoman Nora Vargas, adding "We will not allow our local resources to be used for actions that separate families, harm community trust, or divert critical local resources away from addressing our most pressing challenges. Immigration enforcement is a federal responsibility, and our County will not be a tool for policies that hurt our residents."

Not So Fast

In response, the San Diego County Sheriff says they will ignore the Board's resolution.

"The Sheriff's Office will not change its practices based on the Board resolution and policy that was passed at today's meeting," adding that "The Board of Supervisors does not set policy for the Sheriff's Office.

"The Sheriff as an independently elected official, sets the policy for the Sheriff's Office. California law prohibits the Board of Supervisors from interfering with the independent, constitutionally and statutorily designated investigative functions of the Sheriff."

Vargas doesn't know what to do!

https://www.zerohedge.com/political/san-diego-sheriff-will-not-comply-new-super-sanctuary-protections-illegals

Progressivism & The Murder Of A Health Insurance CEO

 by Connor O'Keeffe via The Mises Institute,

Last week, UnitedHealthcare CEO Brian Thompson was shot to death on a New York City sidewalk in what was clearly a thoroughly planned-out attack. Over the next few days, as authorities hunted for the killer, online progressives did not try hard to hide their delight that a millionaire health insurance executive like Thompson was killed.

Social media was flooded with posts and videos—with different ranges of subtlety—suggesting that Thompson, at the very least, did not deserve to be mourned because of all the health care his company has denied to poor and working people. Progressives framed the shooting as an act of self-defense on behalf of the working class. Before the alleged killer was caught Monday, they promised not to snitch if they saw the shooter themselves and fantasized about a working-class jury nullifying all charges, leading to other CEOs getting gunned down with impunity if they oversaw price increases.

The narrative that these online progressives clearly subscribe to and perpetuate is one where, in the United States, healthcare is a totally unfettered, unregulated industry; where - because of a total lack of government involvement - wealthy CEOs charge whatever prices they want and then refuse to provide customers what they already paid for without facing any bad consequences.

The characterization of healthcare and health insurance companies charging absurdly high prices while treating their customers terribly without the risk of losing them is spot on.

But the idea that what caused this was a lack of government involvement in the healthcare system is completely delusional.

And this delusion conveniently removes all the responsibility progressives bear for the nightmare that is the US healthcare system.

Today, healthcare is one of the most heavily government-regulated industries in the economy - right up there with the finance and energy sectors. Government agencies are involved in all parts of the process, from the research and production of drugs, the training and licensing of medical professionals, and the building of hospitals to the availability of health insurance, the makeup of insurance plans, and the complicated payment processes.

And that is nothing new. The US government has been intervening heavily in the healthcare industry for over a century. And no group has done more to bring this about than the progressives.

It really began, after all, during the Progressive Era, when the American Medical Association maneuvered its way into setting the official accreditation standards for the nation’s “unregulated” medical schools. The AMA wrote standards that excluded the medical approaches of their competitors, which forced half of the nation’s medical schools to close. The new shortage of trained doctors drove up the price of medical services—to the delight of the AMA and other government-recognized doctor’s groups—setting the familiar healthcare affordability crisis in motion.

Around the same time, progressives successfully pushed for strict restrictions on the production of drugs and, shortly afterward, to grant drug producers monopoly privileges.

After WWII, as healthcare grew more expensive, the government used the tax code to warp how Americans paid for healthcare. Under President Truman, the IRS made employer-provided health insurance tax deductible while continuing to tax other means of payment. It didn’t take long for employer plans to become the dominant arrangement and for health insurance to morph away from actual insurance into a general third-party payment system.

These government interventions restricting the supply of medical care and privileging insurance over other payment methods created a real affordability problem for many Americans. But the crisis didn’t really start until the 1960s when Congress passed two of the progressive’s favorite government programs—Medicare and Medicaid.

Initially, industry groups like the AMA opposed Medicare and Medicaid because they believed the government subsidies would deteriorate the quality of care. They were right about that, but what they clearly didn’t anticipate was how rich the programs would make them.

