Last week was quite surreal, even by senile Joe's standards.
Shortly after confirming that the president who is now imploding in the polls could, in fact, act on border security and the illegal alien invasion on the southern border without Congress, something which he claimed as recently as January 2024 he can't possibly do...
Eli Lilly on Saturday released detailed data from the Phase II SYNERGY-NASH study, demonstrating the potential of its best-selling diabetes and weight-loss treatment tirzepatide in metabolic dysfunction-associated steatohepatitis.
At 52 weeks, 51.8% of patients treated with 5-mg tirzepatide saw an absence of metabolic dysfunction-associated steatohepatitis (MASH) without the worsening of fibrosis. This proportion increased to 62.8% and 73.3% in the 10-mg and 15-mg dose groups, respectively, while only 13.2% of placebo counterparts reached the endpoint.
Lilly also reported secondary endpoints from SYNERGY-NASH, with nearly 60% of patients in the 5-mg tirzepatide arm achieving at least a one-stage improvement in fibrosis without the worsening of MASH. A similar percentage of patients in the 10-mg and 15-mg groups hit this endpoint, compared to only 32.8% in the placebo group.
The company reported these data at the 2024 Congress of the European Association for the Study of the Liver, which concluded on Saturday, and simultaneously published them in The New England Journal of Medicine.
Lilly cautioned in its announcement that SYNERGY-NASH was “not designed to prove that tirzepatide improves fibrosis.” Still, the press release stated that “the study results showed the potential for a clinically meaningful treatment effect across all doses.”
Tirzepatide also induced notable improvements in body weight, liver injury markers and biomarkers of fibrosis, inflammation and liver fat, according to Lilly.
Jeff Emmick, senior vice president of product development at Lilly, in a statement said that the pharma is “very pleased” with the magnitude of MASH resolution in SYNERGY-NASH and improvement in fibrosis. “Based on these study results, we believe tirzepatide may have the potential to help people living with this disease.”
Tirzepatide is a dual agonist of the GLP-1 and GIP receptors, which allows the protein-based therapy to promote the release of insulin from the pancreas in response to blood sugar levels. This mechanism of action also enables tirzepatide to temper patients’ appetite to induce weight loss and help address MASH symptoms.
The FDA first approved tirzepatide in May 2022 for type 2 diabetes, carrying the brand name Mounjaro. Since approval, the treatment has become one of Lilly’s best-selling assets, generating more than $1.8 billion in the first quarter of 2024 and over $5.1 billion in 2023.
Tirzepatide won another FDA green light in November 2023 as Zepbound, indicated for chronic weight management. Zepbound has since become a strong market force in obesity, bringing in more than $500 million in its first commercial quarter.
With the latest readout, Lilly positions Zepbound for a potential expansion into MASH. According to Saturday’s announcement, the pharma is currently “engaged with regulatory authorities” regarding the next steps for tirzepatide in this indication.
https://www.biospace.com/article/lilly-s-tirzepatide-improves-liver-fibrosis-in-phase-ii-mash-trial/
GLP-1 receptor agonists are very effective at helping obese and overweight patients lose weight, but reductions in muscle accompany the fat loss. Mounting evidence suggests muscle loss contributes to poor health outcomes, especially for elderly patients, but clinical trials rarely incorporate the quality of weight loss—muscle vs. fat—into their analyses.
Instead, in obesity, primary trial endpoints for glucan-like peptide-1 (GLP-1) receptor agonists usually measure only reductions in body weight or body mass.
Some drug developers are recognizing that body composition matters. Veru Pharmaceuticals, Regeneron and Altimmune, in clinical trials, and Eli Lilly, in preclinical development, are each working on GLP-1 companion therapeutics that either build or conserve muscle mass.
GLP-1 inhibitors were first shown to lower plasma glucose in 1993, but the attention given to fat-vs.-muscle loss is relatively new. Therefore, the FDA, citing its 2007 draft guidance for industry, Developing Products for Weight Management, still does not recommend using changes in either fat mass or lean mass as endpoints in clinical trials for weight loss drugs. As an FDA spokesperson told BioSpace, “To date, we have not identified an adverse clinical impact related to reductions in lean mass.”
