Target to $81 from $60
Friday, October 6, 2023
Thursday, October 5, 2023
GLP-1 Agonists, Like Ozempic and Wegovy, Have Risk of Gut Issues: Study
The use of glucagon-like peptide 1 (GLP-1) agonists for weight loss, such as Novo Nordisk’s Ozempic and Wegovy, is associated with the risk of gastrointestinal adverse events, according to a study published Thursday in the medical journal JAMA.
Specifically, the study found the class of drugs compared with bupropion-naltrexone were linked with an increased risk of pancreatitis, bowel obstruction, and gastroparesis but not biliary disease.
“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes,” the study’s authors wrote.
The authors said they examined gastrointestinal adverse events associated with GLP-1 agonists used for weight loss in a clinical setting because randomized trials evaluating their efficacy “were not designed to capture these events due to small sample sizes and short follow-up.” For their study, researchers used a random sample of 16 million patients taken between 2006 and 2020 from the PharMetrics Plus, a health claims database with 93% of all U.S. outpatient prescriptions and physician diagnoses.
The study identified approximately 4,700 people who had been prescribed either semaglutide (Ozempic, Rybelsus and Wegovy) or liraglutide (Saxenda and Victoza)—focusing on those who took these drugs for weight loss, not diabetes, with a history of obesity and no diabetic diagnosis.
The class of drugs works by stimulating insulin production and reducing glucose production, which has made them a popular treatment for type 2 diabetes. However, the potential of these drugs in assisting with weight loss has caught the attention of patients as well as companies: many of the drugs approved only for diabetes are also prescribed off-label for weight loss. Wegovy was also approved for weight management by the FDA in June 2021.
Eli Lilly is the maker of diabetes drug Mounjaro (tirzepatide), a GIP/GLP-1 receptor agonist. The company is investigating tirzepatide in patients with overweight and obesity who do not have type 2 diabetes, with Mounjaro poised to add the hot indication of chronic weight management to its label by the end of this year.
The findings of Thursday’s JAMA study come as both Novo Nordisk and Lilly face legal challenges. They were sued in August 2023 by a Louisiana woman Jaclyn Bjorklund, who alleged the companies “downplayed the severity of the gastrointestinal events caused by Ozempic and Mounjaro,” and in particular played down the risk of gastroparesis, which is the slowing or stopping of the digestive system.
The suit alleges that she was hospitalized for stomach issues, including being sent to the emergency room, and suffered other adverse events such as losing teeth from excessive vomiting, throwing up whole food, and having to use other medications to alleviate her vomiting.
A Lilly spokesperson reportedly said the company’s “top priority” is patient safety, and that it “actively [engages] in monitoring, evaluating, and reporting safety information” for its medications.
The law firm that filed the lawsuit on Bjorklund’s behalf told CBS News it is investigating 400 other inquiries from clients across 45 states.
The American Society of Anesthesiologists recommended in June 2023 that patients stop taking GLP-1 agonists a week before elective surgeries, due to the increased risk of vomiting during surgery, while CNN reported in July other accounts of patients taking Ozempic and Wegovy suffering gastroparesis, with some claiming to have vomited days-old food.
Both medications note the risk of delayed gastric emptying, among other stomach problems such as nausea, vomiting, and diarrhea, but do not include an explicit warning of gastroparesis.
The drug class is also being investigated for possible suicidal ideation and self-harm risk by the U.K.’s Medicines and Healthcare products Regulatory Agency and the European Medicines Agency.
The Rich Are Flocking to Singapore. Bankers Stick With Hong Kong
In the battle of Asian financial hubs, each city has its own bragging rights
The boldfaced names in money management can’t get enough of Singapore these days. Billionaire Ray Dalio has set up shop to manage some of his personal fortune there. Ken Griffin and Steve Cohen are on hiring sprees.
From Singapore’s earliest years as an independent state, it’s aimed to be one of the key locales through which the world’s money flows. And as a haven for wealth and a hub for asset managers, the “Switzerland of Asia” has been notching up enough wins to shed any regional asterisk. It also saw an influx of finance workers and business escaping Hong Kong’s harsh Covid Zero policies last year, though it still has a long way to go before displacing Hong Kong as a trading center and base for global banks looking for a gateway to China.
Ukraine "Freaking Out" After McCarthy Ouster, Says It's "Hostage" To Washington Turmoil
"We are freaking out. For us it is a disaster," Ivanna Klympush-Tsintsadze, an MP who chairs the committee on Ukraine’s integration into the EU, told Politico in a report published Wednesday. "We are interested in getting things sorted out so American democracy can function, and so we can restore the bipartisan consensus on supporting their own national interest by supporting Ukraine."
Now Ukraine officials are scrambling in the wake of Rep. Kevin McCarthy's ouster as House speaker in a move widely seen as a direct shot at the Biden admin's 'blank check' approach Ukraine aid.
