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Aduhelm by Biogen

Source: Biogen

The FDA’s approval of Biogen’s Alzheimer’s drug Aduhelm was a landmark moment in the life of Dr. Paul Aisen. The director of the Alzheimer’s Therapeutic Research Institute at USC has spent the past three decades focused on treating the neurodegenerative disease, and in recent years helped shepherd this particular drug through the various phases of clinical trials.

But sitting in his sun-drenched office in San Diego in early June, he felt slightly confounded by the manner in which the Food and Drug Administration early June approved its use on an “accelerated” basis, which is usually reserved for cancer medications. This meant its clinical benefits were considered likely, but approval for long-term use would be subject to more extensive study in a fourth phase of trials.

Highlighting the “unusual nature” of the regulator’s green light, given that an advisory board of experts had strongly, and publicly, opposed the approval, Aisen, who works as a paid consultant to Biogen, insists there were still “a lot of questions that I have — that do not yet have answers.”

Three members of the FDA panel overseeing research have resigned since the approval this week, including Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School, who said in a letter the agency’s decision on Biogen “was probably the worst drug approval decision in recent U.S. history.”

Last November, in an 8-1 vote, that panel said Biogen’s late-stage study didn’t provide “strong evidence” showing that aducanumab effectively treated Alzheimer’s; two other panelists said it the data was “uncertain.”

While Aisen considers Aduhelm an “effective treatment” for a disease that affects millions of Americans, he also has concerns about the FDA ruling’s implications for the panoply of other potential treatment options that are in late-stage development.

One immediate challenge facing other teams working on a wider Alzheimer’s drug pipeline, he said in a recent video call, would be to retain participants in ongoing trials, let alone attract new ones.

“In most cases,” he explained, many Alzheimer’s sufferers will drop out of other drug studies to pursue treatment with the newly approved Aduhelm. Their departures would make trial data for those alternative drugs less useful, even though the drugs in question might one day prove safer, more effective, or more appropriate for different stages of the disease’s progression. But perhaps perversely, he still considers Aduhelm’s approval “a boost towards those efforts — a strong boost.”

Over 6 million Americans suffer from Alzheimer’s

In recent years, some major drug companies abandoned efforts to research brain diseases, including Pfizer and Boehringer Ingelheim in 2018 — in fact, Biogen had given up on Aduhelm at one point during the clinical trials in 2019 before reversing its decision— after decades of failure in search of a breakthrough.

The controversy surrounding the Biogen drug, including its potential cost, comes against a landscape of massive, unmet need for dementia treatment and a disease that costs the U.S. as much as $259 billion annually. More than 6 million Americans have Alzheimer’s or another form of dementia, according to estimates from the Alzheimer’s Association, and by 2050 that number could reach over 12 million people at a cost of $1 trillion annually.

That is why some dementia drug experts are focusing on the renewed attention and fresh financing rather than the potential negatives from the Biogen approval, according to Dr. Jeffrey Cummings, a neurologist at the University of Nevada, Las Vegas, who publishes an annual review of the Alzheimer’s drug development pipeline. His research consistently showed the drug-failure rate at 99.6 percent before the Biogen approval, a stark contrast to the 1 out of every 5 cancer drugs (20%) that are successful.

Cummings says any negative side effect for other drug trials in the short term would be “overcome, if anything, by the increased interest that companies and venture capital and biotech has, once they see that there is a way to get an approval for a particular disease.”

In recent history, The National Institutes of Health spent two to three times more on heart disease and cancer research than on dementia, while lack of qualified participants for clinical trials also slowed progress.

Next in the dementia drug pipeline

For the handful of other developmental Alzheimer’s drugs hoping to clear those same regulatory hurdles and prove their efficacy — Eli Lilly’s donanemab, Roche’s gantenerumab and Eisei’s lecanemab among them — there may be a silver lining to ceding first-mover advantage to Aduhelm.

After decades of expensive but thus far largely fruitless research trials, the CEO of pharma giant Eli Lilly, David Ricks, said his firm was “getting closer and closer to the goal” after a positive set of Phase Two results for its offering, donanemab.

Speaking at CNBC’s Healthy Returns Summit in May, a month before the FDA’s approval for rival Biogen’s Aduhelm, he said his team felt “good about the probability of success,” and said he wanted to explore an “accelerated” route too, using what he called “adaptative pathways at the FDA to consider looking at data sooner” that “should be applied in a serious and widespread condition like Alzheimer’s.”

However, he acknowledged that recruitment for the next phase of trials required a significantly larger cohort of participants, and given that it would last 18 months, he did not expect a new approved product before late 2023 at the earliest.

Several experts told CNBC the Biogen drug’s unique threshold for regulatory approval, with treatment potential seeming to trump uncertain real-world benefits, could reinvigorate efforts by competitors like Lilly, who are focused on developing drugs that rely on relatively similar techniques.

