Boeing pleads guilty to a criminal fraud charge

 Boeing has agreed to plead guilty to a criminal fraud conspiracy charge after the US found the company violated a deal meant to reform it after two fatal crashes by its 737 Max planes that killed 346 passengers and crew.

The Department of Justice (DoJ) said the plane-maker had also agreed to pay a criminal fine of $243.6m (£190m).

However, the families of the people who died on the flights five years ago have criticised it as a "sweetheart deal" that would allow Boeing to avoid full responsibility for the deaths.

By pleading guilty, Boeing will avoid the spectacle of a criminal trial - something that victims' families have been pressing for.

The company has been in crisis over its safety record since two near-identical crashes involving 737 Max aircraft in 2018 and 2019. It led to the global grounding of the plane for more than a year.

In 2021, prosecutors charged Boeing with one count of conspiracy to defraud regulators, alleging it had deceived the Federal Aviation Administration (FAA) about its MCAS flight control system, which was implicated in both crashes.

It agreed not to prosecute Boeing if the company paid a penalty and successfully completed a three-year period of increased monitoring and reporting.

But in January, shortly before that period was due to end, a door panel in a Boeing plane operated by Alaska Airlines blew out soon after take-off and forced the jet to land.

No-one was injured during the incident but it intensified scrutiny over how much progress Boeing had made on improving its safety and quality record.

In May, the DoJ said it had found Boeing had violated the terms of the agreement, opening up the possibility of prosecution.

Boeing's decision to plead guilty is still a significant black mark for the firm because it means that the company - which is a prominent military contractor for the US government - now has a criminal record.

It is also one of the world's two biggest manufacturers of commercial jets.

It is not immediately clear how the criminal record would affect the firm's contracting business. The government typically bars or suspends firms with records from participating in bids, but can grant waivers.

However, Paul Cassell, a lawyer representing some families of people killed on the 2018 and 2019 flights, said: "The memory of 346 innocents killed by Boeing demands more justice than this."

In a letter to the government in June, he urged the DoJ to fine Boeing more than $24bn.

Ed Pierson, executive director of Foundation for Aviation Safety and a former senior manager at Boeing, said the plea was "seriously disappointing" and "a terrible deal for justice".

"Instead of holding individuals accountable, they’re just basically giving them another get out of jail free card,” he said.

A Boeing 737 Max plane operated by Indonesia's Lion Air crashed in late October 2018 shortly after take-off, killing all 189 people on board. Just months later, an Ethiopian Airlines plane crashed, killing all 157 passengers and crew.

In the 2021 deal, Boeing also agreed to pay $2.5bn to resolve the matter, including a $243m criminal penalty and $500m to a victims' fund.

The deal outraged family members, who were not consulted on the terms and have called for the company to stand trial.

Senior staff at DoJ recommended in favour of prosecution, CBS News, the BBC's US news partner reported in late June.

At a hearing in June, Senator Richard Blumenthal said he believed that was "near overwhelming evidence" that prosecution should be pursued.

Lawyers for family members said the DoJ was worried it did not have a strong case against the firm.

Mark Forkner, a former Boeing technical pilot who was the only person to face criminal charges arising from the incident, was acquitted by a jury in 2022. His lawyers had argued he was being used as a scapegoat.

Mark Cohen, a professor emeritus at Vanderbilt University, who has studied corporate punishments, said prosecutors often prefer plea deals or deferred prosecution agreements, which allow them to avoid the risk of a trial and can give the government greater power over a company than a typical sentence.

"Because it's easier to get than going to trial, it may ease the burden on the prosecutor but the prosecutor also may believe it's a better sanction [because] they may be able to impose requirements that aren't normally in sentencing guidelines," he said.

He said there was little doubt that Boeing's status as a key government contractor played a role in determining how to proceed.

"They've got to think about the collateral consequences," he said. "You don't take these kinds of cases lightly."

