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Tag: Clinical Trial

  • Exploristics and Exonate announce successful collaboration to enhance clinical trial study design using cloud-based simulation

    Exploristics and Exonate announce successful collaboration to enhance clinical trial study design using cloud-based simulation

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    Exploristics, a world-leading provider of biosimulation software and biostatistics services for designing, analyzing, and reporting clinical trials and real-world studies, and Exonate Ltd., a biotechnology company developing novel, non-invasive, small-molecule therapeutics for patients with retinal vascular diseases, today announced the completion of a successful collaboration to optimize the study design for Exonate’s upcoming Phase IIb study for diabetic eye disease. The collaboration has supported the ongoing development of Exonate’s lead candidate, EXN407, following a recent successful Phase Ib/IIa study in November.

    Using Exploristics’ innovative study simulation software platform, KerusCloud, the companies established a more efficient, data-driven approach to study design and protocol development within Exonate’s clinical development programs in retinal vascular diseases. KerusCloud was successful in delivering valuable quantitative insights into the upcoming clinical study, enabling an enhanced study design that minimizes the risks, costs, and duration of the program.

    The Phase IIb study is planned to initiate in 2024, following the successful completion of the Company’s Phase Ib/IIa trial for EXN407. The study concluded that EXN407 met all pharmacokinetic and safety parameters, as well as showing encouraging signs of biological activity. For more information, please see the press release issued on 5th March.

    Aiden Flynn, CEO, Exploristics, said: “We are delighted to have had the opportunity to work with Exonate to harness KerusCloud’s powerful and realistic simulations to ensure that the company’s clinical trial was primed for success. Exonate recognized the need to implement a data-driven approach to optimize efficiency and minimize the risks of their proof-of-concept studies by using rational design to manage key uncertainties and challenges. We look forward to a continuation of the relationship as Exonate progresses to Phase IIb clinical trials in 2024.”

    Loic Lhuillier, COO, Exonate, commented: “We were pleased to partner with the Exploristics team on our trial design and statistical analysis, which has greatly contributed to the efficiency of the programme. KerusCloud allowed us to develop our study design to recognize the transformative potential of EXN407 whilst ensuring we account for and minimize any potential risks. We thank Aiden and the team for their collaborative model and expertise throughout this project.”

    To stay up to date on the development process of Exonate’s retinal vascular disease treatments, visit: https://www.exonate.com/

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  • Drug-coated balloon shows superiority in coronary in-stent restenosis treatment

    Drug-coated balloon shows superiority in coronary in-stent restenosis treatment

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    In the largest randomized clinical trial and first of its kind to date in the United States, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) assessed the efficacy and safety of using a drug-coated balloon in patients undergoing coronary angioplasty. In an original investigation presented at the Cardiology Research Technology conference in Washington, D.C. and published simultaneously in JAMA, the team reports that patients treated with a balloon coated with paclitaxel, a drug to prevent restenosis, experienced lower rates of failure compared with patients treated with an uncoated balloon.

    The findings of the trial-;which was designed and conducted in consultation with the U.S. Food and Drug Administration (FDA) and funded by Boston Scientific Corp.-;suggest that the drug-coated balloon offers an effective treatment strategy for the management of coronary in-stent restenosis, or blockages recurring within previously placed stents. On March 1, the FDA approved the paclitaxel-coated balloon evaluated by the BIDMC-led team, representing the first such balloon to be approved for the treatment of coronary disease in the United States.

    Drug-coated balloons have emerged internationally as an alternative treatment option, but despite promising international data, they have not been previously evaluated or approved for use in the United States. Even with advances in stent technology, patients with coronary in-stent restenosis continue to comprise approximately 10 percent of individuals undergoing angioplasty interventions each year. In particular, patients with multiple prior stents have very poor long-term outcomes. There’s growing sentiment that drug-coated balloons could address an unmet clinical need among patients with coronary artery disease in the United States.”


    Robert W. Yeh, MD, MSc, MBA, lead investigator, director of the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology and section chief of Interventional Cardiology at BIDMC

    Each year, millions of people around the world undergo coronary angioplasty, a non-surgical intervention to treat blockages in the arteries that supply blood to the heart. In one variation of the procedure known as balloon angioplasty, a deflated balloon attached to a catheter is inserted into a narrowed artery. Once in position, the balloon is inflated, opening up the narrowed blood vessel and restoring blood flow to the heart. While balloon angioplasty is highly effective, five to ten percent of patients experience in-stent restenosis-;a re-narrowing of the treated artery and recurrence of symptoms that requires additional repair-;within a year of the procedure.

    The multicenter randomized trial, known as AGENT IDE, enrolled participants with in-stent restenosis, all of whom had high rates of coronary risk factors; more than half had diabetes and nearly 80 percent previously had two or more major coronary arteries partially or completely blocked. Among the 600 enrollees, 406 were randomized to receive the paclitaxel-coated balloon catheter and194 to receive an uncoated balloon catheter. Clinical follow-up was performed in hospital at 30 days, six months and 12 months following the procedure and will continue through five years.

    Participants were monitored for three primary endpoints: a relapse necessitating revascularization, or another procedure to restore blood flow in the blocked artery; myocardial infarction, or a heart attack caused by lack of blood flow to the heart; and sudden cardiac death.

    At one year out, Yeh and colleagues demonstrated that the drug-coated ballon was superior to an uncoated balloon with respect to the likelihood of patients experiencing one or more of these endpoints. Eighteen percent of participants in the experimental group experienced one or more of the primary endpoints, versus 29 percent in the control group. Similarly, those who received the drug-coated balloon were statistically significantly less likely to require revascularization (13 percent versus 25 percent) or have a myocardial infarction (6 percent versus 11) than those who received an uncoated balloon. The scientists saw no statistically significant difference in the rates of cardiac death between the two groups (3 percent versus 1.6 percent).

