Safety and tolerability of losmapimod for the treatment of FSHD

Evaluate the safety and tolerability of losmapimod in the treatment for FSHD. FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum is developing losmapimod, a small molecule p38 alpha/beta MAPK inhibitor, to treat FSHD. Losmapimod has been generally well-tolerated in more than 3,600 subjects across multiple clinical studies, including >100 subjects with FSHD. Fulcrum has assessed losmapimod in FSHD in one completed phase 1 study (FIS 001-2018) and two ongoing Phase 2 studies in the open label extension period (FIS 001-2019 and FIS 002-2019). Subjects aged 18-65 years with genetically confirmed FSHD1, clinical severity score 2-4, and MRI-eligible muscles for biopsy were exposed to losmapimod 7.5 or 15 mg twice daily PO for 14 days and up to 76 weeks. In study FIS 001-2018, 6 subjects were exposed to 7.5 mg and 11 subjects to 15 mg twice daily dosing for 14 consecutive days. In studies FIS 001-2019 and FIS 002-2019, 14 and 77 subjects respectively, received at least one dose of losmapimod 15 mg twice daily for up to 76 weeks. A total of 108 subjects with FSHD1 have been exposed to losmapimod, with approximately 131 patient-years of exposure. Fifty-seven subjects have been exposed to losmapimod for 12 to 18 months, and 30 have been exposed for over 18 months. Most adverse events (AEs) observed during the studies were considered of mild to moderate in severity. The most common AEs were alanine aminotransferase (ALT) increase, headache, dizziness, dry skin, eczema and gastrointestinal disorders. The majority of AEs resolved with continued dosing. Dosing has been paused for 14 days in four subjects (3 in FIS 001-2019 and 1 in FIS 002-2019) subjects due to COVID-19 infection. There were no reported drug related SAEs, deaths, discontinuations due to AEs, or clinically significant changes in vital signs, clinical laboratory results, or ECG parameters. Losmapimod given as up to 15 mg twice daily in >100 subjects with FSHD1 for up to 76 weeks has been generally well-tolerated, consistent with that previously reported in other patient populations. Therefore, the benefit-risk profile of losmapimod for the treatment of FSHD remains favorable.Copyright © 2022

Online guided meditation training (Isha Kriya) improves self-reported symptoms of anxiety and depression within 2 weeks of practice-An observational study.

Introduction: Anxiety and depression have increased dramatically 2-3-fold with the COVID-19 pandemic. There is an urgent need for safe, cost-effective, and scalable approaches to alleviate this parallel mental health pandemic. Meditation has previously been shown to reduce stress, anxiety, and depression symptoms. Furthermore, online delivery of mind-body interventions will be impactful in addressing disparities in access to mental healthcare. In this observational pilot study, we investigate the impact of a digitally delivered guided meditation followed by daily practice on symptoms of anxiety and depression. Methods: Initially, 57 male and 202 female subjects enrolled in this study. Participants attended a webinar where they learned the Isha Kriya meditation practice. They were subsequently requested to perform the intervention daily for 6 weeks. Subjects were given scales to assess anxiety and depression at baseline, 2, 4, and 6 weeks following the training. The changes in the self-reported anxiety and depression scores were examined by the linear mixed effect models. Results: Participants completed survey responses for the following time points: baseline (n = 82), week 2 (n = 58), week 4 (n = 37), and week 6 (n = 28). During the 6 weeks of the study over 68% of subjects were compliant with their daily practice. When comparing baseline with week 2, the mean anxiety scores decreased from 25.4 to 16.8 (p < 0.01, d = 1.31). Similarly, mean depression scores decreased from 15 to 8.81 (p < 0.01, d = 0.9). The reduced scores for both anxiety and depression were maintained at weeks 4 and 6. Conclusion: This preliminary study assesses the effectiveness of online meditation training on self-reported symptoms of anxiety and depression. After 2 weeks of practice, those with baseline anxiety and depression showed significant improvement with a large effect size. The results from weeks 4 and 6 show sustained reduced anxiety and depression symptoms. These findings suggest that daily Isha Kriya practice could alleviate symptoms of these conditions. Future studies utilizing randomized control trials should be conducted to rigorously evaluate the benefits of this meditation practice on anxiety and depression. Trials registration: ClinicalTrials.gov, identifier: NCT05065476.

