Protein isoform inhibitors may hold the key to making opioids safer

 Researchers at the University of Arizona Health Sciences identified a new way to make opioids safer, increasing the pain-relieving properties of opioids while decreasing unwanted side effects through the spinal inhibition of a Heat shock protein 90 isoform.

Opioids are the gold standard of chronic pain treatment, but they come with a host of negative side effects including constipation, addiction potential and respiratory depression that can lead to death. This study, published in Scientific Reports, offers a potential new way to treat acute and chronic pain by reducing the amount of opioid needed for pain relief while also lowering its addiction potential.

"We have been investigating the role of Heat shock protein 90 in regulating opioid signaling in the spinal cord for some time," said John Streicher, Ph.D., member of the Comprehensive Center for Pain & Addiction at UArizona Health Sciences and a professor in the College of Medicine—Tucson's Department of Pharmacology.

"This study provides proof of principle that Hsp90 isoform inhibitors are effective at improving opioid pain relief and reducing side effects. This is the critical link that makes our work translationally relevant, giving us a clear path forward to develop a new drug that could benefit millions of people who live with chronic pain."

Heat shock protein 90 is a chaperone protein that helps other proteins function, including those that promote tumor growth. It has been studied primarily in the context of cancer. Streicher is leading in a long-term effort to investigate its role in opioid receptor activation and pain relief.

Streicher's prior research showed that Heat shock protein 90 acted upon opioid receptors in the brain differently than in the spinal cord. Inhibiting Hsp90 in the brain blocked the analgesic properties of morphine, meaning the opioid lost its ability to reduce the sensation of pain. But inhibiting Hsp90 in the spinal cord amplified the pain-relieving effects of morphine.

Building on that research, the team tested nonselective Hsp90 inhibitors in mouse models and saw a twofold-to-fourfold increase in the potency of pain relief provided by morphine. At the same time, tolerance was reduced and established tolerance was reversed. Tolerance is a condition where the body gets used to a medication so that more medication or a different medication is needed to achieve the same response.

Early cancer-focused studies, however, found that nonselective Hsp90 inhibitors can cause serious side effects, including macular degeneration. Streicher's solution was to target individual isoforms of Hsp90, of which there are four.

"Isoforms are different versions of the same thing, like trim packages on a car," Streicher said. "They are all slightly different and have similar roles, but not identical roles. So these four Hsp90 isoforms are four proteins that we can target individually."

By using selective inhibitors to target each isoform, they were able to identify and isolate the isoforms that are active in the spinal cord from Hsp90-alpha, the one that is active in the brain. Recent reports have linked Hsp90-alpha with the serious side effect of retinal degeneration.

"We took isoform-selected inhibitors that we got from our collaborator, Brian Blagg, Ph.D., at the University of Notre Dame, and gave them to mice systemically via IV injection," Streicher said. "We found that you can give these isoform-selective inhibitors by a translatable route and get the benefits. Pain relief goes up and side effects go down, and presumably we're going to avoid some of those nasty side effects of the nonselective Hsp90 inhibitors."

The findings suggest that selective Hsp90 inhibitors could be used as part of a dose-reduction plan in conjunction with opioid therapy prescribed by a physician for chronic pain. The goal is for doctors to be able to prescribe lower amounts of opioids that provide patients with the same pain-relieving benefits and fewer negative side effects.

"What I'm envisioning is you'd be given a pill that is a combination therapy of an opioid with one of these isoform inhibitors," Streicher said. "The addition of that Hsp90 inhibitor would make the opioid better—it would increase the effectiveness of the pain relief and decrease the side effects."

Streicher and his team are working to optimize the selective Hsp90 inhibitors to produce a stable drug that can be taken orally.

"Dr. Streicher's research is an excellent example of the innovative, translational science that is needed to transform health care for pain and addiction," said Todd Vanderah, Ph.D., director of the Comprehensive Center for Pain & Addiction, Regents Professor and head of the Department of Pharmacology. "This study is an important step toward developing a novel evidence-based therapy that will provide better treatment options with fewer disruptive side effects, empowering people with chronic pain to thrive."

