FDA Action Alert: Mirum, BMS, Madrigal and More

 The FDA has four big target action dates this week, including one for a much-anticipated non-alcoholic steatohepatitis drug. CAR T cell therapies will also see a lot of action in the coming week, with one upcoming decision and one advisory committee meeting.

Read below for more.

Mirum Eyes Expansion of Livmarli into Familial Intrahepatic Cholestasis

By March 13, the FDA is expected to release its verdict on Mirum Pharmaceuticals’ supplemental New Drug Application (sNDA) to expand Livmarli's label to include cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC).

Livmarli is an orally available selective inhibitor of the ileal bile acid transporter that works by decreasing the reabsorption of bile acids from the terminal ileum. Its mechanism of action is not yet completely elucidated, according to its label. Livmarli first won the FDA’s approval in September 2021 for the treatment of cholestatic pruritus in patients with Alagille syndrome.

Mirum is backing Livmarli’s sNDA, which it submitted to the regulator in February 2023, with data from the Phase III MARCH PFIC trial, which enrolled 93 pediatric patients across various genetic PFIC subtypes. The study showed that Livmarli treatment significantly improved pruritus and serum bile acid levels, as well as bilirubin concentrations and patient growth.

The application also includes data from the Phase II INDIGO study, which focused on the PFIC2 genetic subtype, demonstrating better transplant-free survival in responders.

In October 2023, the regulator extended the review period for Mirum’s sNDA “to allow time for a full review of a submission provided in response to an FDA information request,” which was considered a major amendment.

BMS Targets First CAR-T Approval in CLL, SLL

Bristol Myers Squibb is seeking to expand the label of its CAR-T therapy Breyanzi (lisocabtagene maraleucel) to include chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). The FDA’s decision is due by March 14.

BMS’s supplemental Biologics License Application (sBLA), which the FDA had granted Priority Review, positions Breyanzi as a treatment option for relapsed or refractory CLL and SLL patients with prior exposure to a Bruton tyrosine kinase inhibitor and a B-cell lymphoma 2 inhibitor.

The application is backed by data from the pivotal Phase I/II TRANSCENT CLL 004 trial, an open-label, single-arm study that, in May 2023, met its primary endpoint of complete response, according to a preliminary analysis. After a median follow-up of 21.1 months, 18.4% of patients achieved this endpoint, of whom none died or saw disease progression.

Breyanzi is an autologous CAR-T therapy that works by targeting and binding to the CD19 transmembrane protein, which in turn triggers the activation and proliferation of CAR T cells, promoting their anti-cancer activity and inducing the release of pro-inflammatory cytokines.

Currently, the cell therapy is indicated for large B-cell lymphoma (LBCL), including diffuse LBCL not otherwise specified, high-grade B-cell lymphoma, primary mediastinal LBCL and grade 3B follicular lymphoma refractory to first-line chemoimmunotherapy.

If approved, Breyanzi would be the first CAR-T therapy authorized to treat patients with CLL and SLL. 

Madrigal Eyes First NASH/MASH Approval

Similarly gunning for an industry first is Madrigal Pharmaceuticals, which is proposing resmetirom for the treatment of non-alcoholic steatohepatitis (NASH)—recently renamed metabolic dysfunction-associated steatohepatitis (MASH). The FDA is set to release its verdict by March 14.

Designed to be orally available, resmetirom is a selective agonist of the thyroid hormone receptor (THR)-β, the signaling of which is crucial to maintaining liver health. According to Madrigal’s website, THR-β activity is impaired in MASH, which leads to worse mitochondrial dysfunction, lipotoxicity and fibrosis, thereby driving disease progression.

Resmetirom is backed by a comprehensive clinical development program comprising 18 clinical studies, four of which are Phase III trials. Madrigal is seeking the FDA’s accelerated approval for resmetirom, and the regulator has granted the application Priority Review.

The centerpiece of the application is the MAESTRO-NASH study, which in December 2022 met both of its primary endpoints. Resmetirom’s 80-mg and 100-mg doses led to significantly higher rates of MASH resolution and improvement in liver fibrosis versus placebo.

Last month, Madrigal published more detailed findings from MAESTRO-NASH in The New England Journal of Medicine, demonstrating that the 80-mg dose induced disease resolution without worsening fibrosis in 25.9% of patients, while the 100-mg dose elicited such a response in 29.9%.

If approved, resmetirom would be the first MASH therapy to make it through the regulatory gauntlet for the indication, besting at least 20 other programs that have been dropped, paused or otherwise experienced some sort of clinical roadblock.

