Archive for month: May, 2024

The EMERGENT-2 trial published in The Lancet unveiled the promising efficacy and safety of KarXT, a combination of xanomeline and trospium chloride for schizophrenia. The study was conducted from December 2020 to April 2022 and explored the potential of these drug in managing acute psychosis in individuals with schizophrenia.

KarXT is a dual M1 and M4-preferring muscarinic receptor agonist that doesn’t block D2 dopamine receptors. This unique mechanism could revolutionize schizophrenia treatment, addressing a critical need for new approaches in managing the condition.

This double-blind, placebo-controlled, randomized trial involved a total of 252 participants aged 18–65 with a recent worsening of psychosis requiring hospitalization. The primary endpoint was the change from baseline to week 5 in the Positive and Negative Syndrome Scale (PANSS) total score.

The results found that the KarXT group demonstrated a mean change of –21.2 points compared to the placebo group’s –11.6 points in PANSS total score. This difference with a least squares mean difference of –9.6 emphasized the potential of KarXT as an effective intervention.

All secondary endpoints were also met with further underlining the superiority of KarXT over the placebo. The findings reported a range of common adverse events, including constipation, dyspepsia, headache, nausea, vomiting, hypertension, dizziness, gastro-oesophageal reflux disease, and diarrhea. Also, rates of extrapyramidal motor symptoms, akathisia, weight gain, and somnolence were similar between both the groups.

This suggest that KarXT can effectively reduce both positive and negative symptoms associated with schizophrenia by presenting itself as a potentially well-tolerated alternative to existing antipsychotic medications. This success sets the stage for further investigation, with ongoing trials such as EMERGENT-3, EMERGENT-4, and EMERGENT-5 expected to provide additional insights into the long-term efficacy and safety of KarXT in schizophrenia management.

Reference:

Kaul, I., Sawchak, S., Correll, C. U., Kakar, R., Breier, A., Zhu, H., Miller, A. C., Paul, S. M., & Brannan, S. K. (2023). Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. In The Lancet. Elsevier BV. https://doi.org/10.1016/s0140-6736(23)02190-6

Higher CAC scores among older adults linked to ageing indices and aggregate ageing scores suggest a study published in Atherosclerosis.

Maliheh Akbarpour and team discovered that on the side of Meniere’s disease, the choroid and Haller layer are thicker, along with a higher ratio of subfoveal large choroidal vessel (LCV) thickness to subfoveal CT (SCT) compared to the control group. The findings of this study were published in The Laryngoscope Journal. The purpose of this study was to assess and compare choroidal thickness in individuals with Meniere’s disease and a control group.

In this case-control analytical study, a total of 37 individuals with Meniere’s disease and 37 healthy subjects were examined. Enhanced-depth imaging optical coherence tomography (EDI-OCT) was used to measure subfoveal choroidal thickness (CT), large choroidal vessel layer thickness, and the ratio of mean subfoveal large choroidal vessel thickness to mean subfoveal CT in the eyes on the Meniere’s disease side (ipsilateral), contralateral eyes, and the control group.

The key findings of this study were:

After adjusting for age, sex, and migraine, a statistically significant difference was found in the mean subfoveal choroidal thickness (SCT) values between the ipsilateral and control groups (p = 0.04).

Additionally, there were significant differences in both the mean subfoveal large choroidal vessel (LCV) thickness values (p = 0.006) and the mean subfoveal LCV thickness/mean SCT ratio (p < 0.001) between the ipsilateral and control groups.

Although patients with a disease duration exceeding three years exhibited higher mean subfoveal LCV thickness/mean SCT ratios (67.35 ± 11.56 and 60.66 ± 11.27, respectively), this difference was statistically insignificant.

Individuals with a prolonged disease duration exhibited a reduced ratio of subfoveal large choroidal vessel (LCV) thickness to subfoveal choroidal thickness (SCT). These results suggest a potential involvement of the trigeminal vascular system (TVS) and neurovascular pathophysiology in Meniere’s disease (MD) patients. Further comprehensive studies are necessary to establish more conclusive insights into the relationship between choroidal thickness (CT) and MD.

Source:

Akbarpour, M., Jalali, M. M., Alizadeh, Y., Nemati, S., Akbari, M., & Dourandeesh, M. (2023). The Association Between Choroidal Thickness and Meniere’s Disease: A Cross‐Sectional Study. In The Laryngoscope. Wiley. https://doi.org/10.1002/lary.31136

Fezolinetant reduces the frequency and severity of hot flushes during menopause for 24 weeks, without serious side effects, according to research presented at the 26th European Congress of Endocrinology in Stockholm. These findings provide further evidence of the benefits of using this non-hormonal preventative drug in women experiencing hot flushes during menopause.

Hot flushes and night sweats, also known as vasomotor symptoms (VMS), affect up to 80% of women going through menopause and can severely impact daily life, exercise and sleep. Hormone replacement therapy (HRT) is the most effective treatment, but these drugs are not suitable for some women, such as survivors of endocrine cancer or those who have untreated high blood pressure; and others choose not to take them mainly due to the potential side effects.

The new type of non-hormonal drug, fezolinetant-approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) last year – acts directly on the temperature-control pathway and alleviates these symptoms. Specifically, it works by blocking a brain protein called neurokinin-3 (NK-3), involved in regulating body temperature. But unlike hormone therapy which replaces estrogen, fezolinetant will not alleviate other menopausal symptoms such as mood changes or vaginal dryness.

