'Nations Struggle to Draft 'Pandemic Treaty' to Avoid Mistakes Made During COVID'

 After the coronavirus pandemic triggered once-unthinkable lockdowns, upended economies, and killed millions

opens in a new tab or window, leaders at the World Health Organization (WHO) and worldwide vowed to do better in the future. Years later, countries are still struggling to come up with an agreed-upon plan for how the world might respond to the next global outbreak.

A ninth and final round of talks involving governments, advocacy groups, and others to finalize a "pandemic treaty" is scheduled to end Friday. The accord's aim: guidelines for how the WHO's 194 member countries might stop future pandemics and better share scarce resources. But experts warn there are virtually no consequences for countries that don't comply.

WHO's countries asked the U.N. health agency to oversee talks for a pandemic agreement in 2021. Envoys have been working long hours in recent weeks to prepare a draft ahead of a self-imposed deadline later this month: ratification of the accord at WHO's annual meeting. But deep divisions could derail it.

U.S. Republican senators wrote a letter to the Biden administration last week critical of the draft for focusing on issues like "shredding intellectual property rights" and "supercharging the WHO." They urged Biden not to sign off.

Britain's department of health said it would only agree to an accord if it was "firmly in the U.K. national interest and respects national sovereignty."

And many developing countries say it's unfair that they might be expected to provide virus samples to help develop vaccines and treatments, but then be unable to afford them.

"This pandemic treaty is a very high-minded pursuit, but it doesn't take political realities into account," said Sara Davies, PhD, a professor of international relations at Griffith University in Australia.

For example, the accord is attempting to address the gap that occurred between COVID-19 vaccines in rich and poorer countries, which WHO Director-General Tedros Adhanom Ghebreyesus, PhD, said amounted to "a catastrophic moral failureopens in a new tab or window."

The draft says WHO should get 20% of the production of pandemic-related products like tests, treatments, and vaccines and urges countries to disclose their deals with private companies.

"There's no mechanism within WHO to make life really difficult for any countries that decide not to act in accordance with the treaty," Davies said.

Adam Kamradt-Scott, PhD, a global health expert at Harvard University, said that similar to the global climate agreements, the draft pandemic treaty would at least provide a new forum for countries to try to hold each other to account, where governments will have to explain what measures they've taken.

The pandemic treaty "is not about anyone telling the government of a country what it can do and what it cannot do," said Roland Driece, co-chair of WHO's negotiating board for the agreement.

There are legally binding obligations under the International Health Regulations, including quickly reporting dangerous new outbreaks. But those have been flouted repeatedly, including by African countries during Ebola outbreaks and China in the early stages of COVID-19.

Suerie Moon, PhD, co-director of the Global Health Center at Geneva's Graduate Institute, said it was critical to determine the expected role of WHO during a pandemic and how outbreaks might be stopped before spreading globally.

"If we fail to seize this window of opportunity which is closing ... we'll be just as vulnerable as we were in 2019," she warned.

Some countries appear to be moving on their own to ensure cooperation from others in the next pandemic. Last month, the Biden administration said it would help 50 countriesopens in a new tab or window respond to new outbreaks and prevent global spread, giving the country leverage should it need critical information or materials in the future.

https://www.medpagetoday.com/infectiousdisease/covid19/110068

Strengthening CAR-T Therapy to Work Against Solid Tumors

 Researchers at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC) have shown that a breakthrough therapy for treating blood cancers can be adapted to treat solid tumors—an advance that could transform cancer treatment. The promising findings, reported today in Science Advances, involve CAR-T cell therapy, which supercharges the immune system to identify and attack cancer cells.

“CAR-T cell therapy has revolutionized the treatment of blood cancers such as leukemia and lymphoma but hasn’t worked well against solid tumors,” said Xingxing Zang, Ph.D., the paper’s senior author. “We found that our changes to standard CAR-T cell therapy can significantly boost its effectiveness against solid tumors, including often-fatal pancreatic cancer and glioblastomas.” Dr. Zang is a member of MECCC Cancer Therapeutics Research Program and professor of microbiology & immunology, of oncology, of medicine, and of urology, the Louis Goldstein Swan Chair in Cancer Research and the founding director of MECCC’s Institute for Immunotherapy of Cancer at Albert Einstein College of Medicine. The first author of the paper is Christopher Nishimura, an M.D./Ph.D. student in Dr. Zang’s lab.

