'RNA Interference Therapeutic Shows Promise for Chronic Hepatitis B'

 In adults with chronic hepatitis B infection receiving viral suppression therapy, coupling an investigational small interfering RNA therapy with an immunomodulator led to substantial declines in blood levels of hepatitis B surface antigen (HBsAg), according to a randomized phase II trial.

Out of five medication regimens given for 48 weeks in the open-label Piranga study, combination xalnesiran plus pegylated interferon alfa-2a (Pegasys) therapy had the best results when it came to the proportion of people who achieved a decrease in HBsAg to below 0.05 IU per/mL at 24 weeks after end of treatment.

In that group, 23% met that primary efficacy endpoint, as compared with anywhere from 0% with nucleoside or nucleotide analogue (NA) therapy alone to 3-12% with xalnesiran alone or plus ruzotolimod.

The promising findings with the approach did have two caveats, however: the durability of HBsAg loss appears to be a challenge, and only people who had an HBsAg level below 1,000 IU/mL at screening managed to show HBsAg loss with or without seroconversion, reported Jinlin Hou, MD, of Nanfang Hospital at Southern Medical University in Guangzhou, China, and colleagues in the New England Journal of Medicineopens in a new tab or window.

"To address these challenges, a potential approach could be to specifically target adaptive immunity and restore HBV-specific exhausted T cells," the authors suggested.

"Combination regimens containing checkpoint inhibitors are being explored in chronic hepatitis B, including a liver-targeted locked nucleic acid that degrades programmed death ligand 1 expression and is being evaluated in combination with xalnesiran in other groups of the Piranga platform trial," they noted.

In Piranga, Hou and colleagues had sought to find among the tested treatments a regimen that brings chronic hepatitis B patients closer to a functional cure, defined as off-treatment sustained undetectable levels of both hepatitis B virus (HBV) DNA and HBsAg.

Xalnesiran is an investigational small interfering RNA that silences multiple transcripts from the HBV genome. Ruzotolimod, also investigational, is a toll-like receptor 7 agonist selectively activated in the liver. Peginterferon alfa-2a is a form of recombinant interferon already indicated to treat chronic hepatitis B infection in people who show signs of liver damage.

"Combining drugs with different target engagement can provide a synergistic effect on viral suppression and immune control, leading to functional cure," the study authors wrote.

As for safety, the researchers reported that grade 3/4 adverse events were "not uncommon" in the trial.

"These results herald a new era for combination therapy to treat chronic HBV infection and raise questions about how and when to assess response and how to balance the probability of response with the likelihood of durable clinical benefit and risk of side effects," commented Harry L.A. Janssen, MD, PhD, of Erasmus MC University Medical Center in Rotterdam, the Netherlands, and Milan J. Sonneveld, MD, PhD, of the Toronto Centre for Liver Disease at University Health Network's Toronto General Hospital, in an accompanying commentaryopens in a new tab or window.

Patients were only eligible for the Piranga study if they demonstrated virologic suppression with NA therapy (HBV DNA below 20 IU/mL following at least 12 months of entecavir [Baraclude], tenofovir alafenamide [Biktarvy], or tenofovir disoproxil fumarate [Viread]). The participants were randomly assigned to one of five treatment groups for 48 weeks of treatment, followed by 48 weeks of follow-up observation.

At 24 weeks after end of treatment, the primary efficacy results were as follows for the five groups:

• Xalnesiran 100 mg alone (n=30): 7% of people met criteria for HBsAg loss
• Xalnesiran 200 mg alone (n=30): 3%
• Xalnesiran 200 mg plus ruzotolimod 150 mg (n=34): 12%
• Xalnesiran 200 mg plus pegylated interferon alfa-2a 180 μg (n=30): 23%
• Nucleoside or nucleotide analogue (NA) alone (n=36): 0%

Across the five groups, grade 3/4 adverse events occurred in 17%, 10%, 18%, 50%, and 6%, respectively. The most common high-grade adverse event was an elevated alanine aminotransferase (ALT) level, which was logged in 43-83% of the participants who received xalnesiran. Increased aspartate aminotransferase levels occurred in 20-70% of these participants.

