Alzheimer’s Treatment Landscape: Leqembi vs. Donanemab

 With the demise of Roche’s gantenerumab in November 2022, the Alzheimer’s disease space became a two-horse race between Eisai and Biogen’s Leqembi (lecanemab) and Eli Lilly’s donanemab. One, Leqembi, received full FDA approval in July; the other, donanemab, is widely expected to secure the agency’s approval before the end of 2023.

While discussion about the two anti-amyloid antibodies is possible from a treatment perspective, experts who spoke with BioSpace agreed that direct comparisons on efficacy and safety without a head-to-head trial cannot be made. Leqembi and donanemab also target slightly different patient populations and have distinct mechanisms of action, making treatment decisions even more complex.

Salim Syed, managing director and senior biotechnology analyst, equity research at Mizuho Americas, which covers Biogen, told BioSpace that—at this point—it’s not clear whether there will be a market leader. “We've done a number of discussions with physicians in the KOL community and there are physicians that are on both sides of this debate,” he said. “Both of these drugs [are] the best that we've seen versus prior compounds.”  

BioSpace took a closer look at key data from the Phase III trials of Leqembi and donanemab, and sought expert perspectives on their safety profiles, dosing schedules and potential treatment strategies.

PHASE III TRIALS

	Leqembi's Clarity AD Trial	Donanemab's TRAILBLAZER-ALZ 2 Trial
Indication	Early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing.	Early symptomatic Alzheimer’s disease and amyloid and tau pathology
Duration	18 months	76 weeks (~17 months)
Participants	1,795	1,736
Dosing schedule	Every two weeks	Once a month
Efficacy	Reduced clinical decline compared to placebo by 27% at 18 months based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment.	All amyloid-positive early symptomatic participants: Reduced decline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) by 22% and on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) by 29% compared to placebo Participants with low to medium levels of tau: Reduced decline on the iADRS by 35% on the CDR-SB by 36% compared to placebo Mild cognitive impairment (low-medium tau): 60% (iADRS) and 46% (CDR-SB)
Incidence of amyloid-related imaging abnormalities (ARIA)	ARIA-E (asymptomatic): 12.5% (versus 1.7% of placebo) ARIA-E (symptomatic): 2.8% (versus 0.0% of placebo) ARIA-H (asymptomatic): 17.0% (versus 8.7% of placebo) ARIA-H (symptomatic): 0.7% (versus 0.2% of placebo) Total: 21.3% (versus 9.3% of placebo)	ARIA-E (asymptomatic): 17.9 % (versus 1.9% of placebo) ARIA-E (symptomatic): 6.1% (versus 0.1% of placebo) ARIA-H (all): 31.4% (versus 13.6% of placebo) Total: 36.8 % (versus 14.9% of placebo)
Incidence of serious adverse events	Any adverse event: 14.0% (versus 11.3% of placebo) Deaths Related to Treatment: Double-blind trial: 0 Open-label phase: cited as a contributing cause to 3	Any adverse event: 17.4% (versus 15.8% of placebo) Deaths Related to Treatment: 3 (versus 1 in the placebo group)

 

Safety Profiles

Amyloid-related imaging abnormalities (ARIA) are a well-documented risk associated with anti-amyloid antibodies intended to treat Alzheimer’s disease. ARIA—or brain swelling—is usually transient and mild, but it can be serious and even fatal, “so it needs to be managed carefully, with careful MRI monitoring,” said Stephen Salloway, professor of psychiatry and human behavior and professor of neurology at Brown University’s Warren Alpert Medical School, who was a co-author on the TRAILBLAZER-ALZ 2 JAMA publication and an investigator on Leqembi’s Phase II trial. “When you remove amyloid from the brain . . . there’s a risk of having fluid shifts in the brain,” Salloway told BioSpace.

Syed said that some physicians prefer Leqembi’s profile over that of donanemab, partly because “it's safer than donanemab, from what we can tell, in terms of percentage of ARIA.”

In The New England Journal of Medicine, the authors wrote that “no deaths [in CLARITY-AD] were considered by the investigators to be related to lecanemab or occurred with ARIA.”