Developing Personalized Cancer Killers

Dr. Zang and his colleagues created five CAR-T therapies that they tested on mice implanted with several types of solid human tumors. One of the therapies—which used two novel components—proved superior in safely and effectively shrinking not only glioblastoma and pancreatic tumors but lung cancer tumors as well.

CAR-T cell therapy, short for chimeric antigen receptor (CAR)-T cell therapy, is a marvel of genetic engineering that transforms T cells (a type of immune cell) into cancer-seeking missiles programmed to attack on contact. The therapy involves extracting the patient’s own T cells and equipping them with a single gene that codes for several different proteins. (“Chimeric” comes from the Chimera of Greek mythology with its lion’s head, goat’s body, and serpent’s tail.) The genetically modified T cells are allowed to multiply and are then infused back into the patient.

Their specially designed gene enables the infused T cells to express synthetic CAR receptors on their surface. The CARs can recognize specific proteins, known as antigens, that protrude from cancer cells. Thanks to their new CARs, the T cells are able to home in on cancer cells and then switch to attack mode.

CARs contain four key proteins, and Dr. Zang and his colleagues achieved success against solid tumors by altering two of them. (See illustration of CAR-T cell receptor below.)

Five CAR-Ts Confront Three Types of Cancer

All five CAR-T therapies developed by the Zang team used the same novel targeting protein: a monoclonal antibody that binds to B7-H3, a cancer-cell antigen widely expressed on most solid tumors and their blood vessels. Dr. Zang had previously helped to discover that B7-H3 allows tumors to evade immune attack by interfering with T cells.

“We wanted our CARs to not only attach T cells to solid tumors but also—by binding specifically to B7-H3—to prevent B7-H3 from interfering with the T cells’ ability to attack and destroy cancer cells and their blood vessels,” said Dr. Zang.

Simply attaching CAR-T cells to tumor cells isn’t enough to kill them. CARs must also include a costimulatory protein to help activate T cells once they’ve made contact with cancer cells. Four of the five CAR-T cell therapies developed by Dr. Zang’s lab used previously deployed costimulatory proteins. But their fifth therapy used a protein never before tried in CAR-T cell therapy. In 2015, Dr. Zang discovered that T cells possess a receptor he called TMIGD2 that activates T cells when stimulated. He later realized that incorporating TMIGD2 into CAR-T cells might enable them to overcome the challenges posed by solid tumors.

“Factors such as low-oxygen levels and immune checkpoints inside solid tumors make for a hostile microenvironment that can strongly suppress immune attack by T cells—which also have trouble penetrating solid tumors’ dense connective tissue network,” Dr. Zang said. “It seemed possible that using TMIGD2 as a costimulatory protein could give CAR-T cells the activation boost they need to reach cancer cells and persist within solid tumors.”

These novel CAR-T therapies were tested on mice bearing three solid human tumors: pancreatic, lung, and glioblastoma. All were equally likely to bind their T cells to cancer cells, since their CARs all possessed the same novel antibody aimed at the B7-H3 antigen. The most effective one possessed both the novel antibody and the TMIGD2 protein—a CAR that Dr. Zang calls a TMIGD2 Optimized Potent/Persistent (TOP) CAR.

The TOP Choice

The CAR-T therapy with TOP CAR proved best at keeping mice with pancreatic, lung, and glioblastoma tumors alive. For example, TOP CAR treatment enabled 7 out of 9 mice with glioblastoma tumors to survive, compared with a maximum survival of 3 out of 9 mice achieved by any of the other CAR-T therapies. It was also superior with respect to key effectiveness and safety parameters.