Anyone who’s taken even a single introductory economics class could tell you that prices will rise if supply decreases or demand increases. The government was already keeping the supply of medical services artificially low—leading to artificially high prices. Medicare and Medicaid left those shortages in place and poured a ton of tax dollars into the healthcare sector—significantly increasing demand. The result was an easily predictable explosion in the cost of healthcare.

Fewer and fewer people could afford healthcare at these rising prices, meaning more people required government assistance, which meant more demand, causing prices to grow faster and faster.

Meanwhile, private health “insurance” providers were also benefiting from the mounting crisis. In a free market, insurance serves as a means to trade risk. Insurance works well for accidents and calamities that are hard to predict individually but relatively easy to predict in bulk, like car accidents, house fires, and unexpected family deaths.

Health insurance providers were already being subsidized by all the taxes on competing means of payment, which allowed their plans to grow beyond the typical bounds of insurance and begin to cover easily-predictable occurrences like annual physicals. And, as the price of all of these services continued to shoot up, the costs of these routine procedures were becoming high enough to resemble the costs of emergencies—making consumers even more reliant on insurance.

With progressives cheering on, the political class used government intervention to create a healthcare system that behaves as if its sole purpose is to move as much money as possible into the pockets of healthcare providers, drug companies, hospitals, health-related federal agencies, and insurance providers.

But the party could not last forever. As the price of healthcare rose, the price of health insurance rose, too. Eventually, when insurance premiums grew too high, fewer employers or individual buyers were willing to buy insurance, and the flow of money into the healthcare system started to falter.

The data suggests that that tipping point was reached in the early 2000s. For the first time since the cycle began back in the 1960s, the number of people with health insurance began to fall each year.

Healthcare providers—who had seemingly assumed that the flow of money would never stop increasing—began to panic.

Then came Barack Obama.

Obama’s seminal legislative accomplishment—the Affordable Care Act, or Obamacare—can best be understood as a ploy by healthcare providers and the government to keep the party going.

Obamacare required all fifty million uninsured Americans to obtain insurance, and it greatly expanded what these “insurance” companies covered. Demand for healthcare shot back up, and the vicious cycle started back up again—which is why the bill enjoyed so much support from big corporations all across the healthcare industry.

Before it was passed, economists were practically screaming that the Affordable Care Act would make care less affordable by raising premiums and healthcare prices while making shortages worse. Progressives dismissed such concerns as Reagan-era “free market fundamentalist” propaganda. But that is exactly what happened.

Now, the affordability crisis is worse than ever as prices reach historic levels. And, because Obamacare brought American healthcare much closer to a single-payer system, the demand for healthcare far exceeds the supply of healthcare - leading to deadly shortages.

There are literally not enough resources or available medical professionals to treat everyone who can pay for care. Also, the tax code and warped “insurance” market protect these providers from competition—making it almost impossible for people to switch to a different provider after their claims are unfairly denied. If it were simply greed, denying customers who already paid would be a feature in all industries. But it’s not. It requires the kind of policy protections progressives helped implement.

And on top of all that, despite paying all this money, Americans are quickly becoming one of the sickest populations on Earth.

This is one of the most pressing problems facing the country.

A problem that requires immediate, radical change to solve. But it also requires an accurate and precise diagnosis—something that, this week, progressives demonstrated they are incapable of making.

The American progressive movement is responsible for providing the political class the intellectual cover they needed to break the healthcare market and transform the entire system into a means to transfer wealth to people like Brian Thompson.

Now, they want to sit back, pretend like they’ve never gotten their way, that the government has never done anything with the healthcare market, and that these healthcare executives just popped up and started doing this all on their own—all so they can celebrate him being gunned down in the street. It’s disgusting.

Brian Thompson acted exactly like every economically literate person over the last fifty years has said health insurance CEOs would act if progressives got their way. If we’re ever going to see the end of this century-long nightmare, we need to start listening to the people who have gotten it right, not those who pretend they are blameless as they fantasize online about others starting a violent revolution.

https://www.zerohedge.com/medical/progressivism-murder-health-insurance-ceo