Optinose Eyes First Chronic Rhinosinusitis Treatment

Optinose is likewise looking to make history by winning the FDA’s first approval in chronic rhinosinusitis for its nasal spray XHANCE (fluticasone propionate). The regulator’s decision is due on March 16.

XHANCE is a drug-device combination product that uses Optinose’s proprietary Exhalation Delivery System to deliver fluticasone propionate, an anti-inflammatory agent, into the high and deep regions of the nasal cavity. XHANCE was first approved in September 2017 for the treatment of nasal polyps.

Optinose is backing its sNDA, which the FDA accepted in May 2023, with data from the phase III ReOpen clinical trial program, which was comprised of two randomized, double-blinded and placebo-controlled trials. The first study enrolled patients with and without nasal polyps, while the second focused only on those without polyps. Both studies evaluated symptomatic improvement and change in sinus inflammation.

The FDA’s original target action date was December 16, 2023. A month earlier, however, the regulator asked Optinose to provide additional efficacy analyses in a subset of patients without nasal polyps plus those with nasal polyps of grade one or lower at entry. The FDA deemed this submission a major amendment and extended its review period by three months.

J&J/Legend’s Carvykti and BMS/2seventy’s Abecma Face ODAC Adcomm  

On March 15, the FDA’s Oncologic Drugs Advisory Committee will meet to discuss regulatory applications from Bristol Myers Squibb and 2seventy bio, and Johnson & Johnson and Legend Biotech, which are seeking to move Abecma and Carvykti, respectively, into earlier lines of treatment for multiple myeloma.

Currently, both drugs are approved for the treatment of adults with relapsed and refractory multiple myeloma (RRMM) after four or more prior lines of therapy.

For Carvykti, the panel of external experts will review data from the Phase III CARTITUDE-4 trial, a randomized trial assessing the efficacy and safety of the therapy in patients with lenalidomide-refractory multiple myeloma who had been exposed to at least one previous line of systemic therapy. 

Early data from CARTITUDE-4, which leaked in April 2023, demonstrated that the therapy cut the risk of disease progression by 74% versus standard treatment. Carvykti also showed an overall survival benefit of 22%, though this finding was not statistically significant.

For Abecma, the panel will look at data from the KarMMa-3 study in patients with RRMM. Abecma met its primary endpoint, with a statistically significant improvement in progression-free survival (PFS) compared to standard treatment, impacting both disease progression and death. 

The advisory committee meeting comes after the European Medicines Agency last week backed J&J and Legend. The Committee for Medicinal Products for Human Use (CHMP) recommended the approval of Carvykti as a second-line treatment option in relapsed and refractory multiple myeloma. In January, the CHMP recommended greenlighting Abecma for RRMM after at least two prior therapies.

https://www.biospace.com/article/fda-action-alert-mirum-bms-madrigal-and-more/

FDA Adcomm to Tackle Complexity of CAR-T for Multiple Myeloma

 On March 15, the FDA’s Oncologic Drugs Advisory Committee will meet to discuss two CAR T cell therapies for multiple myeloma—Abecma, from Bristol Myers Squibb and 2seventy bio, and Carvykti, from Johnson & Johnson and Legend Biotech. Both treatments are currently approved for the treatment of adults with relapsed/refractory multiple myeloma (RRMM) after four or more prior lines of therapy, and their makers are seeking to move them into earlier lines of treatment.

As CAR-T therapies have recently come under FDA scrutiny over safety issues, Friday’s meeting is significant, Jack Allen, a senior research analyst with Baird, told BioSpace. “At a high level, this will be an interesting meeting for the CAR-T field as the industry looks to understand how the FDA is thinking about moving these treatments into earlier-line settings,” he said. “I expect many who follow this space to be looking to the FDA’s ‘body language’ here and any read-throughs it may have as it relates to a path forward for broader use of this innovative modality both in oncology settings and beyond.” CAR-T therapy for autoimmune indications has recently been topic of interest as well.  

The morning of the 15th will be devoted to discussing J&J’s CARTITUDE-4 study of Carvykti in lenalidomide-refractory multiple myeloma, while the afternoon will focus on the KarMMa-3 study of Abecma in RRMM. Experts told BioSpace they are optimistic the therapies will gain these additional approvals.

Rahul Banerjee, a physician-researcher specializing in multiple myeloma at the Fred Hutchinson Cancer Center in Seattle, Wash., noted that both Abecma and Carvykti could be poised for approval as earlier lines of treatment in Europe as well. In January, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended greenlighting Abecma for RRMM after at least two prior therapies. A similar CHMP recommendation followed in February for Carvykti, with the committee supporting approval in RRMM after one previous line of treatment.