    “The participants in this trial represented a patient group at very high risk for recurrent restenosis,” said Yeh, who is also the Katz Silver Family Professor of Medicine in the Field of Outcomes Research in Cardiology at Harvard Medical School. “More than 40 percent of participants had multiple prior stents. Nevertheless, treatment with the drug-coated balloon had a consistent relative risk reduction and numerically greater absolute risk reduction in events. A drug-coated balloon may be particularly useful in the setting where additional stenting would result in three or more layers of stent which would limit future therapeutic options.”

    Co-authors included Richard Schlofmiz, MD, of Saint Francis Hospital; Jeffrey Moses, MD, and Ajay J. Kirtane, MD, SM, of Columbia University Irving Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation; William Bachinsky, MD, of University of Pittsburgh Medical Center; Suhail Dohad, MD, of Cedars Sinai Medical Center; Steven Rudick, MD, of Lindner Center for Research and Education at Christ Hospital; Robert Stoler, MD, at Baylor Scott & White Heart and Vascular Hospital; Brian K. Jefferson, MD, at HCA Tristar Centennial Medical Center; William Nicholson, MD, at Emory University Hospital; John Altman, MD, at Saint Anthony Hospital; Cinthia Bateman, MD, at South Denver Cardiology; Amar Krishnaswamy, MD, at Cleveland Clinic Foundation; J. Aaron Grantham, MD, at Saint Lukes Hospital of Kansas City; Frank J. Zidar, MD, at Austin Hart; Steven P. Marso, MD, at Overland Park Regional Medical Center; Jennifer A. Tremmel, MD, MS, at Stanford University Medical Center; Cindy Grines at Northside Hospital Cardiovascular Institute; Mustafa I. Ahmed, MD, at University of Alabama at Birmingham; Azeem Latib, MD, at Montefiore Medical Center Albert Einstein College of Medicine; Benham Tehrani, MD, and Wayne Batchelor, MD, at the Innova Schar Heart and Vascular Institute; J. Dawn Abbott, MD, at Lifespan Cardiovascular Institute, Rhode Island Hospital; Paul Underwood, MD, and Dominic J. Allocco, MD, Boston Scientific Corporation. This study was supported by Boston Scientific Corp. Quantitative coronary angiography was conducted by Baim Institute for Clinical Research, Inc, an independent angiographic core laboratory.

    Yeh reported receiving personal fees and grants from Boston Scientific during the conduct of this study; as well as grants and personal fees from Boston Scientific, Abbott, Vascular and Medtronic, and personal fees from the US Food and Drug Administration, Elixir Medical, Shockwave Medical and infrared X outside the submitted work. 

    Source:

    Beth Israel Deaconess Medical Center

    Journal reference:

    Yeh, R. W., et al. (2024). Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis: The AGENT IDE Randomized Clinical Trial. JAMA. doi.org/10.1001/jama.2024.1361.

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  • New psychological treatment for epileptic children lowers mental health problems

    New psychological treatment for epileptic children lowers mental health problems

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    A new psychological treatment for children with epilepsy, developed by a UCL-led team of scientists, has been shown to reduce mental health difficulties compared to standard care, a new study finds.

    Mental health problems such as worries, low mood and behaviour problems are more common in children and young people with brain conditions such as epilepsy, than in the general population – with up to 60% of those with epilepsy having associated mental health disorders and many having more than one mental health condition.

    These conditions can have a big impact on patients’ quality of life and overall health.

    Currently, mental health problems in children and young people with epilepsy are often not identified because centres that treat epilepsy are usually separated from those that treat mental health difficulties. When mental health difficulties are identified, standard treatment for children who also have epilepsy is usually carried out by specialists, such as child and adolescent mental health services (CAMHS) or hospital-based paediatric psychology services. The treatment given usually involves treating each mental health condition (ie. anxiety, depression, behavioural issues) individually.

    The new treatment, named the Mental Health Intervention for Children with Epilepsy (MICE), is based on the treatments that the National Institute for Health and Care Excellence (NICE) recommends for the treatment of common mental health difficulties, like cognitive behavioural therapy for anxiety and depression. However, it uses a modular approach, that enables multiple mental health conditions to be treated at once, instead of having different treatments for different mental health difficulties.

    It was also modified specifically for children and young people with epilepsy, for example including sessions that explain about the relationship between epilepsy and mental health.

    Additionally, the treatment can be delivered over the phone or via video call so that people did not have to travel to the hospital and miss time from school or work. And rather than being outsourced to services such as CAMHS, it was integrated into epilepsy services – meaning that it could be delivered by non-mental health specialists.

    Lead author Dr Sophie Bennett, who carried out the research while working at UCL Great Ormond Street Institute of Child Health, said: “This treatment breakthrough means that we have a new way to help children and young people with epilepsy who also have mental health difficulties.

    “The treatment can be delivered from within epilepsy services to join up care. It doesn’t need to be delivered by specialist mental health clinicians like psychologists.

    “Integrating the care can help children with epilepsy and their families more effectively and efficiently. We were particularly pleased that benefits were sustained when treatment ended.”

    The new treatment, outlined in The Lancet, was created together with young people and their families and the professionals who care for them, including doctors, nurses and psychologists.

    Patients were given an initial assessment followed by weekly calls with the clinician – although face-to-face therapy was available if preferred. The sessions were delivered to either the young person directly, or via their caregiver, based on their individual circumstances.

    Researchers trialled the treatment with 334 children and young people aged three to 18. Of these, 166 received the new MICE treatment and 168 received the usual treatment for mental health problems in children with epilepsy.

    They assessed adolescents’ mental health and overall well-being from a parent-reported Strengths and Difficulties Questionnaire (SDQ) – covering areas such as emotional problems, conduct, hyperactivity and peer problems.

    The results showed that the children who had the MICE treatment had fewer mental difficulties than those who had the usual treatment, and the change is equivalent to a decrease of 40% in the likelihood of having a psychiatric disorder.

    These groundbreaking findings not only promise brighter futures for children with epilepsy but also pave the way for a revolutionary shift in mental healthcare practices.