More information: David I. Duron et al, Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment, Scientific Reports (2024). DOI: 10.1038/s41598-024-65637-6

https://medicalxpress.com/news/2024-07-proof-principle-protein-isoform-inhibitors.html

Lexicon Dec, 20, 2024 PDUFA Goal Date for Sotagliflozin Type 1 Diabetes NDA Resubmission

 Launch Preparations Actively Underway; Launch Planned for Early 2025

Lexicon Seeks Approval for Zynquista™ (sotagliflozin) as an Adjunct to Insulin Therapy for Glycemic Control in Adults with Type 1 Diabetes and Chronic Kidney Disease

https://www.globenewswire.com/news-release/2024/07/16/2913701/0/en/Lexicon-Pharmaceuticals-Receives-December-20-2024-PDUFA-Goal-Date-for-Sotagliflozin-Type-1-Diabetes-NDA-Resubmission.html

Most major U.S. managed care insurers set for sequential earnings declines in Q2

 An analysis of sell-side analyst forecasts by S&P Global Market Intelligence suggests most US health insurers will report sequential earnings declines.

https://seekingalpha.com/news/4124644-most-major-us-health-insurers-set-for-sequential-earnings-declines-in-q2-sp-analysis

Names That Could Be On Biogen's Buyout Shortlist

 Biogen (BIIB) stock has mostly trended sideways this year, but that could soon change with $8 billion to $10 billion in acquisition-focused dry powder, an analyst said Tuesday.

Wedbush analyst Laura Chico notes Biogen wrapped two high-profile acquisitions last year, taking over Reta Pharmaceuticals and Hi-Bio. Reta developed Skyclarys, which treats a genetic condition called Friedreich's ataxia. Hi-Bio is working on treatments for immune-mediated diseases.

But Biogen has said it still has up to $10 billion to use in acquisitions over the next two years, Chico said in a report. She sees Pharvaris (PHVS), Viridian Therapeutics (VRDN) and Edgewise Therapeutics (EWTX) as potentially powerful takeover candidates for Biogen.

On today's stock market, Biogen stock ticked up 1.6% to 225.02. Viridian shares shot 8.7% to close at 15.97, and Pharvaris stock jumped 3.8% to 18.53. Shares of Edgewise, on the other hand, fell 2.9% to 22.20.

Biogen Stock: 'Fit for Growth' Strategy Underway

To compile her list, Chico screened 455 biotech companies with drugs in Phase 2 testing and market caps of $500 million to $4 billion.

Chico said Biogen is working on its "Fit for Growth" strategy, which aims to generate around $1 billion in operating-expense savings by 2025.

"While Biogen continues to implement its 'Fit for Growth' initiative and valuation appears more attractive, we do think additional revenue-generating assets are necessary for the turnaround to complete," she said.

This year, Biogen stock analysts expect the company's sales to decline roughly 3% before coming in flat in 2025. Analysts call for a return to growth in 2026 as $9.91 billion in sales climb about 4%.

Immunology, Neuromuscular Conditions In Focus

Pharvaris is developing a treatment for a swelling disease called hereditary angioedema, or HAE. The drug is in final-phase testing after "solid" proof-of-concept test results. Pharvaris' drug, known as deucrictibant, is a pill that uses a unique mechanism. This helps differentiate it from the other approaches in the roughly $3 billion market.

"We see deucrictibant fitting into Biogen's specialized immunology franchise," Chico said.

Chico kept her neutral rating on Biogen stock.

Meanwhile, Viridian's thyroid eye disease treatment is in Phase 3 testing with results from two tests expected in September and late 2024. Viridian's drug would go up against Amgen's (AMGN) approved med Tepezza. This acquisition would fit into the specialized immunology division.

Lastly, Edgewise would be an unexpected fit, given the company is focused on cardiac diseases like obstructive hypertrophic cardiomyopathy, or HCM. The company is also working on treatments for neuromuscular diseases like Duchenne muscular dystrophy and Becker muscular dystrophy.

"However, we wonder if a spinout of the Edgewise neuromuscular assets makes sense for both Edgewise and Biogen," she said. "Spinning out Edgewise's assets could generate additional funds for Edgewise and permit greater focus on cardiometabolic efforts."

https://www.investors.com/news/technology/biogen-stock-acquisition-candidates-2024/

'FDR Was Dying, but His Doctors Zipped Their Lips'

 The patient's blood pressure averaged 209/100 mm Hg, a level now considered to be a medical emergency. His heart was enlarged, his skin was gray due to lack of oxygen in the blood, and an ECG showed signs of terminal cardiac disease. His cardiologist later described his condition as "godawful."