“I hope the FDA will view the benefits of earlier treatment similarly,” Banerjee told BioSpace.  

A representative for BMS was also optimistic. “During the upcoming ODAC meeting, we look forward to reinforcing the potential of Abecma to deliver significantly improved outcomes for patients in earlier lines of treatment,” the spokesperson wrote in an email to BioSpace. “We remain confident in the safety profile and clinical value of our cell therapies.”

Overall Survival Isn’t Everything

In November 2023, the agency delayed approval of Abecma for earlier treatment and announced an upcoming advisory committee meeting. That same month, the FDA revealed that CAR-T therapies were under review after several reports of secondary blood cancers in treated patients, and in January, the agency added a class warning to all six currently approved CAR-T therapies.

The FDA’s announcement of the upcoming adcomm for Abecma and Carvykti noted that the survival benefits of both therapies will be reviewed. This was confirmed in a February press release from BMS and 2seventy bio, which stated that the companies “anticipate that the ODAC will review data related to the secondary endpoint of overall survival” from the KarMMa-3 study. 

At first glance, the survival benefit data in KarMMa-3 can be confusing. Abecma met its primary endpoint, with a statistically significant improvement in progression-free survival (PFS) compared to standard treatment, impacting both disease progression and death. It also met a secondary endpoint, slashing patients’ risk of death by 31% in comparison to individuals receiving standard of care.

However, this was a modified crossover trial. More than half of the patients in the control standard-of-care arm were switched to Abecma after their cancers progressed. Data from the KarMMa-3 study presented at the December 2023 American Society of Hematology Annual Meeting and Exposition showed that if the two groups were compared without a statistical adjustment accounting for that change, there was no significant improvement in overall survival.

Banerjee explained that allowing patients to cross over to CAR-T if they have failed standard therapy is fairly typical and also humane. “You can do a study where the moment a patient in the control group experiences any progression, they go straight to CAR-T,” he explained. “That is a statistician’s dream and a perfect study, but it’s not only expensive, it’s tricky because some patients might not have access to CAR-T.” The other extreme, he said, is to forbid any crossover so that patients in the study can never receive CAR-T in their lifetime. “That’s not ethical,” Banerjee said. Most studies leave the decision to move to CAR-T up to the physician based on progression or toxicity of other drugs.  

But he added that survival benefit is not the most important measure of the CAR-T success. While patients may not necessarily live longer, “what we do see is that [they] get a substantial benefit, remission and better quality of life across the board.” Banerjee pointed to the concept of time toxicity in myeloma, where patients in the control arm receiving standard-of-care treatment need to travel to and spend time in the clinic repeatedly in order to receive treatment. “With CAR-T, there’s a one-time infusion and patients are in remission, and by those metrics, CAR-T is a runaway success,” he said.

Gurbakhash Kaur, an oncologist at UT Southwestern Medical Center in Dallas, agreed. “We generally try to give three drugs and patients stay on that for a long time,” she told BioSpace. “They never really get a treatment holiday or a break from therapy.” With CAR-T, following an upfront time investment, patients can be treatment-free “and enjoy a good quality of life,” she said. “We also think the immune system will be less exhausted if they receive CAR-T earlier when T cell responses are more robust.”

Reassessing the Lines of Therapy Concept

J&J and Legend Biotech are basing their supplemental Biologics License Application (sBLA) on the results of the CARTITUDE-4 trial, where treatment with Carvykti led to a 74% reduction in disease progression or death in patients who had received at least one previous line of therapy with an immunomodulatory agent or a proteasome inhibitor. The trial also tested Carvykti in patients refractory to Revlimid, a first-line immunomodulatory treatment for multiple myeloma.

But according to Banerjee, when it comes to CAR-T therapy, the lines of therapy concept may be outdated. Whether or not the approach makes sense is a topic of conversation at meetings and conferences, he said, noting that a line of therapy can be different from a treatment regimen. For example, “if the dose of a medication is lowered, it is not considered a new line,” he explained. “It’s a little bit arbitrary.”

In the KarMMa-3 trial, some patients were triple-class refractory, meaning “the therapies simply failed the patient.” Banerjee added that the first relapse is significant, but that CAR-T prognosis depends more on what therapies patients failed and how long they had worked for than the total number of treatments they had.

Even if earlier treatment is approved, it will not be available to everybody, Kaur noted. “Access remains a big issue. . . . [G]iving CAR-T requires a lot of collaboration, and not all transplant centers can deliver it.” Nonetheless, she is hopeful that moving therapies like Abecma and Carvykti to an earlier line of treatment will allow more patients to access them.

https://www.biospace.com/article/odac-adcomm-to-tackle-complexity-of-car-t-in-multiple-myeloma/

Declining Concerns Among Americans About COVID-19

 A new survey reveals that only 20% of Americans view covid-19 as "a major threat" to the health of the US population - a sharp decline from a high of 67% in July 2020.