However, in the open-label phase, there were three deaths where investigators cited Leqembi as a contributing cause, Michael Irizarry, senior vice president of clinical research and deputy chief clinical officer for Alzheimer’s disease and brain health at Eisai, told BioSpace, adding that the patients had either concurrent ARIA-E or intracerebral hemorrhage. Leqembi’s label states that because intracerebral hemorrhage has been seen with the drug, caution should be used in co-administering antithrombotics or a thrombolytic agents.

Salloway additionally pointed to a higher rate of macrohemorrhage—or larger bleeds—that occurred in patients on anticoagulation therapies taking Leqembi. This was compared to zero large bleeds with donanemab treatment, he said, despite approximately 10% of patients in TRAILBLAZER-ALZ 2 also being on anticoagulation drugs. Salloway said he was surprised by the result, as he had expected a similar rate of macrohemorrhage between the two and called Lilly’s data “encouraging.”

Different Drugs; Different Dosing Schedules

Currently, both Leqembi and donanemab require intravenous (IV) infusion, and hospitals and other treatment sites are racing to build up capacity. Given this requirement, an oft-noted difference is that Leqembi is dosed once every two weeks, while donanemab—at least in the Phase III TRAILBLAZER-ALZ 2 trial—was given once every four weeks.

“For some of these physicians, who have smaller infusion center capacity that they're working with, perhaps once a month is better,” Syed said.

Howard Fillit, co-founder and chief science officer at the Alzheimer's Drug Discovery Foundation, told BioSpace this could also be a big deal for patients but added that he believes this discrepancy will be managed by the industry-wide movement toward subcutaneous injection—a field he said was pioneered by gantenerumab, which he called “kind of a proof of concept.”

“The infusion centers are expensive and there's a heavy burden there,” Fillit said. “It’s doable, but I think the movement to home-administered subcutaneous injections of these antibodies is the future.” 

Another notable difference is that treatment in TRAILBLAZER-ALZ 2 was stopped when amyloid plaque was cleared. In this trial, the treatment effect of donanemab continued to increase relative to placebo over 18 months, even though many participants completed their course of therapy at six or 12 months, an Eli Lilly representative told BioSpace. “This does support the benefits and reduced treatment burden of limited duration dosing,” the representative said.

Fillit said Lilly’s data on stopping rules may give donanemab an advantage but added that he isn’t sure how clinically meaningful this difference would be. He said he hopes that as Leqembi and other drugs in this class enter the market stopping rules will become part of the standard of care, noting that this could reduce the cost of these medications to payers including Medicare.

In Leqembi’s case, Irizarry said there is an advantage to continued treatment. In addition to amyloid plaques, Leqembi preferentially targets amyloid beta protein protofibrils—a soluble aggregated amyloid species. “So even when amyloid plaques are cleared, there’s still activity binding to this soluble aggregated species.” 

Data from Leqembi’s Phase II study, where treatment was stopped and then reinitiated, suggests that when treatment is stopped, amyloid and tau gradually reaccumulate, and that continued treatment can continue to bring these levels down, Irizarry said.

Salloway agreed with this assessment but said that the reaccumulation occurs at a very slow rate. “We don't know how long or which patients need to stay on longer term treatment, and whether or not the dosing interval could either be stopped or spread out.” He suggested that treatment could be individualized and said that having an evidence-based way to guide these decisions—such as a blood test measuring p-tau or a PET scan to measure amyloid—would be helpful.

A $30B Market

With the time required to establish infusion sites, Medicare coverage details still emerging—and the fact that donanemab has yet to be approved—the combined market value for the two prospective leaders is not yet clear.

“Everybody knows, foreseeably, that these drugs are going to get used,” Syed said. “The question is, what is the ramp?”

With the FDA’s traditional approval of Leqembi in July, the Centers for Medicare and Medicaid Services broadened its coverage, allowing the drug to be prescribed outside of a clinical trial. Now, it is available on the market to patients diagnosed with mild cognitive impairment or mild Alzheimer’s disease dementia, with evidence of beta-amyloid deposits in the brain. This coverage criteria is expected to extend to donanemab, if it is approved.