The issues with MCAS were not Boeing's first brush with the law.

It has also paid millions of penalties to the Federal Aviation Administration since 2015 to resolve a series of claims of improper manufacturing and other issues.

The company also continues to face investigations and lawsuits sparked by the incident on the January Alaska Airlines flight.

https://www.bbc.com/news/articles/cjjjj85z0lno

Drug Developers Tap the Immune System to Supercharge ADCs

 The antibody drug conjugate market is one of the fastest growing in the pharmaceutical industry, expanding from $1 billion to $10 billion in yearly sales between 2015 to 2023—and expected to rise to $28 billion by 2028, according to Evaluate.

But despite their high level of efficacy in delivering cytotoxic payloads directly to tumor cells, antibody-drug conjugates (ADCs) are “unfortunately not curing people,” Tim Lowinger, senior vice president and chief science and technology officer at Mersana Therapeutics, told BioSpace. There are real benefits, he said, including prolonged life and extended progression-free survival, yet reemergence occurs.

With 15 ADCs approved as of February 2024 and many more in company pipelines, drug developers are expanding their focus to ask how they can build on the success of ADCs. Enter immunostimulatory ADCs (iADCs), sometimes called immune-stimulating antibody conjugates (iSACs).

Immunotherapies are already proven cancer drugs, and delivering these treatments via ADC offers the potential to precisely target tumor cells while protecting normal cells, said Jane Chung, president and chief operating officer at Sutro Biopharma.

“Engineering very targeted therapies so that you can dial up the potency of whatever payload you’re using, that’s going to . . . really move the needle on advancing cancer care,” Chung told BioSpace.

Hitting the Gas on Immune Response

The excitement around iADCs stems from the success of checkpoint inhibitors, said Nathan Tumey, an associate professor at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences. Tumey told BioSpace that checkpoint inhibitors essentially take the brakes off of the immune system, enabling it to attack cancer cells. iADCs offer the potential to take this further and “step on the gas,” ramping up the immune response.

Some of the cytotoxic payloads carried by current ADCs are also known to cause immunostimulatory cell death by creating more neoantigens in the tumor, Lowinger explained, driving companies like Pfizer to combine its auristatin-based ADC with a checkpoint inhibitor for a synergistic effect.

For Lowinger, this aspect raises the question: “If a secondary mechanism of immunostimulatory cell death can have a benefit, what if you made this your primary mechanism of action?” That idea is driving interest now in iADCs.

Biopharma companies are targeting a number of pathways to activate the innate immune system. Mersana, for example, is developing a stimulator of interferon genes (STING) agonist. While STING activation has known anti-cancer effects, it’s been a historically difficult target because activating it throughout the body can be toxic. The drug needs to be activated only once bound to tumor cells—which is precisely what ADCs were made to do.

Using its immunosynthen platform, Mersana designed its STING agonist to stay put once delivered inside the cell with a stable, cleavable linker scaffold. Its lead asset is currently in Phase I trials against multiple HER2-positive solid tumor types. Instead of using the monoclonal antibody trastuzumab often paired with current HER2-targeting ADCs, Mersana developed a novel antibody. Therefore, it could potentially be used in combination with established, cytotoxic ADCs, as the two would not be competing for the same binding site.

Meanwhile, Burlingame, CA–based Tallac Therapeutics has TAC-001, a TLR9 agonist ADC in a Phase I/II trial for solid tumors. While most ADCs carry small molecule payloads, Tallac’s platform can conjugate an oligonucleotide to an antibody, allowing modalities beyond cytotoxicity, Hong Wan, CEO of Tallac, told BioSpace. Because TLR9 is part of the innate immune system and expressed near-exclusively on immune cells, it has potential for a durable response via “immune memory,” in addition to increased safety and tolerability, Wan said.