Dr. Zang plans to further develop TOP CAR into an “off-the shelf” platform that can simultaneously target B7-H3 as well as other tumor antigens and can readily be tailored for treating many different types of solid tumors. Einstein has intellectual property protection for a portfolio of Dr. Zang’s research and is interested in securing commercial partners to help move his novel TOP CAR therapy into clinical trials in the near future, including for cancer of the brain, liver, pancreas, ovary, prostate, lung, bladder, colon, and others. Over the past several years, Dr. Zang has developed two other anti-cancer drugs that are being evaluated in phase 1 and phase 2 clinical trials in the United States and other countries.

The paper is titled “TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors.” Other Einstein authors are Devin Corrigan, M.S., Xiang Yu Zheng, B.S., Phillip M. Galbo Jr., Ph.D., Shan Wang, M.D., Yao Liu, Ph.D., Yau Wei, M.D., Linna Suo, M.D.,Wei Cui, Ph.D. and Deyou Zheng, Ph.D. Other authors are Nadia Mercado, Sc.M., of Brown University School of Public Health and Cheng Cheng Zhang, Ph.D., of the University of Texas Southwestern Medical Center.

Dr. Zang and Mr. Nishimura are inventors of two pending patents: Chimeric antigen receptors comprising a TMIGD2 costimulatory domain and associated methods of using the same; and Chimeric antigen receptors targeting B7-H3 (CD276) and associated methods. Dr. Zang is an inventor of a pending patent: Monoclonal antibodies against IgV domain of B7-H3 and uses thereof. Other authors declare no conflicts of interest.

https://www.einsteinmed.edu/news/15202/strengthening-car-t-therapy-to-work-against-solid-tumors/

Colon cancer rates have been rising in teens

 Colorectal cancer rates have been rising for decades among people too young for routine screening, new research finds.

Routine screening is recommended every 10 years starting at age 45; the new study focused on rates of the disease in children and adults ages 10 to 44, using data from the Centers for Disease Control and Prevention.

Cases of colorectal cancer were on the rise in all age groups, the researchers found.

“It means that there is a trend,” said Dr. Islam Mohamed, an internal medicine resident physician at the University of Missouri-Kansas City who led the research. “We don’t know what to make of it yet, it could be lifestyle factors or genetics, but there is a trend.”

The findings, which have not yet been published in a peer-reviewed journal, will be presented later this month at the Digestive Disease Week conference in Washington, D.C. 

Despite the increases, the overall number of cases in people younger than 40 was still low. In people under age 30, cases remained exceedingly rare.

But with such low rates to begin with, any increase can take on a larger significance.

The study found that colorectal cancer diagnoses in children ages 10 to 14 jumped from 0.1 cases per 100,000 in 1999 to 0.6 per 100,000 in 2020, a 500% increase. Cases among 15- to 19-year-olds jumped by more than 300%, from 0.3 per 100,000 to 1.3 cases per 100,000 people. In people ages 20 to 24, cases rose from 0.7 to 2 per 100,000 people, a 185% rise. 

“When you are starting off with a very rare disease in 15-year-olds and you add a couple cases, you are going to have a huge percentage increase,” said Dr. Folasade May, an associate professor of medicine in the University of California, Los Angeles Vatche and Tamar Manoukian Division of Digestive Diseases. 

The increases were smaller for people over 25, but they also started with higher rates in 1999 than the younger groups. People older than 25 saw a more moderate, but still significant, rise in cases. The age group that was just too young to be routinely screened — those ages 40 to 44 — saw an increase of 45%, from about 15 per 100,000 people to about 21 cases per 100,000 people in 2020.

“We know this disease is age-related, as you get older you are more likely to develop polyps and those polyps are more likely to develop into cancer,” said May. 

May said that although the overall trend is alarming, it’s reassuring to see that the oldest group had the smallest percentage increase, since that group started with the largest number of cases. The data is still important, she said.

“Anybody who is 15 to 19 years old getting a colorectal cancer diagnosis is bad,” May said. 

‘Changing the face of colorectal cancer’

Colorectal cancer rates have been rising in people younger than 50 over the last few decades. At the same time, cases and deaths from the cancer that was once thought to only affect older people is decreasing in people in their 60s and beyond. 

“This reflects the changing face of colorectal cancer,” said Dr. Christopher Lieu, co-director of gastrointestinal medical oncology at the University of Colorado School of Medicine.