Others, including Fatima Cody Stanford, associate professor of medicine and pediatrics at Harvard Medical School, writing in JAMA, consider weight loss alone an inaccurate measurement of a medication’s efficacy. More concerningly, a literature review notes that low muscle mass contributes to a variety of conditions, including mortality.
In managing weight loss, “There’s a balance between having good quality weight loss and having a metabolic reset so patients don’t have to stay on these therapies for too long,” Mayank Mamtani, head of healthcare research at B. Riley Securities, told BioSpace.
Key opinion leaders recognize that, according to Global Data. When interviewed by the industry analyst, they called for changes in the clinical trial design to assess the quality of weight loss so that healthcare providers can better select therapeutic options for their patients. Specifically, they suggested using bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA) scanning to better assess body composition during weight loss.
“To ensure that drug-induced weight loss is caused primarily by a reduction in fat mass, the FDA recommends that sponsors . . . conduct an evaluation of body composition . . . in a representative sample of subjects enrolled in the clinical trials,” the same FDA spokesperson told BioSpace. “DEXA or a suitable alternative” is recommended.
However, “DEXA and MRI measure lean mass, not muscle mass,” Scott Harris, chief medical officer at Altimmune, told BioSpace. “Lean mass includes muscle, but it also includes integuments and other soft tissue. MRI can distinguish muscle from lean mass, but the techniques are not universally accepted, so studies usually report out on lean mass instead.”
“If the trial is not set up with [either DEXA or magnetic resonance imaging—MRI] modalities in advance, lean mass and fat mass cannot be assessed,” Harris said. Altimmune is developing a dual-action therapeutic, pemvidutide, that, in Phase II trials, reduced appetite and preserved lean muscle mass.
As the FDA notes, weight loss involves the loss of both fat and muscle mass, regardless of whether the loss occurs through pharmacotherapy, bariatric surgery or lifestyle changes.
“A reduction in fat-free mass can occur because, with lower fat mass, there is less weight acting on skeletal muscle (leading to reduction in bone and muscle mass), reduced organ size (liver, kidneys and pancreas), and reduced body water weight. These changes in body composition are not considered adverse,” the FDA spokesperson reiterated.
So far, the spokesperson continued, “Safety data from clinical trials of approved weight loss drugs have not demonstrated adverse effects . . . such as increased incidence of falls, or muscle or tendon injuries,” that would be related to loss of lean body mass. Nor have patient-reported outcomes.
But if they aren’t included among the endpoints, are they being tracked?
“The next wave of innovation will be around muscle preservation,” Mamtani predicted.
Measuring changes in lean mass “is critical for assessing the quality of weight loss,” Harris stressed. “At Altimmune, we believe the quality of weight loss is as important as the quantity. Thus, we took steps to incorporate this into MOMENTUM, our recently completed Phase II obesity trial.”
Additionally, Mamtani called for endpoints to measure weight regain and physical function. “Currently, almost two-thirds of the weight lost comes back when patients quit GLP-1 therapies.” Likewise, he continued, “If you’ve gone from 250 to 200 pounds, has your quality of life improved?”
Several biopharmaceutical companies are building such additional endpoints into their clinical trials for GLP-1 combination therapies.
For example, the percentage change in lean body mass after 112 days is the primary endpoint for Veru’s Phase II dose-finding study of enobosarm, which conserves muscle mass, combined with GLP-1 receptor agonist semaglutide for weight loss. A series of late-stage trials for enobosarm alone indicates significant improvements in muscle mass compared to placebo.
At Regeneron, a small Phase II study for trevogrumab, which builds muscle mass, was enrolling in March. It will be followed by a larger, four-arm study mid-year to compare outcomes for the combination of trevogrumab and semaglutide. That combination will then be compared to outcomes with or without garetosmab, also developed by Regeneron, which preserves muscle. Primary endpoints include the percent change in both total fat mass and body weight. Secondary endpoints include changes in body weight, lean mass, waist circumference and the total lean mass to fat ratio.