Hou and colleagues reported an erosion in the response to xalnesiran/pegylated interferon alfa-2a after treatment was withdrawn: durability of HBsAg loss decreased from 78% to 56% between 24 weeks and 48 weeks after the end of treatment.

This finding of a risk of relapse undermines "the choice of functional cure as an endpoint for these agents, at least when assessed relatively early after the withdrawal of therapy," wrote Janssen and Sonneveld.

"Future trials could evaluate whether alternative treatment regimens, such as drugs with different target engagement, could increase the likelihood of response," the pair suggested. The editorialists also noted the importance of gathering more data "on the durability of the effect achieved with new agents that directly interfere with HBsAg production."

Hepatitis Bopens in a new tab or window, spread through bodily fluids, is the most common liver infection in the world. Acute infections can turn chronic in some cases and cause liver damage, cirrhosis, liver cancer, and even death. A hepatitis B vaccine is recommended for all children as soon as possible after birth.

The Piranga study enrolled 159 participants with chronic hepatitis B infection from July 2020 to November 2021.

Inclusion criteria included an ALT level no more than 1.5 times the upper limit of the normal range for at least 6 months before screening. Participants were not enrolled if they had HIV or another hepatitis type, or if they had clinically significant liver fibrosis or cirrhosis or hepatocellular carcinoma.

Baseline characteristics were similar across the randomly assigned groups in age, BMI, HBsAg levels, hepatitis B DNA levels, ALT levels, and duration of previous NA treatment. Participants were 94% Asian, majority men, and 70% hepatitis B e antigen-negative at enrollment.

Participants randomized to xalnesiran received it subcutaneously every 4 weeks. Patients receiving ruzotolimod took it orally every other day, and peginterferon alfa-2a was given subcutaneously weekly. Participants continued taking oral NA therapy daily until meeting the criteria for stopping.

HBsAg seroconversion remained 24 weeks after the end of treatment in 20% of those given xalnesiran plus peginterferon alfa-2a, compared to 3% with xalnesiran 100 mg, 3% with xalnesiran plus ruzotolimod, and none in the other two groups. At 48 weeks after end of treatment, 17% of those receiving xalnesiran plus peginterferon alfa-2a retained seroconversion.

Hou and co-authors acknowledged study limitations including the lack of patients assigned ruzotolimod or peginterferon alfa-2a alone, the small samples across treatment groups, and the absence of longitudinal immunologic and intrahepatic assessments as part of the protocol.

Disclosures

The research was funded by F. Hoffmann–La Roche.

Hou reported grant funding from F. Hoffmann-La Roche and consulting fees from Aligos Therapeutics, Gilead Sciences, and GSK.

Janssen reported consulting fees and/or grant funding from Aligos, Antios, Enyo, F. Hoffmann-La Roche, Gilead Sciences, GSK, Grifols Therapeutics, Janssen Biotech, Precision BioSciences, Target RWE, VIR Biotechnology, and Wainwright.

Sonneveld reported consulting fees and/or grant funding or other fees from Gilead Sciences, F. Hoffmann-LaRoche, Ipsen, and Roche Diagnostics.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowHou J, et al "Xalnesiran with or without an immunomodulator in chronic hepatitis B" N Engl J Med 2024; DOI: 10.1056/NEJMoa2405485.

Secondary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowJanssen HLA, Sonneveld MJ "Combination therapy for chronic HBV infection" N Engl J Med 2024; DOI: 10.1056/NEJMe2410543.

https://www.medpagetoday.com/infectiousdisease/hepatitis/113224

Target must face shareholder lawsuit over Pride backlash, US judge rules

 Target has failed to persuade a judge in Florida to dismiss a lawsuit that accused the retailer of deceiving shareholders after its sales of LGBTQ-themed merchandise for Pride Month sparked a backlash and a customer boycott.