In public, Ukrainian officials are trying to put on a positive face and downplay the impact of the GOP-led blockage of what was an expected tens of billions more in defense aid for next year. "Until a new speaker is elected, the House cannot vote on laws, but all other work, including in committees, continues," Ukraine's Ambassador to the United States Oksana Markarova has said.
"For now Ukraine still has at least an additional $1.6 billion available for use for defense assistance (PDA) and $1.23 billion in direct budget aid, Markarova, the ambassador, said," wrote Politico.
But below is a key section of the report, wherein a Kiev official expresses that Ukraine has become a hostage of Washington internal politics:
Privately, however, there is dismay and confusion in Kyiv.
“Well, that’s a setup,” one Ukrainian MP told POLITICO.
“Honestly, we are watching for now,” said one Ukrainian government official, who asked not to be identified while discussing sensitive matters.
Ukrainian officials typically avoid expressing public criticism of partners so as not to seem ungrateful. But this week some have expressed shock.
“There is nothing good, but, objectively, we have simply become hostages of their internal politics,” said Ukrainian lawmaker Yaroslav Zheleznyak, first deputy chairman of the parliament committee on finance, after the emergency U.S. budget deal was announced.
But Zhelezniak has also admitted that corruption is a major issue which has played a part in the withholding of external aid. "The biggest (public) complaint about us is corruption," he had earlier conceded in a weekend social media post.
"We have to go through these 45 days without a major corruption scandal," he stated. This comes even after Zelensky in the last two months fired a range of top officials, including his longtime defense minister and a half-dozen other top defense officials.
Small Percentage of Adults with Early Alzheimer’s Eligible for Leqembi: Study
With the FDA’s full approval of Eisai and Biogen’s Leqembi (lecanemab) for the treatment of Alzheimer’s disease, recent data from the Mayo Clinic Study of Aging sheds light on the limited eligibility criteria for the anti-amyloid treatment.
The Mayo Clinic collected data from 237 individuals between the ages of 50 and 90 years of age with mild dementia and evidence of amyloid-ß plaque deposits in the brain. The research, published recently in the journal Neurology, indicates that only a small percentage of individuals with early Alzheimer’s meet the criteria for clinical trial inclusion.
At the same time, researchers found that after the exclusions—including stroke, cardiovascular disease, a history of cancer, and brain scan findings that showed abnormalities like old, small brain bleeds or brain injuries due to insufficient blood supply—only 19 people, or 8%, would have been eligible for a trial.
“Only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” study author Maria Vassilaki, an epidemiologist at Mayo Clinic, said in a statement.
Vassilaki contends that the challenge is that the inclusion and exclusion criteria of the clinical trials that led to FDA accelerated approval “form the basis of how people should be invited or discouraged” from receiving the drug.
Leqembi is a monoclonal antibody that binds to soluble amyloid beta protein species and plaques and is administered intravenously every two weeks. A Phase III clinical trial demonstrated that the drug slowed down the disease’s progression and increased patients’ quality of life.
Its label states that Leqembi should be used in “patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials” as “there are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.”
Eisai’s Deputy Chief Clinical Officer Michael Irizarry acknowledged that because Leqembi is only approved for individuals in the early stages of the disease, its target population is small. “Many patients, by the time they're diagnosed or by the time that they're considered for potential treatment, are already in the moderate or severe stages of Alzheimer's disease,” Irizarry told BioSpace.” Those patients are ineligible for Leqembi.
In addition, if tests show that an individual’s memory problems are not due to elevated amyloid in the brain, they would be disqualified from treatment initiation.
“Amyloid plaque deposits in the brain are required for the diagnosis of Alzheimer’s disease. Lecanemab binds to those and clears [them] from the brain,” Irizarry said.
While over 47% of the Mayo Clinic’s study participants fit the criteria to participate in clinical trials for the drug based on memory test and BMI scores, trial exclusion criteria like prior health conditions narrowed that number to just 8%. However, Irizarry says some of these patients could still be eligible for Leqembi.
“The results have to be interpreted in the context of what they looked at,” Irizarry said, noting that the research narrowly analyzed eligibility based on clinical trial criteria. “That can really vary in terms of the types of patients that are being screened and entered in a clinical trial,” he said.
An individual may not qualify for clinical trials, but based on label indication could still later qualify for treatment if their condition stabilized. “It makes good medical sense to control people's ongoing medical conditions before initiating Leqembi,” Irizarry added.
However, according to Vassilaki, older Black and Hispanic people have been underrepresented in clinical trials, even though they are more likely to have Alzheimer’s or other dementias. Of the 859 people infused with lecanemab during the trial, only 20 were Black.
Vassilaki contends that evaluating the eligibility criteria in more diverse populations is critical.
“Additional research is needed to examine the safety and efficacy of monoclonal antibodies targeting amyloid-ß plaques in larger, more diverse populations, as well as in less healthy populations, before these therapies may be more widely available to people with Alzheimer’s disease,” she said.