What's more, the Pew Research Center survey conducted from Feb. 7 to Feb. 11 showed that just 10% of Americans are concerned that they will  catch the disease and require hospitalization.

"This data represents a low ebb of public concern about the virus that reached its height in the summer and fall of 2020, when as many as two-thirds of Americans viewed COVID-19 as a major threat to public health," reads the report, which was published March 7.

According to the survey, half of the participants understand the significance of researchers and healthcare providers in understanding and treating long COVID - however 27% of participants consider this issue less important, while 22% of Americans are unaware of long COVID.

What's more, while Democrats were far more worried than Republicans in the past, that gap has narrowed significantly.

"In the pandemic’s first year, Democrats were routinely about 40 points more likely than Republicans to view the coronavirus as a major threat to the health of the U.S. population. This gap has waned as overall levels of concern have fallen," reads the report.

More via the Epoch Times;

The survey found that three in ten Democrats under 50 have received an updated COVID-19 vaccine, compared with 66 percent of Democrats ages 65 and older.

Moreover, 66 percent of Democrats ages 65 and older have received the updated COVID-19 vaccine, while only 24 percent of Republicans ages 65 and older have done so.

“This 42-point partisan gap is much wider now than at other points since the start of the outbreak. For instance, in August 2021, 93 percent of older Democrats and 78 percent of older Republicans said they had received all the shots needed to be fully vaccinated (a 15-point gap),” it noted.

COVID-19 No Longer an Emergency

The U.S. Centers for Disease Control and Prevention (CDC) recently issued its updated recommendations for the virus, which no longer require people to stay home for five days after testing positive for COVID-19.

The updated guidance recommends that people who contracted a respiratory virus stay home, and they can resume normal activities when their symptoms improve overall and their fever subsides for 24 hours without medication.

“We still must use the commonsense solutions we know work to protect ourselves and others from serious illness from respiratory viruses, this includes vaccination, treatment, and staying home when we get sick,” CDC director Dr. Mandy Cohen said in a statement.

The CDC said that while the virus remains a threat, it is now less likely to cause severe illness because of widespread immunity and improved tools to prevent and treat the disease.

“Importantly, states and countries that have already adjusted recommended isolation times have not seen increased hospitalizations or deaths related to COVID-19,” it stated.

The federal government suspended its free at-home COVID-19 test program on March 8, according to a website set up by the government, following a decrease in COVID-19-related hospitalizations.

According to the CDC, hospitalization rates for COVID-19 and influenza diseases remain “elevated” but are decreasing in some parts of the United States.

https://www.zerohedge.com/covid-19/survey-shows-declining-concerns-among-americans-about-covid-19

France's Macron wants to make abortion a right at EU level

 French President Emmanuel Macron said on Friday that he wants the European Union to guarantee the right to an abortion in its Charter of Fundamental Rights.

Macron was speaking at a ceremony held in Paris, where Justice Minister Eric Dupond-Moretti used a centuries-old press to seal the right to abortion into the French constitution, following an overwhelming vote by lawmakers on Monday.

"Today is not the end of the story but the start of a fight," Macron told the ceremony, which coincided with International Women's Day.

"We're going to lead this fight in our continent, in our Europe, where reactionary forces are attacking women's rights before attacking the rights of minorities," he told the crowd attending the ceremony in Paris, in front of the Justice Ministry.

"This is why I want to enshrine that guaranteed freedom to abortion in the Charter of Fundamental Rights of the European Union."

Changing the EU charter, which would require unanimity, may prove difficult. While most of Europe has legalised abortion, some countries impose restrictions on women seeking to terminate a pregnancy, and deep divisions over abortion rights remain.

Last year, the government of EU member Malta backed down on a bill which would have allowed the abortion of pregnancies when the mother's health was at serious risk, saying instead that terminations would only be allowed when the mother's life was in danger.

Along with Malta, Poland's anti-abortion laws are among the most restrictive in Europe. Pregnancy can be terminated only in cases of a threat to the mother's life or health or in a case of rape, and the number of abortions fell to 161 in 2022 from over 1,000 in 2020.

Monday's vote by the two houses of the French parliament enshrined in Article 34 of the French constitution that "the law determines the conditions in which a woman has the guaranteed freedom to have recourse to an abortion".