U.S. District Judge John Badalamenti in Fort Myers ruled that the plaintiffs had presented enough information for now to pursue claims that Target misled investors about its efforts to guard against social and political risks.

The lawsuit from investor Brian Craig claims that Target's board focused only on activist groups' calls for diversity, equity and inclusion (DEI) measures and overlooked potential negative responses to the Pride campaign in May 2023.

Target did not immediately respond to a request for comment on Wednesday.

America First Legal, the conservative group that filed the lawsuit last year, in a statement on Wednesday called the court ruling a "warning to publicly traded corporations’ boards and management." The group said the risk of DEI programs and environmental, social, and governance (ESG) initiatives "cannot be whitewashed with boilerplate language or ignored."

Target had urged Badalamenti to dismiss the lawsuit, arguing that there was no evidence backing the allegations, that it had warned investors about a potential DEI backlash, and that the complaint was based merely on Craig's disagreement with the company’s business decisions.

America First filed the lawsuit in Florida federal court in August 2023. The nonprofit group is headed by Stephen Miller, a close adviser to U.S. President-elect Donald Trump.

America First and other conservative groups have accused some major U.S. companies of undertaking diversity and inclusion efforts at the expense of shareholders.

Target pulled some LGBTQ-themed merchandise linked to Pride Month last year, citing increased confrontations between shoppers and employees and incidents of products being thrown on the floor.

https://finance.yahoo.com/news/target-must-face-shareholder-lawsuit-202851198.html

Novartis cannot block generic of best-selling heart drug, US appeals court says

 Novartis failed to convince a U.S. appeals court on Wednesday to halt MSN Pharmaceuticals' proposed generic of Novartis' blockbuster heart drug Entresto.

The U.S. Court of Appeals for the Federal Circuit upheld a Delaware federal judge's August decision that found Novartis failed to prove it was likely to win a patent lawsuit against MSN over the drug, removing a roadblock for MSN's launch of what would be the first U.S. Entresto generic.

Spokespeople and attorneys for the companies did not immediately respond to requests for comment.

Entresto is Switzerland-based Novartis' best-selling drug, bringing the company more than $6 billion in revenue last year. MSN's version of Entresto was approved by the U.S. Food and Drug Administration in July.

Novartis sued MSN and others seeking to launch Entresto generics in Delaware federal court in 2022 for allegedly infringing a patent that expires in 2026. It requested a preliminary injunction after the FDA's approval that would block MSN from launching its generic during the case, which is set to go to trial on Monday.

U.S. District Judge Richard Andrews rejected Novartis' request in August, ruling that it was not sufficiently likely to win on its infringement claims to justify the injunction. The judge paused MSN's launch of its proposed generic while Novartis appealed to the Federal Circuit.

The Washington-based appeals court affirmed Andrews' decision on Wednesday and said it saw "no clear error in the district court's analysis."

https://www.msn.com/en-us/money/companies/novartis-cannot-block-generic-of-best-selling-heart-drug-us-appeals-court-says/ar-AA1vgRTd

CMS names Vertex, bluebird for cell and gene therapy model

 The Centers for Medicare & Medicaid Services has successfully negotiated agreements with two drug manufacturers to participate in the newly created Cell and Gene Therapy Access Model.

Vertex Pharmaceuticals’ drug Casgevy and bluebird bio’s Lyfgenia, both approved by the Food & Drug Administration in December, were selected. Both treat sickle cell disease.

States and U.S. territories in the Medicaid Drug Rebate Program can choose to participate in the voluntary model. Payments will be dealt out depending on whether the drugs improve outcomes for people with Medicaid.

Interested states can begin applying this month and can apply for optional funding by the end of February.

More than 100,000 people have sickle cell disease in the U.S., with approximately more than half enrolled in Medicaid. Sickle cell disease predominantly impacts Black and Hispanic Americans, data from the Centers for Disease Control and Prevention shows, and the life expectancy is around 20 years shorter.