But the public knew none of this. Eight decades ago, President Franklin D. Roosevelt's personal doctor misled the world about his health, allowing a deeply sick man to accept the Democratic party's nomination and win an unprecedented fourth term. He would drop dead of a brain hemorrhage in April 1945, leaving a vice president who'd been left in the dark to manage the last days of a world war.

Now, the health of presidential candidates is in the spotlight as President Joe Biden, 81, faces questions about his frailty and former President Donald Trump, 78, recovers from a gunshot injury. What obligations do White House physicians have -- if any -- to be honest with the public about a president's health?

"It's not the role of a physician to be a snitch," argued neurologist Steven Lomazow, MD, of Belleville, New Jersey, who's written two books about FDR's health. "If they know the president wants them to lie, it's OK for them to lie."

The President's Health Is 'Satisfactory'

On Christmas Eve 1943, an international leader was recovering after a nasty bout of severe pneumonia and atrial fibrillation -- but it was not the U.S. president. FDR, just 7 days after returning from a grueling 5-week international trip to Cairo and Tehran, wished the ill man -- British Prime Minister Winston Churchill -- all the best in a radio speech.

At this time, Roosevelt was "still buoyant" after his meetings with Churchill and Joseph Stalin, where he'd looked like "an animated, alert public man," wrote the late Joseph Lelyveld, a former New York Times executive editor, in his 2016 book, His Final Battle: The Last Months of Franklin Roosevelt.

Then FDR caught the flu and was too sick to give the State of the Union address. Next came tremors, weakness, weight loss, "queer" chest sensations, stomach cramps, headaches -- and falsehoods galore. He was in "robust health," declared White House physician Ross T. McIntire, MD, an otolaryngologist. McIntire, a navy admiral, "would cheerfully go on offering such roseate prognoses and testimonials, without qualifications or the slightest suggestion of concern, until the votes were counted the following November, indeed until the president died," Lelyveld wrote. "Then he'd put his name to a ghostwritten book claiming he'd always spoken the truth."

FDR campaigning in 1944. Credit: Library of Congress via National Park Service

Roosevelt's cardiologist, Howard Bruenn, MD, later said his condition was "shocking" and "godawful." The president was diagnosed with hypertension and congestive heart failure. The recommended treatments: take naps, take it easy, no pack-and-a-half of Camel cigarettes per day, "no irritation." Maybe take a few months off work. Never mind that there was a war going on.

McIntire was "appalled" by the suggestions, Bruenn noted later, reportedly saying "you can't simply say to him, 'Do this or do that.' This is the president of the United States." (Bruenn's notes said McIntire's reaction was "somewhat unprintable.")

McIntire told the press that a presidential physical was "satisfactory."

A low-salt diet and digitalis helped the president to breathe better, but his condition remained poor. On April 12, 1945, just 3 months after Roosevelt had been inaugurated for his fourth term, he died of a brain hemorrhage in Warm Springs, Georgia, at the age of 63. Bruenn estimated his blood pressure was 350/195 mm Hg.

Physician-Patient Confidentiality Rules the Roost

White House physicians have long massaged the truth about several presidential medical crises, including Woodrow Wilson's devastating strokeopens in a new tab or window, James Garfield's struggle to recover from a bullet woundopens in a new tab or window, and Donald Trump's case of COVID-19opens in a new tab or window. Grover Cleveland underwent a secret tumor operationopens in a new tab or window that wasn't disclosed for decades.

FDR's situation stands out because he was commander in chief during a world war and he was running for another term. What obligations do White House clinicians have to their patients, the public, and the truth?

In their 1993 book, When Illness Strikes the Leader, political scientist Robert Robins and psychiatrist Jerrold Post, MD, accused cardiologist Bruenn of taking part in a "conspiracy to misrepresent the president's health status to the president, his family, and the nation."

But Joel T. Wu, JD, MPH, a University of Minnesota bioethicist, said physician-patient confidentiality is iron-clad, with rare exceptions, such as "if we think the patient is going to cause a specific serious kind of harm to someone else, and we can prevent the harm with the disclosure. If patients know that their doctors can disclose information about them that might hurt them without their permission, that could undermine the trust of all patients in physicians and the medical system and result in ineffective or inappropriate care."

Clinicians can refuse to answer questions about a patient's care, he said, but it's unethical to lie about a patient's care or selectively omit information in order to create a false impression.

Will Presidents Ever Be Transparent?

