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Friday, May 3, 2024

FDA’s Accelerated Approval of Sarepta DMD Gene Therapy Comes Under Fire

 The FDA’s authorization of therapies that fail their efficacy endpoints casts doubt on the regulator’s accelerated approval pathway, according to an article from David Rind, chief medical officer of the drug pricing non-profit Institute for Clinical and Economic Review, published Wednesday in the Journal of the American Medical Association.

In his viewpoint piece, Rind specifically called out Sarepta Therapeutics’ gene therapy Elevidys (delandistrogene moxeparvovec-rokl), which won the FDA’s accelerated approval in June 2023—despite falling short of its primary efficacy endpoint in two studies.

To support its decision to grant Elevidys accelerated approval in Duchenne muscular dystrophy (DMD), the FDA pointed to expression levels of the protein micro-dystrophin, which the regulator said was “reasonably likely to predict clinical benefit in individuals 4 to 5 years of age,” for whom Elevidys is indicated.

In DMD, a rare neuromuscular disorder, mutations to the dystrophin gene lead to a dysfunctional protein, which manifests as developmental delays and muscle weakness. Elevidys works by delivering a functional copy of the dystrophin genes to the patients’ muscles.

“In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children, and the urgent unmet medical need,” the regulator noted in its announcement at the time.

Still, the accelerated approval came as a surprise to many, given that Elevidys had failed the primary outcome in a Phase I study, unable to significantly improve patients’ functional performance versus placebo.

Among those that raised concerns about this Phase I miss were the regulator’s own reviewers, who in briefing documents published ahead of an advisory committee meeting said that micro-dystrophin levels “only provides information about expression of the transgene product in cells transduced by SRP-9001, rather than insight into a pharmacologic effect on a biomarker in the pathway of the disease.”

Sarepta narrowly cleared the same advisory committee vote, earning support from eight out of 14 panelists.

To keep Elevidys on the market, Sarepta ran the confirmatory Phase III EMBARK study looking at the clinical benefit of its gene therapy. In October 2023, the biotech announced that EMBARK had failed its primary endpoint, unable to significantly improve functional mobility versus placebo, but Sarepta nevertheless called the findings “robust evidence” of clinically meaningful benefit.

The FDA accepted Sarepta’s supplemental Biologics License Application earlier this year, with a verdict due on June 21, 2024.

Rind in his viewpoint article on Wednesday also blasted the price tag of Elevidys, which Sarepta has set at $3.1 million per dose, making it one of the world’s most expensive therapies.

“This is an enormous price tag for a therapy that has failed to meet its primary end point in the 2 randomized trials in which it has been studied and that is clearly not curative," Rind wrote.

https://www.biospace.com/article/fda-s-accelerated-approval-of-sarepta-dmd-gene-therapy-comes-under-fire/

AstraZeneca Targets First-Line Mantle Cell Lymphoma Therapy with Phase III Data

 AstraZeneca on Thursday revealed high-level results from the Phase III ECHO trial, demonstrating that BTK inhibitor Calquence (acalabrutinib)—when used with standard chemotherapy agents bendamustine and rituximab—yielded significant survival benefits as a first-line therapy in mantle cell lymphoma.

The pharma did not provide specific data in its announcement but said that the Calquence-based regimen resulted in a “statistically significant and clinically meaningful improvement” in progression-free survival, compared with standard of care. ECHO, a randomized, double-blinded and placebo-controlled trial, enrolled nearly 600 patients with previously untreated mantle cell lymphoma (MCL).

Data for overall survival (OS) was not yet mature at the time of the interim analysis, but AstraZeneca noted in its announcement that “a trend was observed in favor of Calquence plus chemoimmunotherapy.” ECHO will continue as planned to assess OS.

In terms of safety, ECHO found no new signals of concern. Calquence’s adverse event profile in the study was consistent with what has been established in prior trials.

Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, in a statement called the results “impactful” and said that “bringing Calquence to the first-line setting significantly delays disease progress and, for the first time, shows potential to extend survival.”