Part C of that trial will evaluate patients’ weight maintenance and function. Once patients cease taking semaglutide, “Roughly half will continue on high-dose trevogrumab to see if the weight can stay off,” Ryan Crowe, senior vice president of investor relations and strategic analysis at Regeneron, said at the Barclays Global Healthcare Conference in March. Regeneron did not respond to BioSpace’s requests for updates. Qualitative endpoints will include how well people can complete day-to-day tasks, such as a stand-and-sit test, he added. “That will probably inform what we do next in terms of measuring functional muscle.”
As Mamtani put it, “It’s the Wild West right now” for obesity drugs, “and having all this clinical data is going to be important.” The future of weight loss drugs may not depend on having the best GLP-1 receptor agonist, he said, but rather a combination of therapeutics that cause weight loss while building or conserving muscle or that improve metabolic health or maintain weight loss.
“Almost every serious company in this space is trying to work on that shift,” Mamtani said.
https://www.biospace.com/article/measuring-muscle-loss-in-the-wild-west-of-weight-loss-drugs-/
With 164 clinical trials assessing 127 drugs in the pipeline, momentum in the Alzheimer’s space is on an upward swing—and while the field has expanded from its initial targets of amyloid beta and tau, experts believe they will remain a pivotal part of the treatment landscape.
Five or 10 years ago, 75% of the drugs in development for Alzheimer’s were anti-amyloid beta (Aβ) or anti-tau drugs, said Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation. “Today that’s completely reversed, as 75% of the drugs in clinical development are non-amyloid, non-tau drugs,” Fillit told BioSpace.
The framework for new approaches coming down the pipeline is to confront the leading risk factor for Alzheimer’s disease: age. The majority of clinical development aims to address age-related issues such as neuroinflammation, epigenetic autophagy, metabolic and mitochondrial disorders, and vascular problems, Fillit noted.
Beta-amyloid has long been a prime suspect in Alzheimer’s disease progression. The protein is chemically sticky and accumulates in plaques that are a hallmark trait of the degenerative disease. While the so-called amyloid hypothesis has been “very exciting” for years, “nobody believes . . . that there’s a single target,” said Lisa Ricciardi, CEO of Cognition Therapeutics, which is focused on neurodegenerative and neuro-ophthalmic diseases.
Fillit concurred, saying that combination therapy is the future and anti-amyloid therapies will remain an important part of treating patients.
With Biogen and Eisai’s Leqembi on the market and an FDA advisory committee convening today to discuss Eli Lilly’s donanemab—both amyloid-clearing antibody treatments—companies developing anti-amyloid therapeutics are pivoting toward next-generation development. Two key areas targeted for improvement are administration and blood-brain barrier penetration, Fillit said.
Both Leqembi and donanemab are administered intravenously, every two weeks for the former and every four weeks for the latter. In addition to infusion center visits, patients on these therapies are looking at a series of imaging requirements to ensure brain health as they’re treated. Long-term data is not yet available for these new antibodies, so length of treatment is still unknown.
Aiming to relieve some of the burdens of treatment, both subcutaneous versions and oral therapies targeting beta-amyloid are currently in development.
Aliada Therapeutics’ monthly, subcutaneous antibody, ALIA-1758—in-licensed from J&J’s Janssen and moving toward Phase I ascending dose clinical studies—is uniquely engineered for both delivery and plaque clearing.
Targeting pyroglutamate amyloid beta, which is similar to the epitope targeted by donanemab, ALIA-1758 utilizes the transferrin receptor to drive its cargo to cells and force degradation and elimination of the plaques, explained John Dunlop, chief scientific officer at Aliada. By transporting the cargo in this way, a higher concentration of the antibodies is delivered across the blood-brain barrier to drive therapeutic benefit, he told BioSpace.
While first-generation anti-amyloid therapies show “some” evidence of efficacy, “I think we all agree in the field: there is significant room for improvement,” Dunlop said.