Whoever emerges as the market leader—if either does—Syed said he projects the market to be around $30 billion between Leqembi and donanemab, with Mizuho guiding toward net sales of $12 billion at Leqembi’s peak. GlobalData concurs, with the data and analytics company forecasting $12.9 billion in sales between 2023 and 2028.

For Leqembi, a company spokesperson told BioSpace that Eisai expects about 10,000 patients to be on the drug in the U.S. by March 31, 2024—the end of its fiscal year­—and projects revenue of up to $7 billion in annual global sales by 2030. 

https://www.biospace.com/article/the-alzheimer-s-treatment-landscape-leqembi-and-donanemab-/

Violent Criminals Continue To Pose as Migrant Children To Enter US; Congress Must Act Now

 by R.J. Hauman and Lora Ries via The Epoch Times (emphasis ours),

Despite all the “victory laps” Biden administration officials have taken as they brag that their unlawful policies and processing programs have reduced illegal immigration, recent border data shows the opposite.

On top of that, there is an undeniable link between the increase in illegal entrants being welcomed into the country and an increase in violent crime, which is posing a significant threat to public safety.

This is a matter that must be addressed when Congress returns in September, and its resolution is so critical that Congress must tie it to the negotiations for funding the federal government for the new fiscal year that starts Oct. 1.

In July, as temperatures soared into the triple digits, Border Patrol agents apprehended more than 132,652 illegal aliens between the ports at the southwest border—a 33 percent increase over June, when 99,539 illegal aliens were apprehended at the U.S.-Mexico line.

The lower total in June was clearly an artificial reduction due to the abuse of the parole system, a tool this administration uses to quickly bring in as many inadmissible aliens without visas through the actual ports of entry (not around them) as possible.

Not all of these illegal aliens are the same, but certain groups present more challenges to an overwhelmed Border Patrol and are able to easily enter the United States—notably adults entering illegally with children as a “family unit” and minors who enter without a parent or guardian, also known as unaccompanied alien children.

On top of increases in both single adult and family unit apprehensions, unaccompanied children at the southwest border increased by nearly 50 percent in July compared to June.

The same Biden administration officials who have repeatedly begged Central Americans not to send their children on the treacherous journey to the United States at the hands of smugglers and traffickers have done absolutely nothing to slow their entries. Instead, their policies and methods of resettlement are encouraging more.

The fact that unaccompanied children are regularly raped and exploited on their journey to the United States is a heartbreaking reality. And sadly, their lives do not improve once they enter the country, where they are then turned over to questionable, if not dangerous, “sponsors.” Many are also forced to work in unsafe conditions that violate child labor laws, go missing, or are sex trafficked.

Furthermore, teenage members of MS-13 and other violent Central American gangs continue to take advantage of current U.S. policy and the easiest, most vulnerable migrant flow and enter the United States as unaccompanied children.

More than 70 percent of unaccompanied children are teens, aged 15 to 17, according to the Department of Health and Human Services, with some adults even posing as minors.

Too many Americans and migrants themselves have needlessly died at the hands of vicious gang members who were welcomed into the country and then released into our communities. Yet another tragic instance of this took place mere weeks ago, with the media refusing to explore the reality of the situation.

Juan Carlos Garcia-Rodriguez, a 17-year-old native of Guatemala, illegally crossed into the United States and self-surrendered in El Paso, Texas, in January. He was quickly turned over to HHS custody as an unaccompanied child and released to a sponsor in Louisiana. On Aug. 19, he was arrested as a suspect in a brutal murder of an 11-year-old migrant girl in Pasadena, Texas.

At the time of his arrest, his address was not in Louisiana with the sponsor but an apartment complex in Texas where the little girl was found after having been sexually assaulted, strangled, put into a trash bag, and hidden under her bed while her father was at work.

The media continue to leave out the immigration details in their coverage of this brutal crime that should have been prevented in a concerted effort to cover for the Biden administration and keep the historic flow of unaccompanied alien children going and viewed in a positive light.