Previous late-stage clinical trials (SKYLIGHT 1 and SKYLIGHT 2) have shown that fezolinetant reduces both the frequency and severity of hot flushes in women with moderate or severe symptoms compared to placebo over 12 weeks. This phase 3b study, known as DAYLIGHT and supported by Astellas Pharma, investigated the effect of fezolinetant use over 24 weeks.

Researchers examined 453 menopausal women aged 40–65 with moderate or severe hot flushes who were unsuitable for hormone replacement therapy, after giving them 45mg of fezolinetant or placebo, and found that women who took fezolinetant had less frequent and severe hot flushes throughout the 24 weeks. Women taking fezolinetant had consistently fewer hot flushes in the first week, with the strongest decrease during the first 3 days. The severity of their hot flushes was also reduced dramatically by the drug in the first week from the second day. No safety issues were found for the 45mg fezolinetant dose over the 24 weeks.

“DAYLIGHT is the first study of fezolinetant to investigate placebo-controlled efficacy over 24 weeks”, said Professor Antonio Cano from the INCLIVA Research Institute in Valencia, Spain, who was involved in the study.

“Fezolinetant was effective and well tolerated for 24 weeks and the effect was observed as early as day 1 of treatment. While there are other NK antagonists, none have shown a similar concurrence of efficacy and safety in clinical studies with a sufficiently high number of participants.”

“A safe and effective non-hormonal molecule may be available for the very high number of menopausal women who suffer from vasomotor symptoms and improve their overall health, quality of life and work performance. However, these symptoms vary in prevalence or intensity depending on ethnicity-for example, VMS are more frequent and severe in black women-so more clinical data are needed in different populations or geographical areas in the world.”

Reference:

Late-stage study finds menopause drug fezolinetant safely reduces hot flushes for almost 6 months, European Society of Endocrinology, Meeting: European Congress of Endocrinology.

Semaglutide reduces the need for loop diuretic use and dose, and has positive effects on symptoms, physical limitations, and body weight in patients with heart failure with preserved ejection fraction (HFpEF) regardless of diuretic use, according to late breaking research presented at Heart Failure 2024, a scientific congress of the European Society of Cardiology (ESC).

HFpEF is a condition in which the heart pumps normally but is too stiff to fill properly, rendering the heart unable to support the body’s need for oxygen-rich blood. The condition is becoming more common as populations age and levels of obesity and sedentary lifestyles rise. Symptoms of HFpEF can include shortness of breath-often with exertion-fatigue, and swollen ankles.

The STEP-HFpEF and STEP-HFpEF DM trials evaluated once-weekly semaglutide treatment vs. placebo in patients with obesity-related HFpEF, without and with diabetes, respectively. Both studies showed a significant improvement with semaglutide for heart failure symptoms, physical limitations, weight loss, and six-minute walk distance compared to placebo. This pre-specified analysis of pooled data from the two trials investigated whether the effects of semaglutide vs. placebo varied according to baseline diuretic use. In addition, the effects of semaglutide vs. placebo on changes in diuretic therapy use and dose during the trials was evaluated.

In both trials, patients had obesity-related HFpEF with left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90, evidence of elevated left ventricular filling pressures, structural heart abnormalities plus elevated natriuretic peptides, or recent heart failure hospitalisation plus structural abnormalities or ongoing need for diuretic therapy. Patients were randomised 1:1 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. The dual primary endpoints were change in KCCQ-CSS (a standard measure of heart failure-related symptoms and physical limitations) and percentage change in body weight from baseline to 52 weeks. Patients were stratified by baseline diuretic use (none, non-loop diuretic only, loop diuretic).

A total of 1,145 patients were included (529 in STEP-HFpEF and 616 in STEP-HFpEF DM) from 129 sites across 18 countries in Asia, Europe, North America, and South America. The average age was ~70 years and ~50% were women. At baseline, 220 patients were not receiving diuretics, 223 were receiving non-loop diuretics only, and 702 were receiving loop diuretics.

Regarding the first primary endpoint of change in heart failure-related symptoms and physical limitations from baseline to 52 weeks, semaglutide improved KCCQ-CSS in all diuretic subgroups, but the magnitude of improvement was greater in patients receiving loop diuretics compared to those not on loop diuretics, with an adjusted mean difference vs. placebo of +9.3 (95% confidence interval [CI] +6.5, +12.1) vs. +4.7 points (+1.3, +8.2), respectively; p interaction=0.042.

For the second primary endpoint of percentage change in body weight from baseline to 52 weeks, semaglutide had a consistent beneficial effect across diuretic use categories. The adjusted mean difference vs. placebo ranged from -8.8% (95% CI -10.3, -6.3) to -6.9% (95% CI -9.1, -4.7) from no diuretics to the highest loop diuretic dose category; p interaction=0.39. Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including six-minute walk distance) across diuretic subgroups (p interaction=0.24-0.92).

Between baseline and 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (p<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67, 95% CI 1.70, 4.18) and less likely to result in loop diuretic dose increase (OR 0.35, 95% CI 0.23, 0.53); p<0.001 for both. There were fewer serious adverse events with semaglutide vs. placebo across diuretic subgroups.

Study author Dr. Kavita Sharma of Johns Hopkins University School of Medicine, Baltimore, US, said: “Semaglutide improved symptoms, physical limitations and led to greater weight loss across diuretic use categories in patients with HFpEF. In addition, there was evidence of a significant reduction in average loop diuretic dose, a lower likelihood of diuretic treatment escalation, and a greater likelihood of diuretic treatment de-escalation with semaglutide versus placebo -parameters that indicate disease-modifying effects of semaglutide, and are associated with better long-term clinical outcomes in this patient population.”