Wan pointed to the high toxicity of many current ADCs and the very high target protein expression required in the tumor to elicit the cytotoxic effect, which can restrict the efficacy to a limited patient population. In contrast, iADCs don’t require very high target expression, she said, so they could potentially benefit a broader patient population.

Though data from a Phase I/II dose escalation trial have not yet been disclosed, Wan indicated the company has seen a positive response to TAC-001 in melanoma. The candidate has also been studied in the preclinical setting alongside a cancer vaccine, with positive results shared in April. And it has been combined with multiple chemotherapies preclinically. Next, Tallac is planning to test the candidate in combination with a PD1 checkpoint inhibitor.

In a twist on the combination approach, South San Francisco’s Sutro—in partnership with Astellas—is taking a dual conjugation approach with its iADC. “When we put both elements, the chemotherapy and the PD1 immune activator, on an antibody . . . we reduce the tumor volume and activate the immune system to get rid of the remaining tumor cells,” said Hans-Peter Gerber, chief scientific officer at Sutro.

Balancing ratios between the two elements can be precarious and the technology is critical, Gerber told BioSpace, adding that he believes Sutro stands alone in being able to dial in the correct balance.

While the Astellas-partnered program does not yet have a disclosed target, Gerber said the obvious strategy would be to start in indications where immune checkpoint inhibitors already work, such as melanoma and lung and kidney cancers, then expand to populations that cannot benefit from a checkpoint inhibitor. Colorectal cancer is a “bold goal” for the company, he added.

A Difficult Path

The path has not been a smooth one for iADCs, though. Thanks to some highly visible clinical failures, “the field has a bad rap,” Tumey said. In 2022, an iADC combining an anti-HER2 MAB with a TLR8 agonist failed. Its developer, Silverback Therapeutics, ceased operations and became a shell company for a reverse merger with a different biotech.

Two years later, Bolt Therapeutics had essentially the same results for a similar treatment. A HER2-targeting iSAC developed by Novartis also failed a Phase I trial for non-breast malignancies in 2021.

“This remains a challenging area for drug discovery with considerable technical risk, as the common targets such as TLR-7, -8, -9 and STING have not yet been successfully drugged with any type of therapy,” Dan Chancellor, vice president of thought leadership at pharma solutions provider Norstella, told BioSpace in an email. He added that the iADC technology is in the beginning stages of development.

However, the aforementioned three failures really amount to one, Tumey said. The companies were doing essentially the same thing—using non-cleavable linkers and effector function ADCs targeting HER2—so if one failed, “of course they’re all going to fail.”

Additionally, “I think maybe a mistake that the field made early on was trying to go after breast cancer,” he said. While it seemed like the lowest hanging fruit, it’s difficult because it is an immunologically cold tumor. Like Gerber, Tumey said he believes iADCs have the highest potential in areas checkpoint inhibitors have been most successful, like non-small cell lung cancer or bladder cancer.

Thanks to the success on the cytotoxic side of the ADC space, Tumey said companies appear to be more willing to take risks, potentially opening the field for meaningful success.

iADCs in the Limelight

In a notoriously tough biopharma funding climate, iADCs are one area drawing investment from companies. Mersana, for example, has partnerships with both GSK and Merck KGaA. The GSK deal, worth up to $1.4 billion, involves a HER2-targeted iADC currently in a Phase I dose-escalation trial. In 2022, Merck KGaA dropped $30 million up front with another $800 million on the line to conjugate Mersana’s preclinical STING-agonist to Merck KgaA’s proprietary antibodies for up to two targets.

Additionally, Astellas Pharma has invested $90 million up front with Sutro to develop iADCs for three targets. Sutro could receive an additional $422.5 million in milestone payments, plus royalties.

Lowinger shared the story of a study Mersana conducted treating tumors in mice with the company’s STING iADC: their tumors disappeared. Mersana then rechallenged the mice, and in mice treated with an iADC, tumors would not regrow.