AstraZeneca will present full data and analyses from ECHO at an upcoming medical congress and will share these with regulatory authorities.

Designed to be orally available, Calquence is a small-molecule BTK inhibitor that works by covalently bonding to the active site of the BTK protein, which deactivates its enzymatic activity. BTK is a signaling molecule involved in the pathways for B-cell proliferation and trafficking, and its inhibition could prevent the division and survival of malignant B-cells.

The FDA first approved Calquence in 2017 for previously treated MCL and the drug has since become one of AstraZeneca’s top-performing assets. In the first quarter of 2024, Calquence brought in $718 million for the pharma, up 6% from its sales during the same period in 2023.

AstraZeneca is also assessing Calquence as a monotherapy for several B-cell blood cancers, including chronic lymphocytic leukemia and diffuse large B-cell lymphoma. In addition, the pharma is studying various Calquence-based combination regimens.

Thursday’s late-stage readout comes a year after AbbVie and J&J voluntarily pulled the accelerated MCL approval for their BTK blocker Imbruvica (ibrutinib). While data from Phase III confirmatory trials showed that Imbruvica can significantly improve PFS versus placebo, the treatment yielded no significant benefit in terms of OS and complete response.

https://www.biospace.com/article/astrazeneca-targets-first-line-mantle-cell-lymphoma-therapy-with-phase-iii-calquence-data/

Arizona Senate Approves Repeal of Near-Total Abortion Ban

 by Samantha Flom via The Epoch Times (emphasis ours),

Arizona’s near-total abortion ban will be repealed just weeks after the state’s Supreme Court ruled it enforceable.

The Arizona House narrowly passed the repeal on April 24 as three Republicans joined with Democrats to approve the measure.

On May 1, the state Senate followed suit in a 16–14 vote—but not before several disappointed senators had the opportunity to air their grievances.

What we’re actually voting on is death,” state Sen. Anthony Kern said, chiding the members of his Republican party who voted with Democrats in support of the repeal.

The Democrat Party stands and runs on death. The Republican Party stands and is supposed to run on life.

State Sen. Sonny Borrelli, meanwhile, objected to the fact that the bill was never sent to a committee, nor was any time allotted for debate or amendments. And during one particularly emotional moment, state Sen. Justine Wadsack recounted her own tragic loss of a child by miscarriage.

God chose when that heartbeat was going to stop,” Ms. Wadsack said, tears streaming down her face. “It is not my place as a senator to determine when a child’s heart stops beating.”

The abortion ban prohibits all abortions in Arizona except those performed to save the mother’s life. It was initially enacted in 1864, before Arizona was a state, though it was later recodified by the Legislature in the late 1970s.

Arizona Gov. Katie Hobbs, a Democrat, has promised to sign the repeal once it reaches her desk, though it will not be effective until 90 days after the Legislature adjourns. At that point, a 2022 law limiting abortions to 15 weeks of pregnancy will become the state’s prevailing law.

In the meantime, however, the abortion ban is slated to take effect on June 27.

Proponents of the repeal, pointing to the ban’s pre-statehood origins, had argued that it was outdated and inconsistent with the state’s more recent laws.

“I don’t want us honoring laws about women, written during a time when women were forbidden from voting because their voices were considered inferior to men,” state Sen. Eva Burch said May 1.

For decades, the law was blocked by a permanent injunction. But a two-year court battle, prompted by the reversal of Roe v. Wade, culminated in the Arizona Supreme Court’s bombshell ruling on April 9.

Although the court initially stayed the law’s enforcement for two weeks, an agreement in a related case pushed back its effective date.

The Arizona vote came on the same day that a six-week abortion limit in Florida took effect.

That law includes limited exceptions for situations involving rape, incest, human trafficking, or a serious threat to the mother’s physical health. But as with the Arizona ban, the law has been the subject of much controversy.

As the Florida law took effect, abortion advocates took to social media to decry what they perceived to be the erosion of women’s rights in the Sunshine State.

“Today, Florida is putting the health of millions of women at risk,” New York Gov. Kathy Hochul posted on social media. “It’s clear: Anti-choice extremists will stop at nothing to deny women their right to make their own health care decisions.”