U.S. Customs and Border Protection statistics show a consistent and alarming increase of convicted criminal aliens that it encounters. As such, this horrific crime by Garcia-Rodriguez is just one of the thousands of murders, rapes, and other violent crimes that occur each year at the hands of illegal aliens in the U.S.

What is even more outrageous is the fact that Democrat politicians in the region and here in Washington continue to ignore such crimes.

The same folks who claim that everything they do related to border security is humanitarian in nature have shown more outrage over inflatable water barriers that Texas erected than the murder of an 11-year-old girl by a now-18-year-old man allowed into the country by their policies.

Enough is enough.

Republicans on Capitol Hill will soon be at a crossroads when it comes to addressing the Biden Border Crisis and funding the federal government.

It is essential that House Republicans unite behind a reasonable demand to include their already passed border security measure as part of any spending agreement that is passed to avert a government shutdown in late September.

The bill, the Secure the Border Act (HR 2), fulfilled promises made to the American people on delivering solutions to a self-inflicted crisis that harms not just cities and states along the border but every city and state around the country.

The bill’s intentions and contents are clear: It would end the crisis and restore sanity, safety, and security at our borders. A key component that helps do that is closing longstanding loopholes in the processing of unaccompanied alien children.

It is vital that this bill is a part of any agreement for the continuation of funding for the federal government.

If the federal government cannot perform the basic task of keeping our border secure and preventing instances like the murder of an innocent 11-year-old girl from happening, it should not be funded.

Views expressed in this article are opinions of the author and do not necessarily reflect the views of The Epoch Times or ZeroHedge.

https://www.zerohedge.com/political/violent-criminals-continue-pose-migrant-children-enter-us-congress-must-act-now

US Childcare Now Costs $1,031 More Than Public College Tuition, On Average

The next time someone asks whether or not you think Joe Biden's "Inflation Reduction Act" is working, you can share with them a new research report showing that childcare is becoming more expensive than in-state college tuition in 28 out of 50 states.

In fact, on average in the United States, childcare now costs $1,031 more than public college tuition, according to a new report from NetCredit.

The report "researched the average annual fees paid for public and private college tuition and the average cost of childcare in each U.S. state" and then "calculated the difference in yearly fees paid for childcare and in-state college tuition". 

As part of their methodology, NetCredit then "compared these costs to local average salaries to find the affordability of childcare and in-state college tuition in every state."

Among other findings in their research was that in Hawaii, annual childcare costs $15,995 more than a year of in-state public college tuition and that childcare is most affordable in Utah, where annual costs are equal to 7.87% of the average annual salary.

The report found that coastal states were the ones where childcare was most expensive and "much of the Midwest and eastern U.S. is priced in favor of childcare".

"Vermont and Pennsylvania are more affordable for childcare since they have the most expensive public college fees in our study," the report noted. 

Those receiving in-state tuition in Vermont spend 24.22% of their annual wage paying for it, the study found:

The average salary in both Vermont and Pennsylvania is around $55,450, putting these states among the top 20 for average wages in the U.S. But public college costs are so high in these states as to make investing in a college education significantly less affordable than elsewhere. “About 6% of UVM’s budget is from the state, but in many states it’s 25-40%,” explains Richard Cate, vice president of finance at the University of Vermont. “Being a small rural state, we don’t have big business to help fuel tax revenue,” says Marie Johnson, director of student financial services.

Here is a glance at the highest annual childcare costs in the U.S., and their difference between in-state college tuition:

The study's full results can be found in the above table, which you can toggle at this link.

https://www.zerohedge.com/markets/childcare-now-costs-1031-more-public-college-tuition-average-united-states

Reparations Backlash: Cal. Voters Oppose "Unfair" Cash Payments For Slavery: Berkeley Poll

 The sprawling social experiment known as California faces an uphill battle on reparations, after a new poll from UC Berkeley and the LA Times reveals that voters overwhelmingly oppose the idea of cash payments for black descendants of slaves by a 2-to-1 margin.

The poll found that 59% of voters oppose cash payments vs. 28% who support the idea. Four out of 10 voters "strongly" opposed the idea.

Interestingly, just 19% of those opposed cited cost as an issue. The majority simply says it's unfair to today's taxpayers and wrong to single out one group for reparations.