Abortion rights are more widely accepted in France than in the United States and many other countries, with polls showing around 80% of French people back the fact that abortion is legal.

https://www.yahoo.com/news/frances-macron-wants-abortion-eu-124138862.html

Ukraine rebuffs Pope Francis calling for talks with Russia

 Ukraine on Sunday rebuffed Pope Francis's call to negotiate an end to the war with Russia, with President Volodymyr Zelenskiy saying the pontiff was engaging in "virtual mediation" and his foreign minister saying Kyiv would never capitulate.

Francis said that when things were going badly for a party to a conflict one had to show the "courage of the white flag" and negotiate. The pope's interview was believed to be the first time Francis has used terms like "white flag" or "defeated" in discussing the Ukraine war, though he has referred in the past to the need for talks.

Zelenskiy made no direct reference to Francis or his comments but mentioned religious figures helping inside Ukraine.

"They support us with prayer, with their discussion and with deeds. This is indeed what a church with the people is," Zelenskiy said in his nightly video address.

"Not 2,500 km away, somewhere, virtual mediation between someone who wants to live and someone who wants to destroy you."

Foreign Minister Dmytro Kuleba, writing on the X messaging platform, said that the strong person in any dispute "stands on the side of good rather than attempting to put them on the same footing and call it 'negotiations'".

"Our flag is a yellow and blue one," Kuleba wrote in English, referring to the Ukrainian national flag. "This is the flag by which we live, die, and prevail. We shall never raise any other flags."

Kuleba also pointed to allegations that Pope Pius XII failed to act against the Nazis in Germany in World War Two.

"I urge (the Vatican) to avoid repeating the mistakes of the past and to support Ukraine and its people in their just struggle for their lives," he wrote.

That was a reference to longstanding arguments that Pius took no action despite evidence that emerged during the war of the extent of the Holocaust. A letter made public last year from the Vatican archives appeared to show that Pius was made aware of details of Nazi actions to exterminate Jews as early as 1942.

Supporters of Pius say he worked behind the scenes to help Jews and did not speak out in order to prevent worsening the situation for Catholics in Nazi-occupied Europe. His detractors say he lacked the courage to speak out on information he had despite pleas from Allied powers fighting Germany.

The head of Ukraine's 5 million-strong Eastern Rite Catholic Church, Archbishop Sviatoslav Shevchuk, also rejected the pope's comments.

"Ukraine is wounded, but not conquered! Ukraine is exhausted, but it stands and will stand!" the church's website quoted Shevchuk as saying in New York.

"Believe me, no one has any idea of ​​surrendering."

Zelenskiy has called for the withdrawal of all Russian troops and the restoration of Ukraine's post-Soviet borders. The Kremlin rules out engaging in talks on terms set by Kyiv.

The pope has upset Ukrainian officials several times in the war, including his call last year to Russian youth to take pride as heirs of tsars like Peter the Great, held up by President Vladimir Putin as an example to justify his actions in Ukraine.

European officials supporting Ukraine in efforts to evict Russian troops denounced the pope's latest comments.

"How about, for balance, encouraging Putin to have the courage to withdraw his army from Ukraine?" Polish Foreign Minister Radoslaw Sikorski wrote on X.

Latvian President Edgars Rinkevics, also writing on X, said:

"One must not capitulate in face of evil, one must fight it and defeat it, so that the evil raises the white flag and capitulates."

https://www.yahoo.com/news/ukraine-minister-responding-pope-francis-183514392.html

'New strategy to treat infertility'

 New research from Oregon Health & Science University describes the science behind a promising technique to treat infertility by turning a skin cell into an egg that is capable of producing viable embryos.

Researchers at OHSU documented in vitro gametogenesis, or IVG, in a mouse model through the preliminary steps of a technique that relies upon transferring the nucleus of a skin cell into a donated egg whose nucleus has been removed. Experimenting in mice, researchers coaxed the skin cell's nucleus into reducing its chromosomes by half, so that it could then be fertilized by a sperm cell to create a viable embryo.

The study is published in the journal Science Advances.

"The goal is to produce eggs for patients who don't have their own eggs," said senior author Shoukhrat Mitalipov, Ph.D., director of the OHSU Center for Embryonic Cell and Gene Therapy.

The technique could be used by women of advanced maternal age or for those who are unable to produce viable eggs due to previous treatment for cancer or other causes. It also raises the possibility of men in same-sex relationships having children who are genetically related to both parents.

Rather than attempting to differentiate induced pluripotent stem cells, or iPSCs, into sperm or egg cells, OHSU researchers are focused on a technique based on somatic cell nuclear transfer, in which a skin cell nucleus is transplanted into a donor egg stripped of its nucleus. In 1996, researchers famously used this technique to clone a sheep in Scotland named Dolly.