The increasing rates in younger people means that the greater risk for the disease will likely stick with them for the rest of their lives, a phenomenon called the birth cohort effect, Lieu said.  That means that a 40-year-old born in 1984 has a higher risk of colorectal cancer than someone born in 1950 did when they were 40.  

“It’s not like when you become a 50-year-old that risk diminishes, you carry that risk with you,” he said. “As younger people age, I worry that we will see increases in colorectal cancer cases in the groups that are getting screened.”

Doctors are still searching for answers as to why colorectal cancer cases are on the rise among younger generations. But the reason does not appear to be genetic, May said. 

“There are a few cancers where we are now seeing an earlier onset and they are probably linked. We don’t know why, but I think what we all agree on is that it is something environmental over something genetic,” she said, noting that it may be tied to more recently developed food processing methods or exposure to plastics. 

The experts agreed that the increases in colorectal cancer rates among younger generations were alarming, but did not support lowering the screening age for people who have an average risk. In 2018, the American Cancer Society dropped its recommendation for routine screening from age 50 to 45. 

“Before we talk about lowering the screening age from 45, we need to get those people screened. Less than 60% of people 45 and over have been screened,” May said. 

Lieu said the data reinforces the importance of everyone, in every age group, being aware of the warning signs of colorectal cancer, and that doctors understand the importance of screening even their young patients if symptoms arise. 

“Young patients wait longer to go to the doctor and also have to wait longer to establish their diagnosis because many of our patients get told they are too young to have colorectal cancer,” Lieu said. “We don’t want our patients to experience that any more, especially based on this data.” 

The most common symptoms patients in the study diagnosed with early onset colorectal cancer reported were changes in bowel habits — either constipation or diarrhea — abdominal pain, rectal bleeding and signs of anemia. Lieu said if anyone, especially a young person, has blood in their stool, that is reason to schedule an appointment with a doctor. 

One of the most powerful things a person can do for their health is to understand their family history, Mohamed said. 

“Knowing their family history can provide them with valuable insights into their own health,” he said, noting that people who have a family history of colorectal cancer should start getting screened 10 years before a sibling or parent was diagnosed.

https://www.nbcnews.com/health/health-news/colon-cancer-rates-rising-decades-younger-people-study-finds-rcna151343

Radiotherapy combined with hormone therapy can help some prostate cancer patients avoid chemo

 Radiotherapy can be used alongside hormone treatment, delaying the need for chemotherapy and therefore significantly protecting their quality of life for some patients with advanced prostate cancer, according to researchers from The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.

Findings from the TRAP (targeting hormone resistant metastases with radiotherapy) study were presented at The European Society for Radiotherapy and Oncology (ESTRO) annual congress.

Treating cancer that has spread

The Phase II trial is the first prospective trial to investigate the use of stereotactic body radiotherapy (SBRT) in patients with hormone-resisistant oligoprogressive prostate cancer. Oligoprogressive cancer occurs when cells from the original tumour travel within the body to fewer than three sites, forming new tumours or lesions.

Currently, disease progression after hormone therapy treatment is taken as a sign that the cancer has become resistant to the treatment. However, findings from the trial revealed that it may just be some tumours that are resistant, and if the tumours are treated with radiotherapy the rest of the cancer will still respond to hormone therapy. The trial demonstrated that the patients’ cancer did not progress for an average of six months (6.4), and two fifths (40.1 per cent) of patients remained progression-free at 12 months.

In the national study, which took place in cancer centres across the UK, researchers investigated whether giving SBRT along with a type of hormone therapy, called androgen receptor targeted agents, to patients with oligoprogressive prostate cancer would delay the time it takes for their cancer to progress.

SBRT, which can be delivered on a CyberKnife or standard radiotherapy machines, allows clinicians to target tumours to sub-millimetre precision. This approach uses advanced imaging and treatment planning techniques to deliver radiation with pinpoint accuracy, minimizing damage to surrounding healthy tissue.

40% had no evidence of cancer growth for 12 months

The patients in the study had advanced prostate cancer that was no longer responding to regular treatment. They had no more than two new areas of cancer that had appeared while they were on two types of hormone therapy, after initially responding well to the treatment. All the patients were treated with five or six treatments SBRT, which is painless and takes about 20-30 minutes for each treatment.