In the Berkeley poll, when voters who oppose reparations were asked why, the two main reasons cited most often were that “it’s unfair to ask today’s taxpayers to pay for wrongs committed in the past,” picked by 60% of voters, and “it’s not fair to single out one group for reparations when other racial and religious groups have been wronged in the past,” chosen by 53%.

Only 19% said their reason was that the proposal would cost the state too much, suggesting that money alone is not the main objection.

Among Democrats, 43% favored and 41% opposed cash reparations. Republicans were strongly against the proposal at 90% with only 5% in favor. Independents were 65% opposed and 22% in favor.

Black California voters were more likely to support cash payments than any other demographic, with 76% in favor and 16% opposed, the survey found. Almost two-thirds of white voters were opposed as were 6 in 10 Latino and Asian voters. -LA Times

"It has a steep uphill climb, at least from the public’s point of view," said poll director Mark DiCamillo, who was obviously disappointed at the results. "The idea of cash reparations is really what’s being strongly opposed," he continued, adding "There could be other solutions that could be much more warmly received."

The sobering reality could put Gov. Gavin Newsom and his fellow Democrats in a tight spot, after state leaders have vocally endorsed the idea of reparations - going so far as to create California’s Reparations Task Force in 2020. The objective was to create a model for national reparations. But as the poll reveals, they are sailing against strong winds.

The task force has indeed been hard at work. They propose payments to all descendants based on a plethora of criteria, ranging from health disparities to housing discrimination. But there’s more: The group also suggests ending the death penalty, restoring voting rights to all incarcerated individuals, and implementing rent caps in historically redlined areas.

Members of the reparations task force previously said convincing non-Black Californians that the harms from slavery are still persisting today could be one of the biggest challenges for proponents.

Much of the task force’s work centered on hearing testimony from academics, economists and other experts to gather evidence of the effects of slavery and to prove the ways in which government-sanctioned policies discriminated against Black people long after slavery was abolished. -LA Times

When asked about his stance on reparations in the spring, Newsom said reparations are more than just cash payments.

"It doesn’t have to be in the frame of writing a check; reparations comes in many different forms. But one cannot deny these historical facts, and I really believe very strongly we have to come to grips with what’s happened," Newsom told Fox News host Sean Hannity.

When asked whether the state is 'doing enough' to ensure that black residents have a fair chance to succeed, 29% said the California is doing too little, 22% said the state is doing too much, and 26% said it's just enough. Nearly 1/4, or 23%, had no opinion.

https://www.zerohedge.com/political/reparations-backlash-california-voters-oppose-unfair-cash-payments-slavery-according

IQVIA started at Buy by HSBC

 Target $260

https://finviz.com/quote.ashx?t=IQV&ty=c&ta=1&p=d

Kenvue shares may gain after FDA comments in Tylenol-Autisim warning label lawsuit

 Kenvue (NYSE:KVUE) shares may see some relief on Monday after they dropped 7.3% last week amid a court filing late Friday in a class action lawsuit alleging prenatal exposure to Tylenol caused a child's autism, according to a UBS note.

https://seekingalpha.com/news/4010432-kenvue-shares-may-gain-after-fda-comments-in-tylenol-autisim-warning-label-lawsuit

State Emergency Powers A Test To See What Americans Will Put Up With?

 During the hysteria of the covid pandemic questions swirled around how the federal government would respond to the events under the declaration of a national health emergency.  What kind of powers would they claim to have and which constitutional rights would they try to suppress?  What many Americans did not consider, however, was the implementation of emergency powers under state governments rather than the White House.

Most of the covid mandates crushing the US economy during that period were not federal mandates, but state mandates, and there's a good reason why covid tyrants chose to focus on state level restrcitions.

There are a number of requirements and obstacles for any president seeking to enforce mandates at the federal level, along with more scrutiny and oversight than is commonly understood.  Though a president can declare emergencies unilaterally, there are still some legal checks and balances (to be sure, these are quietly being eroded with each passing year). 