In that case, researchers created a clone of one parent. In contrast, the OHSU study described the result of a technique that resulted in embryos with chromosomes contributed from both parents. The process involves three steps:

• Researchers transplant the nucleus of a mouse skin cell into a mouse egg that is stripped of its own nucleus.
• Prompted by cytoplasm—liquid that fills cells—within the donor egg, the implanted skin cell nucleus discards half of its chromosomes. The process is similar to meiosis, when cells divide to produce mature sperm or egg cells. This is the key step, resulting in a haploid egg with a single set of chromosomes.
• Researchers then fertilize the new egg with sperm, a process called in vitro fertilization. This creates a diploid embryo with two sets of chromosomes—which would ultimately result in healthy offspring with equal genetic contributions from both parents.

OHSU researchers previously demonstrated the proof of concept in a study published in January 2022, but the new study goes further by meticulously sequencing the chromosomes.

The researchers found that the skin cell's nucleus segregated its chromosomes each time it was implanted in the donor egg. In rare cases, this happened perfectly, with one from each pair of matching egg and sperm chromosomes.

"This publication basically shows how we achieved haploidy," Mitalipov said. "In the next phase of this research, we will determine how we enhance that pairing so each chromosome-pair separates correctly."

Laboratories around the world are involved in a different technique of IVG that involves a time-intensive process of reprogramming skin cells to become iPSCs, and then differentiating them to become egg or sperm cells.

"We're skipping that whole step of cell reprogramming," said co-author Paula Amato, M.D., professor of obstetrics and gynecology in the OHSU School of Medicine. "The advantage of our technique is that it avoids the long culture time it takes to reprogram the cell. Over several months, a lot of deleterious genetic and epigenetic changes can happen."

Although researchers are also studying the technique in human eggs and early embryos, Amato said it will be years before the technique would be ready for clinical use.

"This gives us a lot of insight," she said. "But there is still a lot of work that needs to be done to understand how these chromosomes pair and how they faithfully divide to actually reproduce what happens in nature."

More information: Aleksei Mikhalchenko et al, Induction of somatic cell haploidy by premature cell division, Science Advances (2024). DOI: 10.1126/sciadv.adk9001. www.science.org/doi/10.1126/sciadv.adk9001

https://medicalxpress.com/news/2024-03-strategy-infertility.html

No Borders? No America

 by Justin Smith via The Burning Platform blog,

Americans had better act soon, with or without Congress and with or without the Border Patrol to stop the current flood of illegal invaders across our Southern Border, because the Biden regime has no intention of ever stopping the invasion. To wait and ponder the crisis in the hopes that Donald Trump can stop it, if he wins the presidency, only ensures that millions more will cross, in addition to the twenty-seven million that have already entered the country, during Biden’s presidency — those which were detained at the border and the got-aways; and, intentionally or not, it makes America unsafe and sets in motion the Great Replacement, the replacement of white people and the virtues and principles of freedom and liberty with people of color who are already prone and predisposed to accepting big government controls, e.g. Marxism and Maoism, and the idea that all things come from government rather than individual initiative and independence. To do nothing and remain apathetic or complacent ensures the destruction of traditional America.

One should recall that a 2018 study by both Yale and MIT suggested 22 million to possibly 40 million illegal aliens were already residing in America. It’s to Trump’s discredit that he didn’t pursue the border security issue forcefully in 2017, when the Republicans held a majority in both houses of Congress, rather than listen to the turncoat RINO Speaker Paul Ryan.

In his last year in office, Trump had brought illegal alien entries down to approximately 1100 a day, or less.

Under Joe Biden, the U.S. borders simply no longer exist. His regime’s minions have been ordered to process and parole illegal aliens into America as fast as possibly, virtually waving them on across with little to no scrutiny. And, as a result, we know for a fact that 330 illegals who are on terrorist watch lists have been released into the country, along with the unknown number of potential or actual terrorists within the ranks of the gotaways.

Going all the way back to 1996, Augustin Cebada, radical spokesman for the Brown Berets, militant para-military foot-soldiers of Aztlan [Reconquista] shouted the following declaration, at Americans at an Independence Day rally outside the Federal Building in Westwood, California:

“If anyone’s going to be deported, it’s going to be you! … Get out! We are the future. You’re old and tired. Go on. We have beaten you — leave like beaten rats. You old white people, it is your duty to die. Right now, we’re already controlling those elections, whether it’s by violence or nonviolence. Through love of having children, we’re going to take over.”

Some may actually be coming here to become American citizens and try to live the American Dream, a dream that is crumbling and rapidly disappearing for natural born Americans, thanks to a multitude of bad Biden policies; but the cast majority are not. They simply want to abscond with as much American wealth as they can possibly accumulate while also riding the massive government expenditures of recent programs created to address their invading numbers.