Nikki Fried, chair of the Florida Democratic Party, likewise charged that the law had rolled back women’s rights “by 50 years,” and President Joe Biden called the situation a “nightmare.”

Florida and Arizona are expected to play a key role in deciding the next president, and abortion will be on the ballot in both states come November.

While President Biden has aligned himself with abortion advocates, former President Donald Trump, the presumptive Republican nominee, has shied away from what he’s deemed to be a losing issue for the GOP.

The former president, who claims to be pro-life, has said he believes abortion to be a states’ rights issue, as opposed to a federal issue. In taking that stance, he denounced both the Arizona and Florida laws as too restrictive.

“It’s the will of the people—this is what I’ve been saying. It’s a perfect system,” he said on April 10.

“For 52 years, people have wanted to end Roe v. Wade, to get it back to the states. We did that—it was an incredible thing, an incredible achievement. We did that, and now the states have it, and the states are putting out what they want. It’s the will of the people.”

https://www.zerohedge.com/political/arizona-senate-approves-repeal-near-total-abortion-ban

Every Conservative Party In Europe Needs To Prepare For Mass Censorship, Warns Flemish MEP

 By Thomas Brooke of RMXnews.com

In an exclusive interview with Remix News, Gerolf Annemans, the Vlaams Belang MEP and president of the European Identity and Democracy group, warns that even greater censorship of conservatives is just around the corner, and tells right-wing groups what they must do to ensure their message continues to be heard

Thursday, May 2, 2024

Israeli private eye arrested in London over alleged hacking for US firm

 An Israeli private investigator wanted by the United States was arrested in London over allegations that he carried out a cyberespionage campaign on behalf of an unidentified American PR firm, a London court heard on Thursday.

But an initial attempt to extradite Amit Forlit to the United Sates was thrown out by a judge at Westminster Magistrates' Court on Thursday on a legal technicality.

Amy Labram, a lawyer representing the United States, told the court Forlit "is accused of engaging in a hack for hire scheme".

Labram said that the U.S. allegations include that an unnamed Washington-based PR and lobbying firm paid one of Forlit's companies 16 million pounds ($20 million) "to gather intelligence relating to the Argentinian debt crisis".

Forlit and his lawyer did not immediately return messages seeking comment.

Forlit was arrested under an Interpol red notice at London's Heathrow Airport as he was trying to board a flight to Israel, according to the U.S authorities. It was unclear when Forlit was arrested.

Forlit is wanted in the U.S. on three charges: one count of conspiracy to commit computer hacking, one count of conspiracy to commit wire fraud and one count of wire fraud.

A judge ruled that the attempt to extradite Forlit by the United States could not continue as he was not produced in court within the timeframe required under British extradition law.

"He was not produced at court as soon as practicable and the consequences of that ... he must – I have no discretion – he must be discharged," Judge Michael Snow ruled.

The Federal Bureau of Investigation declined to comment.

Forlit has separately been accused of computer hacking in New York by aviation executive Farhad Azima. Azima, whose emails were stolen and used against him in a 2020 trial in London, is suing Forlit and others in federal court in Manhattan.

Forlit has previously acknowledged retrieving Azima's emails but has denied hacking, telling Reuters he innocently stumbled across the messages "on the web".

https://finance.yahoo.com/news/1-israeli-private-eye-arrested-014141856.html

Missile defense successes in Israel, the Red Sea and Ukraine fuel global urgency to acquire systems

 The success of ballistic missile defences facing their first complex, high-stakes combat scenarios in Israel, the Red Sea and Ukraine will encourage militaries globally to invest in the pricey systems, experts say - and intensify missile arms races.

Iran launched as many as 120 intermediate-range ballistic missiles at Israel on April 13, U.S. and Israeli officials say. U.S. SM-3 and Israeli Arrow interceptors destroyed nearly all of them, leaving drones and smaller threats to the Iron Dome system.