Meanwhile, Cognition is tackling amyloid beta with an oral, brain-penetrant small molecule. Instead of focusing on removing plaques from the brain, Cognition’s candidate, CT1812, prevents the binding of toxic oligomers to synapses in a neuroprotective approach that acts earlier in the amyloid cascade to slow cognitive decline and disease progression, Ricciardi explained. An 18-month Phase II trial is underway with 540 early-to-mild Alzheimer’s patients, and Cognition expects results from an earlier Phase II trial mid-summer, she said.
With the currently approved anti-amyloid antibodies, “a very tiny amount of the drug actually makes it into the brain,” Ricciardi said, so Cognition’s founding scientists prioritized a high degree of blood-brain barrier (BBB) penetration for its lead asset.
Roche is also focused on the BBB dilemma. After a failed attempt at developing an anti-amyloid antibody for Alzheimer’s, the Swiss pharma is now testing an antibody delivered by its Brainshuttle module, which also utilizes the transferrin receptor. Initial data shows trontinemab had “substantially higher CNS exposure due to shuttling” than the first drug, gantenerumab, with dose-dependent amyloid plaque lowering capabilities.
Eisai and Biogen are on board with improving administration, too. The partners initiated a rolling Biologics License Application (BLA) last month for a weekly, subcutaneous version of Leqembi.
Fillit said about 20% of patients experience an adverse event from the current anti-amyloid antibody treatments, but most are not serious. Only around 2% of patients have a serious adverse event, he noted, so with Alzheimer’s being one of the leading causes of death, the “product profile in terms of risk and benefit is favorable.”
However, certain populations are not eligible for treatments like Leqembi. Patients with two copies of APOE4, a gene variant that carries a high risk of Alzheimer’s, and those on anticoagulants who are at higher risk for brain swelling and bleeds, leading to warnings in the product’s label.
“When you look at the criteria for patients who can actually take the [antibody] and you use all the exclusion criteria, it comes down to a fraction of the population. That was surprising to me,” Ricciardi said.
In contrast, Cognition’s trials have been open to all comers with mild-to-moderate Alzheimer’s. So far, Ricciardi said the company has yet to see the amyloid-related imaging abnormalities (ARIA)—a form of brain swelling—that have occurred with Leqembi and donenamab. Since CT1812 works preventatively, it isn’t removing plaques, which can lead to tears in the vessels of the brain or swelling, she explained.
Similarly, due to its mechanism, Aliada’s candidate doesn’t engage the microglia and isn’t associated with release of pro-inflammatory cytokines. The company therefore does not anticipate any ARIA incidence as it begins clinical trials, which Dunlop believes should “open up the possibility to really get into a broad population.”
And Roche’s Brainshuttle delivery may allow for lower doses of the antibody due to superior BBB penetration. Experts believe this could lower ARIA risk. In its Brainshuttle AD trial, Roche reported a “low incidence of ARIA despite robust amyloid lowering,” with two asymptomatic or mild cases of ARIA in the higher 1.8 mg/kg cohort.
Overall, experts believe amyloid beta will be an important target in a multi-pronged approach to treating the progressive, memory-robbing disease.
In the future, “we’re going to have precision medicine for Alzheimer’s disease with combination therapy,” Fillit predicted.
In Cognition’s START trial, patients are allowed to come in on background Leqembi. Those who have been on the antibody for three to four months can be included in the trial in order to see how the drugs work together.
“As far as I know, that’s the first trial looking at real-time combination therapy,” Ricciardi said. Cognition is hoping to find a “great homeostasis” in the combined effort, with Leqembi clearing out old plaques while CT1812 protects the neurons and clears out oligomers.
Amyloid triggers a pathological cascade of immune activation, brain inflammation and changes to the tau protein, Dunlop said. Aliada is thinking carefully about a complementary tau-targeting asset for its pipeline.
As more targets emerge for Alzheimer’s disease, one thing is clear to Aliada’s leadership team, Dunlop added: “Amyloid is always going to be around.”
