Duchenne muscular dystrophy: pathogenesis and promising therapies

In 2023, the U.S. Food and Drug Administration (FDA) granted approval to a total of 55 new drugs, comprising 29 new chemical entities (NCEs) and 25 new biological entities (NBEs). These drugs primarily focus on oncology, the central nervous system, anti-infection, hematology, cardiovascular, ophthalmology, immunomodulatory and other therapeutic areas. Out of the 55 drugs, 33 (60 %) underwent an accelerated review process and received approval, while 25 (45 %) were specifically approved for the treatment of rare diseases. The purpose of this review is to provide an overview of the clinical uses and production techniques of 29 newly FDA-approved NCEs in 2023. Our intention is to offer a comprehensive understanding of the synthetic approaches employed in the creation of these drug molecules, with the aim of inspiring the development of novel, efficient, and applicable synthetic methodologies. 

Synthesis and clinical application of new drugs approved by FDA in 2023.

The goal of this study is to compare ophthalmic emergency room (OER) visits during the Coronavirus disease-19 (Covid-19) pandemic to those during a control period. We compared all visits to the OER to Meir Medical Center in Israel, from March 15th to April 15th, 2020, during the Covid-19 pandemic and government mandated quarantine, to the same period in 2019. Factors analyzed were patient demographics, chief complaints, referral patterns, exam findings, treatments given, hospitalizations and surgical interventions. We included in this study 1311 visits of 1158 patients, 477 during the 2020 Covid-19 pandemic and 834 during the same period in 2019. The demographic distribution (age, gender, and ethnicity) was similar between the two periods. LogMAR visual acuity at presentation was worse during the Covid-19 pandemic (0.42 ± 0.6 and 0.34 ± 0.5 in 2020 and 2019 respectively; p = 0.025) and the number of emergent surgeries was higher (3.7% in 2020 vs 1.8% in 2019, p = 0.026). In 2019 there was a higher likelihood of involvement of both segments of the eye (4.82% versus 1.2%, p < 0.01) and more diagnoses were given to each patient (1 ± 0.5 versus 0.93 ± 0.35, p = 0.001; During the Covid − 19 pandemic medications (both topical and systemic) were prescribed more often (1.22 ± 0.95 in 2020 and 0.84 ± 0.67 in 2019, p < 0.001). OER visits were less frequent during the Covid − 19 pandemic as compared to 2019, though the demographics of the patients remained unchanged. Visits during the pandemic tended to be for more severe ocular conditions, with worse visual acuity at presentation and required more medical and surgical treatment which imply higher necessity of ocular evaluation. This analysis can aid healthcare resource management in similar scenarios in the future.

/pdf/ophthalmic-emergency-room-visits-during-the-covid-19-39d1c1zu7q.pdf

Ophthalmic emergency-room visits during the Covid-19 pandemic - a comparative study.

BACKGROUND AND OBJECTIVES
Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).


METHODS
A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.


RESULTS
A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.


DISCUSSION
Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.


TRIAL REGISTRATION INFORMATION
ClinicalTrials.gov Identifier: NCT03439670.


CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, we generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, we found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery.

A cellular and molecular spatial atlas of dystrophic muscle.

This randomized clinical trial investigates the efficacy and safety of partial receptor agonist vamorolone compared with placebo and prednisone in boys with Duchenne muscular dystrophy.

/pdf/efficacy-and-safety-of-vamorolone-vs-placebo-and-prednisone-2qyoawg3.pdf

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy

Objective This study was conducted to analyze data from emergency ophthalmology referrals after hours from different hospitals to identify the most common pathologies and compare accuracy of diagnoses. Additionally, examination findings, including visual acuity (VA), intraocular pressure (IOP), and pupils from referring service and ophthalmic examination, were compared to assess agreement. Design This was a prospective study that reviewed information collected from referring services to the emergency on-call ophthalmology service and compared it with ophthalmic examination between February 2017 and July 2017. Methods The number of referrals from each hospital was reviewed. Referring physician provisional diagnosis, VA, IOP, and pupil assessment were collected to analyze the agreement between ophthalmic examination and diagnosis. Results The observed agreement rate was 67.0% between referring source and ophthalmic diagnosis. Posterior vitreous detachment (12.2%) was the most common diagnosis, followed by corneal abrasion (7.4%) and retinal detachment (5.3%). Referring services measured VA to be worse than on-call ophthalmology service (right eye Z = −5.47, p Conclusion Data suggest that there is moderate agreement for diagnostic category between referring service and ophthalmology examination in regard to provisional diagnosis and pupillary assessment. Both VA and IOP were measured to be higher by referring services. This study highlights common emergency ophthalmic referrals and suggests potential areas for teaching initiatives for primary care physicians assessing ophthalmic emergency patients.

Prospective analysis of emergency ophthalmic referrals in a Canadian tertiary teaching hospital.

Reduced oral aperture (ROA), resulting from systemic sclerosis (SSc), is a debilitating condition with limited treatment options. Improvement in oral function has been reported with perioral administration of botulinum toxin type A.To prospectively evaluate the efficacy of onabotulinumtoxinA (onabotA) injection in improving oral opening and quality of life in SSc patients with ROA.Seventeen women with SSc and ROA were treated with 16 units of onabotA in 8 different sites around the cutaneous lips. Measurements of maximum mouth opening were taken before treatment, at 2 weeks posttreatment, and at 3 months posttreatment. Function and quality of life were also assessed via surveys.Interincisor and interlabial distances were significantly increased 2 weeks after treatment with onabotA (P < .001) but not 3 months after. Subjective improvement in quality of life was noted.This single-institution study enrolled 17 patients and did not have a placebo control group.OnabotA appears to have a strong short-term symptomatic benefit in patients with ROA due to SSc, with possible benefit to quality of life. 

OnabotulinumtoxinA improves oral aperture in patients with scleroderma: A small clinical trial.

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Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy

Prospective analysis of emergency ophthalmic referrals in a Canadian tertiary teaching hospital.

OnabotulinumtoxinA improves oral aperture in patients with scleroderma: A small clinical trial.