These illegals don’t want to be citizens; they don’t assimilate any more, as they did in days past; they set up shop just as they did in the Old Country and bring the same flawed mindsets that destroyed the nations they have fled.

Through Joe Biden’s Open Borders Policy that don’t have to wait to for the illegal invaders to have children. They are simply flying them over, entire families and all, at the taxpayers’ expense.

That’s part of what makes this all so maddening. Joe knows without a doubt, or at least his handlers know, that he absolutely is charged by the U.S. Constitution and given the authority as President and Commander-in-Chief to protect and defend our borders and sovereign domain. And yet, on March 7th 2024, Biden had the temerity to suggest in his State of the Union Address, that he needed a new immigration bill and more money, before he could do his job, none of which is true.

Along with this, please note that Congress could pass ten great immigration / border security laws, or even 100, and it wouldn’t make a damned bit of difference. Joe Biden and the Democratic Party violate the Constitution and U.S. law — yes, even our existing laws on immigration and border security — with impunity, no qualms or pangs of conscience whatsoever. Biden absolutely would violate any new law, if it served his agenda and that of the radical Marxists and Maoists within the Democratic Party.

Even this last so-called “bipartisan bill” had a loophole in it, actually allowing for 1.8 million illegals to be allowed to cross every year, before it’s safeguards were employed.

That is unless Biden decided to suspend its mechanisms for a “national emergency” as the bill provided. The bill was a farce, a massive joke, and that’s why it was rejected.

That’s the reason so many truly conservative Americans were so angered to hear Biden mock Republicans after some jeered his remarks on his “comprehensive bill to fix our immigration system” — understanding his underlying lie , as he said:

“Oh, you don’t like that bill — huh? — that conservatives got together and said was a good bill? I’ll be darned. That’s amazing.” [transcript at Associated Press]

President Woodrow Wilson sent Brigadier General John “Black Jack” Pershing out of Fort Bliss, Texas on March 15th 1916 to patrol the border between the U.S. and Mexico, in order to stop Pancho Villa’s cross-border raids and capture or kill him. Pershing went a few steps further and pursued Villa into 350 miles into Mexico proper, leading 10,000 soldiers behind him. All of this was done under the premise set forth in the Article IV Section 4 of our Constitution which states the federal government “shall protect each of [the states] against invasion” and Article I Section 10 which expressly guarantees states the sovereign power to repel an invasion and defend U.S. citizens from overwhelming and “imminent danger”. And there isn’t one damned thing preventing Joe Biden from exercising this same exact authority now other than the Democratic Party Communists’ intent to grant millions of illegal foreign invaders amnesty and the right to vote, in order to grow their base and hold power and control over all America for the rest of the century.

For over three years, Joe Biden and Homeland Security [what an oxymoron] Secretary Alejandro Mayorkas have assured all America that the border is secure and the illegal alien invasion is being handled properly, when in fact, the U.S. Immigration and Customs Enforcement and the Border Patrol are being used to speed up the process of receiving illegal aliens into the country, rather than immediately detaining and returning them back across the border, should be the case. And all the while, through his lies, Mayorkas smugly and arrogantly smiles like a fat-headed Cheshire Cat, in his belief that he is untouchable, which has been the case so far.

Biden’s Open Border Policy has been a massive success towards ultimately achieving the Democratic Party’s goals of changing the face of America and fundamentally transforming Her away from Her founding, and it has been an abject and complete catastrophe for Fly Over Country and the everyday average American who loves his country, God and family better than himself. The rising of this anti-American regime has been a sad and disgusting time to be marked as such in the annals of history, should honest historians ever reappear.

And his policies have been a boon to the numerous drug cartels which have expanded their operations by tenfold in every major city in the U.S. and even the smaller cities and towns that once barely had a hint of drug and crime problems,

At some point, anyone having a hand in the most massive betrayal of America in U.S. history must be made to face a day of reckoning, regardless of what form it may take.

In the meantime, our daughters are continuously being assaulted, brutalized, kidnapped, raped and murdered in the most heinous of manners, unimaginable to most good and decent people, by these foreign, illegal alien invaders. Decent Americans of all walks of life, men, women and children, are being murdered by these monsters, the MS-13 drug cartel members and prisoners released from Venezuela’s prisons, much like young Kate Steinle in 2015, a 32 year old sales rep, and now Laken Riley, a 22 year old nursing student, who was bludgeoned to death and disfigured by an illegal alien monster, who entered the country in 2022.