“Cell and gene therapies hold significant potential to improve patient outcomes and transform lives, ultimately reducing long-term health care spending,” said Liz Fowler, deputy administrator and director of the CMS Innovation Center, in a news release. “However, due to the high costs, these therapies can pose challenges to state budgets. This model will afford state Medicaid agencies more budget predictability while helping improve access to these innovative therapies for people with Medicaid with sickle cell disease.”

In February 2023, CMS released its model designed to rein in the cost of gene and cell therapies by collaborating with state Medicaid agencies.

Eleven months later, CMS said to expect sickle cell disease to be one of the first priorities of the model before later expanding to other conditions. That plan was reemphasized Dec. 4.

https://www.fiercehealthcare.com/payers/cms-names-two-drug-manufacturers-cell-and-gene-therapy-model

Merus FDA Approval of BIZENGRI for Pancreatic Adenocarcinoma, Non–Small Cell Lung Cancer

 

• BIZENGRI® is the first and only therapy approved by the FDA specifically for pancreatic adenocarcinoma and NSCLC that harbor NRG1 gene fusions and are advanced unresectable or metastatic1
• Merus and Partner Therapeutics announced a license agreement for U.S. commercialization

https://www.globenewswire.com/news-release/2024/12/04/2991955/37568/en/Merus-Announces-FDA-Approval-of-BIZENGRI-zenocutuzumab-zbco-for-NRG1-Pancreatic-Adenocarcinoma-and-NRG1-Non-Small-Cell-Lung-Cancer-NSCLC-Based-on-Safety-and-Efficacy-Data-From-the-.html

Tucker Carlson Returns To Russia; Warns "We Are Closer To Nuclear War Than Ever"

 by Steve Watson via Modernity.news,

Tucker Carlson has returned to Moscow to interview Russian Foreign Minister Sergey Lavrov as the outgoing Biden administration pushes the US ever closer to a hot war with Russia.

“In the week since we left Russia, Moscow, where we are now in February, after interviewing Vladimir Putin, we’ve watched from the United States as the Biden administration has driven the US ever closer to a nuclear conflict with Russia, the country that possesses the world’s largest nuclear arsenal,” Carlson announced.

He continued, “It has accelerated ever since, and it’s reached its apogee so far in the weeks after Trump’s election. He’s now the President-elect. In that time, just a few weeks ago, the Biden Administration, American military personnel launched missiles into mainland Russia and killed at least a dozen Russian soldiers.”

“So we are, unbeknownst to most Americans, in a hot war with Russia, an undeclared war, a war you did not vote for and that most Americans don’t want, but that is ongoing,” Carlson urged.

“And because of that war because of the fact that the US military is killing Russians in Russia right now, we are closer to nuclear war than at any time in history, far closer than we were during the Cuban Missile crisis,” Carlson warned, adding “That would mean the elimination of Russia, the United States, and most of the rest of the world.”

“We felt there must be someone behind the scenes in Washington working to make sure that this conflict doesn’t become a nuclear Holocaust. But we found out that no, in fact, there is nobody,” he explained, noting that the State Department has cut off all communication with Russia.

Tucker also revealed that he has been trying to sit down with Ukrainian President Zelenskyy but has been prevented from doing so by the US government who have ordered Zelenskyy not to do the interview.

Watch:

Biden’s government refuses to engage in diplomatic exchanges with Russia, despite serious escalation that risks cataclysmic war, and Tucker Carlson is having to try to fill the void.

Disgraceful.

Meanwhile, Democratic strategist James Carville claimed Tuesday on MSNBC’s “The Beat” that Carlson has had the most influence with regards to Trump’s cabinet nominations.

Carville claimed “One person is driving this, I promise you. And it’s Tucker Carlson. Tucker’s an old friend of mine.”

Carville added that Tucker “has more influence in this current administration, way more than Vernon Jordan had in the Clinton administration or any of the kind of wise men that were around,” adding that “Tucker is very, very, very powerful.”