Don’t see the Hunter Biden gun case as an effort to hold the president’s prodigal son to account, but as a political maneuver aimed at protecting the prosecutors, perhaps the defendant, and certainly his father.
This sideshow diverts the public’s gaze from far larger corruption: Felony gun charges are piddling when weighed against the selling out of our country, not to mention the leverage Hunter’s dubious dealings and debauchery might have provided our enemies in the way of kompromat.
Yes, it features many “shiny objects,” some juicy, and others genuinely newsworthy, from the riveting trainwreck that was Hunter Biden’s life at the time he committed the alleged offenses — lurid details of his drug abuse, relationships and recklessness — to the vindicating-for-The-Post-but-still-unbelievable Justice Department decision to enter the “laptop from hell” into evidence.
Yet, while Special Counsel David Weiss and by extension Attorney General Merrick Garland will play this as the Biden Justice Department’s pursuit of even the president’s son without fear or favor, it’s no such thing.
First, Hunter may well be found not guilty, or at least get a hung jury. His team is tugging at the heartstrings of jurors hailing from a state in which the Bidens are royalty.
The defense is diving deep into the tragedies that have befallen their royal family and Hunter’s harrowing struggles with alcohol and drug abuse — struggles with which many of the jurors are likely to sympathize, based on their own experiences.
Biden-friendly media have reported that Joe Biden is concerned about the case, making this a story about a father’s love for his targeted son as well — turning the Bidens not only into potentially sympathetic characters, but victims.
Even a guilty verdict may lose on appeal, gobsmackingly enough, by using as a defense a pro-Second Amendment Supreme Court ruling that Joe Biden has panned.
Yet this case — involving offenses at a remove from Hunter Biden’s father, heard in the most favorable venue for the Bidens that any case could have been brought — was never supposed to happen.
It inadvertently serves as an indictment of prosecution and defense alike.
Recall how we got here: For years, key players at the Justice Department and FBI systematically sabotaged the real case against Hunter Biden.
Prosecutors and investigators ignored or declined to pursue evidence of his serious, compromising, and national-security-imperiling misconduct — ranging from alleged violations of the Foreign Agent Registration Act to tax evasion connected to the Biden family’s international influence-peddling business.
Most egregiously, prosecutors let the statutes of limitation lapse on material offenses most closely linked to then-Vice President Biden’s policy portfolio.
A pair of IRS agents, appalled at seeing their peers tank the investigation, risked everything and came forward as whistleblowers.
They brought forth reams of evidence — all through proper congressional channels — tracking how federal law enforcement had protected the Bidens.
Their evidence was only compounded by the fact that the same federal forces were simultaneously engaging in an ever-intensifying jihad against Donald Trump.
Caught in a potential scandal, the Delaware US Attorney’s Office colluded with Hunter Biden’s legal team to concoct a sweetheart plea deal containing a global immunity get-out-of-jail-free card that insulated Biden from all of the most serious charges he might otherwise have faced.
But the deal collapsed under questioning from Delaware Judge Maryellen Noreika, forcing AG Garland to appoint Weiss special counsel.
Seen in this light, the current trial is clearly a fig leaf aimed at rehabilitating the Justice Department while putting Hunter Biden before the most hospitable possible jury — all at far remove from conduct remotely relating to his father.
The pending Los Angeles case against Hunter Biden is only slightly less deceptive.
It at least deals with alleged financial crimes stemming from his work in the Biden “family business” monetizing his father’s name, including at the tail end of Joe’s vice presidency.
But the indictment never makes reference to that name. And prosecutors further distract from the underlying corruption by focusing, in great detail, on Hunter’s lavish spending on escorts and exotic cars.
The real story of Hunter Biden’s legal troubles isn’t about sex, guns, drugs or even taxes.
Rather, it’s about the now-First Family’s global international influence peddling operation — and a government-wide effort to cover it up.
Benjamin Weingarten is editor at large at RealClearInvestigations.
https://nypost.com/2024/06/09/opinion/hunter-biden-trial-just-a-ploy-to-protect-joe-and-the-doj/