“This allows for the hope and dream that there’s a chance to cure patients,” Lowinger said. “I think that’s the big differentiator and why there’s interest in this approach.”

https://www.biospace.com/article/drug-developers-tap-the-immune-system-to-supercharge-adcs/

Beyond GLP-1s: The Next Obesity Treatments

 Recent Phase Ib trial results showed strong weight reduction and a favorable tolerability profile for Zealand Pharma’s investigational amylin analog petrelintide, highlighting that GLP-1 receptor agonists are not the be-all and end-all of weight-loss treatments. Indeed, Zealand is positioning petrelintide as a competitor to GLP-1s, offering better tolerability and higher-quality weight loss, with preserved lean mass.

These data “further support the potential of this long-acting amylin analog to deliver weight loss comparable to GLP-1 receptor agonists with a better patient experience,” Zealand Chief Medical Officer David Kendall said in a statement.

Expected to reach total sales of more than $110 billion by 2033, there isn’t a hotter drug class than GLP-1 receptor agonists. Novo Nordisk brought in around $1.35 billion from Wegovy in the first quarter of 2024, while Eli Lilly’s Zepbound brought in over $517 million. But while these drugs are extremely effective at helping people to lose weight, reductions in weight loss are accompanied by reduction in muscle—something that can be especially problematic for elderly patients.

“GLP-1s are tantamount to starvation,” Shaharyar Khan, chief scientific officer at Rivus Pharmaceuticals, told BioSpace. “You’re reducing caloric input. Your body is now becoming more stingy with its resources. It starts stealing from muscle to feed itself.”

In addition to Zealand, Rivus and several other biopharma companies are pursuing different approaches. Even Novo and Lilly are not satisfied with the success of Wegovy and Zepbound. In January, Novo struck new partnerships with Cellarity and Omega Therapeutics to develop new cardiometabolic drugs, just six months after Lilly’s July 2023 acquisition of Versanis and its lead asset bimagrumab, a monoclonal antibody that aims to reduce fat without affecting muscle mass.

Michael Vallis, a psychologist and associate professor of family medicine at Dalhousie University in Nova Scotia, said he is excited about new scientific approaches to treating obesity. “I would hope that we’ll really start to see a lot more differentiation because in this field, we really do need more and more medical therapies to help people.”

Mitochondrial Uncoupling

Vallis argued that calorie restriction is necessary for weight loss. “The only way you can lose weight is by calorie reduction,” he told BioSpace. “You either reduce your calories by taking fewer calories in . . . or you reduce your calories by burning off so many calories . . . through activity,” increasing energy expenditure.

While GLP-1s go after the energy input side of the equation, Rivus is targeting the energy expenditure side, Khan said, adding that this approach is more sustainable. “It supports your muscle mass. It doesn’t steal from it,” he said. Specifically, Rivus is leveraging the science of mitochondrial uncoupling. Mitochondria are the powerhouse of the cell, Rivus CEO Jayson Dallas explained. “About 20% of the energy that we consume in a day comes from what’s called [mitochondrial] uncoupling,” which forces the cell to selectively consume fat.

David Lau, a professor emeritus of medicine, biochemistry and molecular biology at the University of Calgary, is intrigued by this strategy as well. “Drugs that target mitochondrial uncoupling can increase energy expenditure and lead to weight loss,” he said.

Mitochondrial uncoupling as a weight loss mechanism is itself not a new idea; the drug 2,4-dinitrophenol (DNP), whose weight-loss effects were discovered in 1933, is highly effective but can be deadly because it can cause users to overheat.

Rivus is targeting mitochondrial uncoupling therapeutically with its lead candidate HU6. While not currently being studied for weight loss specifically, HU6 activates mitochondrial uncoupling and leads to fat-specific weight loss, preservation of muscle mass, reduction of liver and visceral fat, improved glycemic control and reductions in oxidative stress and inflammation, according to the company’s website.