81 men received SBRT and most of them (67 per cent) had one oligoprogressive lesion. The areas treated were bone (59 per cent), lung (1 per cent), lymph node (32 per cent) and prostate (8 per cent).

At an average of 19.2 months, 53 (65 per cent) patients experienced progression of their disease; 32 (40 per cent) progressed within six months following SBRT treatment. Median progression-free survival following SBRT was 6.4 months and 40 per cent of men had no evidence of cancer growth 12 months after treatment.  

PSA levels could indicate whether SBRT will work

PSA levels, in the context of prostate cancer, refer to the level of prostate-specific antigen (PSA) in the blood, the marker which is secreted by the prostate and is elevated by cancer. Among the 43 men whose PSA results were available three months after SBRT and whose cancer didn’t progress within six months, 84 per cent saw a significant decrease in their PSA levels. This was compared to only 45 per cent of those who did progress or die within six months. Therefore, PSA seems to be a good indicator of those in whom SBRT will work for a longer period of time.

The treatment is now being investigated further in the STAR-TRAP trial, led by Dr Julia Murray at The Royal Marsden NHS Foundation Trust, and funded by Prostate Cancer UK, with the hope that the evidence will help change the standard of care for advanced prostate cancer patients.

Dr Alison Tree, consultant clinical oncologist at The Royal Marsden NHS Foundation Trust, Honorary Reader at The Institute of Cancer Research and Chief Investigator of the TRAP trial said:

“These initial results could be fantastic news for advanced prostate cancer patients. We are focused on developing smarter, kinder and better treatments for patients across the UK and internationally. Currently, treatment options for men with advanced prostate cancer are limited, however I hope that after we have conducted larger studies to confirm our findings, we will see this change and we will be able to treat these patients very differently, using radiotherapy as standard to target drug-resistant parts of the cancer. Radiotherapy is well tolerated and significant side effects are rare, so we hope this treatment will in the future delay the need for chemotherapy, protecting quality of life for longer.”

Simon Grieveson, Assistant Director of Research at Prostate Cancer UK, said:

“Radiotherapy can be an extremely effective treatment for men with early stage, localised prostate cancer, however we funded the TRAP trial to explore the use of radiotherapy in men whose cancer had spread to other parts of the body. These are really exciting results suggesting that targeting the radiotherapy to the sites where the cancer has spread can delay further progression of the disease and the need for subsequent treatments, such as chemotherapy.

 “Whilst these results offer great promise for men with advanced prostate cancer who are starting to run out of treatment options, this now needs to be tested in a larger randomised study, and Prostate Cancer UK are funding the STAR-TRAP trial to do just that.”

The TRAP trial was funded by Prostate Cancer UK and sponsored by The Royal Marsden. The two CyberKnife machines at The Royal Marsden were funded by The Royal Marsden Cancer Charity.

https://www.icr.ac.uk/news-archive/new-trial-finds-radiotherapy-combined-with-hormone-therapy-can-help-some-advanced-prostate-cancer-patients-avoid-chemotherapy

'Cancer vaccines are having a renaissance'

 Last week, Moderna and Merck launched a large clinical trial in the UK of a promising new cancer therapy: a personalized vaccine that targets a specific set of mutations found in each individual’s tumor. This study is enrolling patients with melanoma. But the companies have also launched a phase III trial for lung cancer. And earlier this month BioNTech and Genentech announced that a personalized vaccine they developed in collaboration shows promise in pancreatic cancer, which has a notoriously poor survival rate.

Drug developers have been working for decades on vaccines to help the body’s immune system fight cancer, without much success. But promising results in the past year suggest that the strategy may be reaching a turning point. Will these therapies finally live up to their promise?

Long before companies leveraged mRNA to fight covid, they were developing mRNA vaccines to combat cancer. BioNTech delivered its first mRNA vaccines to people with treatment-resistant melanoma nearly a decade ago. But when the pandemic hit, development of mRNA vaccines jumped into warp drive. Now dozens of trials are underway to test whether these shots can transform cancer the way they did covid. 