    The collaborative efforts of scientists, patients, and healthcare professionals have brought forth a new era of treatment of mental health challenges associated with epilepsy, offering a beacon of hope for families in the face of mental health challenges associated with epilepsy.”


    Professor Roz Shafran, Co-Chief Investigator, UCL Great Ormond Street Institute of Child Health and GOSH

    Co-Chief Investigator, Professor Helen Cross (UCL Great Ormond Street Institute of Child Health and GOSH), said: “This study shows real progress for clinicians considering the high rate of mental health problems in children with epilepsy, as we demonstrate the benefit of a therapy that can be implemented within existing epilepsy services.”

    Co-author, Professor Isobel Heyman (UCL Great Ormond Street Institute of Child Health and Clinical Co-Lead for mental health at Cambridge Children’s Hospital), said: “These promising results show that staff working in paediatric settings can be trained to deliver effective mental health treatment to children with a physical health condition (epilepsy).

    “It clearly demonstrates that children’s healthcare needs can be met in a holistic way to treat the ‘whole child’, in the same place at the same time.”

    The work was conducted in collaboration with experts at Great Ormond Street Children’s Hospital (GOSH), King’s College London and UCLA, and with funding from the National Institute for Health and Care Research (NIHR).

    Source:

    University College London

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  • New approach needed to better prepare and support women during menopause transition, experts say

    New approach needed to better prepare and support women during menopause transition, experts say

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    A new approach to menopause that better prepares and supports women during midlife is needed – going beyond medical treatments, to empower women using high-quality information on symptoms and treatments, empathic clinical care and workplace adjustments as required, says a new four paper Series published in The Lancet.

    The misconception of menopause as always being a medical issue which consistently heralds a decline in physical and mental health should be challenged across the whole of society. Many women live rewarding lives during and after menopause, contributing to work, family life and the wider society. Changing the narrative to view menopause as part of healthy aging may better empower women to navigate this life stage and reduce fear and trepidation amongst those who have yet to experience it.”


    Martha Hickey, Series Co-Author, Professor, University of Melbourne and Royal Women’s Hospital, Melbourne

    She continues, “The experience of menopause differs for every person. Our Series calls for an individualized approach where women are empowered with accurate, consistent and impartial information to make informed decisions which are right for them over the menopause transition. This may include taking menopause hormone therapy (aka HRT) for symptoms such as hot flushes and night sweats, which can range from mild to extremely debilitating, after a discussion with their doctor about the risks and benefits. Whilst some women may also choose psychological therapies such as cognitive behavioral therapy to reduce the psychological impact of hot flushes and night sweats and improve sleep.”

    Menopause as a part of healthy aging

    In many societies the topic of menopause has long been a taboo subject. Now, countries such as the UK, the USA and Australia are experiencing a ‘menopause moment’, with more open discussion across politics, workplaces and the media.

    Whilst welcoming the increase in awareness of menopause, the Series’ authors raise concern about the media’s tendency to focus on extreme negative experiences of menopause, depicting it as an unfortunate and distressing experience heralding a critical downturn in women’s health which can only be solved by hormone replacement.

    “Whilst it’s certainly the case that some women have extremely negative experiences of menopause and benefit from hormone therapies, that isn’t the whole picture. The reality is much more complex and varied, with some women reporting neutral experiences and others highlighting good aspects, such as freedom from menstruation and menstrual pain. Menopause is having a cultural moment, and this is an opportunity for it to be recognised as a natural part of healthy ageing for women which, with the right preparation and support, is not something to fear,” says Dr Lydia Brown, University of Melbourne. 

    There is a widely held belief that menopause is associated with poor mental health, however a review of 12 studies, published as part of the Series, which investigates the association between the menopause transition and depression does not confirm this. Two of the 12 studies report increased depressive symptoms over menopause, but three found no such increase and the remaining seven studies report mixed results. After reviewing these studies and others, the Series’ experts conclude there is no robust evidence that risk of anxiety, bipolar disorder, psychosis or suicide increases for all women over the menopause transition. 

    Empowered women with support across society 

    The Series calls for healthcare professionals, researchers, workplaces, and wider society to support the empowerment of women during menopause, ensuring they have the knowledge and self determination to make informed decisions and can seek effective help if needed. 

    Healthcare workers can support their patients by validating their experiences and providing balanced and consistent information about symptoms and treatment options if required, encouraging women to discuss their individual preferences to reach shared decisions. 

    A review of evidence on menopause symptoms highlights that hot flushes and/or night sweats affect up to 80% of women, with over a third (38%) describing these symptoms as moderate to severe at age 50 years. 

    The most effective treatment for hot flushes and night sweats is hormone therapy – often referred to as Menopausal Hormone Therapy (MHT) or Hormone Replacement Therapy (HRT). Treating hot flushes may also improve sleep and mood and MHT prevents fractures in weak bones. However, evidence on the benefit of menopause hormone therapy on other symptoms associated with menopause and ageing in women is lacking.

    “There are several medications for menopause symptoms available as prescriptions that can be crucial tools in helping some women manage hot flushes and night sweats, possibly also leading to improved sleep and quality of life. These include menopause hormone therapy and non-hormonal alternatives, including newer agents targeting the neurokinin receptor such as fezolinetant. Information about these treatments, their benefits, risks, and comparative effectiveness should be made readily available to women seeking medication with the support of healthcare professionals. MHT is the best-known medication and data suggests it’s slightly more effective than alternative medications for treating hot flushes and night sweats. However, no medication can reliably resolve all negative experiences during menopause and commercial interests have influenced how MHT is presented – overshadowing evidence-based alternative options,” says Dr Andrea La Croix, University of California San Diego Herbert Wertheim School of Public Health and Human Longevity Science. 