Aduhelm’s own clinical trial data had shown the drug successfully targets and clears out clusters of a specific type of protein that are believed by many researchers to be responsible for Alzheimer’s. But it offered insufficient evidence to prove the drug provides patients with cognitive benefits.

Debate over targeting beta amyloid formations

Known among scientists as aducanumab, it works by offering an array of identical antibodies that are cloned from white blood cells. These antibodies are chosen for their targeting abilities, since they can identify specific proteins, called beta amyloids, that have constructed particular formations in the body.

There is extensive evidence suggesting that these beta amyloid formations, also known as “pathological aggregates” or “plaques,” are a major driver of Alzheimer’s disease, though the exact causal mechanisms are still not fully understood, according to Christian Pike of USC’s Leonard Davis School of Gerontology. Nonetheless, he says the antibodies can help prevent these plaques from forming, before directing other particles to break them apart, a process that’s clearly identifiable in before-and-after neural imaging.

For an analogy, it may be helpful to think of the beta amyloid proteins as young people walking around a city over the course of the day, where the city is the human body, and the day is a human lifespan. In certain cities, as afternoon turns into evening, individual young people start to congregate, and some of those congregations can turn toxic, and begin to cause problems. The antibodies delivered by Aduhelm act like law enforcement officers, arriving on the scene, identifying troublesome gatherings, surrounding them, separating them, then ordering bystanders to make the young people disperse.

“If you say ‘Well hey, the FDA is buying into this general concept,'” said Pike in a phone call, “if we can remove beta amyloid from the brains of persons that are affected by the disease, even with limited evidence of cognitive benefits,” he continued, “there might be a variety of different therapies that would qualify under these types of criteria.”

The long line of past failures from within the Alzheimer’s pipeline that targeted beta amyloid will continue to weigh on optimism, until conclusive proof is generated — something this week’s controversy over the first new Alzheimer’s drug approved in decades indicates has not been done yet.

“What we’re going to find out from the use of this drug one way or the other is whether or not the amyloid clearing hypothesis is correct,” says USC health economist Darius Lakdawalla, who argues the continued trialing of Biogen’s drug will prove useful to that confirmatory effort.

“If it is correct, then I think it opens the door for a lot of innovation, a lot of drug candidates that are going to try to clear amyloid in the future pursuit of that hypothesis.”

The crime is over. The spirits are high.

Businesses across the United States are struggling with a staggering increase in the number of people who can only be described as “badly behaved”.

Retail workers have been subjected to horrific attacks because of their race, gender, or disability. Flight attendants were verbally – and occasionally physically – assaulted. Aggressive driving has resulted in road anger with fatal consequences. Buyers argue in the aisles.

Experts point to increasing stress levels as a trigger for the increase in this type of incident.

The not so friendly sky is skiing

In May, a Southwest Airlines flight attendant had two teeth knocked out by an angry passenger, according to police who arrested the woman in San Diego. This was just one of the most recent examples of airlines grappling with an unprecedented onslaught of confrontation.

“We can say with confidence that the number of reports we have received in the past few months is significantly higher than in the past,” said Ian Gregor, a spokesman for the Federal Aviation Administration.

The FAA is tracking incidents involving problematic passengers and says face mask-related issues contributed to this.

Union officials have described the situation as an “epidemic of aggression and attack”.

Alcohol can also be a factor. Both Southwest and American Airlines have decided not to resume the sale of alcohol on board for now due to the unruly behavior.

Perpetual bans for NBA fans

The return of NBA fans to the arenas is a welcome sight for the league, which reportedly fell $ 1.5 billion below revenue expectations last season as the pandemic resulted in lost ticket sales. However, the return of fans has brought a number of new problems.

In Boston, for example, a 21-year-old Celtics fan with a dangerous weapon was charged with assault and assault after lifting a water bottle from Brooklyn Nets star Kyrie Irving as he left TD Garden.

In New York, Trae Young was spat at by the Atlanta Hawks during a playoff game against the Knicks at Madison Square Garden. And Washington Wizards star Russell Westbrook was showered with popcorn by a fan when he left the pitch with an injury.

“To be completely honest, this s — is getting out of hand. … The amount of disrespect, the amount of fans who just do whatever they want to do … it’s just out of pocket,” said Westbrook in a press conference after the game.

The league issued a statement on the recent behavior and subsequently changed its fan code of conduct.

“The return of more NBA fans to our arenas has brought great excitement and energy to the start of the playoffs, but it is important that we all show respect for players, officials and our fellow fans,” the NBA said.

Many of the teams involved do not tolerate the bad behavior and indefinitely ban rude fans from participating in future games.

“Something is going to happen to the wrong person and it’s not going to be good,” warned Portland star Damian Lillard.

Retailers are joining forces

It’s not just sports stadiums and arenas. The retail sector is also seeing an increase in bad behavior, often targeting employees. According to Emily May, co-founder and chief executive of the nonprofit Hollaback !, retailers are seeing an alarming surge in discrimination, with ground staff targeting their identities while enforcing security measures.