Recent news has some experts cautiously optimistic. In December, Merck and Moderna announced results from an earlier trial that included 150 people with melanoma who had undergone surgery to have their cancer removed. Doctors administered nine doses of the vaccine over about six months, as well as  what’s known as an immune checkpoint inhibitor. After three years of follow-up, the combination had cut the risk of recurrence or death by almost half compared with the checkpoint inhibitor alone.

The new results reported by BioNTech and Genentech, from a small trial of 16 patients with pancreatic cancer, are equally exciting. After surgery to remove the cancer, the participants received immunotherapy, followed by the cancer vaccine and a standard chemotherapy regimen. Half of them responded to the vaccine, and three years after treatment, six of those people still had not had a recurrence of their cancer. The other two had relapsed. Of the eight participants who did not respond to the vaccine, seven had relapsed. Some of these patients might not have responded  because they lacked a spleen, which plays an important role in the immune system. The organ was removed as part of their cancer treatment. 

The hope is that the strategy will work in many different kinds of cancer. In addition to pancreatic cancer, BioNTech’s personalized vaccine is being tested in colorectal cancer, melanoma, and metastatic cancers.

The purpose of a cancer vaccine is to train the immune system to better recognize malignant cells, so it can destroy them. The immune system has the capacity to clear cancer cells if it can find them. But tumors are slippery. They can hide in plain sight and employ all sorts of tricks to evade our immune defenses. And cancer cells often look like the body’s own cells because, well, they are the body’s own cells.

There are differences between cancer cells and healthy cells, however. Cancer cells acquire mutations that help them grow and survive, and some of those mutations give rise to proteins that stud the surface of the cell—so-called neoantigens.

Personalized cancer vaccines like the ones Moderna and BioNTech are developing are tailored to each patient’s particular cancer. The researchers collect a piece of the patient’s tumor and a sample of healthy cells. They sequence these two samples and compare them in order to identify mutations that are specific to the tumor. Those mutations are then fed into an AI algorithm that selects those most likely to elicit an immune response. Together these neoantigens form a kind of police sketch of the tumor, a rough picture that helps the immune system recognize cancerous cells. 

“A lot of immunotherapies stimulate the immune response in a nonspecific way—that is, not directly against the cancer,” said Patrick Ott, director of the Center for Personal Cancer Vaccines at the Dana-Farber Cancer Institute, in a 2022 interview.  “Personalized cancer vaccines can direct the immune response to exactly where it needs to be.”

How many neoantigens do you need to create that sketch?  “We don’t really know what the magical number is,” says Michelle Brown, vice president of individualized neoantigen therapy at Moderna. Moderna’s vaccine has 34. “It comes down to what we could fit on the mRNA strand, and it gives us multiple shots to ensure that the immune system is stimulated in the right way,” she says. BioNTech is using 20.

The neoantigens are put on an mRNA strand and injected into the patient. From there, they are taken up by cells and translated into proteins, and those proteins are expressed on the cell’s surface, raising an immune response

mRNA isn’t the only way to teach the immune system to recognize neoantigens. Researchers are also delivering neoantigens as DNA, as peptides, or via immune cells or viral vectors. And many companies are working on “off the shelf” cancer vaccines that aren’t personalized, which would save time and expense. Out of about 400 ongoing clinical trials assessing cancer vaccines last fall, roughly 50 included personalized vaccines.

There’s no guarantee any of these strategies will pan out. Even if they do, success in one type of cancer doesn’t automatically mean success against all. Plenty of cancer therapies have shown enormous promise initially, only to fail when they’re moved into large clinical trials.

But the burst of renewed interest and activity around cancer vaccines is encouraging. And personalized vaccines might have a shot at succeeding where others have failed. The strategy makes sense for “a lot of different tumor types and a lot of different settings,” Brown says. “With this technology, we really have a lot of aspirations.”

https://www.technologyreview.com/2024/05/03/1092026/cancer-vaccines-are-having-a-renaissance/

'If at First Zepbound Doesn't Succeed, Keep Trying'

 When using tirzepatide (Zepbound, Eli Lilly) to treat obesity, patience may pay off. 