    “As well as menopausal hormone therapy, clinicians should discuss additional ways to manage some menopausal symptoms, such as cognitive behavior therapy for hot flushes and night sweats. CBT may also reduce stress and improve sleep and mood. Lifestyle changes addressing diet, smoking and exercise may additionally benefit sleep and mood and improve long-term health. Some don’t wish to take menopause hormone treatment unless their symptoms are severe and prefer to use other approaches. Our Series is all about increasing awareness of evidence-based options for women, so they can choose how they wish to navigate menopause, free from judgment and stigma,” adds Professor Myra Hunter, King’s College London. 

    Unfortunately, commercial interests, such as organizations who are marketing menopause products to consumers including pharmaceutical companies and private providers, have strongly influenced media messaging about menopause and MHT. In this messaging, across both news media and social media, the small but serious risks of MHT are often downplayed or ignored. This Series argues that women should have access to accurate and evidence-based information about menopause in a form they can understand, created without undue commercial influence, such as the NIH funded My Meno Plan website in the USA.

    The authors also call for more research into aspects of menopause that are a priority for women. For example, a global Menopause Priority Setting Partnership is underway across more than 40 countries to develop a new, patient-focused research agenda.

    Workplaces, by the creation of open, inclusive and supportive cultures, have a role to play in supporting women during menopause. According to the UK Health and Safety Executive, women aged 45-54 report more work-related stress than men or women of any other age group, associated with high job demands, lack of control and lack of support. A qualitative study of 137 women reported that women want their managers to be informed and empathetic about menopause and understand how the work environment might exacerbate their symptoms.

    The authors highlight how, through resources such Menopause at Work, employers can implement evidence-based and practical policies to support their employees including via education, conversations and flexible working hours. 

    In addition to clinicians, researchers and workplaces, the authors highlight the need for a substantial societal shift in the views of midlife and older women, with a greater appreciation of their considerable contribution to society, their skills in the paid and unpaid workforce and how they often care for families across generations, 

    “There is a lot we can learn about attitudes to menopause and growing older in general from communities, such as many Asian cultures, where ageing in women confers respect and status, rather than stigma. Everyone can play a part in shifting society’s view of older women by engaging in conversation – such as those organized by the Menopause Cafe where people of all genders and ages gather to discuss menopause and share tips, questions and experiences,” says Rachel Weiss (not an author), founder of Menopause Cafe charity.

    She continues, “The pendulum has swung from ‘put up and shut up’ about menopause to sensationalizing it. It’s good that we are talking more about menopause, now we need to swing the pendulum to the middle and normalize menopause, so that anyone who wants to talk about it can, so that people are not scared of it and so that a diverse experience of menopause is depicted in the media, not just celebrity horror stories.” 

    Some women need specific care 

    Globally, around 10% of women experience menopause prematurely (under age 40) or early (between the ages of 40 and 44). There are often delays in diagnosis and some women experience feelings of distress and isolation. There is also evidence to suggest women who enter premature or early menopause may have an increased risk of conditions such as cardiovascular disease, and osteoporosis (fragile bones). Use of MHT may reduce these risks. 

    People with cancer are more likely to experience early menopause or menopause symptoms due to treatment. For example, endocrine therapy for breast cancer can cause hot flushes and/or night sweats that may be more severe and prolonged than natural menopause. Women with cancer often report a lack of centralised care and access to safe and effective treatments for their menopause symptoms. 

    Menopause does not usually cause mental health problems, but those with severe hot flushes/night sweats, previous clinical depression or recent stressful life events are at an increased risk of depression. There should be greater awareness and support for this group. Whilst MHT helps with hot flushes and night sweats, it is not a treatment for depression and clinicians should offer evidence-based treatments depending on severity and patient preference. 

    Greater awareness, better understanding of mechanisms, new treatments and additional support for people who experience early menopause, menopause after cancer treatment and/or who are at a higher risk of depression over the menopause transition, is urgently needed.

    The Series concludes all women should have access to realistic and balanced information about menopause and possible experiences, effective treatment as needed and shared decision-making to better equip them to navigate this life stage. 

    Source:

    Journal reference:

    The Lancet 2024 Series on menopause. https://www.thelancet.com/series/menopause-2024

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  • Exonate first-in-class eye drop Phase Ib/IIa trial data demonstrate safety and biological activity in treatment of diabetic retinopathy and diabetic macular oedema

    Exonate first-in-class eye drop Phase Ib/IIa trial data demonstrate safety and biological activity in treatment of diabetic retinopathy and diabetic macular oedema

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    Exonate Ltd., a biotechnology company developing novel, non-invasive, small-molecule therapeutics for patients with retinal vascular diseases, today announced the data from a successful Phase Ib/IIa trial for lead candidate EXN407. These data demonstrate the safety and tolerability of EXN407, as well as clear indications of biological activity, positioning it well for further development as the first topical treatment for retinal vascular diseases such as diabetic retinopathy and diabetic macular oedema. Exonate is now planning to progress EXN407 to the CLEAR-DM (Clinical Evaluation of a New Eyedrop for Alleviating Retinopathy in Diabetic Macular Oedema) Phase IIb clinical trial.

    EXN407 is a twice-daily formulation, comprised of a small molecule SRPK1 inhibitor. The eye drop formula exploits SRPK1 involvement in the alternative splicing of vascular endothelial growth factor (VEGF), a protein heavily involved in the regulation of blood vessel growth. Through inhibition of SRPK1, EXN407 can selectively target pro-angiogenic isoforms of VEGF that lead to vascular retinal disease progression via aberrant growth of leaky blood vessels within the eye.

    The mild NPDR/DME (NCT04565756) clinical study assessed the safety, tolerability and signals of biological response to EXN407 monotherapy in a double-masked, placebo-controlled Phase Ib/IIa dose-ranging clinical trial in treatment-naïve patients with mild/moderate non-proliferative diabetic retinopathy (NPDR) and mild diabetic macular oedema. The independent Dose Escalation Committee characterised EXN407 as safe and well-tolerated, with 100% of patients completing the study without requiring anti-VEGF rescue, and no major or serious adverse events reported relating to EXN407. Moreover, EXN407 exhibited high levels of tolerability, with drop comfort scores similar to placebo and artificial tears.