HU6 increases resting energy consumption by about 30% at its highest dose, “and it does that 24/7,” Dallas said. “You’re essentially burning 30% more energy than you otherwise would, all day, and therefore you’re burning an extra 3600 to 4000 calories a week in the background.” 

Dallas also suggested that the process by which GLP-1s generate weight loss may be too fast. “The more you shock your body, the more it goes into panic mode, and when you’re losing 30% of your body weight in 12 weeks, that’s a crisis metabolically.” With HU6, Khan explained, “we’re able to increase our patient’s metabolism in modest ways, but that over the treatment durations lead to fat-specific weight loss that is very meaningful.”

Trial participants taking HU6 have lost three to four pounds per month—consistently, Dallas said. “There’s no plateau.”  

HU6 is currently being investigated in a Phase IIa study for obese patients with heart failure with preserved ejection fraction (HFpEF) and a Phase IIb study for patients with metabolic dysfunction-associated steatohepatitis.  

Preserving Muscle Mass

Lilly is also hoping to preserve muscle mass while helping patients lose weight with bimagrumab, an antibody to activin receptors that are found in various tissues around the body. Myostatin and the activin type IIA receptors prevent muscle growth. Bimagrumab attempts to “disinhibit that muscle growth,” explained Ken Attie, vice president of diabetes and metabolic research at Lilly and chief medical officer at Versanis.

Axel Haupt, senior vice president of diabetes and metabolic research at Lilly, told BioSpace that Lilly does not see any safety issues with tirzepatide, the active ingredient in Zepbound. “It’s a normal phenomenon of weight loss that you lose lean body mass,” he said. Patient-reported outcomes show that people are more active and able to do more, “but I think we are aiming to even improve that.” 

Bimagrumab also acts on the adipose tissue “to essentially mobilize fat out of the lipid droplets, and hopefully get those calories to be burned off in the fat tissue,” Attie said. By maintaining or growing muscle, people can have a “longer, more maintained weight loss rate,” Haupt added.

Bimagrumab is currently being evaluated in a Phase II study with or without semaglutide (Wegovy), from which Lilly expects results later this year. Attie said the company plans to combine bimagrumab with other obesity meds, the next of which would be Zepbound, and that the drugs could be given separately or combined into one injection.

Lau said the obesity treatment landscape has completely changed over the past five to ten years. “I think we’re now entering into the era that we expect a minimum of 15% to even upwards of 20% to 30% of weight loss,” he said.

In addition to trying to preserve muscle mass, new weight-loss drugs are also looking to avoid the gastrointestinal (GI) side effects that can come with GLP-1s. Lau said drugs that work along the amylin and calcitonin receptor agonist pathway “are associated with less GI side effects than those caused by GLP-1 receptor agonist drugs.”

The newly launched Metsera—which debuted in April with $290 million in financing—is developing a dual amylin/calcitonin receptor agonist, which it is combining with a GLP-1 agonist.

https://www.biospace.com/article/beyond-glp-1s-the-next-obesity-treatments-/

Hunter Biden’s the real point person in Joe’s White House

 Democrats trying to dislodge Joe Biden will first have to combat the proxy commander in chief: Hunter Biden — and that’s easier said than done.

With the Biden family digging in behind Joe staying put, any staffers or party grandees deputized to strong-arm Joe Biden out of being their candidate in November had better not underestimate the first son.

While the focus has been on four-time Vogue cover girl Jill Biden and her screeching assurances that Joe is hale and hearty and fit for another four years, the first son has flown under the radar.

But Hunter is glued to his father’s side for a reason. He was with him at Camp David to help prepare for the disastrous debate, was there for the vainglorious Annie Leibovitz family photo shoot post-debate, then flew back with the president to the White House where he has been ensconced ever since.

Dad’s pardon power is not something Hunter will relinquish lightly, Devine writes.Getty Images

He reportedly is acting as “gatekeeper” to his father and helping write speeches for him, while White House press secretary Karine Jean-Pierre confirmed that he has been sitting in on Joe’s meetings with senior staff.