New post hoc data from Lilly's SURMOUNT-1 trial of people with overweight or obesity but not diabetes suggest that the drug will almost always produce at least 5% weight loss eventually, even among slow responders. 

"Some obesity treatment guidelines suggest discontinuing anti-obesity medication (AOM) that fails to produce 5% or greater weight reduction within 12 weeks. Newer AOMs may take longer to achieve full weight-loss benefit given their recommended 

dose titration schedule," Kimberly Gudzune, MD, director of the Johns Hopkins Healthful Eating, Activity & Weight Program, Baltimore, Maryland. 

The analysis showed that among participants who had lost less than 5% of their body weight by week 12 of tirzepatide, nearly all went on to lose 5% or more by week 72. Thus, Gudzune said, "It is reasonable to consider treatment for longer than 12 weeks to determine weight loss response to tirzepatide, which takes at least 20 weeks to reach the highest dose."

Session moderator Thanh D. Hoang, DO, director of the endocrinology division at the Uniformed Services University of the Health Sciences, Bethesda, Maryland, told Medscape Medical News that he generally agrees with that conclusion, given that guidelines suggest titrating these new medications beginning with a very low dose, 2.5 mg for a month or so, then to 5 mg, 10mg, and 15 mg, each with 1 or 2 months in between, to ensure tolerability. 

"I would keep them on it past 24 months even if they had very slow weight loss. But after 3 months of medium doses if there's no response at all, I will talk to the patient and give them the option to either discontinue the medication, try a different one, or stay on it for another 3 months. If after about 6 months there's no effect at all, I would likely stop it," Hoang said. 

The current post hoc analysis included a total of 1545 patients who had been randomly assigned to total tirzepatide doses of 5 mg, 10 mg, or 15 mg, and had data available at weeks 0, 12, 24, and 72. Among those, 1267 had lost at least 5% of their body weight by week 12, defined as "early responders," and 278 had lost less than 5% of body weight by then, called "slow responders." 

At baseline, slow responders were significantly more likely to be male (44.8% of slow vs 30.1% of early responders; P < .001), have higher body weight (24.3 kg vs 21.8 kg; P < .001), and lower waist circumference (117.5 cm vs 113.4 cm; P < .001). There were no significant differences by age, body mass index, prediabetes status, or obesity duration. 

By the end of dose titration at week 24, 70% of slow responders had achieved 5% or more of body weight reduction, as had 100% of early responders. By 72 weeks, 90% of the slow responders had achieved at least 5% of body weight loss and 30% had achieved at least 15% reduction. 

Even in the group maintained on the lowest 5-mg dose throughout the trial, 87% had achieved at least 5% weight loss by week 72, with 15% achieving at least 15%. And in the group that had been titrated up to 15-mg tirzepatide, 94% of slow responders achieved at least 5% weight loss.

The mean time to reaching 5% weight loss for slow responders who went on to achieve 5% or greater weight loss was 24.8 weeks. 

Of the total 1545 participants, there were 28 who had lost less than 5% overall body weight on tirzepatide. Of those, four had missed more than three consecutive doses and 13 were on the lowest 5-mg dose. 

"Future studies are warranted to better understand the variability in weight loss response to tirzepatide treatment," Gudzune concluded. 

Hoang said that in his experience using tirzepatide, "most of them respond, but then I don't have 1000 patients."

The study was sponsored by Eli Lilly & Co. Gudzune serves on advisory panels for Eli Lilly and Novo Nordisk, receives research support from Novo Nordisk, and royalties from Johns Hopkins ACG System. Hoang is an employee of the US Department of Defense, but his comments reflected his personal opinions and not those of his employer. He has no further disclosures.  

https://www.medscape.com/viewarticle/if-first-tirzepatide-doesnt-succeed-keep-trying-2024a100090d

Customized Video Games for ADHD, Depression, in Kids

 Targeted video games could help reduce symptoms of attention-deficit/hyperactivity disorder (ADHD) and depression in children and adolescents, results of a new review and meta-analysis suggested.