    In addition to the primary safety and tolerability endpoints, the study concluded that there were promising signals of biological response from EXN407, demonstrating sustained decreases in macular thickness, relative to the placebo group and comparable to previously reported anti-VEGF injections. The trial further noted that EXN407 treatment led to a significant decrease in vascular leakage (60% of EXN407-treated patients relative to 20% placebo) and that EXN407 inhibited further increases to vascular leakage (10% of EXN407-treated patients relative to 50% placebo).

    “The Phase Ib/IIa data demonstrate the clear potential of EXN407 as a non-invasive treatment for these devastating, sight-threatening conditions, and the favourable safety profile and biological activity of EXN407 support its continued clinical development in retinal vascular diseases,” said Catherine Beech, chief executive officer of Exonate: “The results suggest that topical ocular EXN407 may provide clinical benefit and substantially reduce the injection burden for patients with diabetic eye disease. We look forward to engaging with strategic partners to support the CLEAR-DM phase IIb trial, which has been designed to fully demonstrate the clinical benefits of EXN407 in NPDR/DME.”

    Full results of the Phase Ib/IIa will be presented at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in May 2024: https://www.arvo.org/annual-meeting/

    To find out more information about Exonate’s therapeutic pipeline for diabetic complications and other indications, as well as our clinical programmes, please visit: https://www.exonate.com/ 

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  • Mediterranean diet and exercise reshape gut microbiome, aiding weight loss

    Mediterranean diet and exercise reshape gut microbiome, aiding weight loss

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    In a recent study published in The American Journal of Clinical Nutrition, researchers investigate the health benefits of the Mediterranean diet (MedDiet) and physical activity interventions on overweight and obese participants by measuring changes in fecal metabolomic- and gut microbiota.

    Study: Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: A randomized clinical trial. Image Credit: Valentyn Volkov / Shutterstock.comStudy: Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: A randomized clinical trial. Image Credit: Valentyn Volkov / Shutterstock.com

    Health benefits of the MedDiet

    Characterized by a high intake of healthy vegetables, legumes, fruits, whole cereals, and nuts, moderate intake of seafood, low intake of dairy products and processed meats, as well as olive oil comprising the primary fat source, the traditional MedDiet has been growing in global popularity.

    Previous studies have investigated the health benefits of the MedDiet, which include significant cardiovascular disease (CVD), obesity, neurological, and all-cause mortality risk reductions as compared to suboptimal dietary patterns like the Western diet.

    The high concentrations of dietary fiber and anti-inflammatory nutraceuticals in the MedDiet have also been associated with promoting and persisting beneficial gut microbiota. To date, the metabolomic consequences of these associations remain unknown.

    Exploring the blood metabolome provides important insights into how gut microbiota-derived metabolites correlate with cardiometabolic diseases. Through the use of plasma metabolomics and 16S sequencing, researchers can elucidate how diet, circulating metabolites, and gut microbiota impact cardiovascular health.

    Understanding the influence of dietary interventions on both gut microbial composition and metabolomic profiles can support clinical recommendations to follow the MedDiet and other healthy diets, particularly in high-risk patients. Furthermore, these data can provide foundational insights for future studies investigating the indirect effects of diet on other non-cardiovascular somatic systems.

    About the study

    In the present study, researchers used data from the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial to investigate the effects of one year of intensive lifestyle intervention on fecal metabolites, gut microbiota, and cardiovascular risk factors, particularly in overweight and obese patients. The study comprised 400 individuals between the ages of 55 and 75 years from Alicante, Barcelona, Reus, and Valencia who were randomly divided between the intervention group (IG) and control group (CG).

    Data collection included dietary and lifestyle information obtained through the er-MedDiet questionnaire, a 17-item derivation of the 14-item Mediterranean Diet Adherence Screener (MEDAS) questionnaire. Blood and stool samples were also collected during baseline assessments and routine follow-up. Anthropometric measurements and demographic data were further obtained from medical and government records.

    The researchers encouraged all study participants to increase their usual physical activity levels to include at least 45 minutes daily of brisk walking or an equivalent activity. All study participants were also encouraged to perform specific exercises that increase their balance, strength, and flexibility to ultimately complete 150 minutes or more of moderate-to-vigorous physical activity each week.

    Changes in physical activity levels were quantified using questionnaires that assigned the metabolic equivalent of tasks (MET) min/week metrics to physical activity status and MET h/day for sedentary behaviors. The study intervention included lifestyle recommendations for physical activity and diet and in-person behavioral support from a licensed dietitian for the IG group. In contrast, CG was treated ad libitum with a regular MedDiet, which was the only intervention.

    Outcomes of interest were measured using liquid chromatography-tandem mass spectrometry (LC-MS) for metabolomics identification, characterization, and quantification and 16S amplicon sequencing for gut microbiome evaluations. Linear regression models and weighted gene co-expression network analysis (WGCNA) were used to identify between-group differences and metabolomic sub-networks, respectively.

    Study findings

    The present study highlights the combined health benefits of a dietitian-guided MedDiet alongside physical activity compared to an ad libitum MedDiet.

    Overweight and obese participants in the IG cohort exhibited a mean weight reduction of 4.2 kg and 4.4 cm lower waist circumference than their CG counterparts. The body mass index (BMI) and total energy intake estimates of the IG group were 1.5 kg/m2 and 113.9 kcal lower than controls, thus explaining the 0.1% observed reductions in glycated hemoglobin values as compared to controls.

    Fecal metabolomic analysis revealed a total of 532 fecal metabolites, four of which were significantly different between IG and CG following one year. These four metabolites included 4,7,10,13,16-docosapentaenoic acid (DPA) and adrenic acid, both of which decreased following the intervention, as well as oleic acid and 3-methyl-adipic acid (3-MAA), both of which increased following intervention. While preliminary analyses suggested an additional 56 metabolites of interest, these were non-significant following false discovery rate (FDR) corrections.