FDA Adcomm Backs Neuroblastoma Treatment, Even Without RCT Data
The FDA’s Oncologic Drugs Advisory Committee on Wednesday voted in favor of US WorldMeds’ investigational drug eflornithine hydrochloride (DFMO) for the reduction of relapse risk in pediatric patients with high-risk neuroblastoma.
In a 14-6 vote, the panel of external experts found that even without a randomized controlled trial (RCT), US WorldMeds had provided enough evidence to conclude that DFMO boosts event-free survival in its target patient population.
“I believe that the data for event-free survival is compelling,” Christopher Lieu, committee chairperson and director of the Gastrointestinal Medical Oncology Program at the University of Colorado, said during the meeting. Lieu voted yes, but also noted that the lack of randomization likely could have overestimated the benefit of DFMO in the data presented during the session.
“Having said that, this is a therapeutic that has relatively lower toxicity compared to what we typically discuss,” Lieu said in explaining his vote. “I believe that the expected benefits outweigh the risks of treatment.”
Still, in his summary of the panel’s votes and rationales, Lieu pointed to worries that this might lead to a “slippery slope” in terms of the degree of clinical evidence that will be required of future drug applications in similar rare and difficult-to-study indications. The panelists who voted against DFMO raised similar concerns.
“There is a lot of concern from the group about what the future holds for drug development and what level of evidence the FDA will require in similar situations in the future,” Lieu said.
In its application for DFMO, US WorldMeds provided data from a prospective Phase II, multicenter, open-label, single-arm study of DFMO maintenance treatment in patients who had completed multiagent and multimodality therapy.
In a briefing document posted ahead of the adcomm meeting, US WorldMeds said that they had been told by the FDA that an RCT is the “preferred path to registration” for these types of drugs. However, given the challenges of conducting a randomized study in rare diseases, the company instead proposed an external control approach.
The company then drew from a retrospective chart review of patients with high-risk neuroblastoma and also worked collaboratively with the FDA to design a “rigorous propensity score matched analysis” using a landmark study as its external control.
In its own briefing document, the FDA noted that US WorldMed’s use of an external control in this situation is “reasonable” but also conceded that there are “inherent limitations” associated with externally controlled data, such as interpreting the estimated treatment effect of an investigational intervention.
J&J’s Spravato Bests Quetiapine in Phase III Head-to-Head Depression Study
Johnson & Johnson’s nasal spray Spravato (esketamine) CIII outperformed extended-release quetiapine at inducing remission in patients with treatment-resistant depression, the company announced Wednesday at the same time the results were published in The New England Journal of Medicine.
These data come from the Phase IIIb ESCAPE-TRD trial, a randomized, open-label and active-controlled study that enrolled 676 patients with treatment-resistant depression (TRD). After eight weeks of treatment, 27.1% of patients treated with Spravato achieved remission, defined as a score of 10 or below on the Montgomery–Åsberg Depression Rating Scale (MADRS), a validated and clinician-rated tool to measure depression severity.
In contrast, only 17.6% of quetiapine comparators reached remission, and the between-group difference was statistically significant, according to J&J’s announcement.
The head-to-head findings from ESCAPE-TRD can provide doctors with “important data to consider in the management of treatment-resistant depression by comparing the short- and long-term effectiveness of Spravato to an oral antipsychotic,” Reina Benabou, vice president of medical affairs at Janssen Scientific Affairs, said in a statement.
In the Phase IIIb study, Spravato and quetiapine were given on top of continuing selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. In addition to eight-week remission, ESCAPE-TRD also assessed the durability of this effect. Spravato likewise came out on top for this key secondary endpoint, with 21.7% of treated patients remaining relapse-free after 32 weeks, compared to only 14.1% of quetiapine-treated counterparts.
In terms of safety, Spravato’s adverse event profile in ESCAPE-TRD was consistent with what had previously been established. There were more treatment-emergent adverse events in the Spravato group, thought study dropouts due to toxicities were more common in the quetiapine arm.
Spravato is an intranasal, non-competitive NMDA receptor antagonist indicated for TRD, and for depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideations or behaviors. The therapeutic nasal spray has not been proven to be effective at preventing suicide or reducing ideations, and its label comes with a boxed warning for dissociation, potential for misuse and heightened risk of suicidal thoughts and behaviors in young patients.
J&J’s Phase III victory announced on Wednesday continues the industry’s winning streak in the neuropsychiatric space. Last week, Bionomics reported positive Phase IIb data for its investigational ion channel modulator in post-traumatic stress disorder. Patients treated with the candidate experienced significant reductions in PTSD symptoms.
The same day, Fabre-Kramer ended its decades-long regulatory odyssey with a victory, nabbing the FDA’s approval for its extended-release gepirone hydrochloride tablets, now under the brand name Exxua, for the treatment of MDD in adults.
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