Adding insult to injury, Traitor Joe just apologized for calling Laken Riley’s murderer an “illegal”, during his State of the Union address. The apology came today, March 9th 2024, during an interview with MSNBC’s Jonathan Capehart. But that’s exactly what he is — a goddamned foreign, illegal, criminal piece of murderous shit from Venezuela who was also charged and released in New York City after endangering a five year old child [per Olivia Land/New York Post]

On July 13th 2023, the Judiciary Committe’s Subcommittee on Immigration Integrity, Security and Enforcement [The Consequences of Criminal Aliens on U.S. Communities] reported that 33,000 Americans had been killed by murder and manslaughter at the hands of illegal aliens between 2010 and 2015, which begs the question, just how many are now dying at the hands of millions of the anonymous, unvetted illegal aliens Biden has welcomed, even ferried, into America. As reported by this committee, just two weeks prior to its meeting, an illegal alien was sentenced to life in prison for raping and impregnating a nine year old Ohio girl, who later went to Indiana to get an abortion.

I have two adult daughters, and if any illegal alien were to do them harm in any way, they had better hope law enforcement officers get to them before I do, especially now that we are actually seeing stone-cold murderers released without bail by anti-American, anti-law enforcement District Attorneys, bought and paid for by George Soros.

From the Judiciary Committee’s report:

“According to a report covering thirteen years of data from the Executive Office of Immigration Review, over forty-seven percent [of illegals] never even pursue an asylum claim once released into the country. More than eighty-five percent will be denied asylum and receive a deportation order, yet less than five percent ever leave the country. Anyone requesting asylum must be detained or made to remain in Mexico until their hearing is adjudicated. These numbers prove they can’t be trusted to be released.”

These illegal aliens are also overwhelming the capabilities of America’s schools, hospitals, law enforcement and other general services provided at various levels of government. I see that as an extremely serious matter that is certainly facilitating the destruction of our economy, since the taxpayer dollars supporting this invasion means Americans everywhere are being deprived of the benefit of their own labor to support the dregs of the world; but it is much less important to me than knowing that foreign illegal aliens are snuffing out our countrymen’s lives, like they are nothing.

These are real people with real lives and families, not just a data base of statistics, and for every victim of a criminal illegal alien, there is a devastated family. And still, Biden and Company drive on towards the abyss creating a dystopian nightmare along the way for law abiding citizens, watching the end of their country racing toward them like an out-of-control freight train and no Casey Jones at the controls.

Former President Donald Trump has promised to start the largest mass deportation of illegal aliens in U.S. history, if he wins the upcoming election, and he plans to use the military to implement it, rightfully so. As reported in the Washington Post [February 21st 2024], Karoline Leavitt, spokeswoman for the Trump campaign, stated:

“Americans can expect that immediately upon President Trump’s return to the Oval Office, he will restore all his prior policies, implement brand new crackdowns that will send shock waves to all the world’s criminal smugglers, and marshal every federal and state power necessary to institute the largest deportation operation in American history” as she also added that illegal aliens “should not get comfortable because very soon they will be going home.”

We have the absolute right and a duty as sovereign citizens, living in sovereign states, to defend ourselves and our families, in the wake of a lawless federal government, this lawless Biden regime. The authority rests within the Constitution which has always allowed for the use of the States’ militias or the military to be mobilized for just such circumstances, and although we can be certain that Biden and some state governors will keep refusing to utilize the mechanisms at their disposal to fast-track the removal of these invaders, we have the right to gather ourselves armed with pistols and rifles — those of us able with the time and backbone to do so — to go to the border and tell the Border Patrol to do join us and do their Constitutional duty to stop the millions more who will try to cross between now and January 2025.

I oft suggested in years past, half-jokingly, not so much anymore, that we should put them on a plane, parachutes optional, and shove them out over Mexico. This comment has become so much more full of meaning, now that we know the Biden regime has actively been seeking out these illegal caravans and flying their members into America.

No matter how they arrive, by a fast jet, a slow boat or a reliable bus or train, we must send them back on a super-charged bus or jet just as quickly. Set about to deport every last one of them, and then effectively and totally seal the border and place a ten year moratorium on all immigration, legal and illegal, or until we have our nation and our population straightened out in a fashion that puts us back on a path to the same level of exceptionalism that used to be the rule in America and removes or eradicates, with extreme prejudice, those radicals who seek to fundamentally transform America and end our republic.

Don’t let the enemies-from-within end America in so despicable a manner. Don’t let this be how America ends. Fight back like hell, and when the time is right, make the bastards who have committed this treason against America pay with their own lives.

https://www.zerohedge.com/political/no-borders-no-america