    Network analyses grouped the 532 identified metabolites into 16 subnetworks ranging in size from Grey60 to brown. The Black, Midnight Blue, Pink, and Salmon subnetworks significantly differed between IG and CG cohorts following one year of the study.

    The Black subnetwork comprised ceramides and spingosines, whereas the Midnight blue subnetwork consists of purines. The Pink subnetwork metabolites included fatty acids and carnitines, whereas the Salmon network comprised bile acids.

    Compared to the CG, the IG exhibited reduced levels of the Black, Midnight Blue, and Pink subnetworks. Comparatively, the IG exhibited increased levels of the Salmon subnetwork compared to the CG.  

    Gut microbial analysis determined that IG Shannon and Chao1 alpha diversity indices were significantly higher than CG indices by the end of the study, with the top two axes of the principal coordinate analysis (PCoA) explaining 36% of the observed differences. 

    The Eubacterium hallii group exhibited a significant reduction in population size in the IG compared to the CG. A reduced abundance of Dorea was also observed but to a lesser extent than in the Eubacterium hallii group.

    Conclusions

    The present lifestyle intervention-based clinical trial highlights the benefits of stringent dietary supervision and physical activity engagement for at-risk overweight and obese individuals, even when compared to equal-risk subjects consuming a similarly healthy diet. The energy-reduced MedDiet and physical activity intervention in the IG, when compared with an ad libitum MedDiet for the CG, significantly reduced weight metrics, including waist circumference and BMI.

    Even with similar healthy dietary patterns, the high intensity of the dietary intervention and weight-loss intervention components, such as caloric restriction and physical activity, could have significant benefits on CVD risk factors, potentially through modulation of the fecal microbiota and metabolome. Public health policies and interventions can be tailored to individual microbiome profiles, allowing for more precise and effective strategies for preventing and managing cardiometabolic diseases.”

    Journal reference:

    • García-Gavilán, J. F., Atzeni, A., Babio, N., et al. (2024). Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: A randomized clinical trial. The American Journal of Clinical Nutrition. doi:10.1016/j.ajcnut.2024.02.021

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  • SolasCure publishes phase IIa clinical trial report in leading wound care journal

    SolasCure publishes phase IIa clinical trial report in leading wound care journal

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    SOLASCURE Ltd (SolasCure), a biotechnology company developing a novel treatment to transform chronic wound care, has today announced the publication of its CLEANVLU Phase IIa clinical trial report in the International Wound Journal, a leading wound care journal. 

    SolasCure’s first investigational product, Aurase Wound Gel, is a hydrogel releasing tarumase (provisional INN), a recombinant enzyme derived from medical maggots, which aims to promote wound healing through debridement and wound bed preparation.

    The Phase IIa data, which demonstrates proof-of-concept and safety of Aurase Wound Gel in humans, has now been peer-reviewed and published, providing strong validation as SolasCure progresses into further clinical studies, and marks a significant milestone for the Company.

    Chronic wounds are a major healthcare challenge, with around 100 million people suffering from these wounds globally. This represents a significant unmet need as patients and healthcare systems lack safe, pain-free, and effective treatment solutions.

    Recent clinical data suggest that, after 20 weeks of the current standard of care treatment, complete wound closure is achieved in as little as 25%–50% of chronic or hard-to-heal wounds.2 Aurase Wound Gel aims to address this global challenge by being the first treatment to target all elements of wound bed preparation: debridement, moisture provision, infection control and overall promotion of healing.

    SolasCure’s CLEANVLU Phase IIa trial was performed in venous leg ulcer (VLU) patients across centers in the US, UK, and Hungary. The trial compared five escalating dose concentrations to baseline the use of tarumase for enzymatic debridement and wound bed preparation. Patients were treated three times per week, for four weeks.

    The study established proof-of-concept that tarumase successfully debrides wounds, with faster and more complete debridement and improved healing observed at increased enzyme concentrations. The trial also demonstrated a strong safety profile, with no indications of systemic absorption, antibody generation, or systemic effects on coagulation.

    Significantly, application of Aurase Wound Gel was shown to be pain-free, did not add to the patients’ existing pain burden, and had no evidence of local tolerability issues.

    Further Phase II studies plan to use randomized controlled groups over a longer period, with stratification for factors that may affect debridement and wound healing, to explore the efficacy of tarumase at higher concentrations.

    “The opportunity for Aurase Wound Gel to truly transform chronic wound care is very exciting, as no other treatment to date aims to target all elements of wound care management in a single product. The peer-review publication of our Phase IIa data not only provides important validation to enable further Phase II studies, but also highlights the clinical potential of Aurase Wound Gel to treat millions of patients globally safely and effectively, addressing an urgent and unmet medical need. With this excellent data we are now fundraising to support the next phase of SolasCure’s clinical and product development.”   

    Andy Weymann MD, MBA, Chairman of the Board, SolasCure

    “Debridement is a key first step of successful wound bed preparation, itself a prerequisite for wound healing. Achieving timely complete and pain-free debridement which is agnostic of the patient setting is an urgent unmet medical need. SolasCure’s Aurase Wound Gel has shown in this publication positive safety and proof-of-concept results, which bring this product a significant step closer to providing relief to those suffering from chronic wounds worldwide.”

    Rob Kirsner, MD, Ph.D, Head of Medical Advisory Board at SolasCure, Chairman and Harvey Blank Professor of Dermatology at the University of Miami

    For more information about SolasCure, please visit: https://solascure.com/.

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  • Microbial signatures linked to immunotherapy response across cancers

    Microbial signatures linked to immunotherapy response across cancers

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    The microbiome can identify those who benefit from combination immunotherapy across multiple different cancers, including rare gynecological cancers, biliary tract cancers and melanoma.