In previous months, interceptors fired from U.S. Navy destroyers stopped Houthi anti-ship ballistic missiles, while in Ukraine, U.S.-made MIM-104 Patriot batteries have shot down advanced Russian Iskander and Khinzal missiles.

Reuters spoke with six experts who said more militaries would look to invest in ballistic missile defence, a potential windfall for companies such as Lockheed Martin and Raytheon, which build those types of systems.

"It's undeniable that any wealthy country with the technological wherewithal will continue to invest in missile defence," said Ankit Panda of the U.S.-based Carnegie Endowment for International Peace, a defence and security think tank. "All of this is a recipe for a conventional arms race."

European countries such as the Netherlands, Germany, Sweden and Poland already operate RTX subsidiary Raytheon's Patriot batteries, the most common Western advanced ballistic missile defence system.

Saudi Arabia has used its Patriots for years to defend against Houthi attacks; it and the United Arab Emirates also operate the Lockheed Martin Terminal High Altitude Air Defense (THAAD) system. Kuwait, Qatar and Bahrain have Patriot batteries as well, and Oman has expressed interest in missile defence.

In the U.S., Lockheed Martin in April won a $17.7 billion contract for a next-generation interceptor for the Ground-Based Midcourse Defense (GMD) program - designed to shoot down small numbers of intercontinental ballistic missiles (ICBMs) aimed at the continental United States.

But the impact may be most acute in Asia, where China has invested heavily in conventionally armed ballistic missiles. A 2023 Pentagon report said the People's Liberation Army Rocket Force has about 500 DF-26 missiles, designed to accurately strike targets thousands of kilometres away.

That puts U.S. and allied bases in Japan and Guam within range of an attack that may only come with 20 to 30 minutes' warning.

"In the Pacific, you’ll see further interest in missile defence, which will push the Chinese to build more systems," said Jeffrey Lewis, director of the East Asia Nonproliferation Program at the James Martin Center for Nonproliferation Studies at the Middlebury Institute of International Studies in California. "Countries will want to acquire (offensive) missiles because they see other countries using them ... That will drive up demand for missile defences."

U.S. Indo-Pacific Command and China's Ministry of Defence did not respond to requests for comment.

China rarely discusses its missile arsenal beyond statements that its forces are meant to preserve peace and are not aimed at any specific country.

Raytheon did not respond to a request for comment. A Lockheed Martin spokesperson referred questions to the company's first-quarter earnings briefing in late April, in which it said it continued to lead the industry in "missile defence missions, which, given world events, are becoming more critical than ever".

DOLLAR SIGNS

Ballistic missile defence works by spotting an attacking weapon either at launch or in flight, then using a surface-based radar to guide an interceptor to the target.

Interceptions can occur in the atmosphere or in space, and each domain requires different hardware. For instance, fins won't work outside the atmosphere - interceptors must have small steering rockets to function there.

The necessary high-powered computers, far-seeing radars and missiles as large as telephone poles are not cheap, together stretching into the billions. In 2022, for example, the U.S. approved the sale of both Patriots and THAAD systems to Saudi Arabia, in deals worth as much as $5.3 billion.

In the Indo-Pacific region, wealthier countries such as Japan, Australia and South Korea are prime candidates for missile defence, Lewis said, while nearly every country in Asia is already investing in missiles.

Japan's defence ministry said the country "needs to fundamentally and swiftly reinforce its defence capabilities, including integrated air and missile defence". It said it is investing in improved Patriot missiles, better radars and enhanced naval anti-missile capabilities.

In its latest defence budget, South Korea increased funding by 12% for its Korea Air and Missile Defense System to expand it "from the existing lower-level defence concept," the country's defence ministry said in a statement.

"Cases such as the Israel-Hamas conflict and the Russia-Ukraine war have reaffirmed the importance of a 'ballistic missile defence system' to respond to increasingly sophisticated missile threats," the ministry said.

In mid-April, Australia announced a A$500 million ($328 million) contract with Lockheed Martin to deliver its Joint Air Battle Management System for tracking and destroying aircraft and missiles.

The cost of a ballistic missile is often much cheaper than the system meant to stop it.