*  *  *

https://www.zerohedge.com/geopolitical/tucker-carlson-returns-russia-warns-we-are-closer-nuclear-war-ever

Senate Democrats ponder preemptive pardons for Trump’s political foes

Senate Democrats are weighing whether President Joe Biden should use his final moments of power to issue preemptive pardons to shield those who could receive political retribution from President-elect Donald Trump.

The conversations come against the backdrop of Trump’s rhetoric on the campaign trail, in which he threatened to seek revenge on people he considers his political foes, referring to them as “enemies from within.”

These concerns have become even more elevated since announcing his picks for attorney general, Pam Bondi, and FBI director, Kash Patel, who have echoed Trump’s promises to imprison and prosecute political enemies who have skirted laws.

“There have certainly been discussions about this among some. How could there not be after all of the threats Trump has issued,” one Senate Democratic aide said, on the condition of anonymity to speak candidly about the situation.

Trump has circulated social media posts that call for the jailing of House lawmakers who investigated the attack on the U.S. Capitol on Jan. 6, special counsel Jack Smith, and New York Attorney General Letitia James, who oversaw Trump’s civil fraud case. The threats have also extended to Biden, Vice President Kamala Harris, former Vice President Mike Pence, and Senate Majority Leader Chuck Schumer (D-NY).  

He also has suggested that his former Joint Chiefs of Staff Chairman Mark Milley committed a crime once punishable by death, called Sen.-elect Adam Schiff a “sleazebag and traitor,” and insisted he and former House Speaker Nancy Pelosi be “prosecuted.” He also targeted former Wyoming GOP Rep. Liz Cheney, who campaigned for Harris, suggesting he wanted military tribunals to punish her.

Even before Biden issued a pardon for his son Hunter, who was criminally convicted this year on tax and gun charges, on Sunday, Sen. Ed Markey (D-MA) publicly floated the idea that the president should consider “preemptive pardons” to people Trump has threatened to prosecute. 

“I think that without question, Trump is going to try to act in a dictatorial way, in a fascistic way, in a revengeful first year at least of his administration toward individuals who he believes harmed him,” Markey said in an interview with Boston Public Radio.

“If it’s clear by Jan. 19 that that is his intention, then I would recommend to President Biden that he provide those preemptive pardons to people, because that’s really what our country is going to need next year,” he added.

Markey went on to cite Gerald Ford’s pardon of Richard Nixon over the Watergate scandal in 1974, calling it a way to “close that chapter” and move on “to an agenda that deals with ordinary families.”

Sen. Ron Wyden (D-OR) said he’d need more time to think about whether Biden should pursue preemptive pardons, but emphasized he understood why the president recently worked to shield his son.

“Let me just talk about the one that’s on everybody’s mind, the one that’s relevant, given the lengths that Donald Trump has gone to politicize the Justice Department, I consider what was done by the president over the weekend as understandable,” Wyden said.

However, a majority of Senate Democrats are not on board with Markey’s perspective on “preemptive pardons.” Sen. Tim Kaine (D-VA) said the push is something he’d advise Biden “not to do.” Sen. Peter Welch (D-VT) said he’d instead urge Trump to vow that he will not go after his political opponents before taking office.

“I don’t know how you pardon a person that’s not been charged with anything. I don’t think that can happen,” said outgoing Sen. Joe Manchin (I-WV), who went on to say he believed Trump should be pardoned in an effort to “balance things out and calm things down.”

Several Democrats outside of Congress said the idea of Biden pardoning Trump’s political foes causes great concern about optics, especially since no one threatened has currently been charged with a crime.

“The left is hoping that Trump will not be permitted to engage in any interpretive acts for slights once felt in the past, is that possible? Not sure,” said Hank Scheinkopf, a longtime Democratic strategist. “But is it good to be politicizing the Department of Justice more than it has already been done — the answer is no.”

https://www.washingtonexaminer.com/news/senate/3249155/biden-preemptive-pardons-trump-political-foes/