    Researchers from the Wellcome Sanger Institute, the Olivia Newton-John Cancer Research Institute in Australia, and collaborators, have identified specific strains of bacteria that are linked with a positive response to combination immunotherapy in the largest study of its kind.

    The study, published today (1 March) in Nature Medicine, details a signature collection of microorganisms in an individual’s gut bacteria that may help identify those who would benefit from combination immunotherapy and help explain why the efficacy of this treatment is otherwise hard to predict.

    In the future, understanding more about these bacteria strains can help drive the development of next-generation probiotics, known as ‘live biotherapeutic products’, that focus on modulating the microbiome to support combination immunotherapy from the inside.

    Immunotherapy is a type of treatment that harnesses the body’s immune system to target the cancer. While it can be very effective, it only works in a proportion of recipients across a wide range of cancers. As with all cancer treatments, immunotherapy can have multiple side effects. Therefore, being able to predict who is most likely to respond to treatment helps ensure that patients do not endure these unnecessary side effects for no medical benefits.

    This study used samples collected in a large, multi-center Australian clinical trial where combination immunotherapy was effective in 25 per cent of people with a broad range of advanced rare cancers, including rare gynecological cancers, neuro-endocrine neoplasms, and upper gastrointestinal and biliary cancers.

    The clinical trial focused on a type of combination immunotherapy known as immune checkpoint inhibitors. These anti-cancer agents block the body’s immune checkpoint proteins, allowing the immune cells to destroy cancer cells. In this case, the immunotherapy blocked the PD-1 and CTLA-4 checkpoints.

    Researchers used stool samples from clinical trial patients and performed deep shotgun metagenomic sequencing1 to map all the organisms within the participants’ microbiomes, down to the strain-level.

    They discovered multiple strains of bacteria in those who responded well to treatment, many of which had not been cultivated before. This allowed them to identify a microbiome signature that was found in patients who responded well to treatment.

    In addition to this, the team used this signature to train a machine learning model that could predict who would benefit from combination immunotherapy.

    They conducted a meta-analysis of previous studies and found that their signature can be applied to different cancers, such as melanoma, and across countries, to predict individuals whose cancer will likely respond to combination immunotherapy.

    However, when applied to patients who received just one of the immunotherapy drugs, targeting the immune checkpoint receptor PD-1 only, the machine-learning model could not identify those who would respond to treatment.

    This suggests that the relationship between gut microbiota and treatment response is specific for particular therapeutic combinations. The researchers therefore suggest that future development of diagnostics tests or therapeutics that rely on the gut microbiome should be tailored to the immunotherapy regimen, regardless of cancer type.

    This step towards personalized medicine may help extend cancer treatments to more people and can match individuals to therapies that would benefit them the most.

    Dr Ashray Gunjur, first author from the Wellcome Sanger Institute and the Olivia Newton-John Cancer Research Institute, Australia, said: “Our study shows that understanding the microbiome at strain-level, not just species-level, can open up a new level of personalised medicine. Having that extra resolution is crucial if we are to understand what is happening in the human body and the interplay between cancer treatment and the microbiome. Being able to test the specific mechanisms of this relationship between specific strains and response is the next horizon in this research, and one that could benefit human health in a multitude of ways.”

    Rare cancers can be hard to study and treat and while immunotherapy treatment can be incredibly effective in some of these cases, it can also be unpredictable. Our research shows that the microbiome impacts how well someone responds to combination immunotherapy, but that monotherapy gives a different result. This suggests that the microbiome should be taken into account when developing therapeutics going forward. In addition to this, there is a possibility of developing live biotherapeutic products that could provide the bacteria shown to support immunotherapy, helping the microbiome work with the patient to give them the best odds of response possible.”


    Dr David Adams, co-senior author from the Wellcome Sanger Institute

    Dr Trevor Lawley, co-senior author from the Wellcome Sanger Institute, said: “Our microbiomes vary from person to person, all of us containing a different ecosystem of bacteria and other organisms that shape our responses to the world around us. Our research highlights how an individual’s microbiome can predict how they will respond to cancer treatment, which can have a direct clinical impact by identifying those that would benefit the most, and aid in the design of future clinical trials.”

    Source:

    Wellcome Trust Sanger Institute

    Journal reference:

    Gunjur, A., et al. (2024). A gut microbial signature for combination immune checkpoint blockade across cancer types. Nature Medicine. doi.org/10.1038/s41591-024-02823-z.

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  • SickKids study offers new path for pediatric rare disease clinical trials

    SickKids study offers new path for pediatric rare disease clinical trials

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    Using a novel methodology, researchers at The Hospital for Sick Children (SickKids) are the first in pediatric research to use data from an international real-world cohort to overcome the barriers associated with conducting randomized clinical trials in children with rare diseases. 

    The gold standard for evaluating new therapeutics is through randomized clinical trials, where one group of individuals receives treatment while another does not. Unfortunately, conducting this type of clinical trial proves challenging for many rare conditions due to the limited number of individuals with the condition, making meaningful comparisons difficult. Additionally, in pediatrics, it can be unethical to give a potential treatment to some children and not others. 

    In a study published in Hepatology, a team of SickKids scientists developed an innovative and robust statistical approach which may eliminate the need for traditional randomized clinical trials, demonstrating the effectiveness of a medication in reducing disease progression and liver transplants in children with Alagille syndrome (ALGS). 

    By using a global database, we were able to mimic high-quality clinical trial results by comparing present-day outcomes to historical data. Not only do our findings show a marked improvement in liver-related outcomes for children with ALGS treated with this medication, but they also present a path forward for randomized clinical trials for other rare diseases.” 


    Dr. Binita Kamath, Senior Associate Scientist in the Developmental & Stem Cell Biology program and Principal Investigator and senior author of the study

    ALGS is a rare genetic disorder in which a patient has an inadequate number of bile ducts, which usually drain bile from the liver into the intestine. The bile then builds up and causes liver damage. Between 60 to 75 percent of patients with ALGS undergo a liver transplant before they reach adulthood. 