But that isn't the right way to consider cost, said Yoji Koda, former commander in chief of Japan's Self-Defense Fleet, and an advocate of stronger missile defences in his country.

"In a war economy, the cheaper the better. But sometimes what is necessary, is we need to protect key infrastructure, or key command centres, at any cost. Because without them we would lose."

THE CHINA QUESTION

Most of China's conventionally armed ballistic missiles are designed to hit targets on land.

But it also fields steerable warheads meant to hit ships at sea, including the DF-21D and variants of the DF-26, developed by the state-owned China Aerospace Science and Technology Corporation.

Such anti-ship ballistic missiles (ASBMs) had never been used in combat until late 2023, when Houthi forces in Yemen began firing Iranian-made models at ships in the Red Sea.

Between November - the first documented use - and April, U.S. Central Command reported at least 85 ASBMs fired in the region, with 20 interceptions and one civilian ship reported sunk.

CENTCOM has declined to provide specifics about the effectiveness of Iranian ASBMs but has noted missiles posing no threat were not engaged and most that were not intercepted landed harmlessly.

The effectiveness of missile defences on land and at sea will catch China's attention, said Tong Zhao, a senior fellow with the Nuclear Policy Program and Carnegie China.

"It raises the possibility that the U.S. and its allies could depend on missile defence significantly against a ballistic missile attack," Zhao said.

Although the technical specifics of China's missiles are closely held secrets, the country's heavy investment means they are likely to be more reliable, and are widely believed to use complex countermeasures to complicate interception.

"For opponents such as China which have missile stockpiles an order of magnitude larger than that of Russia or Iran and which field more sophisticated systems ... it's not clear that the lessons learned invalidate existing operational constructs," said Sidarth Kaushal, a senior research fellow at the Royal United Services Institute.

But the political and practical incentives to invest in missile defence will be too attractive for many countries to ignore, Lewis said.

"All defence procurement decisions are ultimately about politics," he said. "The politics of this stuff is really simple: do you want to defend the country or not? And the winning answer is always 'Yes'."

https://www.yahoo.com/news/analysis-missile-defence-successes-gulf-020143840.html

Trump: London, Paris Have "Opened Their Doors To Jihad"

  by Steve Watson via modernity.news,

Speaking at a campaign rally in Wisconsin on Wednesday, Donald Trump urged that Europe has “opened its doors to jihad” and as a result, cities including London and Paris are sacrificing their own culture and tradition.

“We’ve seen what happened when Europe opened their doors to jihad,” Trump told the large crowd, adding “Look at Paris, look at London – they’re no longer recognisable.”

“I’m going get myself into a lot of trouble with the folks in Paris and the folks in London, but you know what, that’s the fact,” he continued.

“They are no longer recognisable and we can’t let that happen to our country,” Trump urged, adding “We have incredible culture, tradition – nothing wrong with their culture, their tradition – we can’t let that happen here.”

I’ll never let it happen to the United States of America,” he further promised.

Trump also referred to the pro-Palestine/Anti-Israel encampments and University occupations in several US cities.

“To every college president, I say remove the encampments immediately,” he said, adding “Vanquish the radicals and take back our campuses for all of the normal students who want a safe place from which to learn.”

The protests have followed from regular demonstrations in Europe, particularly in London where they have been ongoing every week since late last year.

Trump has previously slammed London and Paris, noting in 2016 that “London and other places… are so radicalised that the police are afraid for their own lives.”

In Paris, the police have just conducted a fresh round of “social cleansing” illegal migrants off the street and sending them to other areas of the country ahead of the Summer Olympics.

The French government wouldn’t want the city to look “unrecognisable,” to the world, right?

Trump’s comments also come on the heels of Austrian MEP Harald Vilimsky warning that Europe risks becoming “a second Arabia or Africa” and that governments are importing migrants who create security problems then offering ‘solutions’ that only punish native populations.

Top MEP Warns Europe Risks Becoming “A Second Arabia or Africa”

https://www.zerohedge.com/political/trump-london-paris-have-opened-their-doors-jihad