Online guided meditation training (Isha Kriya) improves self-reported symptoms of anxiety and depression within 2 weeks of practice—An observational study

Introduction Anxiety and depression have increased dramatically 2–3-fold with the COVID-19 pandemic. There is an urgent need for safe, cost-effective, and scalable approaches to alleviate this parallel mental health pandemic. Meditation has previously been shown to reduce stress, anxiety, and depression symptoms. Furthermore, online delivery of mind-body interventions will be impactful in addressing disparities in access to mental healthcare. In this observational pilot study, we investigate the impact of a digitally delivered guided meditation followed by daily practice on symptoms of anxiety and depression. Methods Initially, 57 male and 202 female subjects enrolled in this study. Participants attended a webinar where they learned the Isha Kriya meditation practice. They were subsequently requested to perform the intervention daily for 6 weeks. Subjects were given scales to assess anxiety and depression at baseline, 2, 4, and 6 weeks following the training. The changes in the self-reported anxiety and depression scores were examined by the linear mixed effect models. Results Participants completed survey responses for the following time points: baseline (n = 82), week 2 (n = 58), week 4 (n = 37), and week 6 (n = 28). During the 6 weeks of the study over 68% of subjects were compliant with their daily practice. When comparing baseline with week 2, the mean anxiety scores decreased from 25.4 to 16.8 (p < 0.01, d = 1.31). Similarly, mean depression scores decreased from 15 to 8.81 (p < 0.01, d = 0.9). The reduced scores for both anxiety and depression were maintained at weeks 4 and 6. Conclusion This preliminary study assesses the effectiveness of online meditation training on self-reported symptoms of anxiety and depression. After 2 weeks of practice, those with baseline anxiety and depression showed significant improvement with a large effect size. The results from weeks 4 and 6 show sustained reduced anxiety and depression symptoms. These findings suggest that daily Isha Kriya practice could alleviate symptoms of these conditions. Future studies utilizing randomized control trials should be conducted to rigorously evaluate the benefits of this meditation practice on anxiety and depression. Trials registration ClinicalTrials.gov, identifier: NCT05065476.

Safety and Tolerability of Losmapimod for the Treatment of FSHD

Objective: Evaluate the safety and tolerability of losmapimod in the treatment for FSHD. Background: FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum is developing losmapimod, a small molecule p38 α/β MAPK inhibitor, to treat FSHD. Losmapimod has been generally well-tolerated in more than 3,600 subjects across multiple clinical studies, including >100 subjects with FSHD. Fulcrum has assessed losmapimod in FSHD in one completed phase 1 study (FIS 001-2018) and two ongoing Phase 2 studies in the open label extension period (FIS 001-2019 and FIS 002-2019). Methods: Subjects aged 18-65 years with genetically confirmed FSHD1, Clinical Severity Score 2-4, and MRI-eligible muscles for biopsy were exposed to losmapimod 7.5 or 15 mg twice daily PO for 14 days and up to 76 weeks. In study FIS 001-2018, 6 subjects were exposed to 7.5 mg and 11 subjects to 15 mg twice daily dosing for 14 consecutive days. In studies FIS 001-2019 and FIS 002-2019, 14 and 77 subjects respectively, received at least one dose of losmapimod 15 mg twice daily for up to 76 weeks. Results: A total of 108 subjects with FSHD1 have been exposed to losmapimod, with approximately 131 patient-years of exposure. Fifty-seven subjects have been exposed to losmapimod for 12 to 18 months, and 30 have been exposed for over 18 months. Most adverse events (AEs) observed during the studies were considered of mild to moderate in severity. The most common AEs were alanine aminotransferase (ALT) increase, headache, dizziness, dry skin, eczema and gastrointestinal disorders. The majority of AEs resolved with continued dosing. Dosing has been paused for 14 days in four subjects (3 in FIS 001-2019 and 1 in FIS 002-2019) subjects due to COVID-19 infection. There were no reported drug related SAEs, deaths, discontinuations due to AEs, or clinically significant changes in vital signs, clinical laboratory results, or ECG parameters. Conclusion: Losmapimod given as up to 15 mg twice daily in >100 subjects with FSHD1 for up to 76 weeks has been generally well-tolerated, consistent with that previously reported in other patient populations. Therefore, the benefit-risk profile of losmapimod for the treatment of FSHD remains favorable.

Identification of Geographic Specific SARS-Cov-2 Mutations by Random Forest Classification and Variable Selection Methods.

RNA viral genomes have very high mutations rates. As infection spreads in the host populations, different viral lineages emerge acquiring independent mutations that can lead to varied infection and death rates in different parts of the world. By application of Random Forest classification and feature selection methods, we developed an analysis pipeline for identification of geographic specific mutations and classification of different viral lineages, focusing on the missense-variants that alter the function of the encoded proteins. We applied the pipeline on publicly available SARS-CoV-2 datasets and demonstrated that the analysis pipeline accurately identified country or region-specific viral lineages and specific mutations that discriminate different lineages. The results presented here can help designing country-specific diagnostic strategies and prioritizing the mutations for functional interpretation and experimental validations.