Although the video game–based or "gamified" digital mental health interventions (DMHIs) were associated with modest improvements in ADHD symptoms and depression, investigators found no significant benefit in the treatment of anxiety.

"The studies are showing these video games really do work, at least for ADHD and depression but maybe not for anxiety," Barry Bryant, MD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, told Medscape Medical News.

"The results may assist clinicians as they make recommendations to patients and parents regarding the efficacy of using these video games to treat mental health conditions."

The findings were presented on May 6, 2024, at the American Psychiatric Association (APA) 2024 Annual Meeting.

A Major Problem

Childhood mental illness is a "big problem," with about 20% of kids facing some mental health challenge such as ADHD, anxiety, or depression, said Bryant. Unfortunately, these youngsters typically have to wait a while to see a provider, he added.

DMHIs may be an option to consider in the meantime to help meet the increasing demand for treatment, said Bryant.

Gamified DMHIs are like other video games, in that players advance in levels on digital platforms and are rewarded for progress. But they're created specifically to target certain mental health conditions.

An ADHD game, for example, might involve users completing activities that require an increasing degree of attention. Games focused on depression might incorporate mindfulness and meditation practices or cognitive behavioral elements.

Experts in child psychiatry are involved in developing such games along with professionals in business and video game technology, said Bryant.

But the question is do these games really work?

Effective for ADHD, Depression

Investigators reviewed nearly 30 randomized controlled trials of gamified DMHIs as a treatment for anxiety, depression, and/or ADHD in people younger than 18 years that were published from January 1, 1990, to April 7, 2023.

The trials tested a wide variety of gamified DMHIs that fit the inclusion criteria: A control condition, a digital game intervention, sufficient data to calculate effect size, and available in English.

A meta-analysis was performed to examine the therapeutic effects of the gamified DMHIs for ADHD, depression, and anxiety. For all studies, the active treatment was compared with the control condition using Hedges's g to measure effect size and 95% CIs.

Bryant noted there was significant heterogeneity of therapeutic effects between the studies and their corresponding gamified interventions.

The study found gamified DMHIs had a modest therapeutic effect for treating ADHD (pooled g = 0.280; P = .005) and depression (pooled g = 0.279; P = .005) in children and adolescents.

But games targeting anxiety didn't seem to have the same positive impact (pooled g = 0.074; P = .197).

The results suggest the games "show potential and promise" for certain mental health conditions and could offer a "bridge" to accessing more traditional therapies, Bryant said.

"Maybe this is something that can help these children until they can get to see a psychiatrist, or it could be part of a comprehensive treatment plan," he said.

The goal is to "make something that kids want to play and engage with" especially if they're reluctant to sit in a therapist's office.

The results provide clinicians with information they can actually use in their practices, said Bryant, adding that his team hopes to get their study published.

Gaining Traction

Commenting for Medscape Medical News, James Sherer, MD, medical director, Addiction Psychiatry, Overlook Medical Center, Atlantic Health System, said the study shows the literature supports video games, and these games "are gaining traction" in the field.

He noted the app for one such game, EndeavorRx, was one of the first to be approved by the US Food and Drug Administration to treat ADHD in young people aged 8-17 years.

EndeavorRx challenges players to chase mystic creatures, race through different worlds, and use "boosts" to problem-solve while building their own universe, according to the company website.

By being incentivized to engage in certain activities, "there's a level of executive functioning that's being exercised and the idea is to do that repetitively," said Sherer.

Users and their parents report improved ADHD symptoms after playing the game. One of the studies included in the review found 73% of children who played EndeavorRx reported improvement in their attention.

The company says there have been no serious adverse events seen in any clinical trial of EndeavorRx.

Sherer noted many child psychiatrists play some sort of video game with their young patients who may be on the autism spectrum or have a learning disability.

"That may be one of the few ways to communicate with and effectively bond with the patient," he said.

Despite their reputation of being violent and associated with "toxic subcultures," video games can do a lot of good and be "restorative" for patients of all ages, Sherer added.

No relevant conflicts of interest were disclosed.

https://www.medscape.com/viewarticle/customized-video-games-promising-adhd-depression-kids-2024a1000901