    Due to the rarity and severity of the condition, clinical trials have historically been difficult to conduct, especially over longer durations of time, since it is unethical and not feasible to have children take a placebo for several years. 

    In a previous study describing an international cohort of children with ALGS, Kamath and Shannon Vandriel established an international database of clinical, genetic and laboratory data in children and young adults with ALGS called The Global ALagille Alliance (GALA) study. 

    In this study, using the data of 469 untreated patients from GALA, the research team were able to compare their long-term outcomes to 84 children being treated with maralixibat, a medication approved in the US and Europe and recently in Canada for symptomatic relief of the severe itching experienced by patients with ALGS. 

    Using this innovative approach, the research team found that over six years, children taking maralixibat showed a 70 per cent improvement in event-free survival and a 67 per cent improvement in transplant-free survival. 

    “While the current indication for maralixibat is for itching, our data showed that over a longer period, the medication actually reduces the rate of liver transplants in patients with ALGS,” says Kamath, who is also a Staff Physician in the Division of Gastroenterology, Hepatology and Nutrition. 

    In addition to these benefits, the methodology used by the research team has ground-breaking implications for the development and implementation of clinical trials for patients with rare diseases. 

    Kamath and Vandriel believe similar approaches could be applied to any rare disease with enough historical data. 

    “Our research provides an alternative to the challenges associated with recruiting patients with life-threatening conditions or debilitating symptoms for long-term clinical trials,” says Kamath. “While our study was specific to patients with ALGS, I hope this sparks a renewed interest in international databases of individuals with rare diseases which can provide real-world data that can be used to help evaluate new therapies.” 

    Funding for The GALA study was provided by grants from The Alagille Syndrome Alliance, Ipsen Pharmaceuticals and Mirum Pharmaceuticals to SickKids Foundation. 

    Source:

    The Hospital for Sick Children

    Journal reference:

    Hansen, B. E., et al. (2023) Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA. Hepatology. doi.org/10.1097/HEP.0000000000000727.

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  • New blood biomarkers identified to predict cardiovascular risk in rheumatoid arthritis patients

    New blood biomarkers identified to predict cardiovascular risk in rheumatoid arthritis patients

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    Rheumatoid arthritis impacts approximately 2 million people in the United States and is associated with increased risk of cardiovascular disease. However, assessing cardiovascular risk is difficult in patients with rheumatoid arthritis because standard clinical assessments based on factors like age, cholesterol, and smoking status tend to underestimate cardiovascular risk in individuals with rheumatoid arthritis. 

    In a new study published in the Journal of the American Heart Association, a research team led by physicians at Mass General Brigham with expertise in rheumatology and cardiovascular disease identified six blood biomarkers that are associated with cardiovascular risk in patients with rheumatoid arthritis and whose measurements improved the researchers’ ability to predict a future increase in arterial inflammation. The biomarkers hold the potential to clinically assess an individual patient’s risk of cardiovascular disease, but more research is needed to determine whether they are associated with cardiovascular events such as heart attack or stroke.

    We think these biomarkers might improve our ability to predict risk and intervene early to help our patients. The idea is that if we measure biomarkers that are specific to rheumatoid arthritis, we might be able to better identify those at highest risk of cardiovascular events.”


    Daniel H. Solomon, MD, MPH, first author, chief of the Section of Clinical Sciences in the Division of Rheumatology and Matthew H. Liang Distinguished Chair at Brigham and Women’s Hospital, founding member of the Mass General Brigham healthcare system

    To identify rheumatoid arthritis-specific biomarkers of cardiovascular risk, the researchers assembled a panel of 24 candidate biomarkers that had been previously shown to be associated with rheumatoid arthritis and systemic inflammation. Then, they measured the concentration of these biomarkers in 109 patients with rheumatoid arthritis who were taking part in a randomized clinical trial (the TARGET Trial) to compare the efficacy of two different treatments for rheumatoid arthritis at preventing cardiovascular disease. The researchers measured the biomarkers at the beginning of the study and six months later, imaging the patients’ arteries at each time to assess their arterial inflammation-;an indicator of cardiovascular risk.

    “Arterial inflammation can predict future cardiovascular disease risk,” said cardiologist and co-author Ahmed Tawakol, MD, the director of Nuclear Cardiology and co-director of the Cardiovascular Imaging Research Center at Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system. “If you take a snapshot of a person’s blood vessels, the more inflammation that is measured there, the greater the likelihood the person will have progression of their disease, and the greater likelihood that they will have a stroke or a myocardial infarction.”

    Six of the 24 biomarkers were associated with increased cardiovascular risk and using them in predictive models improved the researchers’ ability to predict increases in arterial inflammation compared to standard clinical indices such as the Framingham Risk Score, which is based on factors such as age, sex, cholesterol, blood pressure, diabetes, and smoking.

    “This is an important step towards using blood samples to measure changes in cardiovascular risk with the treatment of rheumatoid arthritis,” said Solomon.

    The study showcases the strength of ongoing collaborations between Brigham and Women’s Hospital and Massachusetts General Hospital, said Solomon and Tawakol, who trained together as residents at the Brigham around 30 years ago. “Having two really great institutions collaborating in the same organization meant we could leverage the strengths of the respective institutions and teams,” said Solomon.

    Now, the team is working to test these biomarkers in a larger and more long-term cohort of rheumatoid arthritis patients, the Brigham and Women’s Rheumatoid Arthritis Sequential Study (BRASS), which has been following over 1,000 patients with rheumatoid arthritis since 2003. This follow-up study will allow the researchers to not only test associations between the biomarkers and arterial inflammation, but also assess whether the biomarkers can predict future cardiovascular events such as heart attack or stroke.

    Source:

    Journal reference:

    Solomon, D. H., et al. (2024) Biomarkers of Cardiovascular Risk in Patients with Rheumatoid Arthritis: Results from the TARGET Trial. Journal of the American Heart Association. DOI: 10.1161/JAHA.123.032095.

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