Psychiatrist Jacob Appel, MD, JD, MPH, a bioethicist at the Icahn School of Medicine at Mount Sinai in New York City, said White House physicians "ideally" should not lie to the public. However, the president calls the shots, and "the result may be omissions that mislead the public."

Appel noted that "some of our sickest presidents, such as FDR, John F. Kennedy, and Ronald Reagan, are viewed by many as our most successful," compared with healthy ones like Millard Fillmore and Rutherford B. Hayes.

He added that "predicting medical outcomes is extremely difficult." In 1940, Roosevelt ran against Republican Wendell Willkie, a lawyer and corporate executive who was a decade younger and seemingly healthier. But, as Appel noted, Willkie died 4 years later of a heart attack at age 52.

John G. Sotos, MD, a historian of presidential medicineopens in a new tab or window, has suggestedopens in a new tab or window that clinicians be required to disclose to the vice president and cabinet when a president has a "disqualifying medical condition," such as those that would keep an Air Force controller off the job.

But the University of Minnesota's Wu cautioned about imposing external mandates on any physician "because then there will be a competing interest beyond the rights and interests of the patient alone."

Of course, the president can ask physicians to be open with the public, as Roosevelt apparently didn't. Keeping his health secret, Lelyveld wrote, would have been "absolutely consistent with his character and methods, his customary slyness, his chronic desire to keep his political options open to the last possible moment."

Theodore N. Pappas, MD, a surgeon at Duke University in Durham, North Carolina, who's studied the illnesses of multiple presidents, doesn't expect full disclosure at the top.

Dwight D. "Eisenhower was the only one that was very open as far as I could tell," he said. (After Eisenhower suffered a heart attack in 1955 while in office, a physician helpfully alerted the pressopens in a new tab or window to his "good bowel movement" a couple days later.) "The rest were not transparent. That's just what they do, and I don't think it's going to change."

https://www.medpagetoday.com/special-reports/features/111112

When Better Informed, More Women in Their 40s Want to Hold Off on Mammograms

 A mammography screening decision aid with information about the benefits and harms of screening increased the percentage of average-risk women in their 40s who wanted to delay mammography, according to a national online survey.

Before viewing the decision aid, 27% of women ages 39 to 49 preferred to delay screening. The decision aid raised that percentage to 38.5%, reported Laura Scherer, PhD, of the University of Colorado in Aurora, and colleagues.

The survey also showed a narrower majority of women preferred to undergo mammography at their current age after viewing the decision aid (57.2% vs 67.6% beforehand) and more preferred to wait until age 50 (18% vs 8.5%).

As to what information shifted their view, 37.4% of women surveyed said they found the information about overdiagnosis in the decision aid "surprising," and 28.1% said it differed from what their doctor had told them, Scherer and colleagues reported in the Annals of Internal Medicineopens in a new tab or window.

While the U.S. Preventive Services Task Force (USPSTF) recommends biennial screeningopens in a new tab or window starting at age 40 years -- compared with a previous recommendation that screening begin at 50 -- it "endorses informed choice and shared decision making at all levels of its recommendations," Scherer's group wrote.

However, "a lack of language promoting informed choice in the guideline itself may create confusion among clinicians about whether they should discuss both screening benefits and harms with patients or instead provide only information that maximizes screening uptake," they added.

How information is presented makes a difference, observed Victoria Mintsopoulos, MD, MSc, and Michelle Nadler, MD, both of the University of Toronto, in an editorial accompanying the studyopens in a new tab or window.

For example, the decision aid in the study presented overdiagnosis risk as a percentage of all screening-detected cancers (12-22%), which may be perceived as more risky than when presented as an absolute number (1-3 cases per 1,000 persons screened), they pointed out.

Presenting all benefits and harms in absolute numbers with a common denominator may be the most transparent for women to make an informed decision, the editorialists suggested.

Considering the benefits and harms of breast cancer screening are closely balanced, Mintsopoulos and Nadler suggested research should focus on determining the best method of providing shared decision making or using decision aids, "ensuring that all women who are eligible for [breast cancer] screening have access to providers who can engage with them using these tools, and ensuring that those who want screening (after informed consent) have access to it."

The study surveyed 495 women ages 39 to 49 years without a history of breast cancer or a known BRCA1/2 gene mutation to assess screening preferences before and after receipt of the decision aid.

Participants were recruited for the survey using the Ipsos KnowledgePanel, which uses address-based sampling to maintain a diverse national panel of participants and provide a statistically valid representation of the U.S. population.