“With the rise in hate violence – which is at an all-time high – frontline workers are more vulnerable than ever,” she said in a statement.

It’s gotten so bad that at least a dozen retailers, including Gap, Dick’s Sporting Goods, and Sephora, have teamed up to work on a campaign with the nonprofit Open to All.

“We are trying to create a movement where everyone comes together to promote the values ​​of inclusion and safety, where we can all be safe, accepted, and be who we are,” said director Calla Devlin Rongerude.

“We weren’t in the crowd, we haven’t negotiated rooms with lots of other people for a long time. I think we are no longer able to be human with one another, ”she added.

As part of the campaign, participating retailers will have access to a toolkit and other resources to support the frontline workers.

Grown men argue over Pokémon cards

“The safety of our guests and team members is our top priority,” Target said in a statement.

The retailer said Pokemon cards have since returned to the store, but customers are subject to a strict purchase limit of two packs per guest. Sales of MLB, NFL, and NBA trading cards are still limited to Target’s website.

Remember “the golden rule”

Whether it’s aggressive driving or temperament in restaurants, gas stations or little league games, the bad behavior is caused by a combination of factors, according to Thomas Plante, professor of psychology at the University of Santa Clara.

“We have a tsunami of mental health issues out there, with anxiety and depression,” Plante said, adding that our collective stress levels have never been higher.

People juggle multiple stressors, he said. Including: pandemic, death, illness, job loss, homeschooling children, isolation and other challenges. This frustration can lead to aggression.

There is also “observational learning,” said Plante, explaining that when people see bad behavior all around them, even from so-called role models, they are more likely to repeat it.

“People model the behavior of others, especially highly valued models like … well-known politicians,” said Plante. “People look at how they act, which was pretty bad, and they go and do it too.”

What will reverse the trend? Plante’s suggestion sounds like something you might hear from the pulpit or a parent: treat others the way you would like to be treated yourself.

“People have somehow got out of practice to behave in public and in a polite civil society,” said Plante.

The Golden Rule can help us get back on track.

Correction: This article has been updated to indicate that Ian Gregor is a Federal Aviation Administration spokesman.

CNBC’s Jim Cramer advises investors looking for entry and exit points to keep a close eye on both stock and cryptocurrency trading in the coming weeks.

The moderator of “Mad Money” checked the chart analysis of Tom DeMark, the founder and head of DeMark Analytics, on Friday.

“The charts interpreted by Tom DeMark suggest that Bitcoin could take another month to bottom while the S&P 500 could peak as soon as next week,” he said. “Given Tom’s track record, that’s a good reason to be patient with Bitcoin and approach the S&P with a little caution.”

DeMark invented the DeMark indicator that some traders use to time the market. The method, which follows patterns to project when a trend could change course, is popular with crypto traders to spot ups and downs, Cramer said.

Cramer checked daily chart action for Bitcoin, which peaked at around $ 65,000 in mid-April. The digital coin will trade above $ 37,300 as of Friday after falling to $ 30,000 in mid-May.

Zoom In Icon Arrows pointing outwards

DeMark, who said the Bitcoin decline was similar to the 1987 crash, predicted the decline could push the token’s value to a floor of $ 32,000 – or at worst, $ 24,000. He now believes Bitcoin will generally hold above the May 19 low, Cramer said.

On October 19, 1987, on so-called “Black Monday”, the Dow Jones Industrial Average collapsed by more than 20%. It was the bookend of a 36 percent decline in the blue chip index since August this year.

“If DeMark is right, you might get a chance to buy Bitcoin in the not too distant future and I could grab it,” Cramer said. “I think that ’87 analogy is good news. After the ’87 crash, the stock market bounced back quickly.”

As for the S&P 500, which closed on a record for the second straight day, DeMark’s indicator suggests the index may be close to a high, Cramer said. DeMark has price targets of $ 4,335 and $ 4,344, about 2% higher than Friday’s end.

With a record number of new golfers teeing off in 2020, Callaway, the maker of golf balls, clubs, bags and apparel, is thriving.

Callaway announced net sales of $ 652 million for the first quarter in May, up 47% year over year.

“Callaway was number one in clubs even before Covid, I’ll call it putters, drivers and irons,” said Jefferies analyst Randy Konik. “They outperformed the industry and were number two behind Titleist.”

Callaway has also moved off the fairway. In March, the company completed its merger with the golf entertainment company Topgolf, which combines virtual driving ranges with food and cocktails.

“This is a transformative merger. It creates an entity that doesn’t really mimic anything that exists today, merging the leading provider of golf equipment with the leading provider of golf entertainment,” said Chip Brewer, CEO of Callaway.

In the past year, nearly 37 million players tee off on a golf course or participated in an off-course activity such as a driving range. Almost a third of the US population saw, read, or played golf in 2020.

But with the expected recovery from movie theaters, travel and concerts, will golf club makers like Callaway and its rival Acushnet be able to maintain their momentum?

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