On the other hand, state governors in 44 states have sweeping authorities under emergency conditions, with very little immediate legal recourse.  As we have seen recently in places like Hawaii and now New Mexico, Democrat governors have been playing with fire (no pun intended) as they seek to push the envelope of emergency controls at the state level.

In Hawaii, the exploitation of state emergency provisions under Governor Josh Green led to possibly thousands of deaths as they refused to release water supplies for fire fighting and even blockaded Maui residents, forcing them back into the blaze.  They have even put an information blackout in place and denied news organizations access to the scene of the disaster.  One has to ask – Was this done out of stupidity?  Or was this a test to see what kinds of trespasses and controls citizens would accept?

In New Mexico we see a similar extreme overstep by Governor Michelle Grisham, who believes she has the authority to dictate the 2nd Amendment rights of  Albuquerque residents due to rising crime.  The level of mental gymnastics on display in her arguments to justify the banning of lawful open carry and conceal carry protections make it clear that this is not about protecting the public.  The lack of logic and reason indicates that this is an ideological decision based in zealotry.  Watch as she struggles to present any reasonable position – turning instead to deflection.

The root of her argument is this:  “I am banning legal firearms carry in Albuquerque because under emergency powers I can.” 

That's it.  That's all she's got. 

But this is not a valid argument and there are a number of reasons why.

First, crime is rising across the nation, predominantly in Democrat controlled cities. 

Albuquerque has a Democrat mayor and New Mexico is a Democrat run state.  If crime is rising, it is the fault of Democrats.  But instead of taking responsibility for their terrible planning and policies, Democrat leaders are once again blaming inanimate objects (guns) and using mass punishment of people who lawfully carry (primarily conservatives).  In other words, Dems are ruining the country and creating a national crime wave, and then making conservatives pay for it with their rights. 

Second, restrictions on open carry and conceal carry are not going to reduce the crime rate because criminals don't care about laws or emergency powers. 

If anything, the violent crime rate will rise as criminals feel emboldened knowing that most citizens are now disarmed. 

Third, Grisham has presented no evidence of a legitimate emergency other than “crime is bad right now.” 

The emergency is ambiguous rather than defined.  Meaning, emergency restrictions could be renewed over and over again, unless citizens step up and do something about them.

Fourth, the focus on open carry and conceal carry seems to be an attempt at a totalitarian tip-toe. 

A large number of gun owners do not carry regularly so they may not feel personally affected by the rules.  Meaning, the governor has reduced the level of opposition by attacking just one aspect of gun rights.  This is usually how authoritarians institute control – They don't remove your rights all at once, they do it a piece at a time.

Fifth, gun carry laws are generally a legislative decision that usually requires a public vote. 

Grisham is attempting to bypass all checks and balances as if the legislative process does not matter.

Sixth, emergency powers are often declared unconstitutional by courts after the fact. 

For example, the Michigan Supreme Court held that the Emergency Powers of the Governor Act (EPGA), which Governor Whitmer used to justify her draconian COVID-19 executive orders, was unconstitutional because it delegated legislative power to the executive branch in violation of the Michigan Constitution.  But these court decisions often come well after the damage has already been done.  It is up to the citizenry to defy such orders when necessary and let the courts sort out the aftermath later.

Seventh, Grisham argues that rising crime is a “public health emergency,” using the same language relegated to the covid response. 

Crime has nothing to do with public health and is a legal concern handled through either social programs or increased police presence.  Disarming the public is not within the purview of a health emergency – Grisham has greatly overstepped her bounds. 

The timing and tone of the state government decision on gun carry in Albuquerque reads like a political maneuver, a test to see what the public will submit to.  Grisham admits that she expects numerous legal challenges to her decision, but she does not seem too concerned with the public reaction.  Maybe she should be?  Or, is she so certain that the New Mexico 2nd Amendment community will sit on their hands that she feels comfortable there will be no protests, no open carry marches and no public defiance to be worried about? 

One thing is inevitable, if Grisham is unopposed in New Mexico, numerous Democrat governors and mayors across the country will try to enforce the exact same emergency powers. 

https://www.zerohedge.com/political/are-emergency-powers-test-see-what-americans-will-put