Hunter has always regarded himself as smarter than his father’s aides, some of whom are telling reporters that they are flabbergasted by his presence at this crucial time.

“What the hell is happening?!” senior White House staff members told NBC News.

Hunter’s role also has caused concern for the powerful House Intelligence committee, with Republican chairman Mike Turner demanding to know if Hunter is “receiving classified information.”

He wrote to White House Chief of Staff Jeff Zients last week requesting “a full accounting [of any] official meetings and phone calls Hunter Biden is participating in and in what capacity and whether these discussions include classified information.”

‘Fight all the way’

Despite the questionable optics, Hunter is not even trying to hide his position of influence, and instead is acting proprietorial, important and in charge. Cameras caught him looking deliriously happy and networking like a pro in the East Room where his father was conducting a Medal of Honor ceremony Wednesday. When the president delivered a teleprompter speech, Hunter stiffened up and stared at him intently, as if willing him not to flub it.

Hunter has always exerted some element of control over his father, especially since the death of his older brother Beau in 2015. But in the addled state Joe is in now, unable to hide his cognitive deficits, Hunter is in the driver’s seat like never before.

A former friend tells Devine the Bidens will have to be “dragged” out of the White House.AFP via Getty Images

That’s bad news for Democrats — and disastrous for the country.

Those who know Hunter well say that, despite his reputation as a crackhead loser, he is highly intelligent, manipulative, methodical and always out for his own ends, which, now more than ever, depend on his father maintaining power.

“Knowing them on a familial level, they [will] have to be dragged out,” said one former friend.

“I think the Bidens are going to fight all the way into the ground,” said another. “[They] only give a s- -t about themselves and the Bidens.”

Hunter also is fearless and willing to fight to the death to get what he wants. That makes him a formidable adversary for any hapless Democrat believing that all they have to do is sweet-talk Jill and Ashley Biden or appeal to Joe’s sense of party loyalty and desire to preserve his legacy.

Hunter has a lot at stake, personally, in Joe remaining in office. He has benefited from Joe’s power all his life, but now his future is in peril, with a looming felony tax trial in California as he awaits sentencing over his felony gun conviction in Delaware.

Prosecutors for special counsel David Weiss are showing no mercy after Attorney General Merrick Garland and the DOJ were humiliated by two IRS whistleblowers who alleged to Congress that the five-year investigation into Hunter had been slow-walked and obstructed to protect his father.

‘Proving ground’

While Joe has claimed he won’t pardon his son, nobody believes it. Dad’s pardon power is not something Hunter will relinquish lightly.

Apart from saving his own skin, Hunter will be enjoying the feeling of control he has at the center of the constitutional crisis facing the nation, says another former friend. He may see it as a “proving ground for his leadership skills and believe that his manifest destiny is playing out.”

In other words, Hunter may view the situation as a dry run for his own political ambitions, perish the thought.

Various communications on his abandoned laptop also show he is not fond of the Obamas, and harbors a resentment that they did not respect his father sufficiently when he was vice president.

In his 2021 memoir, “Beautiful Things,” Hunter wrote that he didn’t like hanging around the Obama White House because “I didn’t want to be in the position of walking into a barbecue on a Sunday with the president and the White House staff after reading about someone throwing my dad under the bus. I knew I couldn’t control my temper and keep my mouth shut.”

If he perceives an Obama push to get rid of his father now, that will only make him dig in harder.

Perhaps the only way to remove the Biden family grift machine is to bribe them out. Or, to put it more politely, for the Democratic donor class to provide a golden parachute of lucrative book deals, a lavish presidential library and a guaranteed pardon for any family members in legal jeopardy.

“That would do the trick,” said one former Biden confidant.

https://nypost.com/2024/07/07/opinion/hunter-bidens-the-real-point-person-in-joes-white-house-dont-underestimate-the-first-son/