This study used a pre-post design in which all participants received the decision aid presenting information on screening recommendations from the USPSTF and American Cancer Society as of 2022, screening benefits, false-positive screening results, overdiagnosis, a personal risk estimate, and decision-making vignettes.

After seeing the decision aid, the proportion of women never wanting mammography didn't increase (5.4% before vs 4.3% after). And notably, those with higher breast cancer risk preferred earlier screening.

Scherer and colleagues reported that commonly stated reasons for preference to delay screening included a lack of family history, low cancer risk, as well as concerns about screening harms.

"These data suggest that many people who want to delay screening are considering the evidence and deciding that, for them, the harms outweigh the benefits at their current age," they wrote.

Disclosures

The study was funded primarily by the National Cancer Institute.

Scherer reported grant support from the National Cancer Institute, National Institutes of Health.

Nadler reported speaker honorarium and consulting fees from Novartis and Exact Sciences.

Primary Source

Annals of Internal Medicine

Source Reference: opens in a new tab or windowScherer LD, et al "Mammography screening preferences among screening-eligible women in their 40s: a national U.S. survey" Ann Intern Med 2024; DOI: 10.7326/M23-3325.

Secondary Source

Annals of Internal Medicine

Source Reference: opens in a new tab or windowMintsopoulos V, Nadler MB "Balancing the benefits and harms of breast cancer screening" Ann Intern Med 2024; DOI: 10.7326/M24-0885.

https://www.medpagetoday.com/radiology/diagnosticradiology/111100

Iran plot to kill Trump prompted Secret Service to boost protection before rally shooting

 The United States obtained intelligence about an Iranian plot to assassinate former President Donald Trump in recent weeks, three officials briefed on the matter told NBC News on Tuesday.

That intelligence led the U.S. Secret Service to increase security around Trump, who is the Republican presidential nominee, the officials said.

The intelligence and boosted Secret Service protection occurred before Trump was targeted in an attempted assassination by 20-year-old gunman Thomas Crooks at a campaign rally in Pennsylvania on Saturday.

CNN first reported the news of the Iranian plot, which raises more questions about the Secret Service’s failure to prevent the shooting by Crooks from a nearby building’s rooftop. There are no known links between Crooks and the Iran plot.

“Upon learning of the increased threat, [the National Security Council] directly contacted [United States Secret Service] at a senior level to be absolutely sure they continued to track the latest reporting,” a national security official told NBC News.

“USSS shared this information with the detail lead, and the Trump campaign was made aware of an evolving threat,” the official said. “In response, Secret Service surged resources and assets for the protection of former President Trump. All of this was in advance of Saturday.”

The Secret Service did not immediately respond to a request for comment by CNBC.

National Security Council spokeswoman Adrienne Watson in a statement to NBC News said that law enforcement authorities investigating the shooting by Crooks have “not identified ties between the shooter and any accomplice or co-conspirator, foreign or domestic.”

“As we have said many times, we have been tracking Iranian threats against former Trump administration officials for years, dating back to the last administration,” Watson said.

“These threats arise from Iran’s desire to seek revenge for the killing of Qassem Soleimani.  We consider this a national and homeland security matter of the highest priority,” she said.

Soleimani, who at the time was Iran’s most powerful general, was killed in January 2020 by a U.S. airstrike in Baghdad, Iraq, when Trump was president.

Iran previously was known to be targeting other former top Trump administration officials who were involved in the operation that led to Soleimani’s death, among than former Secretary of State Mike Pompeo and former National Security Advisor John Bolton, who continue to have security details as a result of those plots.

The Secret Service, which is responsible for protecting former presidents and major presidential candidates, has faced withering criticism for failing to stop Crooks from shooting at Trump and rally attendees.

One man was killed, and two others were seriously injured in the shooting, which occurred two days before Trump was formally nominated as the Republican Party’s presidential candidate at the GOP convention in Milwaukee.

The agency has said that securing the building was the responsibility of local police in Butler Township because it fell outside the security “perimeter” of the rally site, which was the Secret Service’s responsibility.

Secret Service Director Kimberly Cheatle told ABC News in an interview that the shooting “was unacceptable ... and it’s something that shouldn’t happen again.”

“The buck stops with me,” Cheatle said.

But Cheatle said she would not resign over the incident, which is set to be investigated by Congress.

https://www.cnbc.com/2024/07/16/trump-iran-kill-plot-secret-service.html